PAZOPANIB パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид

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Aug 052016

Pazopanib

パゾパニブ塩酸塩

Пазопаниба Гидрохлорид

5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide

Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline.

GW 786034

M.Wt: 437.53
C21H23N7O2S

Pazopanib CAS No.: 444731-52-6

CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)

ChemSpider 2D Image | Pazopanib Hydrochloride | C21H24ClN7O2S

Pazopanib Hydrochloride

CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)

MFC₂₁H₂₄ClN₇O₂S
MW473.979

GW786034;Votrient;Armala;GW 786034;GW-786034

GW786034GW786034, VOTRIENT

5-({4-[(2,3-Dimethyl-2H-indazol-6-yl)(methyl)amino]-2-pyrimidinyl}amino)-2-methylbenzenesulfonamide hydrochloride (1:1)

Antineoplastic; Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors; Renal Cell Carcinoma Therpay; Soft Tissue Sarcoma Therapy

パゾパニブ塩酸塩
Pazopanib Hydrochloride

C₂₁H₂₃N₇O₂S▪HCl : 473.98
[635702-64-6]

Pazopanib (trade name Votrient) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.^[2]^[3]^[4]^[5]

Pazopanib (Votrient®; GlaxoSmithKline, Brentford, U.K.) is currently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of patients with metastatic renal cell carcinoma (mRCC)

Medical uses

It is approved by numerous regulatory administrations worldwide (including the FDA (19 October 2009), EMA (14 June 2010), MHRA(14 June 2010) and TGA (30 June 2010)) for use as a treatment for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas.^[1]^[2]^[3]^[4]^[5] In Australia and New Zealand, it is subsidised under the PBS and by Pharmac respectively, under a number of conditions, including:^[6]^[7]

The medication is used to treat clear cell variant renal cell carcinoma.
The treatment phase is continuing treatment beyond 3-months.
The patient has been issued an authority prescription for pazopanib
The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST)
This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.

It has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer,^[8] though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.^[9]^[10]

Pazopanib

SYNTHESIS

Pazopanib hydrochloride drug substance is manufactured by Glaxo Wellcome Manufacturing Pte. Limited, Jurong, Singapore

NDA 22-465 was submitted by GlaxoSmithKline (GSK) for VOTRIENT™ (pazopanib), an immediate release tablet for oral administration containing either 200 mg or 400 mg of pazopanib free base (GW786034X) as the hydrochloride salt (GW786034B). Pazopanib is a new molecular entity and is submitted for review pursuant to Section 505(b)(1) of the Food, Drug and Cosmetic Act. Reference is made to one active Investigational New Drug application, IND 65,747.

Quality by Design (QbD) approach and risk management to increase their understanding of the process and drug substance properties. A number of Critical Quality Attributes (CQAs) were identified. These are: Identity by IR, Chloride Identity, Crystalline Form, Content by HPLC, Drug-related Impurities (including named impurities and genotoxic (b) (4) (b) (4) (b) (4) (b) (4) Executive Summary Section CMC Review #1 Page 9 of 262 CMC REVIEW OF NDA 22-465 impurities content), Residue on Ignition, Particle Size, Residual Solvents, Water Content by Karl Fischer, Description, Pd Content, and Heavy Metals.

CQA are mainly controlled by controlling starting material attributes, intermediate attributes (e.g. specifications of GW786034 quality process parameters, and by following the manufacturing process. A risk based method (e.g. failure mode and effects analysis (FMEA)) was used to identify the Quality Critical Process Parameters (QCPPs), Quality Process Parameters (QPPs), CQAs and Quality Attributes (QAs) for the pazopanib hydrochloride manufacturing process. The inputs to the FMEA were knowledge gained through the work to develop the impurity fate map, spiking and purging studies, the Design of Experiments (DOE) work to establish potential QCPPs/QPPs, one factor at a time experiments to establish parameter proven acceptable ranges, and 6 years of plant experience preparing over batches of pazopanib hydrochloride in 3 plants throughout the GSK network. It was concluded from this risk assessment that there are no QCPP but a few QPP in the drug substance (DS) manufacturing process. Stages 1 and 2 had no QPP, the few were only present in stages 3 and 4. All the QPP were scale invariant. A combination of multivariate DOE and univariate experimentation was used to determine the Proven acceptable Ranges (PAR) for the variables. The risks for combining univariate and multivariate experimentation were found to be minimal, on the basis of outcome from the robustness study. For this study, all the process parameters were all set at the lower limit of the PARs to create a worst-case scenario for impurity purging. Neither new impurities nor elevated levels of known impurities were detected. This data demonstrated that multivariate interactions will not lead to elevated levels of impurities.

Drug Product Pazopanib Tablets, 200 mg and 400 mg are film-coated IR oral tablets. The two strengths contain 216.7 mg and 433.4 mg pazopanib hydrochloride, respectively, which are equivalent to 200 mg and 400 mg pazopanib (free base), respectively. Excipients in the tablet core are: microcrystalline cellulose, sodium starch glycolate, povidone, and magnesium stearate. Pazopanib Tablets, 200 mg are modified capsule-shaped, gray film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS JT’. Pazopanib Tablets, 400 mg are modified capsule-shaped, yellow film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS UHL’. The tablets are manufactured at Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom. Primary packaging of tablets will be performed by either Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom or GlaxoSmithKline Inc, 1011 North Arendell Avenue, Zebulon, North Carolina 27597, USA.

Pazopanib hydrochloride is a new molecular entity of Biopharmaceutics Classification System (BCS) Class 2 (poor solubility, high permeability) and a crystalline solid. Its solubility in pH 1.1 is 0.65 mg/mL. The conjugate acids of the basic nitrogens have the following acidity constants: pKa – pK1 = 2.1 (indazole), pK2 = 6.4 (pyrimidine), pK3 = 10.2 (sulfonamide).

“Synthetic approaches to the 2009 new drugs”
Kevin K.-C. Liua, Subas M. Sakyab, Christopher J. O’Donnellb, Andrew C. Flickb, Jin Lic,
Bioorganic & Medicinal Chemistry, Volume 19, Issue 3, Pages 1136–1154

“An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals”., Beilstein J. Org. Chem., 2011, 7, 442–495.

PATENT

https://www.google.com/patents/WO2015068175A2?cl=en

Pazopanib is marketed as hydrochloride salt by Glaxoshiithkline under the trade name VOTRIENT^® is tyrosine kinase inhibitor and indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

U.S. Patent No (s). US 7105530 (“the ‘530 patent”), US7262203 (“the ‘203 patent”) and US8114885 (“the ‘885 patent”) discloses a variety of pyrimidineamines and their derivatives such as Pazopanib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof.

The process disclosed in the ‘530 patent is schematically represented as follows:

Patent publication No. WO 2011/050159 (“the Ί59 publication”) disclosed process for preparation of Pazopanib hydrochloride, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dicMoropyrimidine of Formula B in a solvent like industrial methylated sprit and specific reaction conditions like, in presence of a base, sodium bicarbonate having a particle size distribution of > 250μηι or 50 to 150μηι selected to ensure that the pH of the reaction mixture is less than 7 for the reaction time period not more than 300 min to obtain N-(2-c oropyrimidin-4-yl)- 2,3-dimethyl-2H-indazol-6-amine of Formula II. The compound of Formula Π was methylated in presence of a methylating agent in an organic solvent like dimethylformamide by using specific reaction conditions like, in presence of a base i.e. Potassium carbonate having a particle size distribution D99 of > 300μηι or D99 of < 200μηι selected to ensure that the reaction time needs to reduce the starting material to less than 2% in less than 8 his to obtain N-(2-cMoropyrimidin-4-yl)-N-2,3-trimemyl-2H-mdazol-6-amine of Formula III. The resultant methylated compound was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of 4M HC1 and methanol to yield Pazopanib hydrochloride.

WO Ί59 publication disclosed that use of sodium bicarbonate with specific particle size distribution of > 250μπι or 50 to 150μηι is key element in condensation of compound of Formula A and Formula B to niinimize the formation of Impurity of Formula 1 within

WO Ί59 publication also disclosed that use of potassium carbonate with specific particle size distribution D99 of > 300μπι or D99 of < 200μηι is key element in methylation of compound of Formula II to reduce the formation of Impurities of Formula 2, Formula 3 and Formula 4 within the range of about 0.05-3%.

Patent publication No. WO 2012/073254 (“the ‘254 publication”) disclosed a process for preparation of pazopanib hydrochloride, which involves condensation of 2,4-dicMoropyrimidine of Formula B with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of a base like sodium bicarbonate and a solvent like ethanol to yield 5-(4-chloropyrimidm-2-yl-ammo)-2-memylbenzenesulfonamide The resultant compound was condensed with N-2,3-1rimethyl-2H-indazole-6-amine of Formula D in an alcoholic solvent like ethanol. WO ‘254 publication also discloses process for purification of pazopanib hydrochloride from alcoholic solvent and water. The process disclosed in the ‘254 publication is schematically represented as follows:

Patent publication No. IN 2505/CHE/2011 disclosed a process for preparation of pazopanib, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and a phase transfer catalyst like tetrabutyl ammonium bromide in a solvent like methanol to obtain N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine of Formula II. The resultant compound was methylated in presence of methyl iodide, potassium carbonate in a solvent like dimethylformamide to obtain compound of Formula III. The obtained Formula III was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of dimethylformamide and concentrated HC1 to yield pazopanib hydrochloride.

Patent publication No. CN 103373989 (“the ‘989 publication”) disclosed a process for preparation of Pazopanib intermediate of Formula III by condensation of N-2,3-trimethyl-2H-indazole-6-amine of Formula D with 2,4-dicWoropyrimidine of Formula B in

Patent publication No. WO 2014/97152 (“the Ί52 publication”) disclosed a process for preparation of Pazopanib hydrochloride starting from 2,3-dimethyl-6-nitro-2H-indazole.

The processes for preparation of pazopanib described in the above literature have certain drawbacks as it involves: a) use of specific predefined particles of bases like sodium bicarbonate and potassium carbonate, which involves additional process steps like milling, grinding etc, b) use of expensive phase transfer catalysts and c) multiple steps making the process quite expensive, particularly on large scale.

European Medicines Agency (EMA) public assessment report disclosed that pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently produces pazopanib hydrochloride Form 1. However, the EMEA does not describe any particular characterization data for the disclosed polymorph Form 1.

PCT Publication No. WO 2011/058179 (“the Ί79 publication”) discloses pazopanib base crystalline Forms such as Form-I and Form-II and a process for its preparation; also disclosed characterization data of Form-I and Form-II by XRD, IR and melting point. –

PCT Publication No. WO 2011/069053 (“the ‘053 publication”) discloses crystalline pazopanib base and crystalline pazopanib hydrochloride Forms such as Form-II, Form-Ill, Form-TV, Form-V, Form- VI, Form- VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-A, Form-G and also discloses crystalline Pazopanib dihydrochloride Forms such as Form-I, Form-XIV, Form-XV. The crystalline Forms reported in the PCT publication characterized by its XRD pattern.

IN Publication No. 3023/CHE/2010 discloses crystalline pazopanib dihydrochloride Form-I and crystalline pazopanib mono hydrochloride, process for it preparation and characterization by XRD of the same.

IN Publication No. 1535/CHE/2012 discloses crystalline pazopanib hydrochloride Form-SP and a process for its preparation; also disclosed characterization data, of Form-SP by XRD, DSC and TR.

PCT Publication No (s): WO 2007/143483, WO 2007/064753, WO 2006/20564 and WO 2005/105094 as well as US Publication No. US 2008/0293691 disclose anhydrous and hydrated Forms of pazopanib hydrochloride and their process for preparation thereof. ‘

IP. Com journal disclosure Number IPCOM000207426D discloses crystalline Form of pazopanib hydrochloride Form-R, which is characterized by XRD pattern.

Further, IP.Com journal disclosure Number IPCOM000193076D discloses crystalline Forms of N-(2-cUoropyrirnidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine of

Formula III such as Form I and Form II along with characteristic data of XRD pattern

PATENT

https://www.google.com/patents/WO2012073254A1?cl=en

Examples

Example 1:

Preparation of 5-(4-chloropyrimidin-2ylamino)-2-methyIbenzenesulfonamide

To a mixture of 5-amino-2-methylbenzenesulfonamide (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide. Example 2:

Preparation of N,2,3-trimethyI-2H-indazol-6-amine

Sodium methoxide (19 gm) was dissolved in methanol (610 ml) and then added 2,3-dimethyl-2H-indazol-6-amine (13 gm). The reaction mixture was stirred for 15 minutes and then added paraformaldehyde (3.9 gm). The contents were heated to 60°C and stirred for 10 hours. The reaction mass was then cooled to room temperature and maintained for 4 hours 30 minutes. Sodium borohydride (2.8 gm) was added to the reaction mass slowly at room temperature and then heated to reflux. The reaction mass was maintained for 2 hours at reflux and then cooled to room temperature. The reaction mass was stirred for 14 hours at room temperature and then added sodium hydroxide solution (1M, 100 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with hydrochloric acid solution (40 ml) and then added ethyl acetate (400 ml). Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The combined organic layers were washed with sodium chloride solution and dried with sodium sulfate. The organic layer was treated with carbon and filtered through hi-flow bed. The solvent was distilled off under vacuum at below 50°C to obtain a residual mass. To the residual mass was added diisopropyl ether (75 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 10 gm of N,2,3-trimethyl-2H-indazol-6-amine.

Example 3:

Preparation of pazopanib hydrochloride

5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, N,2,3-trimethyl-2H-indazol-6-amine (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%). Example 4:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (5 gm; HPLC Purity: 97.5%) as obtained in example 3 was dissolved in a mixture of methanol (100 ml) and water (10 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and filtered. The filtrate obtained was cooled to room temperature and maintained for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 3.5 gm of pazopanib hydrochloride (HPLC Purity: 99.9%). Example 5:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 98%), methanol (528 ml), water (55 ml) and concentrated hydrochloric acid (0.2 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. Take the filtrate and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents were further cooled to 0 to 5°C, stirred for 1 hour and filtered. The solid obtained was dried to give 19 gm of pazopanib hydrochloride (HPLC Purity: 99.85%).

Example 6:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (10 gm; HPLC Purity: 96%), methanol (250 ml), water (25 ml) and concentrated hydrochloric acid (0.1 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. The filtrate obtained was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents further cooled to 0 to 10°C and stirred for 1 hour. The separated solid was filtered and dried to obtain 6.6 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).

Example 7: Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 97%) was dissolved in a mixture of isopropanol (132 ml) and water (20 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 1 hour at reflux and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 18 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).

Paper

http://pubs.acs.org/doi/full/10.1021/op400139z

Assessment of Predictivity of Semiquantitative Risk Assessment Tool: Pazopanib Hydrochloride Genotoxic Impurities

David P. Elder*†, George Okafo†, and Michael McGuire‡

^† GlaxoSmithKline, Park Road, Ware, Hertfordshire, United Kingdom SG12 0DP

^‡ GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

Org. Process Res. Dev., 2013, 17 (8), pp 1036–1041

DOI: 10.1021/op400139z

Publication Date (Web): July 02, 2013

*E-mail: david.p.elder@gsk.com

Abstract

The recently developed semiquantitative assessment tool for the evaluation of carryover potential of mutagenic impurities (MIs) into the final API was applied to the five identified MIs within pazopanib hydrochloride (dimethyl sulfate (DMS) and compounds II, III, VI, and VIII). The theoretical and predicted purge factors were compared. The tool accurately predicted the purging capacity for the most reactive MI, DMS, giving a theoretical purge factor of 30000 versus an actual value of 29411 (for spiking at stage 1). For the other less reactive MIs, both measured and predicted values agreed reasonably well, and the high values for the purging factors were indicative of an effective process capability that could significantly reduce observed MI levels. The only exception was for compound VI, where although the measured and theoretical purge factors were in agreement, they were significantly lower (<200) than for the other MIs. In this case, a strategy was implemented including a requirement for control of this MI on API specification. The purge-factor assessment tool has the potential to play a key role in GRA (genotoxic risk assessment) processes and subsequent regulatory submissions. This tool could provide regulators with additional confidence to accept these purging arguments without resorting to testing. This could potentially significantly reduce the analytical testing burden for early clinical candidates.

PATENT

WO 2011058179

The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals. Pazopanib has the following formula (I):

H CH,

NH₂

In WO 02/059110 the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride as well as the uses of this compound have been disclosed. In particular, this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.

Alternative methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride are disclosed in WO 03/106416.

In WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed. WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.

Typically Pazopanib is administered orally, as this route provides great comfort and convenience of dosing. Although the hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions

PAPER

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 4, 15 February 2014, Pages 1108–1110

http://www.sciencedirect.com/science/article/pii/S0960894X14000225

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

doi:10.1016/j.bmcl.2014.01.003

Abstract

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7mdemonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

Figure 1.

Chemical structure of pazopanib.

Patent

https://www.google.co.in/patents/WO2002059110A1?cl=en

Example 69

5-({4-[(2,3-dimethyl-2r/-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide

To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2- ethylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCI salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2- yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. Y\ NMR (400 MHz, deDMSO+NaHCOa) δ 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

Example 13

Preparation of Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine

To a stirred solution of the Intermediate 12 (7.37 g) in DMF (50 ml) was added CS2CO3 (7.44 g, 2 eqv.) and Mel (1.84 ml, 1.1 eqv.) at room temperature. Mixture was stirred at rt for overnight The reaction mixture was poured into ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air- dried to afford Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine as an off-white solid (6.43 g, 83%). ‘H NMR (400 MHz, dsDMSO) δ 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).

Intermediate Example 12 Preparation of Λ/-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

to a stirred solution of Intermediate Example 11 (2.97 g, .015 mol) and NaHCOs (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol) at room temperature. After the reaction was stirred for four hours at 85 °C, the suspension was cooled to rt, filtered and washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was triturated with ethyl acetate to yield 3.84 g (89 % yield) of Λ/-(2-chloropyrimidin-4-yl)- 2,3-dimethyl-2tf-indazol-6-amine. ¹H NMR (400 MHz, deDMSO) δ 7.28 (d, J = 9.0 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 5.18 (br s, 1 H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274 (M+H).

Intermediate Example 11

Preparation of 2,3-dimethyl-2r/-indazol-6-amine

To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7W-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2S0₄). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2r/-indazole as a yellow solid (15.85 g, 73 o/o). ¹H NMR (300 MHz, dβDMSO) δ 8.51 (s, I H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).

To a stirred solution of 2,3-dimethyl-6-nitro-2V-indazole (1.13 g) in 2- methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(ll) chloride in 8.9 ml of concentrated HCI dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 %), the HCI salt 2,3-dimethyl-2/7-indazol-6- amine. ¹H NMR (300 MHz, deDMSO) δ 7.77 (d, J = 8.9 Hz, 1 H), 7.18 (s, 1 H), 7.88 (m, 1 H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).

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https://ayurajan.blogspot.in/2014/12/pazopanib.html

WO2003106416A2 (same appears in Drug Future 2006, 31, 7, 585-589)

Pazopanib synthesis: J Med Chem 2008, 51, 4632-4640 (same appears in Beilstein J Org Chem 2011, 7, 442–495)

CLIP

LINK

PAPER

http://www.eurekaselect.com/97375

10.2174/157017812800233714

A Novel Practical Synthesis of Pazopanib: An Anticancer Drug

Author(s): YiCheng Mei, BaoWei Yang, Wei Chen, DanDan Huang, Ying Li, Xin Deng, BaoMing Liu, JingJie Wang, Hai Qian and WenLong Huang

Affiliation: Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, P.R. China.

Abstract:

This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.

PATENT

https://www.google.com/patents/WO2014097152A1?cl=en

Pazopanib is a tyrosine kinase inhibitor of Formula la.

Formula la

Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride, having the structure as depicted in Formula I:

Formula I

U.S. Patent No. 7,105,530 provides a process for the preparation of a hydrochloride salt of a compound of Formula II

Formula II involving the reduction of 2,3-dimethyl-6-nitro-2H-indazole with tin (II) chloride in concentrated hydrochloric acid in the presence of 2-methoxyethyl ether at 0°C. It also describes the preparation of a compound of Formula III

Formula III involving the reaction of a hydrochloride salt of compound of Formula II with 2,4- dichloropyrimidine in the presence of a base and solvent mixture of

tetrahydrofuran/ethanol followed by stirring for 4 hours at 85°C.

PCT Publication No. WO 2007/064752 provides a process for the preparation of a compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10% Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of ammonium formate at a rate that ensures the reaction temperature is maintained at or between 25°C and 30°C. It also discloses the preparation of a compound of Formula III comprising heating the compound of Formula II with sodium bicarbonate in presence of tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to

25°C.

The present invention provides a process for the preparation of a compound of Formula II which offers recycling of the Raney nickel catalyst used in the process, and an easy filtration work-up procedure. Further, the present invention offers selective reduction under mild conditions that is economical to use at an industrial scale.

The present invention also provides a process for the preparation of compound of Formula III which avoids the use of two or more solvents, and additionally, also circumvents heating and cooling procedures during the reaction. The aforesaid advantages yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine (CPDMI) impurity.

The compounds of Formula II and Formula III prepared by the present invention yield a compound of Formula la or its salts in comparable yield and suitable purity required for medicinal preparations.

EXAMPLES

Step 1: Synthesis of 2,3-dimcthyl-6-nitro-2H-indazole

Example 1 :

Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25 °C to 30°C for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4: 1 mixture of dichloromethane:isopropyl alcohol (1080 mL x 5). The solvent was recovered under reduced pressure. Methyl fert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45 °C to 50°C. The reaction mixture was cooled to 25 °C to 30°C and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert- butyl ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3- dimethyl-6-nitro-2H-indazole as a yellow solid.

Yield: 82.4% w/w

Step 2: Synthesis of 2,3-dimethyl-2H-indazol-6-amine

Example 2a:

Raney nickel ( 12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm² – 4.0 kg/cm² at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered completely. «-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue, and the reaction mixture was stirred for 1 hour at 25°C to 30°C. The solid was collected by filtration, washed with n-heptane (50 mL x 2), and dried under vacuum at 40°C to 45 °C to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.

Yield: 95% w/w

Example 2b:

Raney nickel (21.25 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (85 g, 0.45 mol) in methanol (850 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm² – 4.0 kg/cm² at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (85 mL x 3). The filtrates were combined, and the solvent was recovered up to the volume of 850 mL. The 2,3-dimethyl-2H-indazol-6-amine in methanol was used as such in the next step. Step 3: Synthesis of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

Example 3 :

Sodium bicarbonate ( 112 g, 1.34 mol) was added to a stirred solution of 2,3- dimethyl-2H-indazol-6-amine (as obtained from step 2; Examples 2a and 2b) in methanol. 2,4-Dichloropyrimidine (99.35 g, 0.67 mol) was added to the reaction mixture followed by stirring of the reaction mixture for 24 hours at 25°C to 30°C. De-ionized water (850 mL) was added to the reaction mixture followed by stirring of the reaction mixture at 25 °C to 30°C for 1 hour. The solid was filtered. The wet solid was washed with de-ionized water (170 mL x 2) to obtain a wet material. De-ionized water (850 mL) was added to the wet material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes. The solid was filtered, then washed with de-ionized water (170 mL x 2). The wet material obtained was treated with ethyl acetate (340 mL) to obtain a slurry. The slurry was stirred at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C. The slurry was further stirred at 0°C to 5°C for 30 minutes. The solid was collected by filtration, then washed with cold ethyl acetate (170 mL x 2). The solid was dried in an air oven at 50°C for 16 hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an off- white solid.

Yield: 86.7% w/w

Step 4: Synthesis of pazopanib hydrochloride

Example 4a: Synthesis of N-(2-Chloropyrimidin-4-yl)-N.2.3-trimethyl-2H-indazol-6- amine

Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (lOOg, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25°C to 30°C. The reaction mixture was further stirred at 25 °C to 30°C for 6 hours followed by cooling of the reaction mixture to 0°C to 5°C. De-ionized water (300 mL) was added drop-wise to the reaction mixture, then the reaction mixture was stirred at 5°C to 10°C for 30 minutes. The solid was collected by filtration, and washed with de-ionized water (100 mL x 2). The wet material so obtained was dried in an air oven at 50°C for 12 hours to obtain the title compound.

Yield: 90.4% w/w Example 4b: Synthesis of pazopanib hydrochloride

To a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6- amine (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25°C. The reaction mixture was further stirred at 25°C to 30°C for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL x 2), and then dried under vacuum at 45 °C to 50°C for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6- yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid.

Yield: 97% w/w

PATENT

https://www.google.com/patents/CN104557881A?cl=en

pazopanib hydrochloride monohydrate prepared:

(1) chemical reaction formula

(2) Operation process

In the reaction flask pazopanib hydrochloride crude 100g, 700ml of acetonitrile was added under stirring and purified water 200ml, feeding is completed, begin heating to 75~80 ° C, until clear solvent filtration system, slowly dropped 10~20 ° C, keep stirring lh, filtered, and the filter cake washed with purified water and acetonitrile respectively, drained and the filter cake was dried at 60 ° C blast 5h, have pazopanib hydrochloride monohydrate solid 84g, yield 80.9%. For example, crystalline form pazopanib hydrochloride prepared the following examples.

pazopanib hydrochloride polymorph of preparation:

Example 1:

In the reaction flask pazopanib hydrochloride monohydrate 8. 0g, ethanol 50ml and purified water 0.Iml (the volume of water accounted for a mixed solution of 2% of the total volume of the square, ethanol – water mixture total volume was 6.26 times pazopanib hydrochloride monohydrate quality), heated to 75 ° C, stirred at reflux for about 5h, after cooling to 10~20 ° C, keep stirring lh, the filter cake washed with ethanol, then blast drying at 105 ° C 5h, to obtain ultrafine powder solid 6. 8g, yield of 81. 9%, HPLC purity was 99.8%, as measured crystal X- ray powder diffraction pattern of FIG. 1 the basic consistent, as measured with a DSC thermogram consistent FIG. 2, the particle size distribution measurement is basically the same as Fig 3 (D90 <10ym).

CLIP

Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.

Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.

U.S. patent no. 7,105,530 disclosed pyrimidineamines and their derivatives thereof. These compounds are antineoplastic agents, and are useful in the treatment of various cancers and renal cell carcinoma. Among them pazopanib hydrochloride, chemically 5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2- ylamino]-2-methylbenzenesulfonamide hydrochloride. Pazopanib hydrochloride is represented by the following structure:
Pazopanib hydrochloride is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR (Vascular endothelial growth factor receptors)- 1, VEGFR-2, VEGFR-3, PDGFR (Platelet-derived growth factor receptors )-a/p, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib hydrochloride may also be active in ovarian cancer and soft tissue sarcoma. Pazopanib hydrochloride also appears effective in the treatment of non-small cell lung carcinoma. Pazopanib hydrochloride is marketed under the brand name Votrient® by Glaxosmithkline in the form of tablet.

Processes for the preparation of pazopanib hydrochloride and related compounds were disclosed in U.S. patent no. 7,105,530 and U.S. patent no. 7,262,203.

According to U.S. patent no. 7,105,530, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5- amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropanol and ether.

U.S. patent application publication no. 2006/0252943 disclosed a process for the preparation of pazopanib hydrochloride. According to this patent, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in ethanol or methanol or tetrahydrofuran or acetonitrile and dioxane.

Drugs of the Future, 2006, 31 (7): 585-589
WO0306416

CLIP

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann

, Ian R. Baxendale

, Steven V. Ley

and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Corresponding author email

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

Pazopanib (246, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethyl-5-nitroaniline (247) using tert-butyl nitrite. The resulting indazole structure 249 can be methylated entirely regioselectively with either Meerwein’s salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second S_NAr reaction with a sulfonamide-derived aniline affords pazopanib .

Synthesis of pazopanib.

