AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Green Pocketbook® for Research & Development Departments from ViridisChem Inc.

 TOXICITY, Uncategorized  Comments Off on Green Pocketbook® for Research & Development Departments from ViridisChem Inc.
Jul 232016
 

str1


CLICK TO PLAY THE ABOVE MEDIA CLIP……

 

Comprehensive toxicological data on raw material is practically non existent, which means designing green product development processes can be tedious and time consuming.

ViridisChem Inc., is offering a solution that will help scientists make environmentally friendly decisions throughout the product development life-cycle.

Our first product the Green Pocketbook® is a cloud based reference tool that helps scientists assess chemicals of high concern and identify safer alternatives that are less hazardous for people and environmentally friendly.

Containing more than 90 million chemical entries from the worlds best structure, reaction and literature databases, the Green Pocketbook combines the power of a search engine with user friendly decisions support tools.

str1

click  Media

Unlike other chemistry reference products, it is the only software tool in the industry that correlates physical and toxicological properties then calculates a Green Score based on these properties.  The software allows the user to visually compare multiple chemicals side by side for easy assessment and decision making.

str1

Other Features include:

Flexible Search options, search by;

  • Chemical Name, CAS#, IUPAC Name
  • Structure, or draw your own
  • Citation, Reference, Patents

Comprehensive Physical and Toxicological data

  • The software displays many of the properties contained in the MSDS plus more.
  • There over 24 physical properties and over 26 toxicological properties that can be configured and displayed to suite your preferences
  • Displays US and International regulatory concerns

str1

click  Media

 

 

Jose Castanon

Jose Castanon

Marketing Leader, Team Builder

Best,
Jose Castanon
ViridisChem Inc.
408 218 3125
josec@viridischem.com
click  Media
 
Jose Castanon is a marketing professional with over 15 years of experience in medical technology and devices. He specializes in growth strategies and bringing new technologies to market. Prior to ViridisChem Jose was the Director of Marketing for Omnicell, where he led all North American marketing activity for the Medication Automation and Analytics business line. Jose has held commercial leadership roles at Philips Healthcare, Roche and Johnson and Johnson. He holds a BS in Biology from the University of Puget Sound and an MBA from Pepperdine University.

Neelam Vaidya

Neelam Vaidya

Experienced executive with passion to bring most needed solutions to market

Neelam Vaidya is a serial entrepreneur with over 25 years’ experience in both high-tech and bio-tech industry. In 2014, Neelam and Rahul Vaidya cofounded ViridisChem Inc. with the mission to develop a portfolio of software solutions that will provide all the information and analysis capabilities scientists would need to practice “green chemistry” within their everyday research, that will result in environmentally friendly product development processes that are greener, safer, and economical. To enable this goal, the company has built in-house and proprietary
– chemical database with over 60 million chemicals,
– citation database with over 20 million citations and patents,
– reaction database with over 10 million reference reactions

It recently launched its first product Green Pocketbook that is being used both as an educational tool and as a reference guide by universities and industry scientists for their day-to-day research needs. It provides full chemical and toxicological profiles of chemicals, and offers “green scores” based on these properties through easy to understand visual charts. With inclusion of chemicals relevant to most industries, and by providing the most comprehensive information about chemicals in a very easy to use and understand manner, Green Pocketbook is proving to be a “must have” software solution for scientists from most industries for their day-to-day work.

In past she was the founder and CEO of a biotech company ChiroSolve, Inc. that offers products and services that define chiral resolution method for optically active and hard-to-separate chiral molecules. Neelam was also the founder of Software Company called Perfect Solutions that offered enterprise software products for high-tech industry. Before her entrepreneur career, Neelam has lead number high-profile enterprise infrastructure projects

ACS National Fall Symposium, 2015, Boston, MA (August 16-18, 2015)

News/Events – ViridisChem, Inc.

www.viridischem.com

ViridisChem Team

 

 

REFERENCES

http://www.viridischem.com/wp-content/uploads/2016/03/GreenPocket-Datasheet-3-10-2016_V3.pdf

https://library.stanford.edu/swain/databases/green-pocketbook

////////Green Pocketbook, Research & Development Departments, Jose Castanon,  ViridisChem Inc,

Neelam Vaidya

Share

AZD 1981

 Uncategorized  Comments Off on AZD 1981
Jul 222016
 

 

STR1

AZD1981; AZD-1981; 802904-66-1; UNII-2AD53WQ2CX; ; AZD 1981;
Molecular Formula: C19H17ClN2O3S
Molecular Weight: 388.86788 g/mol
      1H-Indole-1-acetic acid, 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-
  • 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methylindol-1-yl]acetic acid
  • Originator AstraZeneca
  • Developer AstraZeneca; Johns Hopkins University
  • Class Antiasthmatics
  • Mechanism of Action Prostaglandin D2 receptor antagonists
    • Phase II Urticaria
    • Discontinued Asthma; Chronic obstructive pulmonary disease

    Most Recent Events

    • 09 Mar 2016 AZD 1981 is still in phase II trials for Urticaria in USA (PO)
    • 07 Mar 2016 Johns Hopkins University in collaboration with AstraZeneca completes a phase II trial in Urticaria in USA (PO) (NCT02031679)
    • 04 Mar 2016 Efficacy and safety data from a phase II trial in Urticaria presented at the Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)

https://ncats.nih.gov/files/AZD1981.pdf

SEE

NMR

HPLC

AZD1981 is a potent, selective CRTh2 (DP2) receptor antagonist with IC50 of 4 nM, showing >1000-fold selectivity over more than 340 other enzymes and receptors, including DP1. Phase 2.

AZD1981.png

118 patients were randomised to treatment (AZD1981 n = 61; placebo n = 57); 83% of patients were male and the mean age was 63 years (range 43-83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981-placebo: -0.015, 95% CI: -0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI: -0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated.

CONCLUSION:

There was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified.

 

STR1

 

STR1

STR1

 

 

Biological Activity

Description AZD1981 is a potent, selective CRTh2 (DP2) receptor antagonist with IC50 of 4 nM, showing >1000-fold selectivity over more than 340 other enzymes and receptors, including DP1. Phase 2.
Targets CRTh2 (DP2) receptor [1]
IC50 4 nM
In vitro AZD1981, as a potent antagonist in a disease relevant cell system, inhibits DK-PGD2-induced CD11b expression in human eosinophils with IC50 of 10 nM. [1] AZD1981 blocks DP2-mediated shape change in human eosinophils and basophils in blood, as well as DP2-mediated chemotaxis of human Th2 cells and eosinophils. Moreover, AZD1981 also blocks the binding of [3H]PGD2 to mouse, rat, guinea pig, rabbit and dog recombinant DP2. [2]
In vivo AZD1981 has high oral bioavailability in male sprague dawley rats. [1] In guinea pig hind limb model, AZD1981 (100 nM) completely inhibits DK-PGD2-induced eosinophil mobilization. [2]
Features An orally available selective DP2(CRTh2) receptor antagonist in clinical development for asthma.

Protocol(Only for Reference)

Kinase Assay: [2]

DP2 binding studies A scintillation proximity assay (SPA) following [3H]PGD2 binding to membranes of HEK cells expressing recombinant DP2 is used. The potency of AZD1981 as an antagonist is determined by quantifying its ability to displace specific radio-ligand binding. Briefly, membranes from HEK293 expressing recombinant human DP2 are pre-bound to Wheat Germ Agglutinin-coated PVT-SPA beads for 18 h at 4°C. Assays were started by the addition of 25 μL of membrane-coated beads (10 mg/mL of beads) to an assay buffer (50 mm HEPES pH 7.4 containing 5 mm MgCl2) containing 2.5 nM [3H]PGD2 in the absence or the presence of increasing concentrations of the tested compounds (50 μL final volume). Non-specific binding is determined in the same conditions but in the presence of 10 μM DK-PGD2. Plates are incubated for 2 h at room temperature, and bead-associated radioactivity is measured using a Wallac Microbeta counter. The concentration of the compounds causing 50% inhibition of binding of [3H]PGD2 to the receptor is calculated (IC50). Ki values have not been derived from IC50, as there is no evidence of a simple competitive interaction with PGD2. The same methodology is used for recombinant human, murine, rat, guinea pig, dog and rabbit DP2. Reversibility of binding to the human receptor was assessed by recovery of [3H]PGD2 binding after removal of AZD1981 by washing of the membrane-coated SPA beads. HEK-membrane-coated beads are incubated in the presence of AZD1981 for 2 h at room temperature to bind the compound to DP2. To remove the bound AZD1981, beads are centrifuged (1 min at 1300× g), and the pellet resuspended in 1 mL of assay buffer. This is repeated four times. Aliquots (30 μL) are transferred to 96-well plates, and [3H]PGD2 binding is evaluated as above. Parallel samples containing (i) 10 μM DK-PGD2 during the 2 h incubation and in the wash buffer; (ii) AZD1981 at 2 μM in the wash buffer; and (iii) vehicle are processed alongside to determine non-specific binding and the ‘no wash’ condition whilst controlling for loss of beads during the washing process. The time from first wash to end of first reading is approximately 13 min.

Animal Study: [1]

Animal Models Male sprague dawley rats.
Formulation
Dosages 1 mg/kg(i.v.), 4 mg/kg(oral)
Administration i.v. or oral administration

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × mouse Km(3)  = 11.2 mg/kg
rat Km(6)

 

References

[1] Luker T, et al. Bioorg Med Chem Lett. 2011, 21(21), 6288-6292.