Pandite, A. N.; Whitehead, B. F.; Ho, P. T. C.; Suttle, A. B. Cancer Treatment Method. WO Patent 2007/064753, June 7, 2007.
Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., III; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. J. Med. Chem.2008,51,4632–4640. doi:10.1021/jm800566m

CLIP

Pazopanib hydrochloride (Votrient)
Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food
and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline. The
synthesis of pazopanib begins with methylation of 3-methyl-6-nitroindazole (82) with trimethyl orthoformate in the presence of BF3OEt to give indazole 83 in 65% yield (Scheme 14).65 Reduction of the nitro group was achieved via transfer hydrogenation to give 84 in 97% yield, and this was followed by coupling the aniline with 2,4-dichloropyrimidine in a THF-ethanol mixture at elevated
temperature to provide diarylamine 85 in 90% yield. The aniline nitrogen was then methylated using methyl iodide to give 86 in
83% yield prior to coupling with 5-amino-2-methylbenzenesulfonamide (87) and salt formation using an alcoholic solution of
HCl to furnish pazopanib hydrochloride (XIV) in 81% yield.

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3
Patent	7262203
Expiration	Dec 19, 2021
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

FDA Orange Book Patents: 2 of 3
Patent	8114885
Expiration	Dec 19, 2021
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

FDA Orange Book Patents: 3 of 3
Patent	7105530
Expiration	Oct 19, 2023
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C₂₁H₂₃N₇O₂S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:

VOTRIENT (pazopanib) Structural Formula Illustration

Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

Tablets of VOTRIENT are for oral administration. Each 200 mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. The inactive ingredients of VOTRIENT are:Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.

FierceBiotech. 2008-09-15. Retrieved 2010-08-10.

Country	Patent Number	Approved	Expires (estimated)
United States	7105530	2009-10-19	2023-10-19
United States	7262203	2009-10-19	2021-12-19
United States	8114885	2009-10-19	2021-12-19

JUNE 4 2013 old article cut paste

GlaxoSmithKline’s (GSK) Votrient (pazopanib) has met the primary objective of a statistically significant improvement in the time to disease progression or death that is the progression-free survival (PFS) against placebo in Phase III ovarian cancer..

http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613

Pazopanib shrinks lung cancers before surgery

Formulation

https://www.google.co.in/patents/US20140255505

Pazopanib is an angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α/-β, and c-Kit. The hydrochloride salt of pazopanib (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide) is marketed by GlaxoSmithKline as Votrient®, which is approved in the United States and other countries for the treatment of renal cell carcinoma (RCC).

Votrient® is currently prescribed to adults in the form of 200 mg tablets for oral administration, with each 200 mg tablet containing an amount of pazopanib hydrochloride equivalent to 200 mg of pazopanib free base.

Though the current tablets are acceptable of use in adults, the tablets are not preferred for use in potential future use for administering pazopanib to children. In pediatric populations, it is often desired that drug be available as a powder for reconstitution to an oral suspension. Manufacture of such a powder requires dry blending of various excipients with the active substance to provide good flow properties and content uniformity of the powder blend.

Several additional challenges exist concerning the use of pazopanib in a pediatric formulation. For instance, the nature of the drug substance favors conversion from the hydrochloride salt to the free base and hydrate forms in an aqueous environment such that standard formulations fail to provide adequate suspension stability at long term storage conditions of 25° C./65% RH or room temperature. Further, the drug has been found to have a bitter taste and, therefore, taste masking is critical.It is desired to invent a pediatric formulation of pazopanib hydrochloride suitable for administration to a pediatric population

References

“Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 27 January 2014.
“VOTRIENT (pazopanib hydrochloride) tablet, film coated [GlaxoSmithKline LLC]”(PDF). DailyMed. GlaxoSmithKline LLC. November 2013. Retrieved 27 January 2014.
“Votrient : EPAR – Product Information” (PDF). European Medicines Agency. Glaxo Group Ltd. 23 January 2014. Retrieved 27 January 2014.
“Votrient 200 mg and 400 mg film coated tablets – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. GlaxoSmithKline UK. 20 December 2013. Retrieved 27 January 2014.
“PRODUCT INFORMATION VOTRIENT® TABLETS” (PDF). TGA eBusiness Services. GlaxoSmithKline Australia Pty Ltd. 25 March 2013. Retrieved 27 January 2014.
“Pharmaceutical Benefits Scheme (PBS) – Pazopanib”. Pharmaceutical Benefits Scheme. Australian Government. Retrieved 27 January 2014.
“Pazopanib – Online Pharmaceutical Schedule”. Pharmaceutical Management Agency. Retrieved 9 June 2015.
^ “Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer”. FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
“GSK pulls bid to extend use of kidney drug to ovarian cancer”. Reuters. 31 March 2014. Retrieved 7 April 2014.
“Regulatory update: Votrient (pazopanib) as maintenance therapy for advanced ovarian cancer in the EU”. GlaxoSmithKline. 31 March 2014. Retrieved 7 April 2014.
Zivi, A; Cerbone, L; Recine, F; Sternberg, CN (September 2012). “Safety and tolerability of pazopanib in the treatment of renal cell carcinoma”. Expert Opinion on Drug Safety. 11 (5): 851–859. doi:10.1517/14740338.2012.712108. PMID 22861374.
Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910.
Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID 24807167.
Verweij, J; Sleijfer, S (May 2013). “Pazopanib, a new therapy for metastatic soft tissue sarcoma”. Expert Opinion on Pharmacotherapy. 14 (7): 929–935.doi:10.1517/14656566.2013.780030. PMID 23488774.
Schöffski, P (June 2012). “Pazopanib in the treatment of soft tissue sarcoma”. Expert Review of Anticancer Therapy. 12 (6): 711–723. doi:10.1586/era.12.41.PMID 22716487.
Pick, AM; Nystrom, KK (March 2012). “Pazopanib for the treatment of metastatic renal cell carcinoma”. Clinical Therapeutics. 34 (3): 511–520.doi:10.1016/j.clinthera.2012.01.014. PMID 22341567.
Rimel, BJ (April 2015). “Antiangiogenesis agents in ovarian cancer”. Contemporary Oncology. 7 (2): 16–19. PMID 21638926.

WO2003106416A2 *	Jun 17, 2003	Dec 24, 2003	Smithkline Beecham Corporation	Chemical process
WO2005054212A2 *	Nov 26, 2004	Jun 16, 2005	Ciba Specialty Chemicals Holding Inc.	Electroluminescent device
WO2007064752A2	Nov 29, 2006	Jun 7, 2007	Smithkline Beecham Corporation	Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema
WO2011069053A1	Dec 3, 2010	Jun 9, 2011	Teva Pharmaceutical Industries Ltd.	Process for the preparation of pazopanip hcl and crystalline forms of pazopanib hcl
WO2012051659A1 *	Oct 20, 2011	Apr 26, 2012	Biota Scientific Management Pty Ltd	Viral polymerase inhibitors
US7105530	Dec 19, 2001	Sep 12, 2006	Smithkline Beecham Corporation	Pyrimidineamines as angiogenesis modulators

Reference
1	*	DAVIES R R: “Indazole derivatives: the synthesis of various amino- and hydroxy-indazoles and derived sulphonic acids“, JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1955 (1955-01-01), pages 2412-2423, XP009176650, ISSN: 0368-1769, DOI: 10.1039/JR9550002412

US20060252943 *	Jun 17, 2003	Nov 9, 2006	Amogh Boloor	Chemical process
US20080269170 *	Jan 9, 2008	Oct 30, 2008	Sanofi-Aventis	Novel 2,4-Dianilinopyrimidine Derivatives, the Preparation Thereof, Their Use as Medicaments, Pharmaceutical Compositions and, in Particular, as IKK Inhibitors

Reference
1	*	LUO G. ET AL.: “Microwave-assisted synthesis of aminopyrimidines“, TETRAHEDRON LETTERS, vol. 43, no. 33, 2002, pages 5739 – 5742, XP004372432
2	*	See also references of EP2646431A4

Citing Patent	Filing date	Publication date	Applicant	Title
WO2014085373A1 *	Nov 26, 2013	Jun 5, 2014	Glaxosmithkline Llc	Combination
CN103232443A *	Feb 1, 2013	Aug 7, 2013	天津药物研究院	Indazole derivative crystal and its preparation method and use
CN104557881A *	Dec 30, 2014	Apr 29, 2015	山东博迈康药物研究有限公司	Preparation method of pazopanib hydrochloride crystal form

Boloor, A.; et. al. Pyrimidineamines as angiogenesis modulators. US7105530B2

2. Boloor, A.; Harris, P. A.; et. al. Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor. J Med Chem 2008, 51(15), 4632–4640.

3. Bhanushali, D. S.; et. al. Compositions and processes. WO2011050159A1

4. Boloor, A.; et. al. Chemical Process. WO2003106416A2

5. Pandite, A. M.; et. al. Cancer treatment method. WO2007064753A2

European Medicines Agency, “CHMP assessment report: Votrient“, pages 1, 5, 6 (2010).

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ChemR.pdf

Pazopanib
Systematic (IUPAC) name


5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide
Clinical data
Trade names	Votrient
AHFS/Drugs.com	Monograph
MedlinePlus	a610013
License data	EU EMA: Votrient US FDA: Pazopanib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	>99%^[1]
Metabolism	Hepatic (CYP3A4, 1A2 and2C8-mediated)^[1]
Biological half-life	31.9 hours^[1]
Excretion	Faeces (primary), urine (<4%)^[1]
Identifiers
CAS Number	444731-52-6
ATC code	L01XE11 (WHO)
PubChem	CID 11525740
ChemSpider	9700526
UNII	7RN5DR86CK
ChEMBL	CHEMBL477772
Chemical data
Formula	C₂₁H₂₃N₇O₂S
Molar mass	437.517 g/mol

////////////PAZOPANIB, GW786034, Votrient, Armala, GW 786034, GW-786034, GW786034GW786034, VOTRIENT, Pazopanib hydrochloride, FDA 2009, Antineoplastic, Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors, Renal Cell Carcinoma Therpay, Soft Tissue Sarcoma Therapy, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид

O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C

Eribulin, エリブリンメシル酸塩 an Antineoplastic

Uncategorized Comments Off

Aug 052016

Eribulin

Eribulin mesylate

エリブリンメシル酸塩

CAS 441045-17-6 MESYLATE

C₄₁H₆₃NO₁₄S, 826.00222 g/mol

halichrondrin B analog, B1939, E7389, ER-086526,Halaven

CAS 253128-41-5 FREE FORM

(1S,3S,4R)-3-tert-butoxycarbonylamino-4-hydroxycyclopentanecarboxylic acid methyl ester;

(1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-Amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.13,32.13,33.16,9.112,16.018,22.029,36.031,35]hentetracontan-24-one;

2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one

(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-((2S)-3-amino-2-hydroxypropyl)-3-methoxy-26-methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′:5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one methanesulfonate (salt)

11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′:5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one, 2-((2S)-3- amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, 2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt)

エリブリンメシル酸塩
Eribulin Mesilate

C₄₀H₅₉NO₁₁▪CH₄O₃S : 826
[441045-17-6]

Eribulin mesylate is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity.

E7389 is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity. Eribulin binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and the assembly of microtubules, resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase, and, potentially, tumor regression.

Halichondrin B, a large polyether macrolide, was isolated 25 years ago from the marine sponge Halichondria okadai

Halichondria okadai

ERBULIN

The anti-cancer drug made from a sea-spongeEribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin mesylate was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline– and taxane-based chemotherapies.^[1] It was approved by Health Canada on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. ^[2]

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.^[3]

Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.

Eribulin mesylate is an analogue of halichondrin B, which in 1986 was isolated from the marine sponge Halichondria okadai toxic Pacific.Halichondrin B has a significant anti-tumor activity. The Eribulin synthetically obtained has a simpler but still complex molecular structure.Taxanes such as to inhibit the spindle apparatus of the cell, but it is engaged in other ways.

Drug substance, eribulin mesylate, is a It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondira okadai. Eribulin mesylate is a white powder which is freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dichloromethane, dimethylsulfoxide, N-methylpyrrolidone and ethyl acetate. It is soluble in acetone, sparingly soluble in acetonitrile, and practically insoluble in tertbutyl methyl ether, n-heptane and n-pentane. Eribulin mesylate is characterized by ion chromatography for counter ion content, and spectroscopic analyses (mass, ultraviolet, nuclear magnetic resonance, single crystal X-ray crystallography, and circular dichroism) for molecular structure and absolute configuration. Bulk drug substance is hygroscopic and sensitive to light, heat, and acid hydrolysis,,,,,,……..http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532orig1s000chemr.pdf

STR1

Melvin Yu received his B.S. from MIT, and both his M.A. and Ph.D. degrees from Harvard University while studying under Professor Yoshito Kishi. In 1985, he joined Eli Lilly, and in 1993 he relocated to Eisai Inc. where he led the chemistry team that discovered Halaven. He was then responsible for the initial route nding and synthesis scale-up effort that ultimately provided the rst multi-gram batch of eribulin mesylate. Mel retains a strong interest in natural products as the inspiration of new chemotherapeutic agents, and in this context recently expanded his area of research to include cheminformatics and compound library design.

STR1

Wanjun Zheng received a Ph.D. in organic chemistry from Wesleyan University in 1994 under the direction of Professor Peter A. Jacobi working on synthetic methodology development and its application in natural product synthesis. He spent over two years as a postdoctoral research fellow in Harvard University under Professor Yoshito Kishi working on the complete structure determination of maitotoxin. He joined Eisai in 1996 and has since been contributing and leading many drug discovery projects including project in the discovery of Halaven.

Boris M. Seletsky earned his PhD in 1987 from Shemyakin Institute of Bioorganic Chemistry in Moscow, Russia working on new methods in steroid synthesis under direction of Dr George Segal and Professor Igor Torgov. Aer several years of natural product research at the same Institute, he moved on to postdoctoral studies in stereoselective synthesis with Professor Wolfgang Oppolzer at the University of Geneva, Switzerland, and Professor James A. Marshall at the University of South Carolina. Boris joined Eisai in 1994, and has contributed to many oncology drug discovery projects with considerable focus on natural products as chemical leads, culminating in the discovery of Halaven.

PAPER

http://www.sciencedirect.com/science/article/pii/S0960894X0401100X

Bioorganic & Medicinal Chemistry Letters

Volume 14, Issue 22, 15 November 2004, Pages 5551–5554

Macrocyclic ketone analogues of halichondrin B

This paper is dedicated to memory of Bruce F. Wels, our friend and colleague

^a Department of Medicinal Chemistry, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA
^b Department of Anticancer Research, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA
^c Advisory Board, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA

doi:10.1016/j.bmcl.2004.08.069

Image for unlabelled figure

PAPER

From micrograms to grams: scale-up synthesis of eribulin mesylate

Melvin J. Yu,*^a Wanjun Zheng^a and Boris M. Seletsky^a

*Corresponding authors

^aEisai Inc., Andover, USA
E-mail: Melvin_Yu@eisai.com

Nat. Prod. Rep., 2013,30, 1158-1164

DOI: 10.1039/C3NP70051H, http://pubs.rsc.org/is/content/articlelanding/2013/np/c3np70051h#!divAbstract

Covering: 1993 to 2002

The synthesis of eribulin mesylate from microgram to multi-gram scale is described in thisHighlight. Key coupling reactions include formation of the C30a to C1 carbon–carbon bond and macrocyclic ring closure through an intramolecular Nozaki–Hiyama–Kishi reaction.

Graphical abstract: From micrograms to grams: scale-up synthesis of eribulin mesylate

The synthesis of the C27–C35 tetrahydrofuran fragment.

The synthesis of the C14–C21 aldehyde subfragment.

CLIP

In 1986, two Japanese chemists Hirata and Uemura [Y. Hirata, D. Uemura, Pure Appl. Chem. 58 (1986) 701.] isolated a naturally-occurring compound from the marine sponge Halichondria okadai (picture above, right). The compound was named Halichondrin B, and it immediately began to generate great excitement when it was realised that it was extremely potent at killing certain types of cancer cells in small-scale tests. As a result of this discovery, it was immediately given top priority to be tested against a wide range of other cancers, and became one of the first compounds to be evaluated using the novel 60-cell line method developed by the US National Cancer Institute (NCI). In this technique, 60 different types of human tumor cells (including leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney) are tested with the potential anti-cancer molecule delivered at a single dose of 10 μM concentration. This process can be run in parallel, with dozens of different molecules being tested against all 60 cancer cell lines at the same time in a huge array. Any molecules which exhibit significant growth inhibition are prioritised, and the test repeated on them, but this time at five different concentration levels.

Halichondrin B – the part of the molecule used to make Eribulin is shown in blue.

Unfortunately, the concentration of Halichondrin B in the sea sponge wasn’t enough to enable commercial production for use in chemotherapy. For example, a ton of sea sponges could only produce 300 mg of Halichondrin B! The race was on to try to synthesise Halichondrin B in the lab, which wasn’t easy due to its large size (molecular weight 1110) and complex structure. However, only 6 years later, chemists at Harvard University published the complete chemical synthesis of this molecule………..T.D. Aicher, K.R. Buszek, F.G. Fang, C.J. Forsyth, S.H. Jung, Y. Kishi, M.C. Matelich, P.M. Scola, D.M. Spero, S.K. Yoon, J. Am. Chem. Soc. 114 (1992) 3162

Although this was a great achievement, Halichondrin B was still far too complex and the sythesis route too expensive to do on a large scale. The molecule needed to be stripped down to its essential components, while keeping, or even improving, its anti-cancer efficacy. Many tests were performed, but eventually the work led to te development of the structurally-simplified and pharmaceutically-optimized analog, which was named Eribulin [3,4]. Eribulin mesylate was approved by the U.S. Food and Drug Administration in 2010, to treat patients with metastatic breast cancer [5], and it is currently being marketed by Eisai Co. under the trade nameHalaven . It is also being investigated for use in a variety of other solid tumors, including lung cancer, prostate cancer and sarcoma .

ERIBULIN

M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M. Seletsk, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. Dipietro, Y. Wang, J.J. Chen, D.A. Quincy, A. Davis, K. Yoshimatsu, Y. Kishi, M.J. Yu, B.A. Littlefield, Cancer Res. 61 (2001) 1013.

M.J. Yu, Y. Kishi, B.A. Littlefield, in D.J. Newman, D.G.I. Kingston, G.M. Cragg, Anticancer agents from natural products, Washington, DC, Taylor and Francis (2005).

http://healthmad.com/conditions-and-diseases/breast-cancer-cure-from-the-sea/

http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389

M.A. Jordan, L. Wilson, Nature Revs: Cancer 4 (2004) 253.

ERIBULIN

Patent Data

Appl No	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N201532	001	6214865	Jul 20, 2023	Y
N201532	001	6469182	Jun 16, 2019			U – 1096
N201532	001	7470720	Jun 16, 2019		Y
N201532	001	8097648	Jan 22, 2021			U – 1096

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N201532	001	NCE	Nov 15, 2015

The substance inhibits the polymerization of tubulin into microtubules and encapsulates tubulin molecules in non-productive aggregates from. The lack of training of the spindle apparatus blocks the mitosis and ultimately induces apoptosis of the cell. Eribulin differs from known microtubule inhibitors such as taxanes and vinca alkaloids by the binding site on microtubules, also it does not affect the shortening. This explains the effectiveness of the new cytostatic agent in taxane-resistant tumor cell lines with specific tubulin mutations.

Structure and mechanism

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B,^[4]^[5] the latter being a potent naturally-occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.^[6]^[7] Eribulin is a mechanistically-unique inhibitor of microtubule dynamics,^[8]^[9] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.^[10] Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.^[11]^[12]

A new synthetic route to E7389 was published in 2009.^[13]

clip

Eisai R&D Management Co., Ltd.

13/9/2013

Halaven is a novel anticancer agent discovered and developed in-house by Eisai and is currently approved in more than 50 countries, including Japan, the United States and in Europe. In Russia, Halaven was approved in July 2012 for the treatment of locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens including an anthracycline and a taxane. Approximately 50,000 women in Russia are newly diagnosed with breast cancer each year, with this type of cancer being the leading cause of death in women aged 45 to 55 years. read all at…………………….

http://www.dddmag.com/news/2013/09/eisai-launches-halaven-cancer-drug-russia

Eribulin mesylate (Halaven; Eisai) — a synthetic analogue of the marine natural product halichondrin B that interferes with microtubule dynamics — was approved in November 2010 by the US Food and Drug Administration for the treatment of metastatic breast cancer.

Family members of the product patent, WO9965894, have SPC protection in the EU until 2024 and one of its Orange Book listed filings, US8097648, has US154 extension till January 2021.

The drug also has NCE exclusivity till November 2015.

HALAVEN (eribulin mesylate) Injection is a non-taxane microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano12,15-methano-9H,15H-furo[3,2-i]furo[2′,3′:5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt).

It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C₄₀H₅₉NO₁₁ •CH₄O₃S. Eribulin mesylate has the following structural formula:

HALAVEN® (eribulin mesylate) Structural Formula Illustration

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).

complete syn is available here

http://www.sciencedirect.com/science/article/pii/S0968089611010674

http://www.drugdevelopment-technology.com/projects/halaven-cancer/halaven-cancer1.html

Nitrogen: dark blue, oxygen: red, hydrogen: light blue
graphics: Wurglics, Frankfurt am Main

clip

Macrocyclization process for preparing a macrocyclic intermediate of halichondrin B analogs, in particular eribulin, from a non-macrocyclic compound, using a carbon-carbon bond-forming reaction.

http://www.pnas.org/content/108/17/6699/F1.expansion.html

http://www.nature.com/nrd/journal/v8/n1/fig_tab/nrd2487_F6.html

UPDATED

WO 2015066729

Eisai has developed and launched eribulin mesylate for treating breast cancer. Follows on from WO2014208774, claiming use of a combination comprising eribulin mesylate and lenvatinib mesylate, for treating cancer.

Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin B

By: Fang, Francis G.; Kim, Dae-Shik; Choi, Hyeong-Wook; Chase, Charles E.; Lee, Jaemoon

Assignee: Eisai R&D Management Co., Ltd., Japan

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compds. useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for prepg. the same.

CLIPS

http://www.chemistry-blog.com/2012/09/15/from-natural-product-to-pharmaceutical/

In a recent discussion (Nicolau), about the suggested move of Prof. NicoIau from Scripps, the issue of the practicality of natural product total synthesis was raised. Here is a wonderful example of just that very usefulness, a wonderful piece of science extending over many years. It concerns the journey from Halichondrin B to Eribulin (E7389) a novel anti-cancer drug. The two compounds have the following structures:

I think you can see the relationship and as a development chemist I am glad they managed to simplify things (a bit).

Both compounds have an enormous number of possible isomers: Halichondrin B, with 32 stereocenters has 2³²possible isomers; Eribulin has 19 with 2¹⁹ isomers (if I have counted correctly, it does not really matter, there are lots of isomers). Remarkable is the fact that only one of these isomers is active in the given area of anti-cancer agents.

An excellent review of the biology and chemistry of these compounds has been published by Phillips etal¹. This review is an excellent read and is to be commended. Another one written by Kishi², is also full of information about the discovery of E7389 and I hope you will all get a chance to read this chapter.

The history of Halichondrin B goes back to 1987 when Blunt^2-5 isolated it with other similar compounds from extraction of 200Kg of a sponge. Independently Pettit isolated the same compound from a different species⁴. The appearance of this compound in different species of sponge may indicate that it is produced by a symbiote.

The biological activity of Halichondrin B is amazing. When evaluated against B-16 melanoma cells it was found to have an IC₅₀ of 0.093ng/mL. Against various cancers, generated in mice, it was shown to be affective at a daily dose of 5ug/kg, which resulted in a doubling of the survival rate. It has also been demonstrated that Halichondrin acts as a microtubule destabiliser and mitoitic spindle poison. It was proven that it is has tremendous in vivo activity against a variety of drug resistant cancers, lung, colon, breast, ovarian to mention a few. Consequently the National Cancer Institute selected it for pre-clinical trials and it’s here that the problems began. According to reference 1 the entire clinical development would require some 10g, and if successful the annual production amount would be between 1-5 kg. Blunt and co-workers managed to isolate 310mg from 1000kg-harvested sponge therefore, the only way to obtain the amounts required is total chemical synthesis. But synthesising 1-5 kg of such a compound would indeed be a mammoth task.

Kishi synthesised this compound⁷ in 1992 starting from carbohydrate precursors employing the Nozaki-Hiyama-Kishi Ni/Cr reaction, several times, in the long synthetic sequence^{8, 9}. Now as an aside I have used this reaction on scale several times and although it works well its success is very dependant upon the quality of the chromium source and also the presence of other trace transition metals.

In collaboration with Eisai work on the SAR of Halichondrin began. They had a good start: Thanks to the total syntheses of Kishi several advanced intermediates were available for biological screening and one popped out of the screen as being very active:

The first active lead compound

As one can see the complete left hand side of Halichondrin has gone! However, this compound was not active in vivo. Many derivatives and analogues of this compound were prepared: furans, diols, ketones and so on and a lead emerged from this complex SAR study, ER-076349. The vicinal diol was used as a handle for further refinement and lead ultimately to E7389, the clinical candidate.

It can be synthesised in around 35 steps from simple starting materials.

Going through all this work in a few sentences really belittles the tremendous amount of effort that went into discovery and development of this compound and the people involved are to be applauded for their dedication.

Kishi continues to optimise the synthesis of Eribulin as judged by a recent publication¹⁰. Where he describes an approach to the amino-alcohol-tetrahydrofuran part of Eribulin (top left fragment, compound 1 below). The retro-synthetic analysis is shown below. The numbering corresponds to that of Eribulin.

The first generation synthesis consisted of 20 steps and delivered compound 1 about 5% yield, the second-generation route was completed in 12 steps with a yield of 48%. One of the highlights includes a remarkable asymmetric hydrogenation¹¹ with Crabtree’s catalyst¹²:

This selectivity was not just luck; it seems to quite general, at least in this system. I always wonder how long it took them to stumble across this catalyst, but then I suppose that Eisai like most of the large pharma. companies has a hydrogenation group that probably indulges in catalyst screening.

The C34-C35 diol was obtained by a Sharpless asymmetric hydroxylation, here the diastereoisomeric ratio was not very high, only about 3:1 in favour of the desired isomer. Fortunately the undesired isomer could be removedcompletely by crystallisation.

This is a remarkable story and references 1 and 2 are worth reading to obtain the complete picture and learn lots of new chemistry as well. Eisai filed a NDA and the FDA approved the compound in 2010 for the treatment of metastatic breast cancer.

Patent

https://www.google.com/patents/WO2013142999A1?cl=en

EXAM PLE 23 : Preparation of Eribulin :

[00120] Compound E-12A (133 mg, 160 μηιοΙ, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0 °C. To this solution was sequentially added 2,6-lutidine (0.09 m L, 0.8 mmol, 5.0 eq), and trimethyl silyl triflate (TMSOTf) (0.12 m L, 0.64 mmol, 4.0 eq) and the cooling bath was removed . The reaction was stirred at room temperature for 1.5 hours and another portion of 2,6-lutidine (5.0 eq) and TMSOTf (4.0 eq) were added at room temperature. The reaction was further stirred for 1 hour and quenched with water (10 m L). The layers were separated and the organic phase was washed with additional water (2x 10 m L), brine (10 m L), dried over MgS0₄ and concentrated under reduced pressure. The residue was dissolved in MeOH (10 m L), a catalytic amount of K₂C0₃ was added at room temperature and the resulting mixture was stirred for 2 hours. The reaction was diluted with dichloromethane and quenched with water (10 mL). The layers were separated and the aqueous phase was further extracted with dichloromethane (5 x 10 m L). The combined organic layers were washed with brine (20 m L), dried over MgS0₄, filtered and concentrated. The residue was dissolved in dichloromethane and purified by column chromatography on silica gel, using 1 : 9 MeOH : CH₂CI₂ to 1 : 9 : 90 N H₄OH : MeOH : CH₂CI₂ as eluent. The product was afforded as a white amorphous solid (103 mg, 88%) . [00121] EXAMPLE 23 : Preparation of compound of formula 4a

D-Gulonolactone 4a

[00122] The compound of formula 4a was prepared from D-Gulonolactone according to the conditions described in PCT publication number WO 2005/118565. [00123] EXAMPLE 24: Preparation of Eribulin mesylate (3)

[00124] Eribulin mesylate (3) was prepared from Eribulin according to the conditions described in US patent application publication number US

2011/0184190.

PATENT

https://www.google.com/patents/EP2528914A1?cl=en

Halichondrin B analogs, e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized from the C14-C35 fragment as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565. In one example described in these references, the C14-C35 portion, e.g., ER- 804028, of the molecule is coupled to the C1-C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):

Scheme 1

eribulin, eribulin mesylate

Scheme 2

ER-804028

Compound AE (280 mg, 0.281 mmol, 1 eq) was dissolved in CH₂C1₂ and cooled to 0 °C. Pyridine (0.045 ml, 0.56 mmol, 2.0 eq) was added followed by Ms₂0 (58.8 mg, 0.338 mmol, 1.20 eq). The reaction was allowed to warm to room temperature, and stirring was continued for an additional 1 h. The reaction mixture was cooled to 0 °C, diluted with MTBE (5.6 ml), washed with saturated NaHC0₃ (0.84 g), and concentrated to give crude product as colorless film. The crude was azeotropically dried with heptane (3 ml ^χ 2) and re-dissolved in THF (7.0 ml). The mixture was cooled to 0 °C and treated with 25 wt% NaOMe (0.13 ml). After 10 min, the reaction was allowed to warm to room temperature, and stirring was continued for an additional 30 min. The mixture was treated with additional 25 wt% NaOMe (0.045 ml), and stirring was continued for an additional 20 min. The reaction mixture was diluted with heptane (7.0 ml) and washed with water (1.4 ml). The organic layer was separated, sequentially washed with: 1) 20 wt% NH₄C1 (0.84 g) and 2) 20 wt% NaCl (3 g), and concentrated to give crude product as brownish oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 2:3 v/v) to give ER-804028 (209 mg, 0.245 mmol, 87%) as pale yellow oil. 1H NMR (400 MHz, CDC1₃): δ 7.89 (2H, m), 7.64 (IH, m), 7.56 (2H, m), 4.85 (IH, d, J= 1.6 Hz), 4.80 (IH, s), 4.72 (IH, s), 4.61 (IH, d, J= 1.6 Hz), 4.23 (IH, br), 3.91 (IH, m), 3.79 (IH, m), 3.76 (2H, m), 3.63 (IH, m), 3.50-3.60 (4H, m), 3.43 (IH, dd, J= 5.6 Hz, 10.0 Hz), 3.38 (3H, s), 3.32 (IH, m), 2.98 (2H, m), 2.61 (IH, br), 2.56 (IH, m), 2.50 (IH, m), 2.08-2.22 (3H, m), 1.96 (IH, m), 1.84 (IH, m), 1.78 (IH, m), 1.70 (IH, m), 1.42-1.63 (6H, m), 1.28-1.42 (2H, m), 1.01 (3H, d, J= 6.8 Hz), 0.84 (18H, s), 0.05 (3H, s), 0.04 (3H, s), 0.00 (3H, s), -0.01 (3H, s); and ¹³C NMR (100 MHz, CDC1₃): δ 150.34, 150.75, 139.91, 134.18, 129.73 (2C), 128.14 (2C), 105.10, 85.97, 80.92, 79.72, 78.50, 77.45, 77.09, 75.53, 71.59, 68.04, 62.88, 58.27, 57.73, 43.51, 42.82, 39.16, 37.68, 35.69, 33.31, 32.41, 31.89, 31.48, 29.79, 26.21 (3C), 26.17 (3C), 18.58, 18.38, 18.13, -3.85, – 4.71, -5.12 (2C).

CLIP

Eribulin mesylate (Halaven)
Eribulin is a highly potent cytotoxic agent approved in the US for the treatment of metastatic breast cancer for patients who have
received at least two previous chemotherapeutic regimens.30 Eribulin was discovered and developed by Eisai and it is currently
undergoing clinical evaluation for the treatment of sarcoma (PhIII) and non-small cell lung cancer which shows progression after platinum-based chemotherapy and for the treatment of prostate cancer (PhII). Early stage clinical trials are also underway to evaluate
eribulin’s efficacy against a number of additional cancers. Eribulin is a structural analog of the marine natural product halichondrin B.
Its mechanism of action involves the disruption of mitotic spindle formation and inhibition of tubulin polymerization which results
in the induction of cell cycle blockade in the G2/M phase and apoptosis.31 Several synthetic routes for the preparation of eribulin have
been disclosed,32–35 each of which utilizes the same strategy described by Kishi and co-workers for the total synthesis of halichondrin B.36 Although the scales of these routes were not disclosed in all cases, this review attempts to highlight what appears to be the production-scale route based on patent literature.37,38 Nonetheless, the synthesis of eribulin represents a significant accomplishment in the field of total synthesis and brings a novel chemotherapeutic option to cancer patients.
The strategy to prepare eribulin mesylate (V) employs a convergent synthesis featuring the following: the late stage coupling of
sulfone 22 and aldehyde 23 followed by macrocyclization under Nozaki–Hiyami–Kishi coupling conditions, formation of a challenging
cyclic ketal, and installation of the primary amine (Scheme 5).Sulfone 22 was further simplified to aldehyde 24 and vinyl triflate 25 which were coupled through a Nozaki–Hiyami–Kishi reaction.

The schemes that follow will describe the preparation of fragments 23, 24 and 25 along with how the entire molecule was assembled.
The synthesis of the C1–C13 aldehyde fragment 23 is described in Scheme 6. L-Mannonic acid-lactone 26 was reacted with cyclohexanone in p-toluene sulfonic acid (p-TSA) to give the biscyclohexylidene ketal 27 in 84% yield. Lactone 27 was reduced with
diisobutylaluminum hydride (DIBAL-H) to give lactol 28 followed by condensation with the ylide generated from the reaction of
methoxymethylene triphenylphosphorane with potassium tertbutoxide to give a mixture of E and Z vinyl ethers 29 in 81% yield.
Dihydroxylation of the vinyl ether of 29 using catalytic osmium teteroxide and N-methylmorpholine-N-oxide (NMO) with concomitant cyclization produced diol 30 in 52% yield. Bis-acetonide 30 was then reacted with acetic anhydride in acetic acid in the presence of ZnCl2 which resulted in selective removal of the pendant ketal protecting group. These conditions also affected peracylation, giving rise to tetraacetate 31 in 84% yield. Condensation of 31 with methyl 3-(trimethylsilyl)pent-4-enoate in the presence of boron trifluoride etherate in acetonitrile provided alkene 32. Saponification conditions using Triton B(OH) removed the acetate protecting groups within 32 and presumably induced isomerization of the alkene into conjugation with the terminal ester, triggering an intramolecular Michael attack of the 2-hydroxyl group, ultimately resulting in the bicylic-bispyranyl diol methyl ester 33 as a crystalline solid in 38% yield over two steps. Oxidative cleavage of the vicinal diol of 33 with sodium periodate gave aldehyde 34 which was coupled to (2-bromovinyl)trimethylsilane under Nozaki–Hiyami–Kishi conditions to give an 8.3:1 mixture of allyl alcohols 35 in 65% yield over two steps. Hydrolysis of the cyclohexylidine ketal 35 with aqueous acetic acid followed by recrystallization gave diastereomerically pure triol 36 which was reacted with tert-butyldimethylsilyl triflate (TBSOTf) to afford the tris-TBS ether 37 in good yield. Vinyl silane 37 was treated with NIS and catalytic tert-butyldimethylsilyl chloride (TBSCl) to give vinyl iodide 38 in 90% yield.
Reduction of the ester with DIBAL-H produced the key C1–C14 fragment 23 in 93% yield.
The preparation of the tetra-substituted tetrahydrofuran intermediate 24 is described in Scheme 7. D-Glucurono-6,3-lactone
39 was reacted with acetone and sulfuric acid to give the corresponding acetonide and the 5-hydroxyl group was then removed by converting it to its corresponding chloride through reaction with sulfuryl chloride (SO2Cl2) followed by hydrogenolysis
to give lactone 40 in good overall yield. Reduction of the lactone 40 with DIBAL-H gave the corresponding lactol which was condensed
with (trimethylsilyl)methylmagnesium chloride to afford silane 41. Elimination of the silyl alcohol of 41 was accomplished
under Peterson conditions with potassium hexamethyldisilazide (KHMDS) to afford the corresponding terminal alkene in 94% yield.
The secondary alcohol of this intermediate was alkylated with benzyl bromide to afford ether 42 in 95% yield. Asymmetric dihydroxylation of the alkene of 42 under modified Sharpless conditions using potassium osmate (VI) dehydrate (K2OsO4), potassium
ferricyanide (K3Fe(CN)6) and the (DHQ)2AQN ligand produced the vicinal diol which was then reacted with benzoyl chloride,
N-methylmorpholine, and DMAP to give di-benzoate 43 in excellent yield as a 3:1 mixture of diastereomeric alcohols. Allyl trimethylsilane was added to the acetal of 43 using TiCl3(OiPr) as the Lewis acid to give 44 in 83% yield. Re-crystallization of 44 from
isopropanol and n-heptane afforded 44 in >99.5% de in 71% yield.
Oxidation of the secondary alcohol of 44 under the modified Swern conditions generated the corresponding ketone which was condensed with the lithium anion of methyl phenyl sulfone to give a mixture of E and Z vinyl sulfones 45. Debenzylation of 45 using iodotrimethylsilane (TMSI) followed by chelation-controlled reduction of the vinyl sulfone through reaction with NaBH(OAc)3, and
then basic hydrolysis of the benzoate esters using K2CO3 in MeOH resulted in triol 46 as a white crystalline solid in 57% yield over the
five steps after re-crystallization. The vicinal diol of 46 was protected as the corresponding acetonide through reaction with 2,2-
dimethoxypropane and sulfuric acid and this was followed by methyl iodide-mediated methylation of the remaining hydroxyl
group to give methyl ether 47. The protecting groups within acetonide 47 were then converted to the corresponding bis-tert-butyldimethylsilyl ether by first acidic removal of the acetonide with aqueous HCl and reaction with TBSCl in the presence of imidazole to give bis-TBS ether 48. Then, ozonolysis of the olefin of 48 followed by hydrogenolysis in the presence of Lindlar catalyst afforded the key aldehyde intermediate 24 in 68% yield over the previous five steps after re-crystallization from heptane.
Two routes to the C14–C26 fragment 25 will be described as both are potentially used to prepare clinical supplies of eribulin.
The first route features a convergent and relatively efficient synthesis of 25, however it is limited by the need to separate enantiomers
and mixture of diastereomers via chromatographic methods throughout the synthesis.37 The second route to 25 is a
much lengthier synthesis from a step-counting perspective; however it takes full advantage of the chiral pool of starting materials
and requires no chromatographic separations and all of the products were carried on as crude oils until they could be isolated as
crystalline solids.38 The first route to fragment 25 is described in Scheme 8 and was initiated by the hydration of 2,3-dihydrofuran (49) using an aqueous suspension of Amberlyst 15 to generate the intermediate tetrahydro-2-furanol (50) which was then immediately reacted with 2,3-dibromopropene in the presence of tin and catalytic HBr to afford diol 51 in 45% for the two steps.

The primary alcohol of 51 was selectively protected as its tert-butyldiphenylsilyl ether using TBDPSCl and imidazole and the racemate was then separated using simulated moving bed (SMB) chromatography to give enantiopure 52 in 45% yield over the two steps. The secondary alcohol of 52 was reacted with p-toluenesulfonyl chloride and DMAP to give tosylate 53 in 78% yield which was used as a coupling partner later in the synthesis of this fragment. The synthesis of the appropriate coupling partner was initiated by condensing diethylmalonate with (R)-2-(3-butenyl)oxirane (54), followed by decarboxylation to give lactone 55 in 71% yield for the two step process. Methylation of the lactone with LHMDS and MeI provided 56 in 68% yield as a 6:1 mixture of diastereomers. The lactone 56 was reacted with the aluminum amide generated by the reaction of AlMe3 and N,O-dimethylhydroxylamine to give the corresponding Weinreb amide which was protected as its tert-butyldimethylsilyl ether upon reaction with TBSCl and imidazole to give 57 in 91% yield over the two steps. Dihydroxylation of the olefin of 57 by reaction with OsO4 and NMO followed by oxidative cleavage with NaIO4 gave the desired coupling partner aldehyde 58 in 93% yield. Aldehyde 58 was coupled with vinyl bromide 53 using an asymmetric Nozaki–Hiyami– Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand 66 (described in Scheme 9 below). The reaction mixture was treated with ethylene diamine to remove the heavy metals and give the secondary alcohol 59. This alcohol was stirred with silica gel in isopropanol to affect intramolecular cyclization to give the tetrahydrofuran 60 in 48% yield over the three step process. The Weinreb amide of 60 was reacted with methyl magnesium chloride to generate the corresponding methyl ketone which was converted to vinyl triflate 61 upon reaction with KHMDS and Tf2NPh. De-silylation of the primary and secondary silyl ethers with methanolic HCl gave the corresponding diol in 85% yield over two steps and the resulting mixture of diastereomers was separated using preparative HPLC to provide the desired diastereomer in 56% yield. The primary alcohol was protected as its pivalate ester with the use of pivaloyl chloride, DMAP and collidine; the secondary alcohol was converted to a mesylate upon treatment with methanesulfonyl chloride (MsCl) and Et3N to give the C15–C27 fragment 25 in high yield.
The preparations of the chiral ligand 66 used in the coupling reaction in Scheme 8 along with the chiral ligand 67 utilized later
in the synthesis are described in Scheme 9. 2-Amino-3-methylbenzoic acid (62) was reacted with triphosgene to give benzoxazine
dione 63 in 97% yield, which then was reacted with either D- or L-valinol in DMF followed by aqueous LiOH to give alcohols 64
and 65, respectively in 65–75% yield for the two steps. Reaction of alcohol 64 or 65 with MsCl in the presence of DMAP effected formation of the dihydrooxazole ring and mesylation of the aniline to give the corresponding (R)-ligand 66 derived from D-valinol or the (S)-ligand 67 derived from L-valinol, respectively in high yield.
An alternative route to intermediate 25 is described in Scheme 10 and although much lengthier than the route described in
Scheme 8, it avoids chromatographic purifications as all of the products are carried on crude until a crystalline intermediate
was isolated and purified by re-crystallization. Quinic acid (68) was reacted with cyclohexanone in sulfuric acid to generate a protected
bicyclic lactone in 73% yield and the resulting tertiary alcohol was protected as its trimethylsilyl ether 69. Reduction of the
lactone 69 was accomplished with DIBAL-H and the resulting lactol was treated with acetic acid to remove the TMS group and the resulting compound was reacted with acetic anhydride, DMAP and Et3N to give bis-acetate 70 in 65% yield for the three steps after re-crystallization. Methyl 3-(trimethylsilyl)pent-4-enoate was coupled to the acetylated lactol 70 in the presence of boron trifluoride etherate and trifluoroacetic anhydride to give adduct 71 in 62% yield. The acetate of 71 was removed upon reaction with sodium methoxide in methanol and the resulting tertiary alcohol cyclized on to the isomerized enone alkene to give the fused pyran ring. Reduction of the methyl ester with lithium aluminum hydride provided pyranyl alcohol 72. Mesylation of the primary alcohol was followed by displacement with cyanide anion to give nitrile 73.

The nitrile was methylated upon reaction with KHMDS and MeI and the resulting product was purified by re-crystallization
to provide nitrile 74 in 66% over the previous five steps in a 34:1 diastereomeric ratio. Acid hydrolysis of the ketal of 74 liberated
the corresponding diol in 72% yield and this was reacted with 2-acetoxy-2-methylpropionyl bromide to give bromo acetate 75.
Elimination of the bromide was accomplished upon treatment with 1,8-diazabicycloundec-7-ene (DBU) to give alkene 76 in 63%
yield for two steps. Ozonolysis of the cyclohexene ring followed by reductive work-up with NaBH4 and basic hydrolysis of the acetate
produced a triol which upon reaction with NaIO4 underwent oxidative cleavage to give cyclic hemiacetal 77 in 75% yield over
the previous four steps. Wittig condensation with carbomethoxymethylene triphenylphosphorane gave the homologated unsaturated
ester 78. Catalytic hydrogenation of the alkene using PtO2 as the catalyst was followed by converting the primary alcohol to the
corresponding triflate prior to displacement with sodium iodide resulted in iodide 79 in 75% yield over four steps. The ester of 79
was reduced to the corresponding primary alcohol upon reaction with LiBH4 in 89% yield and the resulting iodoalcohol was treated
with Zn dust to affect reductive elimination of the iodide and decomposition of the pyran ring system to give the tetrahydrofuran
diol 80 in 90% yield. This diol was treated with methanolic HCl to affect an intramolecular Pinner reaction and this was followed
by protection of the primary alcohol as its tert-butyldiphenylsilyl ether to give lactone 81 The lactone was reacted with the
aluminum amide generated from AlMe3 and N,O-dimethylhydroxylamine and the resulting secondary alcohol was protected as
its tert-butyldimethylsilyl ether to give Weinreb amide 82 in 99% crude yield over four steps. Compound 82 is the diastereomerically
pure version of compound 60 and can be converted to compound 25 by the methods described in Scheme 8 absent the required
HPLC separation of diastereomers. With the three key fragments completed, the next step was to assemble them and complete the synthesis of eribulin. Aldehyde 24 was coupled to vinyl triflate 25 using an asymmetric Nozaki– Hiyami–Kishi reaction using CrCl2, NiCl2, Et3 N and chiral ligand 67 (Scheme 9) to give alcohol 83 (Scheme 11).

Formation of the THP ring was accomplished by reaction with KHMDS which allowed for displacement of the mesylate with the secondary alcohol and provided the THP containing product in 72% yield for the three steps. The pivalate ester group was removed with DIBAL-H to give the western fragment 22 in 92% yield.
The completion of the synthesis of eribulin is illustrated in Scheme 12. The lithium anion of sulfone 22 generated upon reaction
with nBuLi was coupled to aldehyde 23 to give diol 84 in 84% yield. Both of the alcohol functional groups of 84 were oxidized
using a Dess–Martin oxidation in 90% yield and the resulting sulfone was removed via a reductive cleavage upon reaction with
SmI2 to give keto-aldehyde 85 in 85% yield. Macrocyclization of 85 was accomplished via an asymmetric Nozaki–Hiyami–Kishi
reaction using CrCl2, NiCl2, Et3N and chiral ligand 67 to give alcohol 86 in 70% yield. Modified Swern oxidation of the alcohol provided the corresponding ketone in 91% yield and this was followed by removal of the five silyl ether protecting groups upon reaction with TBAF and subsequent cyclization to provide ketone 87. Compound 87 was treated with PPTS to provide the ‘caged’ cyclic ketal 88 in 79% over two steps. The vicinal diol of 88 was reacted with Ts2O in collidine to affect selective tosylation of the primary alcohol and this crude product was reacted with ammonium hydroxide to install the primary amine to give eribulin which was treated
with methanesulfonic acid in aqueous ammonium hydroxide to give eribulin mesylate (V) in 84% yield over the final three steps.

30. Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer, L. A.; Chase, C. E.;
Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.;
Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem.
Lett. 2004, 14, 5551.
31. Wang, Y.; Serradell, N.; Bolós, J.; Rosa, E. Drugs Future 2007, 32, 681.
32. Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600.
33. Choi, H.; Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-
K.; Xie, C. Pure Appl. Chem. 2003, 75, 1.
34. Kishi, Y.; Fang, F.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K. WO 9317690 A1, 1993.
35. Littlefield, B. A.; Palme, M.; Seletsky, B. M.; Towle, M. J.; Yu, M. J.; Zheng, W.
WO 9965894 A1, 1999.
36. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.;
Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992,
114, 3162.
37. Austad, B.; Chase, C. E.; Fang, F. G. WO 2005118565 A1, 2005.
38. Chase, C.; Endo, A.; Fang, F. G.; Li, J. WO 2009046308 A1, 2009.

CLIP

http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product

Eribulin (Halaven)

Halichondrin B is a wicked molecule. In tests in mice, it is an extremely potent cancer cell killer, active at around 80 picomolar concentration. It also possesses a fiendish macrocyclic polyketide structure, with 32 stereocentres meaning that it could adopt over four billion different isomers – with just one that fights cancer.

Eribulin and halichondrin B Eribulin is a cut-down derivative of halichondrin B, which maintains most of its activity with significantly reduced complexity

Its power is therefore inherently hard to harness. Halichondrin B was found in various sea sponge species in the 1980s, but getting 400mg of the compound from a tonne of sponge was doing well. Clinical development required at least 10g, and annual production takes kilograms.

Although developing a synthetic route to halichondrin B looked just as tough as trying to extract it from sponges, Yoshito Kishi’s group at Harvard University in the US accepted the challenge. Frank Fang, one of the team, recalls how the Nozaki–Hiyama–Kishi (NHK) coupling reaction would prove critical. ‘Another feature that was impressed upon me was the importance of crystalline intermediates,’ Fang adds. These allowed simple purification by recrystallisation, rather than expensive and time-consuming chromatography.

Published in 1992, their method used several NHK couplings, forming carbon–carbon bonds between multifunctional vinyl halides and aldehydes via a nickel-catalysed, chromium-mediated process.⁴ The sprawling convergent synthesis, whose longest linear sequence involved 47 steps, prompted Japanese pharmaceutical company Eisai to collaborate with Kishi in exploring halichondrin B’s structure–activity relationship. On screening the team’s intermediates, one featuring the macrocyclic half of halichondrin B proved especially active. A series of medicinal chemistry refinements led to what would eventually becomeeribulin (marketed by Eisai as Halaven), promising a slightly simpler synthesis. It has ‘just’ 19 stereocentres, which along with other structural restrictions cuts the possible number of isomers to a mere 16,384.

Fang joined Eisai in 1998 as it selected eribulin for further development, and worked to develop a production process for a route that produced it from three fragments. He again strove to exploit recrystallisation and use the NHK reaction, although making it reliable enough for manufacturing was challenging. ‘There was an appreciation for the somewhat sensitive nature of the reaction, particularly the asymmetric variant,’ he recalls.

The Eisai researchers therefore studied the NHK procedure as they applied it to redesigning the synthesis for part of the eribulin molecule they refer to as the C14–C26 fragment. Featuring just one ring, this fragment isn’t the most structurally complex of the three, but is still very difficult to make. That’s because it is a long chain with several stereocentres, whose stereochemistry is hard to link together.

Fang’s team initially broke this section down into two sub-fragments, C14–C19 and C20–C26, using asymmetric NHK reactions on each, learning about the reaction’s parameters as they did so.⁵ They then used what they’d found out to devise NHK reactions linking the two sub-fragments and attaching the two fragments on either side, which included closing the eribulin macrocycle. ‘We gained knowledge through our studies on the C19–C20 NHK coupling and were ultimately able to utilise that knowledge to try to execute an asymmetric NHK reaction in fixed equipment on multi-kilogram scale and construct the C19–C20, C26–C27, and C13–C14 bonds,’ Fang explains.

Synthesis of eribulin relies heavily on Nozaki–Hiyama–Kishi (NHK) coupling reactions to make key C–C bonds

Halaven was approved in the US in 2010 to treat breast cancer and earned ¥2.89 billion in sales (£159 million) in 2014. The commercial route initially took 62 steps across a convergent synthesis bringing together three fragments, with a longest linear sequence of 30 steps. Fang’s team has since added seven steps to the C14–C26 fragment route, which counterintuitively cuts costs and waste by 80% by eliminating chromatography.⁶ ‘I am hopeful that we can find the lessons applicable in future work,’ Fang says.

Cheaper synthesis would appear welcome, given that Halaven’s price tag has been criticised. In the UK it currently costs £2,000 per 21 day treatment cycle according to data from the British National Formularyand the country’s National Institute for Health and Clinical Excellence (Nice). As a result, Nice refused to cover the drug, and in January 2015 the remaining funding in England looked set to be closed off with Halaven being taken off the Cancer Drugs Fund (CDF)’s list. But Eisai was told in March that the drug would stay on the list, pending reconsideration, after an appeal against the decision.

In defence, Fang claims that Halaven is actually one of the most affordable breast cancer treatments on the CDF. ‘Eisai was given no opportunity to lower the price of Halaven before NHS England announced that the treatment would be removed from the fund, despite this being something we were, and still are, very willing to do,’ he adds.