[2] Schmidt JA, et al. Br J Pharmacol. 2013, 168(7), 1626-1638.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-09)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02031679 Recruiting Chronic Idiopathic Urticaria Johns Hopkins University|AstraZeneca January 2014 Phase 2
NCT01311635 Completed Healthy AstraZeneca April 2011 Phase 1
NCT01254461 Completed Drug Interaction AstraZeneca February 2011 Phase 1
NCT01265641 Completed Asthma AstraZeneca January 2011 Phase 1
NCT01199341 Completed Pharmakokinetic AstraZeneca October 2010 Phase 1

Patent ID Date Patent Title
US2015210655 2015-07-30 CERTAIN (2S)-N-[(1S)-1-CYANO-2-PHENYLETHYL]-1,4-OXAZEPANE-2-CARBOXAMIDES AS DIPEPTIDYL PEPTIDASE 1 INHIBITORS
US2015072963 2015-03-12 COMPOSITIONS AND METHODS FOR REGULATING HAIR GROWTH
US2014328861 2014-11-06 Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis
US8772305 2014-07-08 Substituted pyridinyl-pyrimidines and their use as medicaments
US8227622 2012-07-24 Pharmaceutical Process and Intermediates 714
US2012178764 2012-07-12 Novel Compounds
US2011263614 2011-10-27 Novel compounds
US7781598 2010-08-24 Process for the preparation of substituted indoles
US7687535 2010-03-30 Substituted 3-sulfur indoles
US2009163518 2009-06-25 Novel Compounds

///////////

CC1=C(C2=C(N1CC(=O)O)C=CC=C2NC(=O)C)SC3=CC=C(C=C3)Cl

 

Share

AZD 3514 MALEATE

 Uncategorized  Comments Off on AZD 3514 MALEATE
Jul 222016
 

STR1

AZD3514; AZD 3514; AZD-3514.

CAS 1240299-33-5
Chemical Formula: C25H32F3N7O2
Exact Mass: 519.25696

1-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)piperazin-1-yl)ethanone

Ethanone, 1-​[4-​[2-​[4-​[1-​[7,​8-​dihydro-​3-​(trifluoromethyl)​-​1,​2,​4-​triazolo[4,​3-​b]​pyridazin-​6-​yl]​-​4-​piperidinyl]​phenoxy]​ethyl]​-​1-​piperazinyl]

6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine

6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine

  • 1-[4-[2-[4-[1-[7,8-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-4-piperidinyl]phenoxy]ethyl]-1-piperazinyl]ethanone
  • Originator AstraZeneca
  • Class Antineoplastics
  • Mechanism of Action Androgen receptor antagonists

AZD-3514 is a potent androgen receptor downregulator with potential anticancer cancer activity. AZD3514 is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

AZD3514 is currently in Phase I trail. This trial is looking at a new drug called AZD3514 for men who have prostate cancer that has spread to other parts of the body and is no longer responding to hormone therapy.  Doctors often use hormone therapy to treat prostate cancer. This may keep it under control for long periods of time. But researchers are looking for treatments that will help men who have prostate cancer that stops responding to hormone therapy.  Prostate cancer needs the hormone testosterone to grow. The testosterone locks into receptors on the cancer cells. AZD3514 works by breaking down these receptors so that testosterone canÂ’t tell the prostate cancer cells to grow.

img

 

 

6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-ihydro[1,2,4]triazolo[4,3-b]pyridazine 

as a white, free flowing solid.

1H NMR (400 MHz, CDCl3): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d);

m/z = 520 [M+H]+. RT = 0.87: 99% purity.

HRMS found 520.26373,

 

Prostate cancer is the second leading cause of death from cancer among men in developed countries, and was projected to account for 25% of newly-diagnosed cases and 9% of deaths due to cancer in the USA in 2010. The androgen receptor (AR), a ligand binding transcription factor in the nuclear hormone receptor super family, is a key molecular target in the etiology and progression of prostate cancer.Binding of the endogenous AR ligand dihydrotestosterone stabilizes and protects the AR from rapid proteolytic degradation. The early stages of prostate cancer tumor growth are androgen dependent and respond well to androgen ablation,  either via surgical castration or by chemical castration with a luteinizing hormone releasing hormone agonist in combination with an AR antagonist, such as bicalutamide.

Although introduction of androgen deprivation therapy represented a major advance in prostate cancer treatment, recurrence within 1–2 years typically marks transition to the so-called castrate-resistant state, in which the tumor continues to grow in the presence of low circulating endogenous ligand and is no longer responsive to classical AR antagonists. Castrate-resistant prostate cancer (CRPC) is a largely unmet medical need with a 5-year survival rate of less than 15%. Antimitotic agents docetaxel and cabazitaxel, testosterone biosynthesis inhibitor abiraterone acetate and second generation AR antagonist enzalutamide (MDV3100) are the currently approved small-molecule drugs that have been shown to provide survival benefit.

Recent evidence from both pre-clinical and clinical studies is consistent with the importance of re-activation of AR signaling in a majority of castrate-resistant prostate tumors. It is also well established that the functional AR in castrate-resistant tumors is frequently mutated or amplified, and that over-expression can convert hormone-responsive cell lines to hormone refractory. Recent second-generation AR antagonists have been designed that retain antagonism in over-expressing cell lines, and among these agents enzalutamide has recently successfully met efficacy criteria in a large Phase III clinical trial.

By analogy with fulvestrant, an estrogen receptor (ER) downregulator approved by the FDA in 2002 for treatment of advanced breast cancer and initially characterized as a pure ER antagonist, a ligand which downregulates the AR represents one of a number of potential approaches to treatment of CRPC via a sustained reduction in tumor AR content. We recently described derivation from a novel 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine ligand of AR inhibitor 1 The compound also causes AR downregulation15 and high plasma levels following oral administration in pre-clinical models compensate for moderate cellular potency

Figure 1.

Structures of lead AR downregulator 1 and chemotype 2.

Structures of lead AR downregulator 1 and chemotype 2.

Scheme 3.

Synthesis of compounds 10, 11a–b, 12. Reagents and conditions: (a) ...

Synthesis of compounds 10, 11ab, 12. Reagents and conditions: (a) 2-(1-Methyl-1H-pyrazol-5-yl)ethanol,27 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C; (b) 2-(4-acetylpiperazine-1-yl)ethanol,28 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C; (c) H2, 10% Pd-C, MeOH, 50 °C.

PATENT

WO 2010092371

 Robert Hugh Bradbury, Gregory Richard Carr,Alfred Arthur Rabow, Korupoju Srinivasa Rao,Harikrishna Tumma,
Applicant Astrazeneca Ab, Astrazeneca Uk Limited

Preparation of 6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-

( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine

Figure imgf000079_0001

A solution of acetyl chloride (0.027 mL, 0.38 mmol) in DCM (0.5 mL) was added dropwise to 6-[4- [4- [2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl] -3 -(trifluoromethyl)- 7,8-dihydro-[l,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 00C under nitrogen. The resulting solution was stirred at 00C for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(4-{4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3- b]pyridazine (80 mg, 49%) as a gum.

IH NMR (399.9 MHz, CDC13) δ 1.69 (2H, m), 1.95 (2H, m), 2.08 (3H, s), 2.56 (4H, m), 2.71 – 2.84 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.48 (2H, m), 3.63 (2H, m), 4.10 (2H, t), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)-7,8- dihydro-[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of tert-butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate DIAD (12.60 mL, 64.00 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6- dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (16.5 g, 53.34 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-l- carboxylate (CAS 77279-24-4) (14.74 g, 64.00 mmol) and triphenylphosphine (16.79 g, 64.00 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness then the residue was stirred in ether (200 mL) for 10 minutes at room temperature. The resulting precipitate was removed by filtration and discarded. The ether filtrate was washed with water (100 mL) followed by saturated brine (100 mL), then dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness to afford tert-butyl 4-[2-[4-(l- (benzyloxycarbonyl)- 1,2,3, 6-tetrahydropyridin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (34.6 g, 82%) as a gum which was contaminated with 34% by weight triphenylphosphine oxide.

IH NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 2.42 – 2.47 (6H, m), 2.71 (2H, m), 3.32 (4H, m), 3.62 (2H, m), 4.03 – 4.10 (4H, m), 5.12 (2H, s), 6.06 (IH, m), 6.92 (2H, d), 7.31 – 7.40 (7H, m); m/z = 522 [M+H]+.

Preparation of tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate tert-Butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate (66% pure by weight) (34.62 g, 43.80 mmol) and 5% palladium on carbon (50% wet) (4.47 g, 1.05 mmol) in MeOH (250 mL) were stirred under an atmosphere of hydrogen at 5 bar and 600C for 4 hours. The catalyst was removed by filtration and the solvents evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with 60% EtOAc in isohexane then 15% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l-carboxylate (15.42 g, 90%) as a solid. IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.62 (2H, m), 1.81 (2H, m), 2.50 – 2.59 (5H, m), 2.73 (2H, m), 2.80 (2H, t), 3.18 (2H, m), 3.44 (4H, m), 4.09 (2H, t), 6.85 (2H, d), 7.13 (2H, d); m/z = 390 [M+H]+.

Preparation of tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)-[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate

DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2 g, 8.99 mmol) and tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (3.68 g, 9.44 mmol) in DMF (30 mL). The resulting solution was stirred at 800C for 2 hours. The reaction mixture was cooled to room temperature and the solvents evaporated to dryness. The resulting solid was triturated with water then collected by filtration, washed with ether and dried to afford tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l -carboxylate (5.02 g, 97%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.76 (2H, m), 2.00 (2H, m), 2.54 (4H, m), 2.75 – 2.86 (3H, m), 3.11 (2H, m), 3.46 (4H, m), 4.11 (2H, m), 4.37 (2H, m), 6.87 (2H, d), 7.13 (3H, m), 7.92 (IH, d); m/z = 576 [M+H]+.