Cited Patent	Filing date	Publication date	Applicant	Title
WO2009124237A1 *	Apr 3, 2009	Oct 8, 2009	Eisai R&D Management Co., Ltd.	Halichondrin b analogs
US6214865 *	Jun 16, 1999	Apr 10, 2001	Eisai Co., Ltd.	Macrocyclic analogs and methods of their use and preparation

Reference
1	*	DONG, C.-G. ET AL.: “New Syntheses of E7389 C 14-C35 and Halichondrin C 14- C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches“, J. AM. CHEM. SOC., vol. 131, 2009, pages 15642 – 15646, XP002629056
2	*	See also references of EP2831082A4
3	*	ZHENG, W. ET AL.: “Macrocyclic ketone analogues of halichondrin B“, BIOORG. MED. CHEM. LETT., vol. 14, 2004, pages 5551 – 5554, XP004598592

Citing Patent	Filing date	Publication date	Applicant	Title
WO2015000070A1 *	May 30, 2014	Jan 8, 2015	Alphora Research Inc.	Synthetic process for preparation of macrocyclic c1-keto analogs of halichondrin b and intermediates useful therein including intermediates containing -so2-(p-tolyl) groups
WO2015066729A1 *	Nov 4, 2014	May 7, 2015	Eisai R&D Management Co., Ltd.	Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b
WO2015131286A1 *	Mar 6, 2015	Sep 11, 2015	Alphora Research Inc.	Crystalline derivatives of (s)-1-((2r,3r,4s,5s)-5-allyl-3-methoxy-4-(tosylmethyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol
CN103483352A *	Oct 18, 2013	Jan 1, 2014	李友香	Medicinal bulk drug for resisting tumors
US9062020	Dec 24, 2012	Jun 23, 2015	Alphora Research Inc.	2-((2S,3S,4R,5R)-5-((S)-3-amino-2-hydroxyprop-1-yl)-4-methoxy-3-(phenylsulfonylmethyl)tetrahydrofuran-2-yl)acetaldehyde derivatives and process for their preparation
US9174956	Dec 14, 2012	Nov 3, 2015	Alphora Research Inc.	Process for preparation of 3-((2S,5S)-4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)propanol derivatives and intermediates useful thereof
US9181152	Nov 29, 2012	Nov 10, 2015	Alphora Research Inc.	Process for preparation of (3R)-2,4-di-leaving group-3-methylbut-1-ene

WO2012129100A1 *	Mar 16, 2012	Sep 27, 2012	Eisai R&D Management Co., Ltd.	Methods and compositions for predicting response to eribulin
WO2012166899A2 *	May 31, 2012	Dec 6, 2012	Eisai R&D Management Co., Ltd.	Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
CA2828946A1 *	Apr 16, 2012	Oct 26, 2012	Eisai R&D Management Co., Ltd.	Therapeutic agent for tumor
US7982060 *	Jun 3, 2005	Jul 19, 2011	Eisai R&D Management Co., Ltd.	Intermediates for the preparation of analogs of Halichondrin B

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

References

^“FDA approves new treatment option for late-stage breast cancer” (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
^Notice of Decision for HALAVEN
^http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389
^ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). “In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B”. Cancer Res.61 (3): 1013–21. PMID 11221827.
^ Yu MJ, Kishi Y, Littlefield BA (2005). “Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B”. In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7.
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^ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). “Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data”. J. Biol. Chem.266 (24): 15882–9. PMID 1874739.
Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). “The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth”. Mol. Cancer Ther.4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666.
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SEE https://wordpress.com/post/newdrugapprovals.org/3955

Eribulin
Systematic (IUPAC) name

2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
Clinical data
Trade names	Halaven
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a611007
License data	US FDA: Eribulin
Pregnancy category	US: D (Evidence of risk)
Routes of administration	Intravenous
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	253128-41-5
ATC code	L01XX41 (WHO)
PubChem	CID 17755248
ChemSpider	21396142
UNII	LR24G6354G
ChEMBL	CHEMBL1237028
Chemical data
Formula	C₄₀H₅₉NO₁₁
Molar mass	729.90 g/mol

////////Halaven, ERIBULIN, anticancer drug , Eisai Co. E7389, ER-086526, US NCI designation, NSC-707389. breast cancer, liposarcoma, halichrondrin B analog, B1939, E7389, ER-086526, 441045-17-6, FDA 2010, 253128-41-5 , ERIBULIN MESYLATE, Antineoplastic, エリブリンメシル酸塩

CC1CC2CCC3C(=C)CC(O3)CCC45CC6C(O4)C7C(O6)C(O5)C8C(O7)CCC(O8)CC(=O)CC9C(CC(C1=C)O2)OC(C9OC)CC(CN)O.CS(=O)(=O)O

C[C@@H]1C[C@@H]2CC[C@H]3C(=C)C[C@@H](O3)CC[C@]45C[C@@H]6[C@H](O4)[C@H]7[C@@H](O6)[C@@H](O5)[C@@H]8[C@@H](O7)CC[C@@H](O8)CC(=O)C[C@H]9[C@H](C[C@H](C1=C)O2)O[C@@H]([C@@H]9OC)C[C@@H](CN)O.CS(=O)(=O)O

CREDIT

http://www.chm.bris.ac.uk/motm/eribulin/eribulinh.htm

253128-41-5 CAS

Eribulin

Arformoterol, (R,R)-Formoterol For Chronic obstructive pulmonary disease (COPD)

GENERIC, Uncategorized Comments Off

Aug 032016

Arformoterol

MF C₁₉H₂₄N₂O₄
MW 344.405

(R,R)-Formoterol

Cas 67346-49-0

Chronic obstructive pulmonary disease (COPD)

Sunovion/Sepracor (Originator)
Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists
LAUNCHED 2007 , Phase III ASTHMA

Formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-

3D STRUCTURE

Arformoterol is a long-acting β₂ adrenoreceptor agonist (LABA) indicated for the treatment of chronic obstructive pulmonary disease(COPD). It is sold by Sunovion, under the trade name Brovana, as a solution of arformoterol tartrate to be administered twice daily (morning and evening) by nebulization.^[1]

Arformoterol inhalation solution, a long-acting beta2-adrenoceptor agonist, was launched in the U.S. in 2007 for the long-term twice-daily (morning and evening) treatment of bronchospasm in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The product, known as Brovana(TM), for use by nebulization only, is the first long-acting beta2-agonist to be approved as an inhalation solution for use with a nebulizer. The product was developed and is being commercialized by Sunovion Pharmaceuticals (formerly Sepracor)

Arformoterol ball-and-stick model

Bronchodilators, in particular β₂-adrenoceptor agonists, are recognized as very effective drugs to treat asthma and other bronchospastic conditions. Important characteristics for these drugs are activity, selectivity, duration of action, and onset. While the first-generation drugs (e.g., isoprenaline or terbutaline) were relatively unselective and short-acting, the current drugs have either a fast onset but only a short duration of action of about 4 h (albuterol) or a slow onset (20 min) with a longer duration of action (salmeterol). Formoterol (IUPAC name: 3-formamido-4-hydroxy-α-[[N-(p-methoxy-α-methylphenethyl)amino]methyl]benzyl alcohol) is unique in that it not only is extremely potent and selective but also has a duration of up to 12 h and a rapid onset of 1−5 min. Most β₂-adrenoceptor agonists are currently marketed as racemates despite regulatory preference and different biological activity of pure enantiomers. In the case of formoterol it has been shown that the (R,R)-isomer is 1000 times more active than the (S,S)-isomer

It is the active (R,R)-(−)-enantiomer of formoterol and was approved by the United States Food and Drug Administration (FDA) on October 6, 2006 for the treatment of COPD.

Arformoterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Arformoterol inhalation is used to prevent bronchoconstriction in people with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The use of arformoterol is pending revision due to safety concerns in regards to an increased risk of severe exacerbation of asthma symptoms, leading to hospitalization as well as death in some patients using long acting beta agonists for the treatment of asthma.

Arformoterol is an ADRENERGIC BETA-2 RECEPTOR AGONIST with a prolonged duration of action. It is used to manage ASTHMA and in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Arformoterol (Brovana)

Arformoterol is a beta2-Adrenergic Agonist. The mechanism of action of arformoterol is as an Adrenergic beta2-Agonist.

Arformoterol is a long-acting beta-2 adrenergic agonist and isomer of formoterol with bronchodilator activity. Arformoterol selectively binds to and activates beta-2 adrenergic receptors in bronchiolar smooth muscle, thereby causing stimulation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increased intracellular cAMP levels cause relaxation of bronchial smooth muscle and lead to a reduced release of inflammatory mediators from mast cells. This may eventually lead to an improvement of airway function.

Formoterol (Foradil) is a long acting β₂-agonist used as a bronchodilator in the therapy of asthma and chronic bronchitis. The (R,R)-enantiomer has been shown to be more active than the other stereoisomers (R,S; S,R; and S,S) of formoterol. (R,R)-Formoterol is extremely potent and selective, having rapid onset (1−5 min) and long duration, and is 1000 times more active than the (S,S) isomer

Arformoterol tartrate

Molecular FormulaC₂₃H₃₀N₂O₁₀
Average mass494.492
cas 200815-49-2
183-185°C

Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]- (1:1) [ACD/Index Name]

N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl]phenyl}formamide 2,3-dihydroxybutanedioate (salt)

N-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (+)-(2R,3R)-Tartaric Acid; (-)-Formoterol 1,2-Dihydroxyethane-1,2-dicarboxylic Acid; (R,R)-Formoterol Threaric Acid; Arformoterol d-Tartaric Acid; Arformoterol d-α,β-Dihydroxysuccinic Acid

(R,R)-Formoterol-L-(+)-tartrate

200815-49-2 CAS

Arformoterol tartrate (USAN)

Brovana

UNII:5P8VJ2I235

Arformoterol Tartrate, can be used in the synthesis of Omeprazole (O635000), which is a proton pump inhibitor, that inhibits gasteric secretion, also used in the treatment of dyspepsia, peptic ulcer disease, etc. Itis also the impurity of Esomeprazole Magnesium (E668300), which is the S-form of Omeprazole, and is a gastric proton-pump inhibitor. Also, It can be used for the preparation of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy.

SYNTHESIS

PATENT

US-9309186

Example 1

Synthesis of (R,R)-Formoterol-L-tartrate Form D

A solution containing 3.9 g (26 mmol) of L-tartaric acid and 36 mL of methanol was added to a solution of 9 g (26 mmol) of arformoterol base and 144 mL methanol at 23.degree. C. Afterwards, the resulting mixture was seeded with form D and stirred at 23.degree. C. for 1 hour. It was then further cooled to 0-5.degree. C. for 1 hour and the product collected by filtration and dried under inlet air (atmospheric pressure) for 16 hours to provide 11.1 g (86% yield) (99.7% chemical purity, containing 0.14% of the degradation impurity (R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy- l]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off white powder. .sup.1H-NMR (200 MHz, d.sub.6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). No residual solvent was detected (.sup.1H-NMR).

PSD: d.sub.50=2.3 .mu.m.

PAPER

Tetrahedron Letters, Vol. 38, No. 7, pp. 1125-1128, 1997

Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol

PAPER

Taking Advantage of Polymorphism To Effect an Impurity Removal: Development of a Thermodynamic Crystal Form of (R,R)-FormoterolTartrate

Gerald J. Tanoury ,*^† Robert Hett , Donald W. Kessler , Stephen A. Wald , and Chris H. Senanayake *^‡

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (6), pp 855–862

DOI: 10.1021/op025531h

http://pubs.acs.org/doi/abs/10.1021/op025531h

Abstract

The development and large-scale implementation of a novel technology utilizing polymorphic interconversion and crystalline intermediate formation of (R,R)-formoterol l-tartrate ((R,R)-FmTA, 1) as a tool for the removal of impurities from the final product and generation of the most thermodynamically stable crystal form is reported. The crude product was generated by precipitation of the free base as the l-tartrate salt in a unique polymorphic form, form B. Warming the resultant slurry effected the formation of a partially hydrated stable crystalline intermediate, form C, with a concomitant decrease in the impurity levels in the solid. Isolation and recrystallization of form C provided 1 in the thermodynamically most stable polymorph, form A.

SYN1

SYN 2

SYN 3

SYN 4

SYN 5

PATENT

http://www.google.co.in/patents/EP2348013A1?cl=en

Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(p-methoxyphenyl)-2-propylamino]ethyl]phenyl]-formamide, is a highly potent and β₂-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. Its chemical structure is depicted below:

Formoterol has two chiral centres, each of which can exist into two different configurations. This results into four different combinations, (R,R), (S,S), (S,R) and (R,S). Formoterol is commercially available as a racemic mixture of 2 diasteromers (R,R) and (S,S) in a 1:1 ratio. The generic name Formoterol always refers to its racemic mixture. Trofast et al. (Chirality, 1, 443, 1991) reported on the potency of these isomers, showing a decrease in the order of (R,R)>(R,S)≥(S,R)>(S,S). The (R,R) isomer, also known as Arformoterol, being 1000 fold more potent than the (S,S) isomer. Arformoterol is commercialised by Sepracor as Brovana

Formoterol was first disclosed in Japanese patent application (Application N° 13121 ) whereby Formoterol is synthesised by N-alkylation using a phenacyl bromide as described in the scheme below:

Afterwards, a small number of methods have been reported so far, regarding the synthesis of the (R,R) isomer, also referred as (R,R)-Formoterol and Arformoterol.

Murase et al. [Chem. Pharm. Bull. 26(4) 1123-1129(1978)] reported the preparation of (R,R)-Formoterol from a racemic mixture of the (R,R) and (S,S) isomers by optical resolution using optically active tartaric acid. Trofast et al. described a method in which 4-benzyloxy-3-nitrostyrene oxide was coupled with a optically pure (R,R)- or (S,S)-N-phenylethyl-N-(1-p-methoxyphenyl)-2-(propyl)amine to give a diastereomeric mixture of Formoterol precursors. These precursors were further separated by HPLC in order to obtain pure Formoterol isomers. Both synthetic processes undergo long synthetic procedures and low yields.

Patent publication EP0938467 describes a method in which Arformoterol is prepared via the reaction of the optically pure (R) N-benzyl-2-(4-methoxyphenyl)-1-(methylethylamine) with an optically pure (R)-4-benzyloxy-3-nitrostyrene oxide or (R)-4-benzyloxy-3-formamidostyrene oxide followed by formylation of the amino group. This method requires relatively severe reaction conditions, 24 h at a temperature of from 110 up to 130 °C as well as a further purification step using tartaric acid in order to eliminate diastereomer impurities formed during the process.

WO2009/147383 discloses a process for the preparation of intermediates of Formoterol and Arformoterol which comprises a reduction of a ketone intermediate of formula:

Using chiral reductive agent with an enantiomeric excess of about 98% which requires further purification steps to obtain a product of desired optical purity.

R,R)-Formoterol (Arformoterol) or a salt thereof from optically pure and stable intermediate (R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (compound II), suitable for industrial use, in combination with optically pure amine in higher yields, as depicted in the scheme below:

Compound (R, R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methylethyl]-(1-phenyl-ethyl)-amino]-ethanol (compound VI), having the configuration represented by the following formula:

Examples(R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (II)

A solution of 90 g (0.25 mol) of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-bromo-ethanol (compound I) in 320 mL of toluene and 50 mL of MeOH was added to a stirred suspension of 46 g (0.33 mol) of K₂CO₃ in 130 mL of toluene and 130 mL of MeOH. The mixture was stirred at 40°C for 20 h and washed with water (400 mL). The organic phase was concentrated under reduced pressure to a volume of 100 mL and stirred at 25 °C for 30 min. It was then further cooled to 0-5°C for 30 min. and the product collected by filtration and dried at 40 °C to provide 67.1 g (97% yield) (98% chemical purity, 100% e.e.) of compound II as an off-white solid. ¹ H-NMR (200 MHz, CDCl₃) δ: 2.80-2.90 (m, 2H); 3.11-3.20 (m, 2H), 3.80-3.90 (m, 1H); 5.23 (s, 2H); 7.11 (d, 2H); 7.41 (m, 5H), 7.76 (d, 2H).

Preparation of (R,R)-[2-(4-Methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amine (III)

A solution of 13 g (78.6 mmol) of 1-(4-Methoxy-phenyl)-propan-2-one and 8.3 g (78.6 mmol) of (R)-1-Phenylethylamine in 60 mL MeOH was hydrogenated in the presence of 1.7 g of Pt/C 5% at 10 atm. and 30 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give compound III as an oil. The obtained oil was dissolved in 175 mL of acetone, followed by addition of 6.7 mL (80.9 mmol) of a 12M HCl solution. The mixture was stirred at 23 °C for 30 min and at 0-5 °C for 30 min. The product collected by filtration and dried at 40 °C to provide 13.8 g of the hydrochloride derivate as a white solid. The obtained solid was stirred in 100 mL of acetone at 23 °C for 1h and at 0-5 °C for 30 min, collected by filtration and dried at 40 °C to provide 13.2 g of the hydrochloride derivate as a white solid. This compound was dissolved in 100 mL of water and 100 mL of toluene followed by addition of 54 mL (54 mmol) of 1N NaOH solution. The organic phase was concentrated to give 11.7 g (55% yield) (99% chemical purity and 100% e.e) of compound III as an oil.¹H-NMR (200 MHz, CDCl₃) δ: 0.88 (d, 3H); 1.31 (d, 3H), 2.40-2.50 (m, 1H); 2.60-2.80 (m, 2H); 3.74 (s, 3H); 3.90-4.10 (m, 1H); 6.77- 6.98 (m, 4H), 7.31 (s, 5H).

Synthesis of (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (IV)

A 1-liter flask was charged with 50g (0.18 mol) of II and 50g (0.18 mol) of III and stirred under nitrogen atmosphere at 140 °C for 20 h. To the hot mixture was added 200 mL of toluene to obtain a solution, which was washed with 200 mL of 1N HCl and 200 mL of water. The organic phase was concentrated under reduced pressure to give 99 g (99% yield) (88% chemical purity) of compound IV as an oil. Enantiomeric purity 100%. ¹H-NMR (200 MHz, CDCl₃) δ: 0.98 (d, 3H); 1.41 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.19 (s, 2H); 6.69-7.42 (m, 16H); 7.77 (s, 1H).

Synthesis of (R, R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (V)

A solution of 99 g (0.18 mol) of IV in 270 mL IPA and 270 mL toluene was hydrogenated in the presence of 10 g of Ni-Raney at 18 atm and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 87 g (92% yield) (83% chemical purity, 100 % e.e.) of compound V as an oil. ¹H-NMR (200 MHz, CDCl₃) δ: 0.97 (d, 3H); 1.44 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.07 (s, 2H); 6.67-6.84 (m, 7H); 7.25-7.42 (m, 10H).

Synthesis of (R,R)-N-(2-Benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl)-phenyl)-formamide (VI)

24 mL (0.63 mol) of formic acid was added to 27 mL (0.28 mol) of acetic anhydride and stirred at 50 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with 100 mL of CH₂Cl₂ and cooled to 0 °C. A solution of 78 g (0.15 mol) of V in 300 mL de CH₂Cl₂ was slowly added and stirred for 1h at 0 °C. Then, 150 mL of 10% K₂CO₃ aqueous solution were added and stirred at 0 °C for 15 min. The organic phase was washed twice with 400 mL of 10% K₂CO₃ aqueous solution and concentrated under reduced pressure to give 80 g (97% yield, 100% e.e.) (75% chemical purity) of compound VI as an oil. ¹H-NMR (200 MHz, CDCl₃) δ: 0.98 (d, 3H); 1.42 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.75 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.09 (s, 2H); 6.67-7.41 (m, 17H); 8.4 (d, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 8.5 g (16 mmol) of VI, previous purified by column chromatography on silica gel (AcOEt/heptane, 2:3), in 60 mL ethanol was hydrogenated in the presence of 0.14 g of Pd/C 5% at 10 atm. and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give 5 g (93% yield) (91% chemical purity, 100% e.e.) of compound VII as foam. m. p.= 58-60 °C. ¹H-NMR (200 MHz, d₆-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 46 g (0.08 mol) of VI, crude product, was dissolved in 460 mL ethanol and hydrogenated in the presence of 0.74 g of Pd/C 5% at 10 atm. and 40 ° C for 28 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 24 g (83% yield) (77% chemical purity, 100% e.e.) of compound VII as a foam. m. p. = 58-60 °C. ¹H-NMR (200 MHz, d₆-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

The HPLC conditions used for the determination of the Chemical purity % are described in the table below:


HPLC Column	Kromasil 100 C-18
Dimensions	0.15 m x 4.6 mm x 5 µm
Buffer	2.8 ml TEA (triethylamine) pH=3.00 H₃PO₄ (85%) in 1 L of H₂O
Phase B	Acetonitrile
Flow rate	1.5 ml miN^-1
Temperature	40 °C
Wavelength	230 nm The HPLC conditions used for the determination of the enantiomeric purity % are described in the table below:


HPLC Column	Chiralpak AD-H
Dimensions	0.25 m x 4.6 mm
Buffer	n-hexane : IPA : DEA (diethyl amine) : H₂O 85:15:0.1:0.1
Flow rate	0.8 ml min^-1
Temperature	25 °C
Wavelength	228 nm

PATENT

https://www.google.com/patents/CN101921201A?cl=en

Example 1

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxy- phenyl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral Intermediate (III) (17. 3g, yield 88%). HPLC: de values of> 90%; MS (ESI) m / z: 541 3 (M ++ 1); 1H-NMR (CDCl3):.. Δ 0. 96 (d, 3H), 1 49 (d, 3H ), 2 · 15 (q, 1Η), 2 · 67 (dq, 2H), 2. 99 (dq, 2H), 3. 74 (s, 3H), 4. 09 (d, 1H), 4. 56 (q, 1H), 5. 24 (s, 2H), 6. 77 (dd, 4H), 7. 10 (d, 1H), 7. 25-7. 5 (m, 11H), 7. 84 ( s, 1H).

Example 2

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and toluene 100ml, 110 ° C0-flow reactor 36 hours, the solvent was distilled off succeeded intermediates (III) (16. 8g, yield 85%).

Example 3

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene After [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and dichloromethane 100ml, 30 ° C for 48 hours, and the solvent was distilled off – yl) -N succeeded intermediates (III) (15. Sg, yield 80%).

Example 4

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (8. 75g, 32mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (16. 3g, 83% yield).

Example 5

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (14. 6g, 54mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (17. 5g, 89% yield).

Scheme

chirality 1991, 3, 443-50

Fumaric acid (0.138 mmol, 16 mg) was added to the residue dissolved in methanol. Evaporation of the solvent gave the
product (SS) W semifumarate (109 mg) characterized by ‘HNMR (4-D MSO) 6 (ppm) 1.00 (d, 3H, CHCH,), 4.624.70 (m, lH,
CHOH), 3.73 (s, 3H, OCH,), 6.M.9 (m, 3H, aromatic), 7.00 (dd,4H, aromatic), 6.49 (s, 1@ CH = CH fumarate). MS of disilylated
(SS) W: 473 (M +<H3,7%); 367 (M ‘<8H90, 45%); 310 61%). The (RSS) fraction was treated in the same manner
giving the product (R;S) W semifumarate, which was characterized by ‘H-NMR (4-DMSO) 6 (ppm) 1.01 (d, 3H, CHCH,),
3.76 (s, 3H, OC&), 6.49 (s, lH, CH=CH, fumarate) 6.M.9 (m, 3H, aromatic), 7.0 (dd, 4H, aromatic). MS of disilylated (R;S)
(M’X~~HIGNO1,7 %); 178 ( C I ~H~ ~N95O%,) ; 121 (CsH90, W. 473 (M’4H3, 5%); 367 (M’4gH90, 48%); 310
(M +–CI~HIGNO18, %); 178 (CIIHIGNO, 95%); 121 (CsH90, 52%). The structural data for the (RR) and (S;R) enantiomers
were in accordance with the proposed structures. The enantiomeric purity obtained for the enantiomers in each batch is
shown in Table 1.

Scheme

The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).

Org Process Res Dev1998,2,(2):96

Large-Scale Synthesis of Enantio- and Diastereomerically Pure (R,R)-Formoterol^†

Robert Hett ,* Qun K. Fang , Yun Gao ,* Stephen A. Wald , and Chris H. Senanayake

Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752

Org. Proc. Res. Dev., 1998, 2 (2), pp 96–99

DOI: 10.1021/op970116o

http://pubs.acs.org/doi/abs/10.1021/op970116o

Abstract

(R,R)-Formoterol (1) is a long-acting, very potent β₂-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (R,R)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).

(R,R)-formoterol fumarate (53.5 g, 70%) as white crystals: mp = 139 °C dec; [α]²⁰_D = −45.5 (c = 1, H₂O); ee, de > 99.5%; ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 9.64 (s), 9.35 (d), 8.55 (d), 8.29 (s), 8.15 (s), 7.14 (d, 2 H), 7.0 (m), 6.95 (d, 2 H), 6.51 (s, 1 H), 4.82 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 1 H), 3.10 (m, 3 H), 2.58 (m, 1 H), 2.50 (br s, 2 H), 1.06 (d, 3 H).

Anal. Calcd for C₄₂H₅₂N₄O₁₂: C, 62.67; H, 6.51; N, 6.96. Found: C, 62.34; H, 6.57; N, 6.85.

Scheme

The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.

The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4′-(benzyloxy)-3′-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.

PATENT

https://www.google.com/patents/EP2285770A1?cl=en

Formoterol is a long-acting β₂-adrenoceptor agonist and has a long duration of action of up to 12 hours. Chemically it is termed as Λ/-[2-hydroxy-5-[1-hydroxy-2-[[2-(4- methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]-formamide. The structure of formoterol is as shown below.

The asterisks indicate that formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four diastereomers which have the following configurations: (R,R), (S₁S), (S₁R) and (R₁S).

(R₁R) and (S₁S) are mirror images of each other and are therefore enantiomers. Similarly (S₁R) and (R₁S) form other enatiomeric pair.

The commercially-available formoterol is a 50:50 mixture of the (R₁R)- and (S₁S)- enantiomers. (R,R)-formoterol is an extremely potent full agonist at the β_2-adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S,S)-enantiomer, has no bronchodilatory activity and is proinflammatory.

Murase et al. [Chem.Pharm.Bull., .26(4)1123-1129(1978)] synthesized all four isomers of formoterol and examined for β-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.

In another attempt by Trofast et al. [Chirality, 3:443-450(1991 )], racemic 4-benzyloxy-3- nitrostryrene oxide was coupled with optically pure N-[(R)-1-phenylethyl]-2-(4- methoxyphenyl)-(R)1-methylethylamine to give diastereomeric mixtures of intermediates, which were separated by column chromatography and converted to the optically pure formoterol.

In yet another attempt, racemic formoterol was subjected to separation by using a chiral compound [International publication WO 1995/018094].

WO 98/21175 discloses a process for preparing optically pure formoterol using optically pure intermediates (R)-N-benzyl-2-(4-methoxyphenyl)-1-methylethyl amine and (R)-4- benzyloxy-3-formamidostyrene oxide.

Preparation of optically pure formoterol is also disclosed in IE 000138 and GB2380996.

Example 7

Preparation of Arformoterol

4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p- methoxyphenylethyl)aminomethyl]benzyl alcohol (120gms, 0.23M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-30⁰C for 3 hrs. The catalyst was removed by filtration and the, clear filtrate concentrated under reduced pressure below 40⁰C to yield the title compound. (63 gms, 80%).

Example 8

Preparation of Arformoterol Tartrate

Arformoterol base (60 gms, 0.17M), 480 ml IPA , 120 ml toluene and a solution of l_(+)- tartaric acid (25.6 gms, 0.17M) in 60 ml distilled water were stirred at 25-30⁰C for 2 hrs and further at 40°- 45°C for 3 hrs. The reaction mass was cooled to 25-30⁰C and further chilled to 20⁰C for 30 mins. The solid obtained was isolated by filtration to yield the title compound. (60 gms, 70%),

The tartrate salt was dissolved in hot 50% IPA-water (0.3 lit), cooled as before and filtered to provide arformoterol tartrate. (30 gms, 50 % w/w). having enantiomeric purity greater than 99%.

PAPER

Organic Process Research & Development 2000, 4, 567-570

Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate………..http://pubs.acs.org/doi/abs/10.1021/op000287k

Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate

H. Scott Wilkinson , Robert Hett , Gerald J. Tanoury ,* Chris H. Senanayake ,* and Stephen A. Wald

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.

Org. Proc. Res. Dev., 2000, 4 (6), pp 567–570

DOI: 10.1021/op000287k

In the synthesis of the β₂-adrenoceptor agonist (R,R)-formterol, a key step in the synthesis was the development of a highly chemoselective reduction of (1R)-2-bromo-1-[3-nitro-4-(phenylmethoxy)phenyl]ethan-1-ol to give (1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol. The aniline product was isolated as the corresponding formamide. The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a secondary benzylic hydroxyl group, and a primary bromide, and with no racemization at the stereogenic carbinol carbon atom. The development of a synthetic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, the oxidation state of the poison, and the substituents on the sulfur atom had a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulfide was the poison of choice, possessing all of the required characteristics for providing a highly chemoselective and high yielding reaction. The practicality and robustness of the process was demonstrated by preparing the final formamide product with high chemoselectivity, chemical yield, and product purity on a multi-kilogram scale.

PAPER

Tetrahedron: Asymmetry 11 (2000) 2705±2717

An ecient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
Francisco Campos, M. Pilar Bosch and Angel Guerrero*

formoterol (R,R)-1 as amorphous solid. Rf: 0.27 (SiO2, AcOEt:MeOH, 1:1).20D=-41.5 (CHCl3, c 0.53).

IR, : 3383, 2967, 2923, 1674, 1668, 1610, 1514, 1442, 1247, 1033,815 cm^1.

1H NMR (300 MHz, CDCl3), : 8.11 (b, 1H), 7.46 (b, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.9±6.7 (c, 4H), 4.46 (m, 1H), 4.34 (b, 3H interchangeable), 3.74 (s, 3H), 2.90±2.45 (c, 5H), 1.02 (d,J=5.7 Hz, 3H) ppm.

13C NMR (75 MHz, CDCl3), : 160.2, 158.3, 147.7, 133.4, 130.6, 130.2 (2C),125.7, 123.7, 119.5, 117.8, 114.0 (2C), 71.3, 55.3, 54.7, 53.6, 42.0, 19.4 ppm.

CI (positive, LC-MS)(m/z, %) 435 (M+1, 100).

The tartrate salt was prepared by dissolving 13.8 mg (0.04 mmol) of(R,R)-1 and 6.0 mg (0.04 mmol) of (l)-(+)-tartaric acid in 150 mL of 85% aqueous isopropanol.
The solution was left standing overnight and the resulting crystalline solid (7.6 mg) puri®ed on areverse-phase column (1 g, Isolute SPE C18) using mixtures of MeOH±H2O as eluent. The solventwas removed under vacuum and the aqueous solution lyophilized (^35C, 0.6 bar) overnight. The(l)-(+)-tartrate salt of (R,R)-1 showed an 20D=-29.4 (H2O, c 0.61) (>99% ee based on the
reported value 34). 34=Hett, R.; Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998, 39, 1705.