Preparation of tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro-

[1 ,2,4] triazolo [4,3-b] pyridazin-6-yl)piperidin-4-yl] phenoxy] ethyl] piperazine- 1- carboxylate

10% Palladium on carbon (0.924 g, 0.87 mmol) was added to tert-butyl 4-[2-[4-[l-(3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl]phenoxy]ethyl]piperazine-l -carboxylate (2.5 g, 4.34 mmol) and ammonium formate (2.74 g, 43.43 mmol) in ethanol (100 mL). The resulting mixture was stirred at 78°C, with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (100 mL) followed by brine (50 mL), then the solvents were evaporated to afford tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02O g, 81%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.69 (2H, m), 1.95 (2H, m), 2.52 (4H, m), 2.71 – 2.82 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.45 (4H, m), 4.09 (2H, m), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 578 [M+H]+.

Preparation of 6- [4-[4- [2-(piperazin-l-yl)ethoxy] phenyl] piperidin-1-yl] -3- (trifluor omethyl)-7,8-dihydr o- [ 1 ,2,4] triazolo [4,3-b] pyridazine

TFA (10 mL) was added to tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02 g, 3.50 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia/MeOH and the solvents were evaporated to afford 6-[4-[4- [2-(piperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyridazine (1.660 g, 99%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.68 (2H, m), 1.95 (2H, m), 2.55 (4H, m), 2.70 – 2.80 (5H, m), 2.91 (4H, m), 3.00 (2H, m), 3.22 (2H, t), 4.09 (2H, t), 4.30 (2H, m), 6.87 (2H, d), 7.11 (2H, d); m/z = 478 [M+H]+.

Example 5.2

Larger scale preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-dihvdro [ 1 ,2,41 triazolo [4,3- blpyridazine

Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 700C for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 700C for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 700C for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 700C for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 700C for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 700C for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL x 2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4- acetylpiperazin- 1 -yl)ethoxy]phenyl}piperidin- 1 -yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-

(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of 4-(piperidin-4-yl)phenol Benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (37.7 g, 121.86 mmol) and 5% palladium on carbon (7.6 g, 3.57 mmol) in methanol (380 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25°C for 2 hours. The catalyst was removed by filtration, washed with MeOH and the solvents evaporated. The crude material was triturated with diethyl ether, then the desired product collected by filtration and dried under vacuum to afford 4-(piperidin-4-yl)phenol (20.36 g, 94%) as a solid. IH NMR (399.9 MHz, DMSO-d6) δ 1.46 (2H, m), 1.65 (2H, m), 2.45 (IH, m), 2.58 (2H, m), 3.02 (2H, m), 6.68 (2H, d), 7.00 (2H, d), 9.15 (IH, s); m/z = 178 [M+H]+.

Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol

DIPEA (48.2 mL, 276.86 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (24.65 g, 110.74 mmol) and 4-(piperidin-4-yl)phenol (20.61 g, 116.28 mmol) in DMF (200 mL). The resulting solution was stirred at 800C for 1 hour. The reaction mixture was cooled to room temperature, then evaporated to dryness and re-dissolved in DCM (1 L) and washed with water (2 x 1 L). The organic layer was washed with saturated brine (500 mL), then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether to afford 4-{l-[3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (36.6 g, 91%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.

Preparation of 2-(4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6- yl]piperidin-4-yl}phenoxy)ethanol

A solution of ethylene carbonate (121 g, 1376.13 mmol) in DMF (200 mL) was added dropwise to a stirred suspension of 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl}phenol (100 g, 275.23 mmol) and potassium carbonate (76 g, 550.45 mmol) in DMF (200 mL) at 800C over a period of 15 minutes under nitrogen.

The resulting mixture was stirred at 800C for 20 hours. The reaction mixture was cooled to room temperature, then concentrated and diluted with DCM (2 L), and washed sequentially with water (1 L) and saturated brine (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with EtOAc (150 mL). The resulting solid was washed with further EtOAc (50 mL) and ether then dried to give 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol. The filtrate was evaporated and further purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with ether, dried and combined with the material previously collected to afford 2-(4- { 1 -[3-

(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 79%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.66 (2H, m), 1.88 (2H, m), 2.80 (IH, m), 3.10 (2H, m), 3.70 (2H, m), 3.95 (2H, t), 4.41 (2H, m), 4.85 (IH, t), 6.87 (2H, d), 7.18 (2H, d), 7.67 (IH, d), 8.25 (IH, d); m/z = 408 [M+H]+.

Preparation of 2-(4-{ 1- [3-(trifluoromethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazin-6- yl] piperidin-4-yl}phenoxy)ethyl methanesulfonate

A solution of methanesulfonyl chloride (20.37 mL, 262.16 mmol) in DCM (300 mL) was added to 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol (89 g, 218.46 mmol) and triethylamine (60.9 mL, 436.93 mmol) in DCM (900 mL) at 00C over a period of 30 minutes under nitrogen. The resulting solution was stirred at 00C for 1 hour. The reaction mixture was diluted with DCM (1 L), and washed with water (2 L). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethyl methanesulfonate (104 g, 98%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.67 (2H, m), 1.89 (2H, m), 2.83 (IH, m), 3.11 (2H, m), 3.23 (3H, s), 4.23 (2H, t), 4.41 (2H, m), 4.52 (2H, t), 6.91 (2H, d), 7.21 (2H, d), 7.66 (IH, d), 8.24 (IH, d); m/z = 486 [M+H]+. Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{l-[3-

(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 1100C for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basifϊed to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (IL), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid. IH NMR (399.9 MHz, DMS0-d6) δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.

Example 5.5

Alternative route for the preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine Form A

Methanol (375.0 mL) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine (25.0 g, 48 m mol) in a 2.0 L autoclave reactor and to this was added 10% Pd/C (12.5 g, 50% w/w) paste at 22-25°C under nitrogen gas atmosphere. The reaction was performed under hydrogen pressure (5.0 bar) at 500C temperature for 10.0 h. The reaction mass was cooled to room temperature and the catalyst removed by filtration. Filtered cake was washed with methanol. The solvent was evaporated and the residue was azeotropically distilled by ethylacetate (2 x 125.0 mL) at 400C under reduced pressure to 3.0 rel vol (75.0 mL). Drop wise addition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass resulted in solid material, which was collected by filtration and washed with MTBE (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo [4,3-b]pyridazine (22.3 g, 88%) as a white color free flowing solid. The isolated material was confirmed by XRPD as Form A. IH NMR (400.13 MHz, CDC13): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol: Dimethylacetamide (250.0 mL) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine [CAS: 40971-95-7] (50.0 g, 225 m mol) at 22-25°C in a suitable round bottom flask followed by 4-(piperidin-4-yl)phenol [CAS: 62614-84-0] (60.9 g, 236 m mol) at 22-25°C. The reaction mass was stirred to obtain a clear solution. Triethylamine (79.1 mL, 561 m mol) was slowly added to the reaction mass by drop wise addition over a period of 60 min at 25-300C. Temperature was raised to 400C and the reaction mass stirred for 1.0 h. After completion of reaction, water (500.0 mL) was added to the reaction mass by drop wise addition over a period of 30 min at 40-430C. The slurry mass was stirred for 30 min at 400C and then filtered under reduced pressure. The wet material was slurry washed using water (500.0 mL) for 30 min at 400C. The solid was collected by filtration and the material washed with water (125.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (75.1 g, 89.9%) as a free flowing solid. IH NMR (400.13 MHz, DMSO-d6): δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.

Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine:

Dichloromethane (225.0 mL) and 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin- 6-yl]piperidin-4-yl} phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25°C. Triphenylphosphine (72.2 g, 275 m mol) and l-[4-(2-hydroxy- ethyl)piperazin-l-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25°C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-300C over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-300C to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25°C and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25°C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dired under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4] triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.

IH NMR (400.13 MHz, DMSO-d6): δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.

Example 5.8

Preparation of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluor omethyl)-7,8-dihydr 0 [1 ,2,4] triazolo [4,3-b] pyridazine maleate

Figure imgf000096_0001

A clear solution of maleic acid (0.445 g, 3.84 m mol) in methanol (1.0 mL) was added to a clear solution of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3-b]pyridazine, obtained as described in Example 5.5, (2.0 g, 3.84 m mol) in methanol (2.0 mL) at 22-25°C and the resulting clear solution heated to 500C for 30 min. The reaction mass was cooled to 22-25°C and ethylacetate (16.0 mL) added drop wise to the reaction mass at 22-25°C. The reaction mass was then stirred for 60 min at 22-25°C. The resulting white color material was collected by filtration and washed with ethylacetate (5.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-(4- {4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine maleate (2.21 g, 90.0%) as free flowing white color material.

IH NMR (400.13 MHz, DMSO-d6): δ 1.62 (2H, m), 1.77 (2H, m), 2.02 (3H, s), 2.75 (IH, m), 2.77 (2H, m), 2.80 (2H, m), 2.95 (4H, m), 3.16 (2H, t), 3.36 (6H, m), 4.22 (4H, m), 6.08 (2H, s), 6.91 (2H, d), 7.17 (2H, d).

PAPER

Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8

Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer

  • Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK

 

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

Image for unlabelled figure

http://www.sciencedirect.com/science/article/pii/S0960894X13002321

 

SYNTHESIS

STR1AZD 3514

6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine AZD 3514

 

 

 

STR1

 

 

SYNTHETIC ROUTE 2ND GENERATION

STR1

 

 

STR1

SYNTHETIC ROUTE 4TH GENERATION

STR1

 

REFERENCES

1: Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, Hatter G, Hayter BR,  Hill KJ, Howe NJ, Jones RD, Jude D, Lamont SG, Loddick SA, McFarland HL, Parveen  Z, Rabow AA, Sharma-Singh G, Stratton NC, Thomason AG, Trueman D, Walker GE, Wells SL, Wilson J, Wood JM. Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8. doi: 10.1016/j.bmcl.2013.02.056. Epub 2013 Feb 21. PubMed PMID: 23466225.

 

Some pics, Team at Astrazeneca , Bangalore, INDIA

Vijaykumar Sengodan Chellappan

Vijaykumar Sengodan Chellappan

 

Jagannath V, PMP®

Jagannath V, PMP®

 

Dr. Vidya Nandialath

Associate Research Scientist II at AstraZeneca India Pvt Ltd

Rifahath Mon

Rifahath Mon

Associate Research Scientist at AstraZeneca

Dr Kagita Veera Babu

Route Scouting, Process Design, Technology Transfer, Trouble shooting, QbD, Green Chemistry

Srinivasa Rao Korupoju

Srinivasa Rao Korupoju

Harikrishna Tumma Ph. D.

Harikrishna Tumma Ph. D.

 

Rashmi HV

Anandan Muthusamy

Anandan Muthusamy

Partha Pratim Bishi, PMP®

Partha Pratim Bishi,

Ranga Nc

 

 ASTAZENECA BANGALORE

 

 

///////////////AZD 3514 MALEATE, AZD 3514 , AZD-3514, Prostate cancer, Androgen receptor downregulator, AZD3514, 1240299-33-5

 

Share

Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices

 Uncategorized  Comments Off on Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices
Jul 212016
 

Simi Gunaseelan Ph.D  Author

Assistant Professor of Pharmaceutical Sciences, The University of Texas at Tyler, TEXAS, USA

S. Gunaseelan : R. Maskiewicz (*)

Department of Pharmaceutical Sciences( School of Pharmacy Loma Linda University 11175 Campus Street, Chan Shun Pavilion 21018 Loma Linda, California 92350, USA e-mail: rmaskiewicz@llu.edu

Purpose

Use of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.

Methods

Tenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.

Results

Drug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.

Conclusion

Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

 

Sustained Local Delivery of Structurally Diverse HIV-1 Microbicides Released from Sublimation Enthalpy Controlled Matrices

Simi Gunaseelan,1 Philippe A. Gallay,2 Michael D. Bobardt,2 Charlene S. Dezzutti,3,4 Timothy Esch,3 and Richard Maskiewiczcorresponding author1

1Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350 USA
2Department of Immunology and Microbial Science, IMM-9 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 USA
3Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213 USA
4Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213 USA
Richard Maskiewicz, Phone: +1-909-5589473, Fax: +1-909-5580446, ude.ull@zciweiksamr.
corresponding authorCorresponding author.

//////////enthalpically controlled release, HIV-1, intravaginal delivery, prolonged antiviral effect, subliming solid matrix,

Share

Lobeglitazone sulfate (Duvie)

 FDA 2014, Uncategorized  Comments Off on Lobeglitazone sulfate (Duvie)
Jul 212016
 

 

 

STR1

 

Lobeglitazone.svg

Lobeglitazone Sulfate, CKD-501, IDR-105

(Duvie®)Approved KOREA

Chong Kun Dang (Originator)

Adjunct to diet and exercise to improve glycemic control in adults with type 2 Diabetes mellitus

A dual PPARα and PPARγ agonist used to treat type 2 diabetes.

Trade Name:Duvie®MOA:Dual PPARα and PPARγ agonistIndication:Type 2 diabetes

CAS No. 607723-33-1(FREE)

CAS 763108-62-9(Lobeglitazone Sulfate)

2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);

Duvie Tab.

  • Developer Chong Kun Dang; EQUIS & ZAROO
  • Class Antihyperglycaemics; Pyrimidines; Small molecules; Thiazolidinediones
  • Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists; Peroxisome proliferator-activated receptor gamma agonists
  • MarketedType 2 diabetes mellitus
  • Most Recent Events

    • 01 May 2016Chong Kun Dang Pharmaceutical completes two phase I drug-interaction trials in Healthy volunteers in South Korea (PO) (NCT02824874; NCT02827890)
    • 01 Apr 2016Chong Kun Dang Pharmaceutical initiates two phase I drug-interaction trials in Healthy volunteers in South Korea (PO) (NCT02824874; NCT02827890)
    • 01 Mar 2016Chong Kun Dang completes a phase I pharmacokinetic trial in Impaired hepatic function in Healthy volunteers in South Korea, NCT02007941)
    • Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

 

 

Lobeglitazone sulfate.png

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.[3]

Chong Kun Dang

STR1

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC50:  0.02 μM, PPARγ EC50:  0.018 μM, rosiglitazone; PPARα EC50:  >10 μM, PPARγ EC50:  0.02 μM, pioglitazone PPARα EC50:  >10 μM, PPARγ EC50:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKAy mice than rosiglitazone and pioglitazone.17 Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.[4][5]

SYNTHESIS

STR1

 

Chong Kun Dang’s Modcol Flu Dry Syrup is released in four different versions: All-Day, Night, Nose and Cough. [CHONG KUN DANG]

 

STR1

 

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

Process Research and Development Laboratory, Chemical Research Group, Chong Kun Dang Pharmaceutical Cooperation, Cheonan P. O. Box 74, Cheonan 330-831, South Korea, and Department of Chemistry, Korea University, 5-1-2, Anam-Dong, Seoul 136-701, Korea
Org. Process Res. Dev., 2007, 11 (2), pp 190–199
DOI: 10.1021/op060087u

http://pubs.acs.org/doi/abs/10.1021/op060087u

Abstract Image

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC Rf = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH2Cl2/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1;

1H NMR (400 MHz, CDCl3) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH);

13C NMR (100 MHz, CDCl3) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5;

MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C24H26N4O9S2:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

 

Clip
Lobeglitazone sulfate (Duvie) Lobeglitazone sulfate, an oral peroxisome proliferator-activated receptor (PPARa/c) dual agonist with IC50 = 20 and 18 nM respectively, was developed by Chong Kun Dang Pharmaceutical in Korea for the treatment of diabetes.135 This drug is differentiated from two other PPAR agonists available—pioglitazone and rosiglitazone —which lack PPARa activity.135 The most likely processscale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical.136

Commercially available 4,6-dichloropyrimidine (152) was treated with a stoichiometric equivalent of p-methoxyphenol (153) in the presence of KF in warm DMF (Scheme 24). Upon completion of this reaction, 2-methylaminoethanol was added to the mixture to provide pyrimidine 154 in high yield.137

Next, alcohol 154 underwent a substitution reaction with p-fluorobenzaldehyde (155) under basic conditions to provide alkoxy benzaldehyde 156 which was converted to the benzylidene thiazolidindione 158 upon subjection to Knoevenagel conditions with 2,4-thiazolidinedione (157) in 90% yield.

Finally, reduction of olefin 158 was facilitated by treatment with the Hantzsch ester (159) in the presence of silica gel followed by treatment with methanolic sulfuric acid (96%) at low temperature to ultimately furnish lobeglitazone sulfate in 90% yield.

STR1
135. Jin, S. M.; Park, C. Y.; Cho, Y. M.; Ku, B. J.; Ahn, C. W.; Cha, B.-S.; Min, K. W.;Sung, Y. A.; Baik, S. H.; Lee, K. W.; Yoon, K.-H.; Lee, M.-K.; Park, S. W. Diab.Obes. Metab. 2015, 17, 599.
136. Lee, H. W.; Ahn, J. B.; Kang, S. K.; Ahn, S. K.; Ha, D.-C. Org. Process Res. Dev.2007, 11, 190.
137. Lee, H. W.; Kim, B. Y.; Ahn, J. B.; Kang, S. K.; Lee, J. H.; Shin, J. S.; Ahn, S. K.; Lee,S. J.; Yoon, S. S. Eur. J. Med. Chem. 2005, 40, 862.

 

References

  1. Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ. (2015). “Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.”.Journal of Pharmaceutical sciences 104 (9): 3049–3059.doi:10.1002/jps.24378. PMID 25648999.
  2.  Kim JW, Kim JR, Yi S, Shin KH, Shin HS, Yoon SH, Cho JY, Kim DH, Shin SG, Jang IJ, Yu KS. (2011). “Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects.”. Clinical therapeutics 33 (11): 1819–1830.doi:10.1016/j.clinthera.2011.09.023. PMID 22047812.
  3.  Lee JH, Woo YA, Hwang IC, Kim CY, Kim DD, Shim CK, Chung SJ. (2009). “Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies.”. Journal of Pharmaceutical and Biomedical Analysis 50 (5): 872–877.doi:10.1016/j.jpba.2009.06.003. PMID 19577404.
  4.  “MFDS permission information of Duvie Tablet 0.5mg”(Release of Information). Ministry of Food and Drug Safety. Retrieved2014-10-23.
  5.  “국내개발 20번째 신약‘듀비에정’허가(20th new drug developed in Korea ‘Duvie Tablet’ was approved)”. Chong Kun Dang press release. 2013-07-04. Retrieved 2014-10-23.
Lobeglitazone
Lobeglitazone.svg
Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names Duvie
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%[1]
Metabolism liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life 7.8–9.8 hours[2]
Identifiers
CAS Number 607723-33-1
PubChem CID 9826451
DrugBank DB09198 Yes
ChemSpider 8002194
Synonyms CKD-501
Chemical data
Formula C24H24N4O5S
Molar mass 480.53616 g/mol

Identifications:

1H NMR (Estimated) for Lobeglitazone

Experimental: 1H NMR (400 MHz, CDCl3) δ 3.12 (m, 4H), 3.45 (m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31 (s, 1H), 8.89 (bs, NH).