PAPER

Diethylanilineborane: A Practical, Safe, and Consistent-Quality Borane Source for the Large-Scale Enantioselective Reduction of a Ketone Intermediate in the Synthesis of (R,R)-Formoterol

H. Scott Wilkinson , Gerald J. Tanoury ,*^† Stephen A. Wald , and Chris H. Senanayake *

Chemical Research and Development, Sepracor Incorporated, 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (2), pp 146–148

DOI: 10.1021/op015504b

http://pubs.acs.org/doi/abs/10.1021/op015504b

Abstract

The development of a process for the use of N,N-diethylaniline−borane (DEANB) as a borane source for the enantioselective preparation of a key intermediate in the synthesis of (R,R)-formoterol l-tartrate, bromohydrin 2, from ketone 3 on kilogram scale is described. DEANB was found to be a more practical, safer, and higher-quality reagent when compared to other more conventional borane sources: borane−THF and borane−DMS.

PAPER

http://nopr.niscair.res.in/bitstream/123456789/8917/1/IJCB%2044B(1)%20167-169.pdf

PAPER

http://www.bioorg.org/down/Hetetorcycles_07_2243.pdf?ckattempt=1

PAPER

Drugs R D. 2004;5(1):25-7.

Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol.

Abstract

Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.

CLIP

PAPER

doi:10.1016/j.cclet.2008.01.012

http://www.sciencedirect.com/science/article/pii/S1001841708000132

Chinese Chemical Letters

Volume 19, Issue 3, March 2008, Pages 279–280

New method in synthesizing an optical active intermediate for (R,R)-formoterol

Key Laboratory of Drug Targeting Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China\

Abstract

(R)-1-(4-Methoxyphenyl)propan-2-amine 2a, an optical active intermediate for (R,R)-formoterol, was synthesized from d-alanine in 65% overall yield by using a simple route, which contained protecting amino group, cyclization, coupling with Grignard reagent, reduction and deprotection.

IR spectra of (a) (R,R)-formoterol tartrate/form A, (b) (R,R)-formoterol tartrate/form B, (c) (R,R)-formoterol tartrate/form C.

References

Muller, P., et al.: Arzneimittel-Forsch., 33, 1685 (1983); Wallmark, B., et al.: Biochim. Biophys. Acta., 778, 549 (1984); Morii, M., et al.: J. Biol. chem., 268, 21553 (1993); Ritter, M., et al.: Br. J. Pharmacol., 124, 627 (1998); Stenhoff, H., et al.: J. Chromatogr., 734, 191 (1999), Johnson, D.A., et al.: Expert Opin. Pharmacother., 4, 253 (2003); Bouyssou, T., et al.: Bio. Med. Chem. Lett. 20, 1410, (2010);

“Brovana Prescribing information, Dosage and Administration section”. Archived from the original on 13 February 2008. Retrieved2008-03-14.
SEE http://pubs.acs.org/doi/abs/10.1021/jm5013227

External links

Brovana website

EP0390762A1 *	23 Mar 1990	3 Oct 1990	Aktiebolaget Draco	New bronchospasmolytic compounds and process for their preparation
EP0938467A1	7 Nov 1997	1 Sep 1999	Sepracor, Inc.	Process for the preparation of optically pure isomers of formoterol
EP1082293A2	20 May 1999	14 Mar 2001	Sepracor Inc.	Formoterol polymorphs
WO2009147383A1	2 Jun 2009	10 Dec 2009	Cipla Limited	Process for the synthesis of arformoterol

Reference
1	*	HETT R ET AL: “Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol” TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL LNKD- DOI:10.1016/S0040-4039(97)00088-9, vol. 38, no. 7, 17 February 1997 (1997-02-17), pages 1125-1128, XP004034214 ISSN: 0040-4039
2	*	LING HUANG ET AL.: “The Asymmetric Synthesis of (R,R)-Formoterol via Transfer Hydrogenation with Polyethylene Glycol Bound Rh Catalyst in PEG2000 and Water” CHIRALITY, vol. 22, 30 April 2009 (2009-04-30), pages 206-211, XP002592699
3		MURASE ET AL. CHEM. PHARM. BULL. vol. 26, no. 4, 1978, pages 1123 – 1129
4		TROFAST ET AL. CHIRALITY vol. 1, 1991, page 443
5	*	TROFAST J ET AL: “STERIC ASPECTS OF AGONISM AND ANTAGONISM AT BETA-ADRENICEPTORS: SYNTHESIS OF AND PHARMACOLOGICAL EXPERIMENTS WITH THE ENANTIOMERS OF FORMOTEROL AND THEIR DIASTEREOMERS” CHIRALITY, WILEY-LISS, NEW YORK, US LNKD- DOI:10.1002/CHIR.530030606, vol. 3, no. 6, 1 January 1991 (1991-01-01) , pages 443-450, XP002057060 ISSN: 0899-0042
6		WILKINSON, H.S ET AL. ORGANIC PROCESS RESEARCH AND DEVELOPMENT vol. 6, 2002, pages 146 – 148

Durham E-Theses A Solid-state NMR Study of Formoterol Fumarate

https://core.ac.uk/download/pdf/6115604.pdf

Arformoterol
Systematic (IUPAC) name


N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl) propan-2-yl]amino]ethyl] phenyl]formamide
Clinical data
Trade names	Brovana
AHFS/Drugs.com	Monograph
MedlinePlus	a602023
License data	US FDA: Arformoterol
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Inhalation solution fornebuliser
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	52–65%
Biological half-life	26 hours
Identifiers
CAS Number	67346-49-0
ATC code	none
PubChem	CID 3083544
IUPHAR/BPS	7479
DrugBank	DB01274
ChemSpider	2340731
UNII	F91H02EBWT
ChEBI	CHEBI:408174
ChEMBL	CHEMBL1201137
Chemical data
Formula	C₁₉H₂₄N₂O₄
Molar mass	344.405 g/mol

Formoterol

CAS Registry Number: 73573-87-2

CAS Name: rel–N-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide

Additional Names: 3-formylamino-4-hydroxy-a-[N-[1-methyl-2-(p-methoxyphenyl)ethyl]aminomethyl]benzyl alcohol; (±)-2¢-hydroxy-5¢-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-a-methylphenethyl]amino]ethyl]formanilide

Molecular Formula: C19H24N2O4

Molecular Weight: 344.40

Percent Composition: C 66.26%, H 7.02%, N 8.13%, O 18.58%

Literature References: Selective b2-adrenergic receptor agonist. Mixture of R,R (-) and S,S (+) enantiomers. Prepn: M. Murakamiet al., DE 2305092; eidem, US 3994974 (1973, 1976 both to Yamanouchi); K. Murase et al., Chem. Pharm. Bull. 25, 1368 (1977). Absolute configuration and activity of isomers: eidem, ibid. 26, 1123 (1978). Toxicity studies: T. Yoshida et al., Pharmacometrics26, 811 (1983). HPLC determn in plasma: J. Campestrini et al., J. Chromatogr. B 704, 221 (1997). Review of pharmacology: G. P. Anderson, Life Sci. 52, 2145-2160 (1993); and clinical efficacy: R. A. Bartow, R. N. Brogden, Drugs 55, 303-322 (1998).

Derivative Type: Fumarate dihydrate

CAS Registry Number: 43229-80-7

Manufacturers’ Codes: BD-40A

Trademarks: Atock (Yamanouchi); Foradil (Novartis); Oxeze (AstraZeneca)

Molecular Formula: (C19H24N2O4)2.C4H4O4.2H2O

Molecular Weight: 840.91

Percent Composition: C 59.99%, H 6.71%, N 6.66%, O 26.64%

Properties: Crystals from 95% isopropyl alcohol, mp 138-140°. pKa1 7.9; pKa2 9.2. Log P (octanol/water): 0.4 (pH 7.4). Freely sol in glacial acetic acid; sol in methanol; sparingly sol in ethanol, isopropanol; slightly sol in water. Practically insol in acetone, ethyl acetate, diethyl ether. LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida).

Melting point: mp 138-140°

pKa: pKa1 7.9; pKa2 9.2

Log P: Log P (octanol/water): 0.4 (pH 7.4)

Toxicity data: LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida)

Derivative Type: R,R-Form

CAS Registry Number: 67346-49-0

Additional Names: Arformoterol

Derivative Type: R,R-Form L-tartrate

CAS Registry Number: 200815-49-2

Additional Names: Arformoterol tartrate

Molecular Formula: C19H24N2O4.C4H6O6

Molecular Weight: 494.49

Percent Composition: C 55.86%, H 6.12%, N 5.67%, O 32.36%

Literature References: Prepn: Y. Gao et al., WO 9821175; eidem, US 6040344 (1998, 2000 both to Sepracor). Pharmacology: D. A. Handley et al., Pulm. Pharmacol. Ther. 15, 135 (2002).

Properties: Off-white powder, mp 184°.

Melting point: mp 184°

Therap-Cat: Antiasthmatic.

Keywords: ?Adrenergic Agonist; Bronchodilator; Ephedrine Derivatives.

//////Arformoterol, (R,R)-Formoterol, (R,R)-Formoterol-L-(+)-tartrate, 200815-49-2, Arformoterol tartrate , Brovana, UNII:5P8VJ2I235, Sepracor, Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases, COPD , RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists, Phase III, 2007, Sunovion

COC1=CC=C(C[C@@H](C)NC[C@H](O)C2=CC(NC=O)=C(O)C=C2)C=C1

USFDA approves Indoco’s Allopurinol ANDA

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USFDA approves Indoco’s Allopurinol ANDA… Indoco Remedies Limited (India)’s … Indoco Remedies Limited (India) added a new photo

Allopurinol, sold under the brand name Zyloprim and generics, is a medication used primarily to treat excess uric acid in the bloodand its complications, including chronic gout. It is a xanthine oxidase inhibitor and is administered orally.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron

Aditi Kare Panandikar, Managing Director, Indoco Remedies

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Aditi Kare Panandikar gets award

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Gemfibrozil

GENERIC, Uncategorized Comments Off

Aug 022016

Gemfibrozil

CAS: 25812-30-0

5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid

2,2-dimethyl-5-(2,5-xylyloxy)valeric acid

Manufacturers’ Codes: CI-719

Trademarks: Decrelip (Ferrer); Genlip (Teofarma); Gevilon (Pfizer); Lipozid (Pfizer); Lipur (Pfizer); Lopid (Pfizer)

MF: C15H22O3

MW: 250.33

Percent Composition: C 71.97%, H 8.86%, O 19.17%

Properties: Crystals from hexane, mp 61-63°. bp0.02 158-159°. LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz).

Melting point: mp 61-63°

Boiling point: bp0.02 158-159°

Toxicity data: LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz)

Therap-Cat: Antilipemic.

Gemfibrozil

5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid

Gemfibrozil is classified as a fibric acid derivative and is used in the treatment of hyperlipidaemias. It has effects on plasma-lipid concentrations similar to those described under bezafibrate. The major effects of gemfibrozil have been a reduction in plasma-triglyceride concentrations and an increase in high-density lipoprotein (HDL) cholesterol concentrations. A reduction in very-low-density lipoprotein (VLDL)-triglyceride appears to be largely responsible for the fall in plasma triglyceride although reductions in HDL and low-density lipoprotein (LDL)-triglycerides have also been reported.

The effects of gemfibrozil on total cholesterol have been more variable: in general, LDL-cholesterol may be decreased in patients with pre-existing high concentrations and raised in those with low concentrations. The increase in HDL-cholesterol concentrations has resulted in complementary changes to the ratios of HDL-cholesterol to LDL-cholesterol and to total cholesterol. Gemfibrozil has successfully raised HDL-cholesterol concentrations in patients with isolated low levels of HDL-cholesterol but otherwise normal cholesterol concentrations.The Helsinki heart study assessed gemfibrozil for the primary prevention of ischaemic heart disease in middle-aged men with hyperlipidaemia. The usual dose, by mouth, is 1.2 g daily in two divided doses given 30 min before the morning and evening meals. Gemfibrozil is available as tablets for oral administration (Lopid: USP).

IR (KBr, cm^–1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75;

¹H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H);

¹³C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH₃), 20.94 (CH₃), 24.67 (CH₂), 24.87 (CH_3, CH₃), 36.43 (CH₂), 40.91 (C), 67.57 (CH₂), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C);

MS M/_Z (ESI): 251.16 [(MH)⁺].

Solvent:CDCl3Instrument Type:JEOLNucleus:1HFrequency:400 MHzChemical Shift Reference:TMS

¹H NMR spectrum of C₁₅H₂₂O₃ in CDCL3 at 400 MHz

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid. Other brand names include Jezil and Gen-Fibro.

history

Gemfibrozil was selected from a series of related compounds synthesized in the laboratories of the American company Parke Davisin the late 1970s. It came from research for compounds that lower plasma lipid levels in humans and in animals.^[1]

Actions

Is an activator of peroxisome proliferator-activated receptor-alpha (PPARα), a nuclear receptor that is involved in metabolism ofcarbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides.^{[citation needed]}

Therapeutic effects

Reduce triglyceride levels ^[2]
Reduce very low density lipoprotein (VLDL) levels
Modest reduction of low density lipoprotein (LDL) levels
Moderate increase in high density lipoprotein (HDL) levels

Nontherapeutic effects and toxicities

GI distress
Musculoskeletal pain
Increased incidence of gallstone
Hypokalemia (low blood potassium)
Increased risk of cancer

Indications

Hyperlipidemia (Type III): Gemfibrozil is the drug of choice for therapy.
Hypertriglyceridemia (Type IV): Gemfibrozil, though not as effective as niacin, is better tolerated.^{[citation needed]}

Contraindications and precautions

Gemfibrozil should not be given to these patients:
- Hepatic dysfunction
Gemfibrozil should be used with caution in these higher risk categories:
- Biliary tract disease
- Renal dysfunction
- Pregnant women
- Obese patients

Drug interactions

Anticoagulants: Gemfibrozil potentiates the action of warfarin and indanedione anticoagulants.^{[citation needed]}
Statin drugs: Concomitant administration of fibrates (including gemfibrozil) with statin drugs increases the risk of muscle cramping, myopathy, andrhabdomyolysis.
Gemfibrozil inhibits the activation of the liver’s Cytochrome P450 system, reducing hepatic metabolism of many drugs, and prolonging their half lives and duration of action.
- Drugs metabolized by the Cytochrome P450 system include:
  - Many antidepressants
  - Many antipsychotics
  - Many antiepileptics
  - Theophylline and other methylxanthine drugs
  - Several anesthetic agents
  - Oral contraceptive pills
  - Statins
  - Warfarin

Environmental data

Gemfibrozil has been detected in biosolids (the solids remaining after wastewater treatment) at concentrations up to 2650 ng/g wet weight.^[3] This indicates that it survives the wastewater treatment process.

SYNTHESIS

The sodium isobutyrate (I) is metallated with lithium diisopropylamide, and the resulting compound is alkylated with 3- (2,5-dimethylphenoxy) propyl bromide.

PATENT

Paul, L. C. 2,2-Dimethyl-ω-aryloxy alkanoic acids and salts and ester thereof. U.S. 3,674,836, 1972.

http://www.google.co.in/patents/US3674836

CLIP

Production of Gemfibrozil
(1)2,5-Dimethylphenol and 1-Bromo-3-chloropropane reaction of 1-(2,5-dimethylphenoxy)-3-chloropropane. The reaction is carried out in toluene, adding new clean off reflux 5h. Just as follows:

Production of Gemfibrozil

(2)N/A can be used to manufacture Gemfibrozil.

Production of Gemfibrozil

PAPER

Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic

Suri Babu Madasu†‡, N. A. Vekariya*†, Hero Velladurai†, Aminul Islam†, Paul Douglas Sanasi‡, and Raghu Babu Korupolu‡

^† Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 and 72, Indrakaran (V), Sangareddy (M), Medak District-502329, Andhra Pradesh, India

^‡ Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India

Org. Process Res. Dev., 2013, 17 (7), pp 963–966

DOI: 10.1021/op400034f, http://pubs.acs.org/doi/full/10.1021/op400034f

*E-mail: navekariya1@rediffmail.com.

An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.

Literature References:

Serum lipid regulating agent. Prepn: P. L. Creger, DE 1925423; eidem, US 3674836 (1969, 1972, both to Parke, Davis).

Production: O. P. Goel, US 4126637 (1978 to Warner-Lambert).

Pharmacology: A. H. Kissebach et al.,Atherosclerosis 24, 199 (1976); M. T. Kahonen et al., ibid. 32, 47 (1979).

Series of articles on metabolism, clinical pharmacology, kinetics and toxicology: Proc. R. Soc. Med. 69, Suppl 2, 1-120 (1976).

Toxicity data: S. M. Kurtz et al., ibid. 15.

Clinical trial in hyperlipidemia: J. E. Lewis et al., Pract. Cardiol. 9, 99 (1983).

Clinical reduction of cardiovascular risk in patients with low HDL levels: H. B. Rubins et al., N. Engl. J. Med. 341, 410 (1999).

References

Rodney, G; et al. (1976). “The Hypolipidemic Effect of Gemfibrozil (CI-719) in Laboratory Animals”. Proc. roy. Soc. Med. 69 (Supplement 2): 6–9. PMC 1864017. PMID 828263.
“Gemfibrozil.” WebMD.com Accessed 14 June 2014. http://www.webmd.com/drugs/drug-11423-gemfibrozil+oral.aspx
http://water.epa.gov/scitech/wastetech/biosolids/tnsss-overview.cfm

External links

DrugBank Gemfibrozil
NIH Gemfibrozil Drug Info
Lopid International Study
Author (2004). “Safety of Statins”. Circulation. 109: III–50–III–57. doi:10.1161/01.cir.0000131519.15067.1f.
http://www.ihs.gov/nptc/documents/NPTC%20Lipid%20Review.pdf

Gemfibrozil
Systematic (IUPAC) name

5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid
Clinical data
Trade names	Lopid
AHFS/Drugs.com	Monograph
MedlinePlus	a686002
Pregnancy category	Category C
Routes of administration	Oral
Legal status
Legal status	By Prescription
Pharmacokinetic data
Bioavailability	Close to 100%
Protein binding	95%
Metabolism	Hepatic (CYP3A4)
Biological half-life	1.5 hours
Excretion	Renal 94% Feces 6%
Identifiers
CAS Number	25812-30-0
ATC code	C10AB04 (WHO)
PubChem	CID 3463
IUPHAR/BPS	3439
DrugBank	DB01241
ChemSpider	3345
UNII	Q8X02027X3
KEGG	D00334
ChEBI	CHEBI:5296
ChEMBL	CHEMBL457
Chemical data
Formula	C₁₅H₂₂O₃
Molar mass	250.333 g/mol

LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white; polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)2,2-dimethylpentanoic acid, with the following structural formula:

LOPID® (gemfibrozil) Structural Formula Illustration

The empirical formula is C₁₅H₂₂O₃ and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.

/////////Gemfibrozil, Antilipemic, Fibrates, 25812-30-0,

CC1=CC(OCCCC(C)(C)C(O)=O)=C(C)C=C1

New Antiarthritic Drug Candidate S-2474

phase 2, Uncategorized Comments Off

Aug 012016

S-2474

(E)-(5)-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide

Shionogi Research Laboratories

cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO)

mp 135−137 °C.

S-2474,158089-95-3, 158089-96-4 ((Z)-isomer),C20-H31-N-O3-S,

E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethylisothiazolidine 1,1-dioxide

Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-5-isothiazolidinylidene)methyl]-, S,S-dioxide, (E)-
2,6-Bis(1,1-dimethylethyl)-4-[(E)-(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]phenol
Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]-, (E)-

(E)-(5)-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474, ), which was discovered at Shionogi Research Laboratories, shows potent inhibitory effects on both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) and is anticipated to be promising as an antiarthritic drug

synthesis of novel γ-sultam derivatives containing the di-tert-butylphenol antioxidant moiety. Several compounds with lower alkyl groups at the 2-position of the γ-sultam skeleton showed potent inhibitory activities against PGE₂ production via the COX pathway and LTB₄ production via the 5-LO pathway, as well as production of IL-1 in in vitro assays. Extensive pharmacological characterizations revealed that 2-ethyl-γ-sultam derivative 10b displays multiple inhibition of COX, 5-LO, and IL-1 production similar to tenidap and also good selective COX-2 inhibition like NS-398 and celecoxib. It exerted excellent antiinflammatory activity without any ulcerogenic effects and was designated as S-2474 an agent having both NSAID and cytokine modulating properties. S-2474 is now being developed as a promising alternative antiarthritic drug candidate

SYNTHESIS

17th Symp Med Chem (Nov 19 1997 , Tsukuba), EP 0595546; JP 1994211819; US 5418230

The intermediate gamma-sultam (III) was prepared by condensation of 3-chloropropylsulfonyl chloride (I) with ethylamine, followed by cyclization of the resulting chloro sulfonamide (II) under basic conditions. Condensation of 3,5-di- tert-butyl-4- (methoxymethoxy) benzaldehyde (IV) with sultam (III) in the presence of LDA produced the aldol addition compound (V). Then, acid-promoted dehydration and simultaneous methoxymethyl group deprotection gave rise to a mixture of the desired E-benzylidene sultam and the corresponding Z-isomer (VII), which were separated by column chromatography.

PAPER

Novel Antiarthritic Agents with 1,2-Isothiazolidine-1,1-dioxide (γ-Sultam) Skeleton: Cytokine Suppressive Dual Inhibitors of Cyclooxygenase-2 and 5-Lipoxygenase

Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan, and Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan

J. Med. Chem., 2000, 43 (10), pp 2040–2048

DOI: 10.1021/jm9906015

Various 1,2-isothiazolidine-1,1-dioxide (γ-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the γ-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure−activity relationships (SAR) examined and some pharmacological evaluations are described.

http://pubs.acs.org/doi/abs/10.1021/jm9906015

PAPER

Highly E-Selective and Effective Synthesis of Antiarthritic Drug Candidate S-2474 Using Quinone Methide Derivatives

Masanao Inagaki , Nobuhiro Haga , Makoto Kobayashi , Naoki Ohta , Susumu Kamata , and Tatsuo Tsuri *

Shionogi Research Laboratories, Shionogi & Company, Ltd., Fukushima-ku, Osaka 553-0002, Japan

J. Org. Chem., 2002, 67 (1), pp 125–128

DOI: 10.1021/jo0106795

http://pubs.acs.org/doi/suppl/10.1021/jo0106795

We have developed an efficient and E-selective synthesis of an antiarthritic drug candidate (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), in which α-methoxy-p-quinone methide is used as a key intermediate. α-Methoxy-p-quinone methide was revealed to be an equiv. to a p-hydroxy protected benzaldehyde. It reacts smoothly with α-sulfonyl carbanion to give 1,6-addn. intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.

An improved synthesis has been reported. Acid -catalyzed ketalization of aldehyde (VIII) with trimethyl orthoformate provided the dimethyl acetal (IX) which, upon thermal decomposition in refluxing xylene, gave rise to the alpha-methoxy methylenequinone derivative (X ). This was then condensed with the lithio derivative of sultam (III) to form selectively the desired E-adduct. in an analogous procedure, aldehyde (VIII) was converted to the chloromethylene compound (XI) with methanesulfonyl chloride and triethylamine in refluxing CH2Cl2 . Condensation of (XI) with the lithiated sultam (III) furnished the desired E-benzylidene sultam.

PAPER

Development of One-Pot Synthesis of New Antiarthritic Drug Candidate S-2474 with High E-Selectivity

Katsuo Oda^†, Takemasa Hida*^†, Teruo Sakata^‡, Masahiko Nagai^‡, Yoshihide Sugata^‡, Toshiaki Masui^† and Hideo Nogusa^†

Chemical Development Department, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan, and Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan

Org. Process Res. Dev., 2008, 12 (3), pp 442–446

DOI: 10.1021/op800008w

http://pubs.acs.org/doi/full/10.1021/op800008w

* To whom correspondence should be addressed. Telephone: +81-6-6401-8198 . Fax: +81-6-6401-1371. E-mail:takemasa.hida@shionogi.co.jp., †

Chemical Development Department, CMC Development Laboratories.

, ‡Shionogi Research Laboratories.

A one-pot synthesis of S-2474 was developed to overcome the problems of a large number of steps, low stereoselectivity, low yield, a large amount of waste, and severe reaction conditions. Aldol-type condensation of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-ethyl-γ-sultam was carried out with LDA and then quenched with water. Dehydration proceeded under basic conditions, providing S-2474 directly as a single isomer on the benzylidene double bond. The reaction mechanism appears to involve a quinone methide intermediate. Environmental assessment of the development of this compound is also discussed in this paper.

///////New, Antiarthritic , Drug Candidate, S-2474, Shionogi Research Laboratories, cyclooxygenase-2, (COX-2), 5-lipoxygenase , (5-LO), PHASE 2, 158089-95-3, 158089-96-4, S2474, S 2474

Supporting Info

CCN2CC\C(=C/c1cc(c(O)c(c1)C(C)(C)C)C(C)(C)C)S2(=O)=O

ANIDULAFUNGIN

Uncategorized Comments Off

Aug 012016

Anidulafungin

V-Echinocandin


CAS Number	166663-25-8

N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0^9,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide

LY-307853
LY-329960
LY-333006
LY303366
VEC
VER-002

¹H NMR (700 MHz, d₆-DMSO) δ 0.91 (t, 3H), 1.12 (d, 3H), 1.36 (m, 2H), 1.41 (m, 2H), 1.74 (p, 2H), 1.88 and 1.97 (overlapped, 2H), 3.85 (overlapped, 1H), 4.01 (t, 2H), 4.35 (overlapped, 1H), 4.44 (m, 1H), 4.76 (m, 1H), 4.80 (m, 1H), 5.02 (m, 1H), 5.07 (d, 1H), 5.52 (d, 1H), 7.04 (d, 1H), 7.66 (d, 1H), 7.74 (d, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.14 (broad s, 1H), 8.60 (d, 1H). IR (cm⁻¹)

KBr ν_max; 3450 (O−H), 2932 (C−H), 2871 (C−H), 1632 (C═O), 1517 (Ar), 1488 (Ar), 1248 (C−O), 821 (C−H out-of-plane bending Ar 2 adj H’s).

Anidulafungin (brand names: Eraxis (in U.S. and Russia), Ecalta (in Europe)) is a semisynthetic echinocandin used as anantifungal drug. Anidulafungin was originally manufactured and submitted for FDA approval by Vicuron Pharmaceuticals.^[1] Pfizeracquired the drug upon its acquisition of Vicuron in the fall of 2005.^[2] Pfizer gained approval by the Food and Drug Administration(FDA) on February 21, 2006;^[3] it was previously known as LY303366. Preliminary evidence indicates it has a similar safety profile tocaspofungin. Anidulafungin has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive Candidainfection;^[4]^[5]^[6] it may also have application in treating invasive Aspergillus infection. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.

Pharmacodynamics and pharmacokinetics

Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.^[7]

Distribution: 30–50 L. Protein binding: 84%.

Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. Thirty percent is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.^[8]^[9]^[10]

Mechanism of action

Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.^[11]

Semisynthesis

Anidulafungin is manufactured via semisynthesis. The starting material is echinocandin B (a lipopeptide fermentation product ofAspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis;^[12] in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin^[11]^[13] is synthesized.

Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.

ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-dihydroxy-N -[[4“-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:

50 mg/vial – fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

100 mg/vial – fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

The empirical formula of anidulafungin is C₅₈H₇₃N₇O₁₇ and the formula weight is 1140.3. The structural formula is

ERAXIS™ (anidulafung in) Structural Formula Illustration

Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% DextroseInjection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).

SYNTHESIS

J MED CHEM 1995, 38 3271-3281

Semisynthetic Chemical Modification of the Antifungal Lipopeptide …

pubs.acs.org/doi/abs/10.1021/jm00017a012

by M Debono – ‎1995 – ‎Cited by 113 – ‎Related articles

Aug 1, 1995 – J. Med. Chem. , 1995, 38 (17), pp 3271–3281. DOI: 10.1021/jm00017a012 … Journal ofMedicinal Chemistry 2001 44 (16), 2671-2674

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide “nucleus” as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.

PATENT

US 5965525

http://www.google.co.in/patents/US5965525

PATENT

US 4293482

http://www.google.co.in/patents/US4293482

Paper

Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/d-Fructose (Eraxis)

Timothy Norris*, John VanAlsten, Stephen Hubbs, Marcus Ewing, Weiling Cai, Matthew L. Jorgensen, Jon Bordnerand Grace O. Jensen

Chemical Research and Development, Pfizer Inc. Global Research and Development Laboratories, Eastern Point Road, Groton, Connecticut 06340, U.S.A.

Org. Process Res. Dev., 2008, 12 (3), pp 447–455

DOI: 10.1021/op800055h

http://pubs.acs.org/doi/abs/10.1021/op800055h

* Corresponding author. E-mail: timothy.norris@pfizer.com. Telephone: +860 441 4406 . Fax: +860 686 5340.

Abstract Image

Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and d-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN·HCl) and the active ester 1-({[4′′-(pentyloxy)-1,1′:4′,1′′-terphenyl-4-yl]carbonyl}oxy)-1H-1,2,3-benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.

References

PRNewswire. Vicuron Pharmaceuticals Files New Drug Application (NDA) for Anidulafungin for Treatment of Invasive Candidiasis/Candidemia 08-18-2005.
Jump up^ PRNewswire. Vicuron Pharmaceuticals Stockholders Approve Merger With Pfizer 08-15-2005
“FDA Approves New Treatment for Fungal Infections”. FDA News Release. Food and Drug Administration. 2006-02-21. Archived from the original on 10 July 2009. Retrieved 2009-08-01.
Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T (2004). “Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia”. Antimicrob Agents Chemother 48 (6): 2021–4.doi:10.1128/AAC.48.6.2021-2024.2004. PMC 415613. PMID 15155194.
Jump up^ Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ (2005). “In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole”. J Clin Microbiol 43 (11): 5425–7.doi:10.1128/JCM.43.11.5425-5427.2005. PMC 1287823. PMID 16272464.
J Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP (2005). “Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis”. Antimicrob Agents Chemother 49 (11): 4795–7. doi:10.1128/AAC.49.11.4795-4797.2005.PMC 1280139. PMID 16251335.
Jump up^ “Eraxis at RxList”. 2009-06-24. Retrieved 2009-08-01.
Trissel LA and Ogundele AB, “Compatibility of Anidulafungin With Other Drugs During Simulated Y-Site Administration,”Am J Health-Sys Pharm, 2005, 62:834-7.
Vazquez JA, “Anidulafungin: A New Echinocandin With a Novel Profile,” Clin Ther, 2005, 27(6):657-73.
Jump up^ Walsh TJ, Anaissie EJ, Denning DW, et al., “Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America,” Clin Infect Dis, 2008, 46(3):327-60
Denning DW (1997). “Echinocandins and pneumocandins – a new antifungal class with a novel mode of action”. J Antimicrob Chemother 40 (5): 611–614. doi:10.1093/jac/dkf045.PMID 9421307.
Lei Shao; Jian Li; Aijuan Liu; Qing Chang; Huimin Lin; Daijie Chen (2013). “Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains”. Applied and Environmental Microbiology 79 (4): 1126–1133. doi:10.1128/AEM.02792-12. PMC 3568618. PMID 23220968.
“Anidulafungin EMA Europa” (PDF).

Anidulafungin
Systematic (IUPAC) name

N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0^9,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide
Clinical data
Trade names	Eraxis
AHFS/Drugs.com	Monograph
Pharmacokinetic data
Protein binding	84 %
Biological half-life	40–50 hours
Identifiers
CAS Number	166663-25-8
ATC code	J02AX06 (WHO)
PubChem	CID 166548
DrugBank	DB00362
ChemSpider	21106258
UNII	9HLM53094I
KEGG	D03211
ChEBI	CHEBI:55346
ChEMBL	CHEMBL1630215
Chemical data
Formula	C₅₈H₇₃N₇O₁₇
Molar mass	1140.24 g/mol

//////////FUNGIN, ANIDULAFUNGIN, Eraxis , Ecalta, semisynthetic echinocandin, anantifungal drug, FDA 2006, PFIZER, LY-307853, LY-329960, LY-333006, LY303366, VEC, VER-002, 166663-25-8, Eli Lilly and Company Inc.

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]6C[C@@H](O)[C@@H](O)NC(=O)C4[C@@H](O)[C@@H](C)CN4C(=O)C(NC(=O)C(NC(=O)C5C[C@@H](O)CN5C(=O)C(NC6=O)[C@@H](C)O)[C@@H](O)[C@H](O)c7ccc(O)cc7)[C@@H](C)O

Supporting Info

GSK-2041706A, Potent GPR119 Receptor Agonists

Uncategorized Comments Off

Jul 312016

GSK-2041706A

[2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine]

2-[((1S)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

CAS 1032824-43-3

Potent GPR119 Receptor Agonists

Molecular Formula:	C₂₃H₂₉N₅O₄S
Molecular Weight:	471.57246 g/mol

G protein-coupled receptor 119 (GPR119) is a G protein-coupled receptor expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment of type 2 diabetes, with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706 [2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine], a GPR119 agonist, and metformin as monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30 mg/kg b.i.d.) or metformin at 30 and 100 mg/kg b.i.d. alone caused a 7.4%, 3.5%, and 4.4% (all P < 0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30 or 100 mg/kg resulted in a 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100 mg/kg caused a significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100 mg/kg, respectively. The combination of GSK2041706 with metformin caused greater reductions in cumulative food intake (22.2% at 30 mg/kg and 37.5% at 100 mg/kg) and higher fed plasma glucagon-like peptide 1 and peptide tyrosine tyrosine levels and decreased plasma insulin and glucose-dependent insulinotropic polypeptide levels compared with their monotherapy groups. In addition, we characterized the effect of GSK2041706 and metformin as monotherapy or in combination on neuronal activation in the appetite regulating centers in fasted DIO mice. In conclusion, our data demonstrate the beneficial effects of combining a GPR119 agonist with metformin in the regulation of body weight in DIO mice.

Diabetes mellitus is an ever-increasing threat to human health. For example, in the United States current estimates maintain that about 16 million people suffer from diabetes mellitus.

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic β-cells, and necessitates regular administration of exogenous insulin. Without insulin, cells cannot absorb sugar (glucose), which they need to produce energy. Symptoms of Type I diabetes usually start in childhood or young adulthood. People often seek medical help because they are seriously ill from sudden symptoms of high blood sugar (hyperglycemia).

Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. Type II diabetes may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from Type II diabetes have too little insulin or cannot use insulin effectively. Insulin resistance refers to the inability of body tissues to respond properly to endogenous insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time. Type II diabetes, sometimes called mature or adult onset diabetes, can develop at any age, but most commonly becomes apparent during adulthood. The incidence of Type II diabetes in children, however, is rising

In diabetics, glucose levels build up in the blood and urine causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. If left untreated, diabetes mellitus may cause life-threatening complications, including blindness, kidney failure, and heart disease.

Type II diabetes accounts for approximately 90-95% of diabetes cases, killing about 193,000 U.S. residents each year. Type II diabetes is the seventh leading cause of all deaths. In Western societies, Type II diabetes currently affects 6% of the adult population with world-wide frequency expected to grow by 6% per annum.

Although there are certain inheritable traits that may predispose particular individuals to developing Type II diabetes, the driving force behind the current increase in incidence of the disease is the increased sedentary lifestyle, diet, and obesity now prevalent in developed countries. About 80% of diabetics with Type II diabetes are significantly overweight. As noted above, an increasing number of young people are developing the disease. Type II diabetes is now internationally recognized as one of the major threats to human health in the 21^stcentury.

Type II diabetes currently is treated at several levels. A first level of therapy is through the use of diet and/or exercise, either alone or in combination with therapeutic agents. Such agents may include insulin or pharmaceuticals that lower blood glucose levels. About 49% of individuals with Type II diabetes require oral medication(s), about 40% of individuals require insulin injections or a combination of insulin injections and oral medication(s), and about 10% of individuals may use diet and exercise alone.

Current therapies for diabetes mellitus include: insulin; insulin secretagogues, such as sulphonylureas, which increase insulin production from pancreatic-cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptor—(PPAR-), such as the thiazolidinediones, which enhances insulin action; and α-glucosidase inhibitors which interfere with gut glucose production. There are, however, deficiencies associated with currently available treatments, including hypoglycemic episodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema.

There are several areas at which research is being targeted in order to bring new, more effective, therapies to the marketplace. For example, on-going research includes exploring a reduction in excessive hepatic glucose production, enhancing the pathway by which insulin transmits its signal to the cells such that they take up glucose, enhancing glucose-stimulated insulin secretion from the pancreatic-cells, and targeting obesity and associated problems with fat metabolism and accumulation.

One particular target is GPR119. GPR119 is a member of the rhodopsin family of G-protein-coupled receptors. In addition to the “GPR119” identifier, several other identifiers exist, including but not limited to RUP 3, Snorf 25, 19 AJ, GPR 116 (believed to be erroneous), AXOR 20, and PS1. GPR119 is expressed in human gastrointestinal regions and in human islets. Activation of GPR119 has been demonstrated to stimulate intracellular cAMP and lead to glucose-dependent GLP-1 and insulin secretion. See, T. Soga et al., Biochemical and Biophysical Research Communications 326 (2005) 744-751, herein incorporated by reference with regard to a background understanding of GPR119.

In type 2 diabetes the action of GLP-1 on the β-cell is maintained, although GLP-1 secretion, itself, is reduced. More recently, therefore, much research has been focused on GLP-1. Studies show glucose-lowering effects in addition to GLP-1’s ability to stimulate glucose-dependent insulin secretion including, but not limited to, an inhibition of the release of the hormone glucagon following meals, a reduction in the rate at which nutrients are absorbed into the bloodstream, and a reduction of food intake. Studies demonstrate that treatments to increase GLP-1, therefore, may be used for a variety of conditions and disorders including but not limited to metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic, depressive, and neuropsychiatric disease including but not limited to diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control and satiety, weight loss, stress, inflammation, myocardial ischemia/reperfusion injury, Alzheimer’s Disease, and other diseases of the central nervous system.

The use of exogenous GLP-1 in clinical treatment is severely limited, however, due to its rapid degradation by the protease DPP-IV. There are multiple GLP-1 mimetics in development for type 2 diabetes that are reported in the literature, all are modified peptides, which display longer half-lives than endogenous GLP-1. For example, the product sold under the tradename BYETTA® is the first FDA-approved agent of this new class of medications. These mimetics, however, require injection. An oral medication that is able to elevate GLP-1 secretion is desirable. Orally available inhibitors of DPP-IV, which result in elevation in intact GLP-1, are now available, such as sitagliptin, marketed under the brand name JANUVIA®. Nevertheless, a molecule which may stimulate GLP-1 secretion would provide a therapeutic benefit. A molecule which could stimulate both GLP-1 secretion and insulin secretion through effects on the L-cell and direct effects on the β-cell would hold much promise for type 2 diabetes therapy.

The present invention identifies agonists of GPR119 which increase glucose-disposal in part through elevation of GIP, GLP-1, and insulin. Moreover, studies demonstrate that GPR119 agonists such as the compounds of the present invention can stimulate incretins independently of glucose. GIP and GLP-1 are peptides, known as incretins, secreted from enteroendocrine K and L cells, respectively, in response to ingestion of nutrients, and have a wide variety of physiological effects that have been described in numerous publications over the past two decades. See, for example, Bojanowska, E. et al.,Med. Sci. Monit., 2005, August 11(8): RA271-8; Perry, T. et al., Curr. Alzheimer Res., 2005, July 2(3): 377-85; and Meier, J. J. et al.,Diabetes Metab. Res. Rev., 2005, March-April; 21(2); 91-117 (each herein incorporated by reference with regard to a background understanding of incretins). Moreover, although the mechanisms regulating GLP-1 secretion remain unclear, the initial rapid rise in GLP-1 following a meal may be a result of hormonal stimulation of neuronal afferents involving GIP. See, for example, J. N. Roberge and P. L. Brubaker, Endocrinology 133 (1993), pp. 233-240 (herein incorporated by reference with regard to such teaching). Furthermore, later increases in GLP-1 may involve direct activation of L-cells by nutrients in the distal small-intestine and the colon. GIP and GLP-1 are potent stimulators of the body’s ability to produce insulin in response to elevated levels of blood sugar. In Type 2 diabetes, patients display a decreased responsiveness to GIP but not GLP-1, with respect to its ability to stimulate insulin secretion. The mechanism behind the decreased responsiveness to GIP remains unclear since type 2 diabetics retain sensitivity to a bolus administration of GIP but not to a continuous infusion (Meier et al. 2004 Diabetes 53 S220-S224). Moreover recent studies with a long-acting fatty-acid derivative of GIP showed beneficial effects on glucose homeostasis in ob/ob mice following 14 days of treatment (Irwin N. et al. (2006) J. Med. Chem. 49, 1047-1054.)

Agonists to GPR119 may be of therapeutic value for diabetes and associated conditions, particularly type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, and atherosclerosis.

NMR

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (bs, 1H), 8.40 (bs, 1 H), 8.28 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 5.17–5.09 (m, 1H), 4.09–3.95 (m, 2H), 3.27 (s, 3H), 3.16–2.99 (m, 2H), 2.80 (q, J = 6.9 Hz, 1H), 1.98–1.85 (m, 2H), 1.83–1.70 (m, 1H), 1.47–1.33 (m, 2H), 1.31 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).

¹³C NMR (100.6 MHz, DMSO-d₆) 175.3, 170.9, 159.8, 142.6, 141.2, 141.0, 139.1, 135.7, 128.1, 126.9, 75.7, 46.0, 45.9, 44.0, 40.2, 27.1, 27.0, 26.7, 20.7, 16.9.

HRMS calcd for C₂₃H₃₀N₅O₄S (M + H)⁺ 472.2013, found, 472.2009.

PATENT

Jing Fang, Jun Tang, Andrew J. Carpenter,Gregory Peckham, Christopher R. Conlee,Kien S. Du, Subba Reddy Katamreddy,

http://www.google.co.ug/patents/US20120077812

Example 156(±)-2-[(1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

Step 1: A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (prepared as in Example 158, Alternative synthesis, Step 3, 179 g, 0.78 mol) in MeOH (300 mL) was treated with 4-piperidinemethanol (108 g, 0.94 mol) and stirred and heated at 50° C. overnight. The solvent was removed and the residue was purified by flash chromatography on a silica gel column to give {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (60 g, 34%) as a pale yellow oil.

Step 2: A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (1.50 g, 6.66 mmol) in CH₂Cl₂(50 mL) at 0° C. was treated with Dess-Martin periodinane (2.91 g, 6.66 mmol). The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction was quenched with aqueous 20% Na₂S₂O₃(100 mL) and aqueous saturated NaHCO₃(100 mL) and then stirred for 10 minutes. The CH₂Cl₂layer was separated and washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated to give the crude product as a cloudy colorless oil. The crude product was dissolved in 100 mL of 1:1 EtOAc/hexanes, filtered through a pad of silica gel, washed with 200 mL of 1:1 EtOAc/hexanes. The filtrate was concentrated to give 1.07 g (72%) of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde as a clear colorless oil, which was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 9.68 (s, 1H), 4.15-4.00 (m, 2H), 3.30-3.20 (m, 2H), 2.86 (septet, 1H, J=7.0 Hz), 2.55-2.45 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 2H), 1.26 (d, 6H, J=6.8 Hz).

Step 3: (±)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 49%) was prepared as a light brown oil from 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde (1.07 g, 4.79 mmol) and methylmagnesium bromide (3M in Et₂O, 3.51 mL, 10.54 mmol) then methanesulfonyl chloride (0.22 mL, 2.81 mmol) and Et₃N (0.66 mL, 4.68 mmol) in a manner similar to Example 139, Steps 1-2. The crude product was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 4.70-4.60 (m, 1H), 4.30-4.15 (m, 2H), 3.10-2.95 (m, 5H), 2.87 (septet, 1H, J=7.0 Hz), 1.95-1.70 (m, 3H), 1.55-1.35 (m, 5H), 1.26 (d, 6H, J=6.8 Hz).

Step 4: The title compound (0.212 g, 26%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 0.43 g, 1.72 mmol), (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 2.32 mmol) and K₂CO₃(0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 152, Steps 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/CH₂Cl₂, followed by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give (±)-2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethypoxy]-5-[4-(methylsulfonyl)phenyl]pyrazine as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 8.25 (s, 1H), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.28 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 472 (M+H).

Example 1572-[((1R)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazin

The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO₂: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 23.42 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.

Example 158

2-[((1S)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO₂: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 25.83 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis. Alternative preparation from enantiomerically enriched material:

Step 1: Triethylamine (315 mL, 2.26 mol) was added dropwise to formic acid (150 mL, 3.91 mol) with overhead stirring while maintaining the internal temperature below 60° C. with ice-bath cooling. Neat 4-acetylpyridine (100 mL, 0.904 mol) was then added rapidly while maintaining the temperature below 50° C. Following this addition, the reaction was allowed to cool to 28° C. and the chiral ruthenium catalyst [N-[(1R,2R)-2-(amino-N)-1,2-diphenylethyl]-2,4,6-trimethylbenzenesulfonamidato-N]chloro[(1,2,3,4,5,6-n)-1-methyl-4-(1-methylethyl)benzene]ruthenium (CAS#177552-91-9; for catalyst preparation, see: Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.; J. Am. Chem. Soc. 1996, 118, 4916-4917) (3 g, 4.46 mmol) was added. The mixture was stirred under house vacuum for 4 h and then overnight under an atmosphere of nitrogen. The reaction mixture was added dropwise to a stirred solution of 10% Na₂CO₃(4 L) and then extracted with EtOAc (3×1 L). The combined EtOAc layers were washed once with brine (1 L), treated with MgSO₄and Darco G-60 decolorizing charcoal and filtered through a 100 g plug of silica gel washing with 10% MeOH/EtOAc (1 L). The filtrate was concentrated to provide a dark oil that crystallized upon standing. The solid was dissolved in warm t-butyl methyl ether (250 mL) and the warm solution was filtered to remove a small amount of insoluble material. The filtrate was allowed to stir with cooling to room temperature and then to −15° C. The solids were collected by filtration, washing with cold t-butyl methyl ether and heptane, and then dried under high vacuum to yield (1R)-1-(4-pyridinyl)ethanol as a dark beige solid (62 g, 52.9% yield). This solid material was 96% ee based on chiral HPLC(HPLC conditions: AS-H column, 5% MeOH/CO₂, 40° C., 140 bar, 2 mL/min). The filtrate was combined with the insoluble solid from the crystallization and concentrated in vacuo to yield additional (1R)-1-(4-pyridinyl)ethanol as a dark oil (37.5 g, 32% yield). This oily material was 78% ee based on chiral HPLC (see HPLC conditions above). ¹H NMR (400 MHz, DMSO-d₆): δ 8.47-8.43 (m, 2H), 7.32-7.28 (m, 2H), 5.37 (d, 1H, J=4.4 Hz), 4.72-4.64 (m, 1H), 1.44 (d, 3H, J=6.6 Hz).

Step 2: A solution of (1R)-1-(4-pyridinyl)ethanol (37 g, 0.3 mol, 78% ee) in MeOH (2 L) was charged with PtO₂(5 g) under nitrogen atmosphere followed by acetic acid (19 mL). The mixture was evacuated and purged with hydrogen several times and then stirred under an atmosphere of hydrogen for 2 d at room temperature. The mixture was filtered to remove catalyst and the filtrate was concentrated in vacuo and triturated with EtOAc to yield a cream-colored solid which was collected by filtration. The filter cake was dissolved in MeOH (500 mL) and 50% NaOH (15.8 g) was added. The resulting solution was stirred at 25° C. for 30 min and concentrated. The resulting solid was triturated with Et₂O (700 mL) and stirred at 25° C. for 30 min, the solids were removed by filtration and the filtrate was dried over MgSO₄and filtered again. The final filtrate was concentrated to yield (1R)-1-(4-piperidinyl)ethanol (22 g, 57% yield) as a light beige solid. ¹H NMR (400 MHz, CDCl₃): δ 3.50 (quint, 1H, J=6.3 Hz), 3.13-3.01 (m, 2H), 2.61-2.47 (m, 2H), 1.88 (br, 2H), 1.84-1.73 (m, 1H), 1.63-1.52 (m, 1H), 1.41-1.27 (m, 1H), 1.23-1.05 (m, 2H), 1.13 (d, 3H, J=6.2 Hz).

Step 3: A stirred solution of N-hydroxy-2-methylpropanimidamide (16.33 g, 160 mmol) in pyridine (16.81 mL, 208 mmol) and dichloromethane (165 mL) at −15° C. was treated with trichloroacetyl chloride (19.63 mL, 176 mmol) over 40 min. The reaction was allowed to warm to ambient temperature and stirred for 42 h. Water (100 mL) was added and the reaction was stirred for 30 min. The dichloromethane was removed and the residue was diluted with water (50 mL) and extracted with ether (300 mL). The ether layer was washed with water, dried over MgSO₄and concentrated to afford 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (28.0 g, 76% yield) as an orange liquid.¹H NMR (400 MHz, CDCl₃): δ 3.13 (septet, 1H, J=7.0 Hz), 1.36 (d, 6H, J=7.0 Hz).

Step 4: A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (25.8 g, 112 mmol) and (1R)-1-(4-piperidinyl)ethanol (13.4 g, 104 mmol) in MeOH (15 mL) was stirred at ambient temperature under a stream of nitrogen for 7 days. The reaction was diluted with MeOH (40 mL), cooled in an ice bath and 1N NaOH (25 mL) was added. The mixture was allowed to warm to ambient temperature and stir for 1 h. The reaction was partitioned in EtOAc (300 mL)/1N NaOH (75 mL) and the layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (200 mL). The combined EtOAc layers were dried over MgSO₄, concentrated and placed under high vacuum for 18 h to afford (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (16.75 g, 68%) as an orange oil. ¹H NMR (400 MHz, CDCl₃): δ 4.14 (m, 2H), 3.57 (quint, 1H, J=6.3 Hz), 2.98 (m, 2H), 2.83 (septet, 1H, J=7.0 Hz), 1.90 (m, 1H), 1.86 (br, 1H), 1.67 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.23 (d, 6H, J=7.0 Hz), 1.16 (d, 3H, J=6.3 Hz); LRMS (ESI), m/z 240 (M+H).

Step 5: A solution of (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (1.68 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. was treated with Et₃N (1.98 mL, 14.0 mmol) followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol). The mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with 1M NaH₂PO₄(75 mL×2) and brine, and dried over Na₂SO₄and concentrated to give (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 100% yield) as a brown oil, which was used without further purification.

Step 6: A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 1.3 g, 5.19 mmol), (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 70% ee) and K₂CO₃(1.45 g, 10.4 mmol) in DMF (35 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (75 mL×2). The combined organic extracts were washed with water, brine and dried over Na₂SO₄, filtered, and the filtrate was concentrated to a brown oil, which was by chromatography on a silica gel column eluted with 50% EtOAc/hexanes followed by chromatography on an ISCO silica gel column using 0 to 60% EtOAc/hexanes to give 2-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (0.73 g, 70% ee, 30%) as a white solid. The solid was subjected to chiral separation (similar to conditions used above for Example 158) to yield 0.30 g of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (d, 1H, J=1.3 Hz), 8.25 (d, 1H, J=1.3 Hz), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.90 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.3 Hz), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 472 (M+H).

Paper

Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

Richard T. Matsuoka^*†, Eric E. Boros#, Andrew D. Brown†, Kae M. Bullock†, Will L. Canoy‡, Andrew J. Carpenter#, Jeremy D. Cobb†, Shannon E. Condon†, Nicole M. Deschamps†, Vassil I. Elitzin†, Greg Erickson†,Jing M. Fang#, David H. Igo§, Biren K. Joshi‡, Istvan W. Kaldor#, Mark B. Mitchell†, Gregory E. Peckham#, Daniel W. Reynolds‡, Matthew C. Salmon†, Matthew J. Sharp†, Elie A. Tabet#, Jennifer F. Toczko†, Lianming Michael Wu‡, and Xiao-ming M. Zhou†

^†API Chemistry Department, ^‡Analytical Science & Development Department, ^#Medicinal Chemistry Department, and^§Particle Sciences and Engineering Department, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00157, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00157

Publication Date (Web): July 13, 2016

*E-mail: richard.t.matsuoka@gsk.com.

Abstract

Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an S_NAr synthetic strategy.

Patent ID	Date	Patent Title
US2012077812	2012-03-29	BICYCLIC COMPOUNDS AND USE AS ANTIDIABETICS
US8101634	2012-01-24	BICYCLIC COMPOUNDS AND USE AS ANTIDIABETICS

/////////////GSK2041706A, GSK 2041706A, GSK-2041706A, GSK2041706, GSK 2041706, GSK-2041706

Supporting Info

O=S(c4ccc(c3cnc(OC(C2CCN(c1nc(C(C)C)no1)CC2)C)cn3)cc4)(C)=O

GSK-1292263A Glucose-Dependent Insulinotropic Receptor (GDIR, GPR119) Agonists

phase 2, Uncategorized Comments Off

Jul 312016

str1

GSK-1292263

CAS 1032823-75-8

3-isopropyl-5-(4-(((6-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole

5-[1-(3-Isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ylmethoxy]-2-[4-(methylsulfonyl)phenyl]pyridine

5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine

MF C23H28N4O4S

MW: 456.18313

1292263
GSK-1292263
GSK-1292263A
GSK-263A

Smithkine Beecham Corp, INNOVATOR

GSK-1292263 is a novel GPR119 receptor agonist that is currently under development for the treatment of type 2 diabetes. Treatment of male Sprague-Dawley rats with a single dose of GSK-1292263 (3-30 mg/kg) in the absence of nutrients correlated with increased levels of circulating gastrointestinal peptides; glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY) and glucagon.

GSK-1292263 had been evaluated in phase II clinical studies at GlaxoSmithKline for the oral treatment of type 2 diabetes and as monotherapy or in combination with sitagliptin for the treatment of dyslipidemia; however no recent development has been reported for this research.

Following administration of glucose in the oral glucose tolerance test (OGTT), greater increases in total GLP-1, GIP and PYY were seen in GSK-1292263-treated rats than in control animals. Despite significant decreases in the glucose AUC, no statistically significant differences in insulin responses and insulin AUC were observed between rats administered GSK-1292263 and those receiving vehicle control.

In the intravenous glucose tolerance test, significant increases in the peak insulin response and insulin AUC(0-15 min) of 30-60% were reported in the GSK-1292263 treatment group, compared with values in the vehicle control cohort. This insulin upregulation correlated with a significant increase in the glucose disposal rate (Brown, K.K. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 407).

The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a recently completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549).

A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250-mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-OGTT hypoglycemia.

NMR

¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J = 3.0 Hz, 1H), 8.28 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.99 (bd, J = 8.5 Hz, 2H), 7.54 (dd, J = 8.8, 3.0 Hz, 1H), 4.03 (d, J = 6.3 Hz, 2H), 4.03–3.97 (m, 2H), 3.25 (s, 3H), 3.20–3.09 (m, 2H), 2.81 (q, J = 6.7 Hz, 1H), 2.13–2.00 (m, 1H), 1.88 (bd, J = 12.8 H, 2H), 1.42–1.29 (m, 2H), 1.18 (d, J = 7.0 Hz, 6H).