///Lobeglitazone Sulfate, CKD-501, Duvie®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes, CKD 501, 763108-62-9, 607723-33-1, IDR-105

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

Share

Novel Intravaginal Delivery of Antiretroviral-based Microbicides for HIV prevention

 Uncategorized  Comments Off on Novel Intravaginal Delivery of Antiretroviral-based Microbicides for HIV prevention
Jul 212016
 

view above or
See ppt at

Biography

Gunaseelan’s research expertise is in drug delivery. For the past 10 years she has been working towards developing ‘Novel Drug Delivery Systems’ for HIV Prevention & HIV and Cancer Therapeutics. Her research works resulted in 5 patents, more than 20 publications in high-impact journals and presentations in 20 national and international conferences. Her dedication towards research work at Rutgers University School of Pharmacy New Jersey, led her to be a recipient of Merit Award for 3 consecutive years. She is currently a journal reviewer for Advanced Drug Delivery Reviews, Pharmaceutical Research, and Controlled Release Society Meeting Abstracts

STR1

Abstract

Objectives: Microbicides, products applied vaginally or rectally, are effective at preventing HIV transmission. However, many products (e.g., peptides, antiretroviral drugs) are reactive or incompatible in the existing diffusion/hydrolysis/dissolution based delivery systems. To overcome the issues of extended delivery and product compatibility, the use of a novel subliming solid matrix-based delivery system is described here. Methods: The microbicides C5A, tenofovir fumarate, emtricitabine, dapivarine, UC-781 and IQP0528 were employed as representatives of a range of molecular structures and physicochemical properties. Hydrophobic, chemically inert subliming solid matrices, utilized for microbicide formulations and achieving a defined range of sustained release rates, included norbornane, hexamethylcyclotrisiloxane, perfluoroundecane, perfluorododecane and cyclododecane. Rates of matrix sublimation and concomitant microbicide release were determined in vitro. Formulations were tested for cellular toxicity, and durations of anti-HIV-1 activity by constant release of microbicides from the sublimable matrices. Results: Subliming solid matrices release microbicides by surface erosion achieved through sublimation. Zero order sustained microbicide release was achieved in vitro, at rates independent of microbicide structures and properties, and controlled exclusively by sublimation enthalpies of each hydrophobic matrix material. The matrices provided prolongation of anti-HIV-1 activity relative to bolus microbicide administration, when evaluated in cultured human ectocervical tissue, macrophages, and TZM reporter cells. No evidence of matrix toxicity was observed after continuous exposure to macrophages, T-lymphocytes, PBMC cells and ectocervical explants. Implications: Subliming matrices offer unique attributes that will allow steady-state delivery of any microbicide, over durations ranging from weeks to months, by employing, simple, stable, and readily available matrix materials, suggesting novel delivery capabilities.

Speaker Presentations

 

Share

Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩 依利格鲁司特 エリグルスタット,サーデルガ

 FDA 2014, Uncategorized  Comments Off on Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩 依利格鲁司特 エリグルスタット,サーデルガ
Jul 192016
 

Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩

依利格鲁司特

エリグルスタット,サーデルガ

FOR TREATMENT OF GAUCHERS DISEASE

ELIGLUSTAT; Cerdelga; Genz 99067; Genz-99067; UNII-DR40J4WA67; GENZ-112638;

CAS 491833-29-5 FREE FORM

Molecular Formula: C23H36N2O4
Molecular Weight: 404.54294 g/mol

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide;(2R,3R)-2,3-dihydroxybutanedioic acid
Mechanism of Action: glucosylceramide synthase inhibitor
Indication: Type I Gaucher Disease
Date of Approval: August 19, 2014 (US)

US patent number:US6916802 , US7196205 , US7615573
Patent Expiration Date: Apr 29, 2022 (US6916802, US7196205, US7615573)
Exclusivity Expiration Date:Aug 19, 2019(NCE), Aug 19, 2021 (ODE)
Originator:University of Michigan
Developer: Genzyme, a unit of Sanofi

Eliglustat, marketed by Genzyme as CERDELGA, is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease. Patients selected for treatment with Eliglustat undergo an FDA approved genotype test to establish if they are CYP2D6 EM (extensive metabolizers), IM (intermediate metabolizers), or PM (poor metabolizers), as the results of this test dictate the dosage of Eliglustat recommended. Eliglustat was approved for use by the FDA in August 2014.

Eliglustat (INN, USAN;[1] trade name Cerdelga) is a treatment for Gaucher’s disease developed by Genzyme Corp that was approved by the FDA August 2014.[2] Commonly used as the tartrate salt, the compound is believed to work by inhibition ofglucosylceramide synthase.[3][4] According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in “significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count” in untreated adults with Gaucher disease Type 1.[5]

Cerdelga, capsule, 84 mg/1, oralGenzyme Corporation, 2014-09-03, Us

ELIGLUSTAT.pngELIGLUSTAT

ChemSpider 2D Image | Eliglustat tartrate | C50H78N4O14

Eliglustat tartrate

  • Molecular FormulaC50H78N4O14
  • Average mass959.173 Da
  • UNII-N0493335P3
  • Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl]octanamide (1:2)
  •  eliglustat hemitartrate
  •  eliglustat L-tartrate

CAS 928659-70-5

 

CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23H36N2O4+½(C4H6O6) with the following chemical structure:

 

CERDELGA (eliglustat) Structural Formula Illustration

Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2.

Cost

In 2014, the annual cost of Cerdelga hard gelatin capsules taken orally twice a day was $310,250. Genzyme’s flagship Imiglucerase(brand name Cerezyme) cost about $300,000 for the infusions if taken twice a month.[6] Manufacturing costs for Cerdelga are slightly lower than for Cerezyme. Genzyme’s maintains higher prices for orphan drugs—most often paid for by insurers— in order to remain financially sustainable.[6]

Chemically Eliglustat is named N-[(1 R,2R)-2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-hydroxy-1 -(1 -pyrrolidinylmethyl)ethyl]-Octanamide(2R!3R)-2,3-dihydroxybutanedioate and the hemitartarate salt of eliglustat has the structural formula as shown in Formula I.

Formula I

Eliglustat hemitartrate (Genz-1 12638), currently under development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase, and is currently under development by Genzyme.

U.S. patent No. 7,196,205 discloses a process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 discloses process for preparation of Eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of Eliglustat, (ii) a hemitartrate salt of Eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailablity patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailabihty pattern may be favoured over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.

 

CLIP

Eliglustat tartrate, developed and marketed by Genzyme Corporation (a subsidiary of Sanofi), was approved by the US FDA in August 2014 for the treatment of nonneuropathic (type 1) Gaucher disease (GD1) in both treatment-naïve and treatment-experienced adult patients.98

It is the first oral treatment to be approved for first-line use in patients with Gaucher disease type 1, which is a rare lysosomal storage disease characterized by accumulation of lipid glucosylceramide (GL-1) due to insufficient production of the enzyme glucosylceramidase.99,100

Clinical complications include hepatosplenomegaly, anemia, thrombocytopenia, and bone involvement.101 Eliglustat is a specific inhibitor of glucosylceramide synthase with an IC50 of 10 ng/mL and acts as substrate reduction therapy for GD1;102 it has demonstrated non-inferiority to enzyme replacement therapy, which is the current standard of care, in Phase III trials.99

While the process-scale route has not yet been disclosed,103 the largest scale route to eliglustat tartrate reported to date is described in Scheme 15.104

Condensation of commercially available S-(+)-2-phenyl glycinol (87) with phenyl bromoacetate (88) in acetonitrile in the presence of N,N-diisopropylethylamine (DIPEA) provided morpholin-2-one 89 upon treatment with HCl.Neutralization with NaHCO3 followed by coupling with aldehyde 90 in refluxing EtOAc/toluene yielded oxazine adduct 91, which was isolated as a precipitate from methyl-tert-butyl ether (MTBE).

The stereochemistry of the three new stereocenters in 91 can be rationalized through the cycloaddition of an ylide intermediate in the sterically-preferred S-configuration (generated by the reaction of the morpholinone 89 with aldehyde 90) with a second equivalent of the aldehyde. With the morpholinone in a chair conformation in which the phenyl group is equatorial, endo axial approach of the dipolarophile to the less-hindered face of the ylide and subsequent ring flip of the morpholinone ring to a boat conformation positions all exocyclic aryl substituents in a pseudoequatorial configuration. 105

Opening of oxazine 91 with pyrrolidine in refluxing THF followed by addition of HCl in refluxing MeOH gave amide 92, which was reduced to amine 93 using LiAlH4 in refluxing THF.

Subsequent hydrogenation with Pd(OH)2 in EtOH cleaved the phenylethanol group to give the free amine, which was converted to dioxalate salt 94 by treatment with oxalic acid in methyl isobutylketone (MIBK). Subjection of aminoethanol 94 to aqueous sodium hydroxide followed by coupling with palmitic acid Nhydroxysuccinimide (NHS)-ester (95) gave eliglustat as the corresponding freebase (96) in 9.5% overall yield from 87.

Salt formation with L-tartaric acid (0.5 equiv) then provided eliglustat tartrate (XII).106

STR1

STR1

98. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm.
99. Poole, R. M. Drugs 2014, 74, 1829.
100. Kaplan, P. Res. Rep. Endocr. Disord. 2014, 4, 1.
101. Pastores, G. M.; Hughes, D. Clin. Invest. 2014, 4, 45.
102. Shayman, J. A. Drugs Future 2010, 35, 613.
103. Javed, I.; Dahanukar, V. H.; Oruganti, S.; Kandagatla, B. WO Patent2,015,059,679, 2015.
104. Hirth, B.; Siegel, C. WO Patent 2,003,008,399, 2003.
105. Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahedron:Asymmetry 1991, 2, 1343.
106. Liu, H.; Willis, C.; Bhardwaj, R.; Copeland, D.; Harianawala, A.; Skell, J.;Marshall, J.; Kochling, J.; Palace, G.; Peterschmitt, J.; Siegel, C.; Cheng, S. WO Patent 2,011,066,352, 2011.