¹³C NMR (100.6 MHz, DMSO-d₆) 175.3, 170.9, 155.5, 147.0, 143.5, 140.5, 138.6, 127.9, 127.0, 122.4, 122.3, 72.5, 45.7, 44.1, 35.0, 28.0, 26.7, 20.8.

HRMS calcd for C₂₃H₂₉N₄O₄S (M + H)⁺ 457.1904, found, 457.1900.

Anal. Calcd for C₂₃H₂₈N₄O₄S: C, 60.51; H, 6.18; N, 12.27. Found: C, 60.64; H, 6.16; N, 12.24.

str1

Hypoglycemia was not reported with the 5-day dosing schedule. Pharmacokinetic profiling revealed dose-proportional AUC and Cmax at single lower doses, but not at single higher ones. Following repeated once-daily dosing (5 days), drug accumulation was observed consistent with a mean half-life of 12-18 hours. A dose-dependent increase in glucose AUC(0-3 h) during OGTT was seen in GSK-1292263-treated subjects. The treatment was also associated with an increase in PYY during the prandial periods.

Coadministration with sitagliptin led to increases in the plasma concentrations of active GLP-1 but reduced the levels of total GLP-1, GIP and PYY. Sitagliptin affected the exposure to GSK-1292263 (50% increase) but GSK-1292263 did not affect sitagliptin exposure. The data support further evaluation of GSK-1292263 for the treatment of type 2 diabetes (Source: Nunez, D.J. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 80-OR).

WO 2008070692

http://www.google.com.au/patents/WO2008070692A2?cl=en

Example 169: 5-[({1 -[3-(1 -Methylethyl)-1,2,4-oxadiazol-5-yl]-4- piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine hydrochloride

Step 1 : A mixture of 6-bromo-3-pyridinol (7 g, 40 mmol), [4-(methylsulfonyl)phenyl]boronic acid (8 g, 40 mmol), 2M Na₂CO₃ (30 ml_), PdCI₂(PPh₃)₂ (1 g) and DME (60 ml.) under N₂ was heated at 80 ⁰C overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water. The resulting precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The aqueous phase was also concentrated. Each of the residues was recrystallized from MeOH. The solid material from the organic phase recrystallization and the mother liquors from both aqueous and organic recrystallizations were combined, concentrated and purified by chromatography on a silica gel column using 0 to 10% MeOH/CH₂CI₂ to give 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (2.9 g, 29%) as a tan solid. Step 2: Diisopropyl azodicarboxylate (0.175 ml_, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh₃ (233 mg, 0.89 mmol), and THF (10 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH₃CN:H₂O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH₂CI₂ and free-based with saturated NaHCO₃ (aq) to give 5-[({1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine (220 mg) as a white solid. Step 3: A mixture of the resulting white solid (50 mg, 0.1 1 mmol) in THF (3 ml.) was stirred at ambient temperature as 4Λ/ HCI in dioxane (28 μl_) was added dropwise. The resulting white precipitate was filtered, air-dried, then triturated with diethyl ether to give 35 mg (65%) of the title compound as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 8.46 (d, 1 H, J = 0.7 Hz), 8.18 (bs, 2H), 8.05 (bs, 2H), 7.83 (bs, 1 H), 7.61- 7.45 (m, 1 H), 4.24 (d, 2H, J = 10.4 Hz), 4.00 (d, 2H, J = 0.6 Hz), 3.21-3.03 (m, 5H), 2.89 (m, 1 H), 2.15 (d, 1 H, J = 1.1 Hz), 1.96 (bs, 2H), 1.50 (bs, 2H), 1.28 (d, 6H, J = 6.9 Hz); LRMS (ESI), m/z 457 (M+H).

PATENT

http://www.google.co.ug/patents/US20120077812

Example 100

5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine[0480]

Step 1: A mixture of 2-methylpropanenitrile (100 g, 1.45 mol), hydroxylamine hydrochloride (111 g, 1.59 mol) and NaOH (64 g, 1.59 mol) in EtOH (2 L) and water (500 mL) was stirred at reflux overnight. The mixture was evaporated to dryness and extracted with dichloromethane. The organic extract was dried over Na₂SO₄and concentrated to afford the desired N-hydroxy-2-methylpropanimidamide (50 g, 34%).

Step 2: A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH₂Cl₂(1 L) was treated with a slurry of NaHCO₃(205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH₂Cl₂, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH₂Cl₂. The combined organic extracts were dried over Na₂SO₄, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile. Step 3: A solution of 1N ZnCl₂in Et₂O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K₂CO₃. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol.

Step 4: A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Step 3, 174 g, 0.77 mol) and triethylamine (140 mL, 1.0 mol) in dichloromethane (1 L) at 5° C. was treated with a solution of methanesulfonyl chloride (69 mL, 0.89 mol) in dichloromethane (150 mL) over a 1 h period. The mixture was stirred at 5° C. for 30 min, and then was quenched by the addition of water (400 mL). The mixture was stirred for 30 min, and then the organic extract was washed with water (2×400 mL), dried (MgSO₄) and concentrated. The residue was treated with heptane (1 L), stirred for 3 h, and the resulting solid was collected by filtration (heptane wash) and air-dried to afford {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (219.7 g, 94%) as an off-white solid. ¹NMR (400 MHz, CDCl₃): δ 4.21-4.15 (m, 2H), 4.08 (d, 2H, J=6.6 Hz), 3.04 (m, 2H), 3.01 (s, 3H), 2.86 (septet, 1H, J=6.9 Hz), 2.05-1.93 (m, 1H), 1.88-1.81 (m, 2H), 1.43-1.31 (m, 2H), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 304 (M+H).

Step 5: A mixture of 6-bromo-3-pyridinol (36 g, 207 mmol), [4-(methylsulfonyl)phenyl]boronic acid (50 g, 250 mmol), 2M Na₂CO₃(315 mL) and DME (500 mL) was degassed with N₂for 30 min, and then Pd(PPh₃)₄(12 g, 10 mmol) was added and the mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to room temperature and was diluted with dichloromethane (500 mL) and water (500 mL) and stirred for 30 min. The reaction was filtered and the solids were rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic extracts were extracted with 1N NaOH (2×600 mL), and then cooled to 5° C. and the pH was adjusted to ˜8 with 6N HCl. The resulting precipitate was collected by filtration (water wash) and air-dried to afford a yellow solid. This procedure was repeated and the solids were combined to provide (71.2 g, 68%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol. ¹H NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H), 8.25 (d, 1H, J=2.7 Hz), 8.21 (d, 2H, J=8.5 Hz), 8.00-7.90 (m, 3H), 7.27 (dd, 1H, J_a=8.7 Hz, J_b=2.8 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 250 (M+H).

Step 6: A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (82.3 g, 271 mmol), 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (71.0 g, 285 mmol), powdered potassium carbonate (118 g, 855 mmol) and N,N-dimethylformamide (750 mL) was mechanically stirred and heated at 80° C. under nitrogen for 20 h. The reaction was cooled to ambient temperature, poured onto ice water (3 L) and allowed to stand for 1 h. The resulting solid was filtered, rinsed with water (2×500 mL) and air-dried. The solid was taken up in dichloromethane (300 mL) and methanol (500 mL). The dichloromethane was slowly removed via rotovap at 55° C. The methanol solution was allowed to stand at ambient temperature for 16 h. The resulting crystalline solid was filtered, rinsed with cold methanol and dried under vacuum at 60° C. for 18 h to afford the desired product (105.7 g, 84%) as a light tan solid. ¹H NMR (400 MHz, CDCl₃): δ 8.41 (d, 1H, J=2.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, J_a=8.7 Hz, J_b=3.0 Hz), 4.24 (d, 2H, J=13.1 Hz), 3.95 (d, 2H, J=6.2 Hz), 3.17-3.04 (m, 5H), 2.94-2.84 (m, 1H), 2.11 (bs, 1H), 1.97 (d, 2H, J=12.6 Hz), 1.54-1.42 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 457 (M+H).

Alternative preparation: Step 1: 2-Bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 29%) was prepared as a white solid from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 348 mg, 2.0 mmol), 6-bromo-3-pyridinol (348 mg, 2.0 mmol) and Ph₃P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.51 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. ¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 7.08 (d, 1H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.95-2.76 (m, 1H), 2.11-1.96 (m, 1H), 1.98-1.88 (m, 2H), 1.52-1.36 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 381/383 (M+H).

Step 2: 5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (51 mg, 21%) was prepared from 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 0.52 mmol), [4-(methylsulfonyl)phenyl]boronic acid (105 mg, 0.52 mmol), 2M Na₂CO₃(5 mL), Pd(PPh₃)₄(50 mg, 0.04 mmol) and DME (5 mL) in a manner similar to Example 21, Step 3.

Paper

Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00157, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00157

Publication Date (Web): July 13, 2016

*E-mail: richard.t.matsuoka@gsk.com.

Abstract

///////////1292263, GSK-1292263, GSK-1292263A, GSK-263A, GSK1292263, GSK1292263A, GSK 1292263, GSK 1292263A, GSK 263A, GSK263A, 1032823-75-8

O=S(C1=CC=C(C2=CC=C(OCC3CCN(C4=NC(C(C)C)=NO4)CC3)C=N2)C=C1)(C)=O

Supporting Info

VELPATASVIR (GS-5816), GILEAD SCIENCES, велпатасвир, فالباتاسفير , 维帕他韦 ,

FDA 2016, Uncategorized Comments Off

Jul 302016

VELPATASVIR (GS-5816), GILEAD SCIENCES

CAS 1377049-84-7

Molecular Formula:	C₄₉H₅₄N₈O₈
Molecular Weight:	883.00186 g/mol

Hepatitis C virus NS 5 protein inhibitors

KEEP WATCHING AS I ADD MORE DATA, SYNTHESIS……………

Gilead Sciences, Inc. INNOVATOR

Elizabeth M. Bacon, Jeromy J. Cottell, Ashley Anne Katana, Darryl Kato, Evan S. Krygowski, John O. Link, James Taylor, Chinh Viet Tran, Martin Teresa Alejandra Trejo, Zheng-Yu Yang, Sheila Zipfel,

Elizabeth Bacon

Senior Research Associate II at Gilead Sciences

Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4′,3′:6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate

Sheila Zipfel

Research Scientist I at Gilead Sciences

{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(Méthoxycarbonyl)amino]-2-phénylacétyl}-4-(méthoxyméthyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-1,11-dihydroisochroméno[4′,3′:6,7]naphto[1,2-d]imidazol-2-yl)-5 -méthyl-1-pyrrolidinyl]-3-méthyl-1-oxo-2-butanyl}carbamate de méthyle

Carbamic acid, N-[(1R)-2-[(2S,4S)-2-[4-[1,11-dihydro-2-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4′,3′:6,7]naphth[1,2-d]imidazol-9-yl]-1H- imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-, methyl ester

Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}-1,11-dihydro[2]benzopyrano[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Description	Pan-genotypic HCV NS5A inhibitor
Molecular Target	HCV NS5A protein
Mechanism of Action	HCV non-structural protein 5A inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase II
Standard Indication	Hepatitis C virus (HCV)
Indication Details	Treat HCV genotype 1 infection; Treat HCV infection

Gilead Sciences
Class Antivirals; Carbamates; Chromans; Imidazoles; Naphthols; Phenylacetates; Phosphoric acid esters; Pyrimidine nucleotides; Pyrrolidines; Small molecules
Mechanism of Action Hepatitis C virus NS 5 protein inhibitors

Registered Hepatitis C

Most Recent Events

14 Jul 2016 Registered for Hepatitis C in Canada (PO)
08 Jul 2016 Registered for Hepatitis C in Liechtenstein, Iceland, Norway, European Union (PO)
30 Jun 2016 Gilead Sciences plans a phase III trial for Hepatitis C (Combination therapy, Treatment-experienced) in Japan (PO (NCT02822794)

Darryl Kato works on a hepatitis treatment at Gilead Sciences Inc.’s lab

Velpatasvir, also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. GS-5816 has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

WO 2013/075029. Compound I has the formula:

PAPER

Patent Highlights: Recently Approved HCV NS5a Drugs

David L. Hughes^*

Cidara Therapeutics, 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00241, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241

*E-mail: dhughes@cidara.com.

Abstract

Five inhibitors of the NS5a enzyme have been approved as part of oral regimens for the treatment of hepatitis C virus, including daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences), ombitasvir (AbbVie), elbasvir (Merck), and velpatasvir (Gilead Sciences). This article reviews worldwide patents and patent applications that have been published on synthetic routes and final forms for these five drugs.

PATENT

https://google.com/patents/WO2013075029A1?cl=en

Example NP

Methyl {(2S)-l-[(2S,5S)-2-(5-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-l,ll dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9- yl}-lH-imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate

The synthesis of this compound was prepared according to the procedure of example LR-1 with the following modification. During the Suzuki coupling, (2S)-l-[(2S,5S)-2-(5-iodo-lH-imidazol- 2-yl)-5-methylpyrrolidin-l-yl]-2-[(l-meth^ was used in lieu of

(2S)-l -[(2S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl]-2-[(l-methoxyethenyl)amino]-3- methylbutan-l-one. The crade material was purified by preparative HPLC to provide methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate as a white solid (17 mg, 0.019 mmol, 17%). ^lU NMR (400 MHz, cd₃od) δ 8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H), 7.52 – 7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m, 1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99 (m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H).

PATENT

US 20150361073 A1

Scheme 1

Compound (J)

Compound (I) H CO- Com pound (G)

^st alkylation: Conversion of Compound (I-a) to Compound (G-a)

Compound (I-a) (45 g, 1.0 equiv.), Compound (J-a) (26.7g, 1.03 equiv.) and potassium carbonate (20.7g, 1.5 equiv.) in dichloromethane (450 mL) were stirred at about 20 °C for approximately 3-4 hours. After the completion of the reaction, water (450 mL) was charged into the reactor and the mixture was stirred. Layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 2 wt% NaH₂PO4/10wt% NaCl solution (450 mL). The organic layer was then concentrated and the solvent was swapped from dichloromethane into tetrahydrofuran. A purified sample of Compound (G-a) has the following spectrum: ¾ NMR (400 MHz,

CDC1₃) δ 7.90-7.94 (m, 1H), 7.81-7.85 (m, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 5.19-5.56 (2dd, 2H), 5.17 (s, 2H), 4.73 (t, 1H), 4.39-4.48 (m, 1H), 3.70-3.77 (m, 1H), 3.37-3.45 (m, 2H), 3.33-3.35 (d, 3H), 3.28-3.32 (m, 1H), 3.20-3.25 (dd, 1H), 2.92-2.96 (dt, 1H), 2.44-2.59 (m, 4H), 1.97-2.09 (m, 1H), 1.44 (d, 9H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may be Compound (I) where X may be -CI, -Br, -OTs, -OS0₂Ph, -OS0₂Me, -OS0₂CF₃, -OS0₂R, , and -OP(0)(OR)₂ and Y may be -CI, -Br, -OTs, -OS0₂Ph, -OS0₂Me, -OS0₂CF₃, -OS0₂R, and -OP(0)(OR)₂. R may be alkyl, haloalkyl, or an optionally substituted aryl.

Various bases may also be employed, such as phosphate salts (including but not limited to KH₂P0₄, K₃P0₄, Na₂HP0₄, and Na₃P0₄) and carbonate salts (including but not limited to Na₂C0₃,Cs₂C0₃, and NaHC0₃). Where the starting material is Compound (J), KHC0₃ or preformed potassium, sodium, and cesium salts of Compound (J) may also be used.

Alternative solvents can include 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, dimethylformamide, acetone, MEK, and MIBK.

The reaction temperature may range from about 10 °C to about 60 °C.

” alkylation: Conversion of Compound (G-a) to Compound (B-a):

A solution of Compound (G-a) (prepared as described earlier starting from 45 g of Compound (I-a)) was mixed with Compound (H) (42.9g, 1.5 equiv.), and cesium carbonate (26. lg, 0.8 equiv.). The reaction mixture was stirred at about 40-45 °C until reaction was complete and then cooled to about 20 °C. Water (450 mL) and ethyl acetate (225 mL) were added and the mixture was agitated. Layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). Combined organic phase was concentrated and solvent was swapped to toluene. A purified sample of Compound (B-a) has the following spectrum: ¾ NMR (400 MHz, CDC1₃) 57.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H), 7.63-7.64 (d, 1H), 7.59-7.60 (d, 1H), 5.52-5.63 (m, 1H), 5.30-5.43 (q, 1H), 5.13-5.23 (s+m, 3H), 4.56-4.64 (m, 2H), 4.39-4.48 (m, 1H), 4.20-4.27 (m, 1H), 3.62-3.79 (m, 2H), 3.66 (s, 2H), 3.36-3.45 (m, 2H), 3.34-3.35 (d, 3H), 3.07-3.25 (m, 3H), 2.59-2.37 (m, 5H), 1.97-2.16 (m, 3H), 1.60 (s, 3H), 1.38-1.45 (m, 12H), 0.91-1.03 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may include Compound (G) where Y may be -CI, -Br, -OTs, -OS0₂Ph, -OS0₂Me, -OS0₂CF₃, -OS0₂R, , or -OP(0)(OR)₂. where R is alkyl, aryl, or substituted aryl. In some embodiments, the substituted aryl may be an aryl having one or more substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, and others as discussed above.

Various bases may be employed. Non-limiting examples can include phosphate salts (including but not limited to KH₂P0₄, K₃P0₄, Na₂HP0₄, and Na₃P0₄) and carbonate salts (including but not limited to K₂C0₃ or Na₂C0₃). If Compound (H) is used as the starting material, Li₂C0₃ or preformed potassium, sodium, and cesium salt of Compound (H) may be employed.

Alternative solvents may include 2-methyltetrahydrofuran, dichloromethane, toluene, mixtures of THF/Toluene, isopropyl acetate, ethyl acetate, l-methyl-2-pyrrolidinone, Ν,Ν-dimethylacetamide, acetone, MEK,and MIBK. An alternative additive may be

potassium iodide, and the reaction temperature may range from about 40 °C to about 60 °C or about 40 °C to about 50 °C.

A toluene solution of Compound (B-a) (604 g solution from 45 g of Compound (I-a)) was charged to a reaction vessel containing ammonium acetate (185.2 g) and isopropanol (91.0 g). The contents of the reactor were agitated at about 90 °C until the reaction was complete (about 16 to 24 hours). The reaction mixture was cooled to about 45 °C, and then allowed to settle for layer separation. Water (226 g) was added to the organic phase, and the resulting mixture was separated at about 30 °C. Methanol (274 g), Celite (26.9 g) and an aqueous solution of sodium hydroxide (67.5 g, 50%) and sodium chloride (54.0 g) in water (608 g) were added to the organic phase, and the resulting mixture was agitated for a minimum of 30 minutes. The mixture was then filtered through Celite and rinsed forward with a mixture of toluene (250 g) and isopropanol (1 1 g). The biphasic filtrate was separated and water (223 g) was added to the organic phase, and the resulting mixture was agitated at about 30 °C for at least 15 minutes. The mixture was filtered through Celite and rinsed forward with toluene (91 g). The organic layer was concentrated by vacuum distillation to 355 g and was added over 30 minutes to another reactor containing w-heptane (578 g). The resulting slurry is filtered, with the wetcake was washed with w-heptane (450 mL) and dried in a vacuum oven to afford Compound (C-a). A purified sample of Compound (C-a) has the following spectrum: *H NMR (400 MHz, CDC1₃) δ 12.27-11.60 (m, 1 H), 1 1.18-10.69 (m, 1 H), 7.83 – 7.44 (m, 4 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.28 – 7.05 (m, 1 H), 5.65 – 5.25 (m, 1H), 5.25 – 4.83 (m, 4 H), 4.34 – 4.03 (m, 2 H), 3.93 – 3.63 (m, 4 H), 3.52 (s, 1 H), 3.35 (d, J = 2.4 Hz, 4 H), 3.19 – 2.94 (m, 4 H), 2.88 (dd, J = 12.0, 7.9 Hz, 3 H), 2.66 – 1.85 (m, 5 H), 1.79 (s, 5 H), 1.37 – 1.12 (m, 6H), 1.04-0.98 (m, 6 H), 0.82 (t, J = 7.7 Hz, 2 H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative reagents, in lieu of ammonium acetate, can include hexamethyldisilazane, ammonia, ammonium formate, ammonium propionate, ammonium hexanoate, and ammonium octanoate. Various solvents, such as toluene, xylene, an alcohol

(including but not limited to isopropanol, 1-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, and glycols, such as ethylene glycol and propylene glycol) may be employed. Alternative catalyst/additives may include magnesium stearate, acetic acid, propionic acid, and acetic anhydride. The reaction temperature may range from about 60 °C to about 110 °C or about 85 °C to about 95 °C.

Preparation of Compound (D-a) using DDQ as oxidant:

A solution of Compound (C-a) (255.84 g) in 2-methyltetrahydrofuran (1535 mL) was cooled to about 0 °C and acetic acid (0.92 mL) was added. To this mixture was added a solution of DDQ (76.98 g) in 2-methyltetrahydrofuran (385 mL) over about 30 minutes. Upon reaction completion, a 10 wt% aqueous potassium hydroxide solution (1275 mL) was added over about 30 minutes and the mixture was warmed to about 20 °C. Celite (101.5 g) was added and the slurry was filtered through Celite (50.0 g) and the filter cake was rinsed with 2-methyltetrahydrofuran (765 mL). The phases of the filtrate were separated. The organic phase was washed successively aqueous potassium hydroxide solution (1020 mL, 10 wt%), aqueous sodium bisulfite solution (1020 mL, 10 wt%), aqueous sodium bicarbonate solution (1020 mL, 5 wt%) and aqueous sodium chloride solution (1020 mL, 5 wt%). The organic phase was then concentrated to a volume of about 650 mL. Cyclopentyl methyl ether (1530 mL) was added and the resulting solution was concentrated to a volume of about 710 mL. The temperature was adjusted to about 40 °C and Compound (D-a) seed (1.0 g) was added. The mixture was agitated until a slurry forms, then methyl tert-butyl ether (2300 mL) was added over about 3 hours. The slurry was cooled to about 20 °C over about 2 hours and filtered. The filter cake was rinsed with methyl tert-butyl ether (1275 mL) and dried in a vacuum oven at about 40 °C to provide Compound (D-a). A purified sample of Compound (D-a) has the following spectrum: ¾ NMR (400 MHz, CDC1₃) δ 13.05-10.50 (comp m, 2H), 8.65-6.95 (comp m, 8H), 5.50-5.35 (m, 2H), 5.25^1.60 (comp m, 3H), 4.35-4.20 (m, 1H), 4.00-3.65 (comp m, 4H), 3.60-3.45 (m, 1H), 3.45-3.25 (comp m, 4H), 3.25-3.00 (comp m, 2H), 2.95-1.65 (comp m, 6H), 1.47 (br s, 9H), 1.40-1.25 (comp m, 2H), 1.20-0.70 (comp m, 9H).

Alternative Preparation of Compound (D-a) using Mn02 as oxidant:

A mixture of Compound (C-a) (50.0 g), manganese (IV) oxide (152.8 g) and dichloromethane (500 mL) is stirred at about 20 °C. Upon completion of the reaction, Celite (15 g) was added. The resulting slurry was filtered through Celite (20 g) and the filter cake was rinsed with dichloromethane (500 mL). The filtrate was concentrated and solvent exchanged into cyclopentyl methyl ether (250 mL). The resulting solution was warmed to about 60 °C and treated with an aqueous potassium hydroxide solution (250 mL, 10wt%). The biphasic mixture is stirred at about 45 °C for about 12 hours. The phases are then separated and the organic phase is concentrated to a volume of about 150 mL. The concentrate is filtered, seeded with Compound (D-a) seed and agitated at about 40 °C to obtain a slurry. Methyl tert-butyl ether (450 mL) was added to the slurry over 30 minutes and the resulting mixture was cooled to about 20 °C. The precipitated solid was filtered, rinsed with methyl tert-butyl ether (250 mL) and dried in a vacuum oven at about 40 °C to obtain Compound (D-a).

Alternative Preparation of Compound (D-a) through catalytic dehydrogenation

A mixture of Compound (C-a) (2.5 g, 2.7 mmol, 1 equiv), 5% Pd/Al₂0₃ (2.5 g) and 1-propanol (25 mL, degassed) was stirred at reflux under inert environment for about 5.5 hours. The reaction mixture was then cooled to ambient temperature and filtered through Celite, and the residue rinsed with 1-propanol (2 x 5 mL) to obtain a solution of Compound (D-a).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in a reaction scheme employing stoichiometric oxidants, alternative oxidants may include manganese(IV) oxide, copper(II) acetate, copper(II) trifluoroacetate, copper(II) chloride, copper(II) bromide, bromine (Br₂), iodine (I₂), N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1 ,4-benzoquinone, tetrachloro-l,4-benzoquinone (chloranil), eerie ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, άϊ-tert-butyl peroxide, benzoyl peroxide, oxygen ((¾), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, Oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene. Various additives may be employed, and non-limiting examples may be carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like), amines (e.g., triethylamine, diisopropylethylamine and the like), and acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid), sodium acetate, potassium acetate, and the like). The reaction temperature may range from about -10°C to 80 °C. The reaction may take place in solvents, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), aromatic solvents (e.g., toluene, xylenes, etc.), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1 ,2-dimethoxyethane, diglyme, triglyme, etc.), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glycol, etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, etc.), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, etc.), amine solvents (e.g., triethylamine, morpholine, etc.), acetic acid, and water.

In reaction schemes employing catalytic oxidants, alternative catalysts may include palladium catalysts (e.g., palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) benzoate, palladium(II) sulfate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-iert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, palladium on carbon, palladium on alumina, palladium on hydroxyapatite, palladium on calcium carbonate, palladium on barium sulfate, palladium(II) hydroxide on carbon), platinum catalysts (e.g., platinum on carbon, platinum(IV) oxide, chloroplatinic acid, potassium chloroplatinate), rhodium catalysts (e.g., rhodium on carbon, rhodium on alumina,

bis(styrene)bis(triphenylphosphine)rhodium(0)), ruthenium catalysts (e.g., ruthenium(II) salen, dichloro(para-cymene)ruthenium(II) dimer), iridium catalysts (e.g., iridium(III) chloride, (l,5-cyclooctadiene)diiridium(I) dichloride, bis(l,5-cyclooctadiene)iridium(I) tetrafluoroborate, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) carbonyl chloride, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) tetrafluoroborate), copper catalysts (e.g., copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) iodide, copper(II) iodide, copper(II) acetate, copper(II) trifluoroacetate, copper(I) trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate, copper(II) sulfate), iron catalysts (e.g., iron(II) sulfate, iron(II) chloride, iron(III) chloride), vanadium catalysts (e.g., dichloro(ethoxy)oxovanadium, dichloro(isopropoxy)oxovanadium), manganese catalysts (e.g., manganese(rV) oxide, manganese(III) (salen) chloride), cobalt catalysts (e.g., cobalt(II) acetate, cobalt(II) chloride, cobalt(II) salen), indium(III) chloride, silver(I) oxide, sodium tungstate, quinone catalysts (e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, 1,4-benzoquinone, and tetrachloro-l,4-benzoquinone (chloranil)).

Alternative co-oxidants can include, but are not limited to, sodium nitrite, copper(II) acetate, sodium persulfate, potassium persulfate, ammonium persulfate, sodium perborate, nitrobenzenesulfonate, 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO), pyridine-N-oxide, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide, oxygen (0₂), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene.