CLIP

TAKEN FROM

http://www.xinbiaopin.com/a/zuixindongtai/huaxuepinshuju/2015/0310/2383.html

str1

Nmr predict

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide H-NMR spectrum

13 C NMR

N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide C-NMR spectrum

CAS NO. 491833-29-5, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide

C-NMR spectral analysis

 

str1

 

str1

PATENT

http://www.google.com/patents/WO2013059119A1?cl=en

Figure imgf000024_0001

http://www.google.com/patents/US7196205

Compound 7

(1R,2R)-Nonanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide

Figure US07196205-20070327-C00026

This compound was prepared by the method described for Compound 6 using Nonanoic acid N-hydroxysuccinimide ester. Analytical HPLC showed this material to be 98.4% pure. mp 74–75° C.

1H NMR (CDCl3) δ 6.86–6.76 (m, 3H), 5.83 (d, J=7.3 Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 4.24 (s, 4H), 4.24–4.18 (m, 1H), 2.85–2.75 (m, 2H), 2.69–2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55–1.45 (m, 2H), 1.70–1.85 (m, 4H), 1.30–1.15 (m, 10H), 0.87 (t, J=6.9 Hz, 3H) ppm.

Intermediate 4(1R,2R)-2-Amino-1-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-3-pyrrolidin-1-yl-propan-1-ol

Figure US07196205-20070327-C00023

Intermediate 3 (5.3 g, 13.3 mmol) was dissolved in methanol (60 mL). Water (6 mL) and trifluoroacetic acid (2.05 m/L, 26.6 mmol, 2 equivalents) were added. After being placed under nitrogen, 20% Palladium hydroxide on carbon (Pearlman’s catalysis, Lancaster or Aldrich, 5.3 g) was added. The mixture was placed in a Parr Pressure Reactor Apparatus with glass insert. The apparatus was placed under nitrogen and then under hydrogen pressure 110–120 psi. The mixture was stirred for 2–3 days at room temperature under hydrogen pressure 100–120 psi. The reaction was placed under nitrogen and filtered through a pad of celite. The celite pad was washed with methanol (100 mL) and water (100 mL). The methanol was removed by rotoevaporation. The aqueous layer was washed with ethyl acetate three times (100, 50, 50 mL). A 10 M NaOH solution (10 mL) was added to the aqueous layer (pH=12–14). The product was extracted from the aqueous layer three times with methylene chloride (100, 100, 50 mL). The combined organic layers were dried with Na2SO4, filtered and rotoevaporated to a colorless oil. The foamy oil was vacuum dried for 2 h. Intermediate 4 was obtained in 90% yield (3.34 g).

Intermediate 3(1R,2R,1″S)-1-(2′,3′-Dihydro-benzo[1,4]dioxin-6′-yl)-2-(2″-hydroxy -1′-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol

Figure US07196205-20070327-C00022

To a 3-neck flask equipped with a dropping funnel and condenser was added LiAlH4 (Aldrich, 1.2 g, 31.7 mmol, 2.5 equivalents) and anhydrous THF (20 mL) under nitrogen. A solution of Intermediate 2 (5.23 g, 12.68 mmol) in anhydrous THF (75 mL) was added dropwise to the reaction over 15–30 minutes. The reaction was refluxed under nitrogen for 9 hours. The reaction was cooled in an ice bath and a 1M NaOH solution was carefully added dropwise. After stirring at room temperature for 15 minutes, water (50 mL) and ethyl acetate (75 mL) was added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL). After drying with Na2SO4 the solution was filtered and rotoevaporated to yield a colorless to yellow foamy oil. Intermediate 3 was obtained in 99% yield (5.3 g).

PATENT

WO 2016001885

EXAMPLES

Example 1 : Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 14 mL of dichloromethane at 26°C and stirred for 15 min. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 45°C. After distillation the solid was dried under vacuum at 45°C.

PATENT

str1

 

PAPER

Journal of Medicinal Chemistry (2012), 55(9), 4322-4335

 

 

OLD CLIPS

Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease


Eliglustat tartrate (USAN)

CAS:928659-70-5
February 15, 2013
Genzyme , a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented today at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrateThe data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease”The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”ENGAGE Study Results:In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported today at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).

Genzyme

Eliglustat tartate (Genz-112638)

What is Eliglustat?

  • Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.
  • Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.
  • This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.
  • The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.

Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:

(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,

(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,

(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,

(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=234E6BE008E68831F6875FB703760826.wapp2nA?docId=WO2015059679&recNum=1&office=&queryString=FP%3A%28dr.+reddy%27s%29&prevFilter=%26fq%3DCTR%3AWO&sortOption=Pub+Date+Desc&maxRec=364

WO 2015059679

Process for the preparation of eliglustat free base – comprising the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.
Dr Reddy’s Laboratories Ltd
New crystalline eliglustat free base Form R1 and a process for its preparation are claimed. Also claimed is a process for the preparation of eliglustat free base which comprises the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.Further eliglustat oxalate, its crystalline form, and a process for the preparation of crystalline eliglustat oxalate, are claimed.

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.

Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:

(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,

(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,

(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,

(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride

To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath

temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%

Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4] dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.

5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30°C. 1 ,4-benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105°C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10°C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 %

Example 3: Preparation of (2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 ”^henyl-ethy^

(1 R,3S,5S,8aS)-1 !3-Bis-(2′!3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to pH 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55°C to afford (2S,3R,1″S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %

Example 4: Preparation of (1 R,2R,1 “S)-1-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.

(2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)-3-hydroxy-2-(2”-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50°C to afford (1 R,2R, 1″S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %

Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.

(1 R,2R,1 “S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) 2(40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H2, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the PH reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9%

Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.

(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.

Example 7: Preparation of Eliglustat oxalate.

Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] +> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

References

  1.  Eligustat (PDF), AMA By subscription only
  2. FDA approves new drug to treat a form of Gaucher disease, U.S. Food and Drug Administration, 19 August 2015, retrieved 18 July 2015
  3. Lee, L.; Abe, A.; Shayman, J. A. (21 May 1999). “Improved Inhibitors of Glucosylceramide Synthase”. Journal of Biological Chemistry 274(21): 14662–14669. doi:10.1074/jbc.274.21.14662.
  4.  Shayman, JA (1 August 2010). “Eliglustat Tartrate: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease.”. Drugs of the future 35 (8): 613–620. PMID 22563139.
  5.  Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Dominick Amato, Hagit Baris, Majed Dasouki, Marwan Ghosn, Atul Mehta, Seymour Packman, Gregory Pastores, Milan Petakov, Sarit Assouline, Manisha Balwani, Sumita Danda, Evgueniy Hadjiev, Andres Ortega, Suma Shankar, Maria Helena Solano, Leorah Ross, Jennifer Angell, M. Judith Peterschmitt (17 February 2015), “Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1: The ENGAGE Randomized Clinical Trial”, Journal of the American Medical Association 313 (7): 695–706, doi:10.1001/jama.2015.459
  6.  Robert Weisman (2 September 2014), New Genzyme pill will cost patients $310,250 a year, The Boston Globe, retrieved 18 July 2015

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3
Patent 6916802
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
FDA Orange Book Patents: 2 of 3
Patent 7196205
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
FDA Orange Book Patents: 3 of 3
Patent 7615573
Expiration Apr 29, 2022
Applicant GENZYME CORP
Drug Application N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE)
Patent ID Date Patent Title
US8003617 2011-08-23 Methods of Treating Diabetes Mellitus
US2010298317 2010-11-25 METHOD OF TREATING POLYCYSTIC KIDNEY DISEASES WITH CERAMIDE DERIVATIVES
US7763738 2010-07-27 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS
US7615573 2009-11-10 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US2009105125 2009-04-23 Methods of Treating Fatty Liver Disease
US7265228 2007-09-04 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US7196205 2007-03-27 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US6855830 2005-02-15 Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
Patent ID Date Patent Title
US2016068519 2016-03-10 INHIBITORS OF THE ENZYME UDP-GLUCOSE: N-ACYL-SPHINGOSINE GLUCOSYLTRANSFERASE
US2015148534 2015-05-28 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYL TRANSFERASE INHIBITORS
US2015051261 2015-02-19 Methods of Treating Fatty Liver Disease
US8779163 2014-07-15 Synthesis of UDP-Glucose: N-acylsphingosine glucosyl transferase inhibitors
US2013137743 2013-05-30 AMORPHOUS AND A CRYSTALLINE FORM OF GENZ 112638 HEMITARTRATE AS INHIBITOR OF GLUCOSYLCERAMIDE SYNTHASE
US2013095089 2013-04-18 GLUCOSYLCERAMIDE SYNTHASE INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
US2012322786 2012-12-20 2-ACYLAMINOPROPOANOL-TYPE GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
US8138353 2012-03-20 SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS
US2012022126 2012-01-26 Method Of Treating Diabetes Mellitus
US8003617 2011-08-23 Methods of Treating Diabetes Mellitus
Eliglustat
Eliglustat.svg
Systematic (IUPAC) name
N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide
Clinical data
Trade names Cerdelga
Legal status
Legal status
Identifiers
CAS Number 491833-29-5
ATC code A16AX10 (WHO)
PubChem CID 23652731
ChemSpider 28475348
ChEBI CHEBI:82752 Yes
Chemical data
Formula C23H36N2O4
Molar mass 404.543 g/mol

 

Patent Number Pediatric Extension Approved Expires (estimated)
US6916802 No 2002-04-29 2022-04-29 Us
US7196205 No 2002-04-29 2022-04-29 Us
US7615573 No 2002-04-29 2022-04-29 Us

///////////491833-29-5, 928659-70-5, eliglustat hemitartrate, eliglustat L-tartrate, ELIGLUSTAT,  Cerdelga,  Genz 99067,  Genz-99067,  UNII-DR40J4WA67,  GENZ-112638, エリグルスタット酒石酸塩 , FDA 2014,  GAUCHERS DISEASE, 依利格鲁司特, エリグルスタット,サーデルガ

CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O

Share

Doravirine, MK-1439

 Phase 3 drug, Uncategorized  Comments Off on Doravirine, MK-1439
Jul 182016
 

Doravirine.svg

 

Image for unlabelled figure

Doravirine.png

Doravirine, MK-1439……….. AN ANTIVIRAL

3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile

Benzonitrile, 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]-

3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile

(3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile)

1338225-97-0 CAS

MF  C17H11ClF3N5O3
MW 425.7  Merck Sharp & Dohme Corp

Merck Frosst Canada Ltd. INNOVATOR

Jason Burch, Bernard Cote, Natalie Nguyen,Chun Sing Li, Miguel St-Onge, Danny Gauvreau,

Reverse transcriptase inhibitor

UNII:913P6LK81M

  • Originator Merck & Co
  • Class Antiretrovirals; Nitriles; Pyridones; Small molecules; Triazoles
  • Mechanism of Action Non-nucleoside reverse transcriptase inhibitors
  • Phase III HIV-1 infections

Most Recent Events

  • 16 Jul 2016 No recent reports of development identified for phase-I development in HIV-1-infections(Monotherapy, Treatment-naive) in Germany (PO, Tablet)
  • 01 Jun 2016 Merck Sharp & Dohme completes a phase I pharmacokinetics trial in subjects requiring methadone maintenance therapy in USA (PO, Tablet) (NCT02715700)
  • 01 May 2016 Merck completes a phase I trial in severe renal impairment in USA (NCT02641067)

 

SYNTHESIS COMING………

WO  2015084763

STR1

 

CONTD………………………

 

STR1

img_pgene01.jpg

SPECTRAL DATA

19F DMSOD6
STR1

13C NMR DMSOD6

STR1

1H NMR DMSOD6

STR1

3-chloro-5-((2-oxo-1-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile.

1H NMR (400 MHz, DMSO-d6) δ 11.47 (br. s., 1H), 11.40 (s, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.75 (t, J =1.5 Hz, 1H), 7.58 (dd, J = 1.2, 2.3 Hz, 1H), 7.51 (t, J = 2.1 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 5.02 (s, 2H)

13C NMR (101 MHz, DMSO-d6) δ 157.25, 156.20, 155.97, 142.52, 140.09 (q, JC-F = 2.0 Hz), 137.74,134.97, 130.17 (q, JC-F = 31.2 Hz), 126.53, 121.70 (q, JC-F = 274.7 Hz), 121.16, 118.37, 116.96, 113.70,99.96 (q, JC-F = 4.0 Hz), 44.90

19F NMR (376 MHz, DMSO-d6) δ -62.24 (s, 1F)
HRMS [M + H]+ for C16H10ClF3N5O3 calcd, 412.0419; found, 412.0415.
mp 148.46-156.11 °C

REF Org. Process Res. Dev., Article ASAP, DOI: 10.1021/acs.oprd.6b00163

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00163

 

 

STR1

 

 

str2

 

 

 

Doravirine (MK-1439) is a non-nucleoside reverse transcriptase inhibitor under development by Merck & Co. for use in the treatment of HIV/AIDS. Doravirine demonstrated robust antiviral activity and good tolerability in a small clinical study of 7-day monotherapy reported at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013. Doravirine appeared safe and generally well-tolerated with most adverse events being mild-to-moderate.[2][3]

Highly active antiretroviral therapy (HAART) is the standard of care for the treatment of HIV infection. Typically, this protocol recommends the combination of two nucleoside reverse-transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor or an integrase inhibitor. 

NNRTI-based combinations have become first-line therapy mainly because of their demonstrated efficacies, convenient dosing regimen and relatively low toxicities. These inhibitors block the polymerase activity of the HIV reverse transcriptase by binding to an allosteric hydrophobic pocket adjacent to the active site. Efavirenz (1, ) is a first generation NNRTI that has been conveniently co-formulated with NRTIs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) as a once-a-day fixed-dose combination (Atripla®). Although recommended for the therapy of treatment-naïve patients, efavirenz suffers from neurocognitive side effects, teratogenicity and exacerbation of hyperlipidemia. Moreover, the low barrier to genetic resistance of first generation NNRTIs led to the emergence of resistant viruses bearing mutations K103N and Y181C in patients failing therapy.

Structures of marketed and lead NNRTIs.

Figure .

Structures of marketed and lead NNRTIs.

Second generation NNRTIs etravirine (2) and rilpivirine (3) efficiently suppress the replication of the K103N resistant mutants as shown by an improved activity in cell culture assays . Etravirine (200 mg, bid) is approved for use in treatment-experienced adult patients with multi-drug resistance. With an improved pharmacokinetic profile, the close analog rilpivirine (25 mg, qd) was recently approved for use in treatment-naïve patients. Phase III data reveal that at the 96-week point, a rilpivirine/truvada®  combination was better tolerated than efavirenz/truvada®. However, the virologic failure rate was twice as high for rilpivirine (14%) than it was for efavirenz (8%). For patients with viral load greater than 500,000 copies/mL, the response rate is 62% (rilpivirine) versus 81% (efavirenz). As a result, rilpivirine is not recommended for treating HIV patients with viral load >500,000 copies/mL. This difference in treatment durability could be explained by the much higher ratio of trough concentration over the antiviral activity for efavirenz versus rilpivirine.

Investigational next-generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), at the 21st Conference on Retroviruses and Opportunistic Infections (CROI). Interim data demonstrating potent antiretroviral (ARV) activity for four doses (25, 50, 100 and 200 mg) of once-daily, oral doravirine in combination with tenofovir/emtricitabine in treatment-naïve, HIV-1 infected adults after 24 weeks of treatment were presented during a late-breaker oral session. Based on these findings as well as other data from the doravirine clinical program, Merck plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.

“Building on our long-standing commitment to the HIV community, Merck continues to evaluate new candidates we believe have the potential to make a meaningful difference in the lives of HIV patients,” said Daria Hazuda, Ph.D., vice president, Infectious Diseases, Merck Research Laboratories. “We look forward to advancing doravirine into Phase 3 clinical trials in the second half of 2014.”

Doravirine Clinical Data

This randomized, double-blind clinical trial examined the safety, tolerability and efficacy of once-daily doravirine (25, 50, 100 and 200 mg) in combination with once-daily tenofovir/emtricitabine versus efavirenz (600 mg), in treatment-naïve, HIV-1 infected patients. The primary efficacy analysis was percentage of patients achieving virologic response (< 40 copies/mL).

At 24 weeks, doravirine doses of 25, 50, 100, and 200 mg showed virologic response rates consistent with those observed for efavirenz at a dose of 600 mg. All treatment groups showed increased CD4 cell counts.

Proportion of Patients with Virologic
Response at 24 weeks (95% CI)

Mean CD4 Change
from Baseline (95% CI)

Treatment* Dose (mg) n/N

% <40
copies/mL

cells/μL

Doravirine 25 32/40 80.0 (64.6, 90.9) 158 (119, 197)
50 32/42 76.2 (60.5, 87.9) 116 (77, 155)
100 30/42 71.4 (55.4, 84.3) 134 (100, 167)
200 32/41 78.0 (62.4, 89.4) 141 (96, 186)
Efavirenz 600 27/42 64.3 (48.0, 78.4) 121 (73, 169)
Missing data approach: Non-completer = Failure Observed Failure

*In combination with tenofovir/emtricitabine

The incidence of drug-related adverse events was comparable among the doravirine-treated groups. The overall incidence of drug-related adverse events was lower in the doravirine-treated groups (n=166) than the efavirenz-treated group (n=42), 35 percent and 57 percent, respectively. The most common central nervous system (CNS) adverse events at week 8, the primary time point for evaluation of CNS adverse experiences, were dizziness [3.0% doravirine (overall) and 23.8% efavirenz], nightmare [1.2% doravirine (overall) and 9.5% efavirenz], abnormal dreams [9.0% doravirine (overall) and 7.1% efavirenz], and insomnia [5.4% doravirine (overall) and 7.1% efavirenz].

Based on the 24-week data from this dose-finding study, a single dose of 100 mg doravirine was chosen to be studied for the remainder of this study, up to 96 weeks.

About Doravirine

DORAVIRINE

Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being evaluated by Merck for the treatment of HIV-1 infection. In preclinical studies, doravirine demonstrated potent antiviral activity against HIV-1 with a characteristic profile of resistance mutations selected in vitro compared with currently available NNRTIs. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and did not show a significant food effect.

Merck’s Commitment to HIV

For more than 25 years, Merck has been at the forefront of the response to the HIV epidemic, and has helped to make a difference through our proud legacy of commitment to innovation, collaborating with the community, and expanding global access to medicines. Merck is dedicated to applying our scientific expertise, resources and global reach to deliver healthcare solutions that support people living with HIV worldwide.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on TwitterFacebook and YouTube.

PATENT

WO 2014089140

The compound 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 – yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile has the following chemical structure.