Varoius hydrogen acceptors may be employed. Non-limiting examples can include unsaturated hydrocarbons (e.g., tert-butylethylene, tert-butyl acetylene, 2-hexyne, cyclohexene, and the like), acrylate esters (e.g., methyl acrylate, ethyl acrylate, isopropyl acrylate, tert-butyl acrylate, and the like), maleate esters (e.g., dimethyl maleate, diethyl maleate, diisopropyl maleate, dibutyl maleate, and the like), fumarate esters (e.g., dimethyl fumarate, diethyl fumarate, diisopropyl fumarate, dibutyl fumarate, and the like), and quinones (e.g. chloranil, 1 ,4-benzoquinone, etc.).

Alternative additives may be employed, such as carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.), amine bases (e.g., triethylamine, diisopropylethylamine, etc.), phosphines (e.g., triphenylphosphine, tri(ort zotolyl)phosphine, tricyclohexylphosphine, tri-w-butylphosphine, tri-tert-butylphosphine, etc.), acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid, etc.), sodium acetate, N-hydroxyphthalimide, salen, 2,2 ‘-bipyri dine, 9,10-phenanthroline, and quinine.

The reaction can proceed at temperatures ranging from about 10 °C to about 120 °C. Various solvents can be employed, including but not limited to halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, and the like), aromatic solvents (e.g., toluene, xylenes, and the like), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, triglyme, and the like), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, w-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glyco, and the like), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, and the like), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, and the like), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, and the like), amine solvents (e.g., triethylamine, morpholine, and the like), acetic acid, and water.

Acetyl chloride (135 mL, 5 equiv.) was added slowly to methanol (750 mL) under external cooling maintaining reaction temperature below 30 °C. The resulting methanolic hydrogen chloride solution was cooled to about 20 °C, and added slowly over about 1 hour to a solution of Compound (D-a) (300 g, 1 equiv.) in methanol (750 mL) held at about 60 °C, and rinsed forward with methanol (300 mL). The reaction mixture was agitated at about 60 °C until reaction was complete (about 1 hour), and then cooled to about 5 °C. The reaction mixture was adjusted to pH 7-8 by addition of sodium methoxide (25 wt. % solution in methanol, 370 mL) over about 20 minutes while maintaining reaction temperature below about 20 °C. Phosphoric acid (85 wt. %, 26 mL, 1 equiv.) and Celite (120 g) were added to the reaction mixture, which was then adjusted to about 20 °C, filtered, and the filter cake was rinsed with methanol (1050 mL). The combined filtrate was polish filtered and treated with phosphoric acid (85 wt. %, 104 mL, 4 equiv.). The mixture was was adjusted to about 60 °C, seeded with Compound (E-a) seed crystals (1.5 g), aged at about 60 °C for 4 hours and cooled slowly to about 20 °C over about 7.5 hours. The precipitated product was filtered, washed with methanol (2 x 600 mL), and dried in a vacuum oven at about 45 °C to provide

Compound (E-a). ^!H NMR (400 MHz, D₂0) δ 7.53-6.77 (comp m, 8H), 5.24-4.80 (comp m, 3H), 4.59-4.38 (comp m, 2H), 4.15-3.90 (m, 1H), 3.65-3.38 (comp m, 5H), 3.36-3.14 (comp m, 4H), 2.75 (s, 1H), 2.87-2.66 (m, 1H), 2.29-1.60 (comp m, 6H), 1.27 (d, 3H), 0.76 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. Various deprotection agents are well known to those skilled in the art and include those disclosed in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (4th edition) J. Wiley & Sons, 2007, hereby incorporated by reference in its entirety. For example, a wide range of acids may be used, including but not limited to phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, thionyl chloride,and trimethylsilyl chloride. A wide range of solvents may be employed, including but not limited to water, ethanol, acetonitrile, acetone, tetrahydrofuran, 1 ,4-dioxane, and toluene. Deprotection may proceed at temperatures ranging from about 20 °C to about 110 °C or from about 55 °C to about 65 °C.

A wide range of bases may be employed as a neutralization reagent. Non-limiting examples can include sodium phosphate dibasic, potassium phosphate dibasic, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, N, N-diisopropylethylamine, and 4-methylmorpholine. Various solvents may be used for neutralization, such as water, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 2-butanone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, and dichloroethane.

Neutralization may proceed at temperatures ranging from about -20 °C to about 60 °C or about 5 °C to about 15 °C.

Various crystallization reagents can be employed. Non-limiting examples may be hydrochloric acid, hydrobromic acid, sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid, oxalic acid, and glucuronic acid. Solvents for crystallization can include, but is not limited to, water, ethanol, 1-propanol, 2-propanol, and acetonitrile. Crystallization may proceed at temperatures ranging from about -20 °C to about 100 °C.

Free-Basing of Compound (E-a) to Prepare Compound (E)

ompound (E-a) OCH, H3CO- Compound (E)

Compound (E-a) (10.0 g, 10.1 mmol) was dissolved in water (100 g) and then dichloromethane (132 g) and 28% ammonium hydroxide (7.2 g) were added sequentially. The biphasic mixture was stirred for 45 minutes. Celite (2.2 g) was added, the mixture was filtered through a bed of additional Celite (5.1 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). ‘H NMR (400 MHz, CD₃OD) δ 8.35-7.17 (m, 8H), 5.6^1.68 (m, 3H), 4.41-3.96 (m, 2H), 3.96-3.72 (br s, 1H), 3.74-3.48 (m, 2H), 3.42 (d, 2H), 3.33 (s, 3H), 3.28 (s, 1H), 3.19-3.01 (m, 1H), 3.00-2.79 (m, 1H), 2.69-1.82 (m, 6H), 1.80-1.45 (m, 3H), 1.21-0.73 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-hydrochloride salts of Compound (E) may be used. Various bases may be employed, such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Various solvents, such as 2-methyltetrahydrofuran and ethyl acetate, may be employed. The temperature may range from about 15 °C to about 25 °C.

Alternative Free-Basing of Compound (E-b) to Prepare Compound (E)

Compound (E-b) (15.2 g) was dissolved in water (100 g) and then dichloromethane

(132 g) and 28% ammonium hydroxide (7.4 g) were added sequentially. The biphasic mixture was stirred for about 45 minutes. Celite (2.1 g) was added, the mixture was filtered through a bed of additional Celite (5.2 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). *H NMR (400 MHz, CD₃OD) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H), 4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

Salt Conversion of Compound (E-a) to Compound (E-b)

A solution of Compound (E-a) (10.0 g, 10.1 mmol), a solution of 37% HCI (10 g) in water (20 g), and acetonitrile (30 g)was warmed to about 50 °C and agitated for about lh. The solution was cooled to about 20 °C and acetonitrile (58 g) was charged to the reactor during which time a slurry formed. The slurry was stirred for about 21 h and then additional acetonitrile (39 g) was added. The slurry was cooled to about 0 °C, held for about 60 min and the solids were then isolated by filtration, rinsed with 7% (w/w) water in acetonitrile (22 g) previously cooled to about 5 °C. The wet cake was partially deliquored to afford

Compound (E-b). *H NMR (400 MHz, D₂0) δ 7.92-6.73 (m, 8H), 5.51^1.90 (m, 2H),

4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

A flask was charged sequentially with 2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine (“CDMT”) (2.2 giv) and methanol (8.9 g) and the slurry was cooled to about 0 °C. To the mixture was added NMM (1.3 g) over about 5 minutes, maintaining an internal temperature of less than 20 °C. The solution was stirred for about 20 minutes to produce a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol.

To a solution of Compound (E) (7.1 g) in dichloromethane (170 g) was added

Compound (Γ) (2.8 g). The solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol was added over 2 minutes followed by a rinse of methanol (1.1 g). After about 2.5 h, the completed reaction solution was washed sequentially with aqueous 10% potassium bicarbonate solution (40 mL), 3% hydrochloric acid (40 mL), and aqueous 10% potassium bicarbonate solution (40 mL). The lower organic phase was washed with water (40 mL), filtered, and then concentrated by rotary evaporation to produce Compound (A). ¾ NMR (400 MHz, CD₃OD) δ 8.56-6.67 (m, 13H), 5.76^1.94 (m, 4H), 4.86-4.67 (m, 1H), 4.47-3.98 (m, 1H), 3.98-2.72 (m, 15H), 2.74-1.77 (m, 7H), 1.77-1.40 (m, 2H), 1.39-0.53 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-phosphate salts or tris-hydrochloride salts of Compound (G) may be used as alternative starting material. The reaction may take place at a temperature range of from about 10 °C to about 20 °C. Alternative coupling agents include, but are not limited to, EDC/HOBt, HATU, HBTU, TBTU, BOP, PyClOP, PyBOP, DCC/HOBt, COMU, EDCLOxyma, T3P, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate. An alternative bases that may be employed can be diisopropylethylamine. The reaction may proceed in DMF and at temperatures ranging from about -20 °C to about 30 °C.

Salt Formation and Crystallization of Compound (A)

Crystallization of Compound (A-a)

A flask was charged with Compound (A) (10 g) and ethanol (125 mL) and was then warmed to about 45 °C. Concentrated hydrochloric acid (2.3 mL) was added followed by Compound (A-a) seed crystals (5 mg). The mixture was cooled to about 20 °C over about 5 h and held for about an additional 1 1 h. The solids were isolated by filtration, washed with ethanol (2 x 20 mL), and deliquored to produce Compound (A-a). ^!H NMR (400 MHz, CD₃OD) δ 8.94-7.22 (m, 14H), 5.78-5.1 1 (m, 5H), 4.53-4.04 (m, 1H), 3.99-3.57 (m, 10H), 3.57-3.41 (m, 2H), 2.99-2.24 (m, 5H), 2.24-1.85 (m, 3H), 1.80-1.50 (m, 2H), 1.39-0.73 (m, 8H).

Alternative Crystallization of Compound (A-b)

A reaction vessel was charged with Compound (A) (25.0 g) followed by ethanol (125 mL) and 10% H₃PO₄ (250 mL). The solution was seeded with Compound (A-b) (100 mg) and stirred for about 17.5 h. The solids were isolated by filtration, washed with ethanol (2 x 5 mL), deliquored, and dried in a vacuum oven to produce Compound (A-b). ^JH NMR (400 MHz, D₂0) δ 7.76-6.48 (m, 13H), 5.53^1.90 (m, 3H), 4.60-4.32 (m, 2H), 4.29-3.76 (m, 1H), 3.70-2.75 (m, 14H), 2.66-1.51 (m, 8H), 1.51-1.09 (m, 3H), 1.05-0.45 (m, 7H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative acids may be hydrochloric acid, hydrobromic acid, L-tartaric acid. Various solvents may be employed, such as methanol, ethanol, water, and isopropanol. The reaction may proceed at temperatures ranging from about 5 °C to about 60 °C.

Free-Basing of Compound (A)

Free-Basing of Compound (A-a) to Prepare Compound (A)

A reaction vessel was charged with Compound (A-a) (18.2 g) followed by ethyl acetate (188 g) and 10% potassium bicarbonate (188 g) and the mixture was stirred for about 25 minutes. The phases were separated and the upper organic phase was then washed with water (188 mL). The resulting organic solution was concentrated, ethanol (188 g) was added, and the solution was evaporated to produce a concentrate (75 g). The resulting concentrate added into water (376 g) to produce a slurry. The solids were isolated by filtration, washed with water (38 g), de liquored and dried in a vacuum oven at about 50 °C to produce

Compound (A).

Alternative Free-Basing of Compound (A-b) to Prepare Compound (A)

om poun –

A reaction vessel was charged with Compound (A-b) (3.0 g) followed by EtOAc (15 mL) and 10% KHCO₃ (15 mL) and agitation was initiated. After about 5 h, the phases were separated and the organic phase was washed with water (15 mL) and then concentrated by rotary evaporation under vacuum. The residue was taken up in EtOH (4.5 mL) and then added to water (30 mL) to produce a slurry. After about 15 min, the solids were isolated by filtration rinsing forward water (3 x 3 mL). The solids were dried at about 50 to 60 °C vacuum oven for about 15 h to produce Compound (A).

PATENT

US 2015/0361085

https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true

Compound I Form I

An additional stable form screen was performed using the same procedure as described above but included a crystalline intermediate (Compound II shown below) as seeds.

Compound II can be synthesized according to the methods described in WO 2013/075029 or U.S. Provisional Application No. 62/010,813. Needle-like particles were formed in butyronitrile, propionitrile, MEK/toluene, MEK/IPE and 2-pentanone/toluene. XRPD patterns of the wet solids were mostly consistent with each other with minor shifting in the peaks. The new form is named Compound I Form I, which is believed to be isostructural channel solvates with the respective solvents. After air drying all solids afforded amorphous XRPD patterns.

Another stable form screen was performed using carbon (Darco G-60) treated Compound I, solvents, antisolvent (diisopropyl ether (IPE)), and seeds of Compound I Form I. This screen afforded crystalline solids from additional solvents as summarized in Table 1. The XRPD patterns of all of these solvates are consistent with Form I. The solvates were observed to convert to amorphous solids after drying. The XRPD patterns of Compound I were obtained in the experimental setting as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 2-40°, step size 0.0167°, counting time: 15.875 s.

[TABLE-US-00002]

TABLE 1

Stable form screen of carbon treated Compound I

Solvents	PLM	Comments

Water	Amorphous	Slurry
Water/EtOH	Amorphous	Sticky phase coating
ACN/IPE	Birefringent	Slurry of needles
MeOH/IPE	Solution	Seeds dissolved
EtOH/IPE	Solution	Seeds dissolved
Acetone/IPE	Birefringent	Thick slurry of
		needles
IPA/IPE	Amorphous	Sticky coating
MEK/IPE	Birefringent	Thick slurry of
		needles
MIBK/IPE	Birefringent	White paste
DCM/IPE	Birefringent	Thick slurry of small
		needles
THF/IPE	Solution	Seeds dissolved
2-MeTHF/IPE	Amorphous	slurry
EtOAc/IPE	Birefringent	Thick slurry of
		needles
IPAc/IPE	Amorphous	slurry
Toluene	Amorphous	Sticky coating

The crystallinity of Compound I Form I can be improved by using a butyronitrile/butyl ether (BN/BE) mixture according to the following procedure.

The crystallization experiment was started with 40 to 75 mg Compound I in 1.1 to 3.0 mL of a BN/BE in a ratio of 7:4 (anhydrous solvents). The sample was held at RT over P₂O₅for 23 days without agitation, and crystals formed in the solution. Afterwards, the liquid phase was replaced with butyl ether and the solids were obtained by centrifuge. These solids, corresponding to Compound I Form I, were used for the subsequent step as seed.

Purified Compound I (709.8 mg) was prepared from reflux of ethanol solution with Darco G-60 and was added to a new vial via a filter. While stirring, 7 mL of anhydrous butyronitrile (BN) was added. A clear orange solution was obtained. While stirring, 4 mL of anhydrous butyl ether (BE) was added slowly. To the solution was added 7.7 mg of Compound I Form I (from previous BN:BE crystallization experiment) as seed. The solution became cloudy and the seeds did not dissolve. The sample was stirred for ˜10 minutes before the agitation was stopped. The vial was capped and placed into a jar with some P₂O₅solids at room temperature. After 6 days, a thin layer of bright yellow precipitate was observed on the wall and the bottom of the vial. The liquid phase was withdrawn and 3 mL of anhydrous butyl ether was added. Solids were scraped down with a spatula from the vial. The suspension was heated to about 30° C. for over half hour period and was held for ˜1 hour before cooling to 20° C. at about 0.1° C./min (without agitation). The sample was stored in ajar with P₂O₅solids for 5 days. The sample was vacuum filtered using 0.22 μm nylon filter, washed with 2×200 μL of anhydrous butyl ether, and air dried under reduced pressure for about 5 minutes.

XRPD analysis of the sample showed good very sharp peaks as shown in FIG. 1. The XRPD analysis setting was as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 1-40°, step size 0.0167°, counting time: 36.83 s. The characteristic peaks of crystalline Compound I Form I include: 2.9, 3.6, 4.8, 5.2, 6.0° 2θ (FIG. 1). The XRPD pattern of Form I was successfully indexed, indicating that Form I is composed primarily of a single crystalline phase. Extremely large unit cell volume containing up to ˜60 API molecules in the unit cell was observed. The amorphous halo observed in the XRPD pattern could be a result of the size of the unit cell. Butyl ether stoichiometry could not be estimated. Two alternative indexing solutions were found: monoclinic and orthorhombic.

DSC and TGA data confirmed that Form I is a solvated form. DSC shows a broad endotherm with onset at 109° C. and small endotherm with onset at 177° C. (FIG. 2). TGA shows 22% weight loss below 150° C. (FIG. 3).

PATENT

CN 105294713

https://www.google.com/patents/CN105294713A?cl=en

https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf

Example 12

Under nitrogen, was added l〇2g1 said, adding methylene burn 500 blood dissolved, 4mol / L fertilizer 1 1,4-dioxane SOOmL, football for 1 hour at room temperature, of the C (already burned: ethyl acetate 1: 1) point in the control board, the starting material spot disappeared, the reaction was stopped, the solvent was concentrated, was added (R & lt) -2- (methoxy several yl) -2-phenylacetic acid 29g, COMU60g, DMF blood 500, diisopropylethylamine 223M1,25 ° C reaction I h, ethyl acetate was added IL diluted, purified water is added IL painted twice, dried over anhydrous sulfate instrument, and concentrated, methanol was added SOOmL temperature 60 ° C dissolved, 250mL of purified water was slowly added dropwise, to precipitate a solid, the addition was completed, cooled to 50 ° C for 1 hour, cooled to room temperature, filtered, and concentrated to give Velpatasvir (GS-5816) product 90. 5g, 78. 2〇 yield / billion. H-NMR (400MHz, CDs isolated) 5 7. 94 – 7.67 (m, 4H), 7.59 of J = 9.1 Hz, 1H), 7. 52 (S, 1H), 7.48 – 7. 33 (m, 4H) , 7.11 of J = 18. 7Hz, 1H), 5.68 of J = 6.3Hz, 1H), 5.48 – 5.33 (m, 1H), 5.23 (dd, J = 24.1, 15.7Hz, 1H), 5.17 -5.03 (m, 3H), 4.22 (dd, J = 17.0, 9.6Hz, 1H), 4.16 – 4.01 (m, 1H), 3.91 (d, J = 24. 1 Hz, 1H), 3 83 -. 3. 68 (m, 1H), 3 68 -. 3. 59 (m, 3H), 3 59 -. 3. 49 (m, 3H), 3.38 (ddd, J = 15.9, 9.6, 5.7Hz, 2H), 3.28 – 3.14 (m, 5H), 3.10 (dd, J = 14.0, 8.2 Hz, 1H), 3.00 (dd, J = 17.8, 9.6Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H), 2.73 – 2.41 (m, 2H), 2.40 – 2.11 (m, 2H), 2. 11 – 1.83 (m, 2H), 1.54 deduction J = 9. 7 Hz, 2H), 1.24 of J = 6.2Hz, 1H), 1.06 (t, J = 8.0 Hz, 1H), 0.99 of J = 6.8 Hz, 1H), 0. 94 (d, J = 6. 6Hz, 2H), 0. 85 (d, J = 6. 7Hz, 2H ).

Construction

Clip and foot notes

Velpatasvir only got its name last year and was previously known as GS-5816. That compound was only announced back in 2013 when Gilead showed the initial in vitrostudies on a handful of posters. [1] [2] Very little information is available on this follow-up compound. The following was pretty much the summary of their poster presentation.

To understand the medical significance of this study, Sofosbuvir is the best-in-class NS5B inhibitor from Gilead (see link for more information). [3] These inhibitors work the fastest when paired with a NS5A inhibitor like Daclatasvir or Ledipasvir (making up the Sofosbuvir+Ledipasvir = Harvoni combination) or the Viekira Pak combo. Disclosure: I am an employee of Bristol-Myers Squibb which produces Daclatasvir. However, HCV comprises of 7 different genotypes. Harvoni and Viekira Pak are approved against genotypes 1a, 1b. Harvoni is indicated for genotypes 4, 5, and 6. For the treatment of genotypes 2 and 3, sofosbuvir is generally combined with ribavirin or interferon which has notable side effects. While 70% of patients have genotype 1, for the remainder of patients with the other variants, they are still stuck with the more risky (and more expensive and longer) therapy.

I think this is the structure of GS-5816. It’s not yet published in any journal. [4]

For comparison, here is the structure of Ledipasvir, the first generation NS5A inhibitor used in Harvoni. Structurally speaking, they are pretty similar so it seems like GS-5816 is the product of good old fashioned medchem.

The clearest summary of the 4 Phase III trials can be found on Gilead’s website. [5]ASTRAL-1 was run on genotypes 1, 2, 4, 5, 6. [6] ASTRAL-2 focused on genotype 2. ASTRAL-3 focused on genotype 3. [7] ASTRAL-4 focused on HCV patients with Child-Pugh cirrhosis. [8] These patients previously had interferon treatment but had a poor response and are generally very sick.

I think that a few interesting things stand out. ASTRAL-1 occurred from July 2014 to December 2014 but upon a request from the FDA, ASTRAL-2 and 3 were started in September 2014-July 2015 in order to have an isolated study on genotypes 2 and 3. For a 24 week study that’s incredibly fast. As discussed elsewhere, clinical trials are often limited by the speed of patient enrollment and these studies can take years. [9] Here, they were able to find volunteers for a 1000 patient study within weeks. An interesting note about the clinical trial design, the ASTRAL-1 team knew that the historical cure rate was 85% and were able to correctly power the trial to get a statistically significant study on the first try. Also, deep sequencing was used to identify and stratify the HCV genotypes. In ASTRAL-1, 42% of the patients had NS5A resistance and 9% had NS5B resistance.

The market impact may be significant to Achillion which was a former partner of Gilead and a potential acquisition target. Achillion was working with Janssen on its own second generation NS5A inhibitor, odalasvir. This announcement may kill the market for a competing product as well as remove the acquisition hype.

How did Gilead come up with Velpatasvir? It really sounds like good solid science. Ledipasvir was developed to be a best-in-class NS5A inhibitor and it was recognized that it worked well with NS5B inhibitors. It was also understood that most of the NS5A inhibitors specific only towards certain N5SA genotypes and that there was a clear unmet need for patients with HCV genotypes 2 and 3. With the help of some computational modeling [10]Gilead developed assays for all of the HCV genotypes to screen for a pan-genotype NS5A inhibitor to follow up to their 2014 Ledipasvir trials and leveraging their strategic advantage in the HCV market, were able to quickly ramp up 4 major clinical trials to demonstrate the clinical efficacy of their next gen drug combination.

That’s really good science. Not long ago, Gilead stated that it was planning on eradicating HCV. This compound is a part of the Gilead license with Indian generic manufacturers but it seems like MSF is contesting that decision. [11] [12] With this drug Gilead is now another step closer towards that goal. [13]

Footnotes

[1] GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier

[2] Page on journal-of-hepatology.eu

[3] Christopher VanLang’s answer to How was Sovaldi (the drug now being marketed by Gilead), first discovered by Pharmasset?

[4] CAS # 1377049-84-7, Velpatasvir, GS 5816, Methyl [(2S)-1-[(2S,5S)-2-[9-[2-[(2S,4S)-1-[(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

[5] Page on gilead.com

[6] Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection — NEJM

[7] Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection — NEJM

[8] Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis — NEJM

[9] Why do clinical trials for new drugs take several years? Remarkably, 72% of Americans are willing to be in them.

[10] Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.

[11] Page on gilead.com

[12] MSF response to Gilead announcement on inclusion of hepatitis C drug GS-5816 in voluntary licence

[13] Gilead and Georgia to attempt Hep C eradication by Christopher VanLang on Making Drugs

09338-acsnews1-gileadcxd

SAVING LIVES

The Gilead team responsible for Harvoni: Front row, from left: John Link, Chris Yang, Rowchanak Pakdaman, Bob Scott, and Benjamin Graetz. Back row, from left: Erik Mogalian and Bruce Ross. Not pictured: Michael Sofia.

Credit: Gilead Sciences

Gilead’s Harvoni is a combination of two antiviral agents, sofosbuvir and ledipasvir. “In hepatitis C, the virus mutates so rapidly that to overcome resistance, we use a combination of drugs, and each one pulls their own weight in the process,” says John Link, who discovered ledipasvir.

Link says that the amount of interdisciplinary collaboration on the drug was unprecedented for the company. “Once ledipasvir was discovered, the process chemists were right there with us understanding the kinds of things we were doing, and medicinal chemists and process chemists worked on making material to scale for preclinical studies,” he says. “We all realized this was our moment to make a difference for patients with hepatitis C.”

Harvoni is the first once-a-day pill for treatment of chronic hepatitis C, and it has a cure rate in the U.S. of 94-99%. The drug is an alternative to injected interferon treatment, which has been associated with significant side effects.

“The high cure rates that we saw in our clinical trials are really amazing,” Link says. “Before we had these compounds, I had only hoped that we could equal something like interferon-type regimens in cure rates, without all the horrible side effects. To dramatically exceed them is important for patients.”

Harvoni patients can attest to the drug’s effectiveness. Mark Melancon, who had contracted hepatitis C 25 years ago, says that after taking Harvoni, he now has no trace of the virus in his body, and his liver is beginning to repair itself. “Four weeks into it, and the virus was gone. Not detectable,” he says. “To have this virus hanging over my head for 25 years and then it was just gone, I can’t explain the feeling. The people who worked hard on this medication, they need to know that I appreciate it.”

REFERENCES

https://www.eiseverywhere.com/file_uploads/c2a2b5664a374fe807c0b95bb546321d_JordanFeld.pdf

WO2013075029A1 *	Nov 16, 2012	May 23, 2013	Gilead Sciences, Inc.	Condensed imidazolylimidazoles as antiviral compounds

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Velpatasvir
Systematic (IUPAC) name

(2S)-2-{[hydroxy(methoxy)methylidene]amino}-1-[(2S,5S)-2-(17-{2-[(2S,4S)-1-[(2R)-2-{[hydroxy(methoxy)methylidene]amino}-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-21-oxa-5,7-diazapentacyclo[11.8.0.0³,¹¹.0⁴,⁸.0¹⁴,¹⁹]henicosa-1(13),2,4(8),6,9,11,14(19),15,17-nonaen-6-yl)-5-methylpyrrolidin-1-yl]-3-methylbutan-1-one
Identifiers
CAS Number	1377049-84-7
PubChem	CID 67683363
ChemSpider	34501056
UNII	KCU0C7RS7Z
Chemical data
Formula	C₄₉H₅₄N₈O₈
Molar mass	883.02 g·mol⁻¹

//////////////VELPATASVIR, GS-5816, GILEAD SCIENCES, Epclusa , FDA 2016, велпатасвир,فالباتاسفير , 维帕他韦 , велпатасвир, فالباتاسفير , 维帕他韦 , Elizabeth Bacon, Sheila Zipfel

UNII:KCU0C7RS7Z

C[C@H]1CC[C@H](N1C(=O)[C@H](C(C)C)NC(=O)OC)C2=NC3=C(N2)C=CC4=CC5=C(C=C43)OCC6=C5C=CC(=C6)C7=CN=C(N7)[C@@H]8C[C@@H](CN8C(=O)[C@@H](C9=CC=CC=C9)NC(=O)OC)COC

RNA virus antivirals (primarily J05, also S01AD and D06BB)

Hepatitis C

NS3/4A protease inhibitors (–previr)	Asunaprevir Boceprevir Faldaprevir^‡ Grazoprevir Paritaprevir Simeprevir Telaprevir

NS5A inhibitors (–asvir)	Daclatasvir Elbasvir Ledipasvir MK-3682 MK-8408 Odalasvir^† Ombitasvir Ravidasvir^† Samatasvir^† Velpatasvir

NS5B RNA polymerase inhibitors (–buvir)	Beclabuvir^† Dasabuvir Deleobuvir^§ Filibuvir^§ Setrobuvir^§ Sofosbuvir Radalbuvir^†

Combination drugs	Elbasvir/grazoprevir Ledipasvir/sofosbuvir Ombitasvir/paritaprevir/ritonavir Velpatasvir/sofosbuvir