Figure imgf000017_0001

Anhydrous 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile is known to exist in three crystalline forms – Form I, Form II and Form III. The differential scanning calorimetry (DSC) curve for crystalline anhydrous Form II shows an endotherm with an onset at 230.8° C, a peak maximum at 245.2°C, and an enthalpy change of 3.7 J/g, which is due to polymorphic conversion of anhydrous Form II to anhydrous Form I, and a second melting endotherm with an onset at 283.1°C, a peak maximum at 284.8°C, and an enthalpy change of 135.9 J/g, due to melting of Anhydrous Form I. Alternative production and the ability of this compound to inhibit HIV reverse transcriptase is illustrated in WO 201 1/120133 Al, published on October 6, 201 1, and US 201 1/0245296 Al, published on October 6, 201 1, both of which are hereby incorporated by reference in their entirety.

The process of the present invention offers greater efficiency, reduced waste, and lower cost of goods relative to the methods for making the subject compounds existing at the time of the invention. Particularly, the late stage cyanation and methylation steps are not required.

The following examples illustrate the invention. Unless specifically indicated otherwise, all reactants were either commercially available or can be made following procedures known in the art. The following abbreviations are used:

 

EXAMPLE 1

Figure imgf000018_0001
Figure imgf000018_0002

Step 1

Figure imgf000018_0003

1 2

3-(Chloromethyl)-l-(2-methoxypropan-2-yl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (2): A

100 ml round bottom flask equipped with stir bar and a nitrogen inlet was charged with 1 (5 g, 33.9 mmol) and (lS)-(+)-10-camphorsulfonic acid (0.39 g, 1.694 mmol) at ambient temperature. After 2,2-dimethoxy propane (36.0 g, 339 mmol) was charged at ambient temperature, the resulting mixture was heated to 45°C. The resulting mixture was stirred under nitrogen at 45°C for 18 hours and monitored by HPLC for conversion of the starting material (< 5% by HPLC). After the reaction was completed, the batch was taken on to the next step without further workup or isolation. ‘H NMR (CDCI3, 500 MHz): 4.45 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 1.83 (s, 6H).

Step 2

Figure imgf000019_0001

3-Fluoro-l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-4-(trifluoromethyl)pyridin-2(lH)-one (3): A mixture of 2 (100 mg, 93.1% purity, 0.49 mmol), pyridone (1 17 mg, 97.6% purity, 0.49 mmol) and K2CO3 (82 mg, 0.59 mmol) in DMF (0.5 ml) was aged with stirring at ambient temperature for 3h. After the reaction was completed, the batch was taken on to the next step without further work up or isolation.

Step 3

Figure imgf000019_0002

3-Chloro-5-((l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (4): To a mixture of compound 3 in DMF (reaction mixture from the previous step) was added 3-chloro-5- hydroxybenzonitrile (1.77 g, 1 1.5 mmol) at ambient temperature. The resulting mixture was then heated to 95-100°C and held for 20 hours.

Upon completion (typically 18-20 hours), the reaction was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous cut was back extracted with ethyl acetate. The organic layers were combined and then concentrated to an oil. MeOH (80 ml) was added and the resulting slurry was taken on to the next step. XH NMR (CDC13, 500 MHz): 7.60 (d, IH), 7.42 (s, IH), 7.23 (s, IH), 7.12 (s, IH), 6.56 (d, IH), 5.14 (s, 2H), 3.30 (s, 3H), 3.22 (s, 3H), 1.82 (s, 6H).

Step 4

Figure imgf000020_0001

4 5

3-Chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (5): To a solution of 4 (5.74 g., 1 1.53 mmol) in MeOH (from previous step) was added concentrated hydrochloric acid (lml, 12.18 mmol) at ambient temperature. The resulting mixture was agitated for 1 hour at room temperature.

The resulting solids were collected by filtration and dried under a nitrogen sweep, providing 5 as a white solid (2.63 g, 46% yield): XH NMR (DMSO, 400 MHz): 1 1.74 (S, IH), 7.92 (d, IH), 7.76 (s, IH), 7.61 (s, IH), 7.54 (s, IH), 6.69 (d, IH), 5.15 (s, 2H), 3.10 (s, 3H)

EXAMPLE 2

Figure imgf000021_0001

Step 1

Figure imgf000021_0002

Phenyl methylcarbamate: 40% Aqueous methylamine (500 g, 6.44 mol) was charged to a 2 L vessel equipped with heat/cool jacket, overhead stirrer, temperature probe and nitrogen inlet. The solution was cooled to -5 °C. Phenyl chloroformate (500.0 g, 3.16 mol) was added over 2.5 h maintaining the reaction temperature between -5 and 0 °C. On complete addition the white slurry was stirred for lh at ~0 °C.

The slurry was filtered, washed with water (500 mL) and dried under 2 sweep overnight to afford 465g (96%> yield) of the desired product as a white crystalline solid; 1H NMR (CDCI3, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).

Step 2

Figure imgf000022_0001

2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide: Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 °C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 °C for 6 h.

Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 °C for 10-12 h. The reaction mixture is initially a clear colorless solution. The mixture is seeded with product (0.5 g) after 4h at 83-85 °C. The slurry was slowly cooled to 20 °C over 2h and aged for lh.

The slurry was filtered and washed with IPA (600 mL). The cake was dried under 2 sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: XH NMR (D20, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).

Step 3

Figure imgf000022_0002

3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 2-(2-Hydroxyacetyl)-N- methylhydrazinecarboxamide (130 g @ ~95wt%, 0.84 mol), w-propanol (130 mL) and water (130 mL) were charged to a 1 L vessel with jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. Sodium hydroxide (pellets, 16.8 g, 0.42 mol) was added and the slurry warmed to reflux for 3h. The reaction mixture was cooled to 20 °C and the pH adjusted to 6.5 (+/- 0.5) using cone hydrochloric acid (28.3 mL, 0.34 mol). Water was azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content should be <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and dried to provide 125g (85% yield) of an off- white crystalline solid. The solid is ~73 wt% due to residual inorganics (NaCl): ‘H NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).

Step 4

Figure imgf000023_0001

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3- (Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCI2 (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. Monitor reaction progress by HPLC. On complete reaction (>99.5% by area at 210nm.), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to -10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under 2 sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: ‘H NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).

EXAMPLE 3

Figure imgf000023_0002

3-fluoro-4-(trifluoromethyl)pyridin-2(lH)-one (2): To a 250 ml round bottom flask equipped with overhead stirring and a nitrogen inlet was added a mixture of sulfuric acid (24.31 ml, 437 mmol) and water (20.00 ml). To this was added 2,3-difluoro-4-(trifluoromethyl)pyridine (6.83 ml, 54.6 mmol) and the mixture was heated to 65 °C and stirred for 4 h. By this time the reaction was complete, and the mixture was cooled to room temperature. To the flask was slowly added 5M sodium hydroxide (43.7 ml, 218 mmol), maintaining room temperature with an ice bath. The title compound precipitates as a white solid during addition. Stirring was maintained for an additional lh after addition. At this time, the mixture was filtered, the filter cake washed with 20 mL water, and the resulting white solids dried under nitrogen. 3-fluoro-4- (trifluoromethyl)pyridin-2(lH)-one (2) was obtained as a white crystalline solid (9.4g, 51.9 mmol, 95 % yield): ¾ NMR (CDC13, 400 MHz): 12.97 (br s, 1H), 7.36 (d, 1H), 6.44 (m, 1H).

EXAMPLE 4

Step 1 – Ethyl Ester Synthesis Experimental Procedure;

Figure imgf000024_0001

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL FLO). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0- 5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H20 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temp at 0-5 °C. Additional FLO (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/FLO ratio is 1 : 1.5 (10 vol). The resulting slurry was typically aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL, 3 vol), followed by water (200 mL, 4 vol). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C; note: heat must not be applied during drying as product mp is 42 °C. The cake is considered dry when H20 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield (corrected), 99.5 LCAP: XH NMR (CDC13, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Step 2 – Pyridone Synthesis

Synthetic Scheme; batch

TEA, TFAA, 10 °C;

then MeOH, rt

Figure imgf000025_0001

[isolated solid, A] [PhMe exit stream, B]

Figure imgf000025_0002

[PhMe/MeOH solution, C] [PhMe/MeOH/NH3 solution, D] [isolated solid, E]

Experimental Procedures;

Aldol Condensation, Ester A to Diene C

(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4- dienoate (C): Ester A (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL, 5.24 vol) and 4-ethoxy-l, l, l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.

The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.

The ester solution was pumped to one flow reactor inlet. Potassium tert-pentoxide solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel. The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-pentoxide solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.

Charged toluene (50 mL, 2 vol) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.

The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 area percent diene C by HPLC analysis.

The solution of diene C (573 mL) was used without purification in the subsequent reaction. Cyclization, Diene C to E

3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene C in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical C) was charged methanol (25 mL, 0.61 vol). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical C) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL, 8 vol) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.

The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: XH NMR (DMSO-i/6, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.

Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile

Figure imgf000027_0001

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH- l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface N2 (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).

3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicates <1% 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seed with anhydrate Form II (134 g). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried over a 2 sweep to give 2.53 kg (85% yield – corrected) of a white solid that was confirmed to be crystalline Form II by X-ray powder detraction analysis.

PATENT

WO 2015084763

The following scheme is an example of Step 3A.

EXAMPLE 1

1

Step 1

c| 0. h CH3NH3 Me.NA0.Ph

H

Phenyl methylcarbamate: 40% Aqueous methylamine (500 g, 6.44 mol) was charged to a 2 L vessel equipped with heat/cool jacket, overhead stirrer, temperature probe and nitrogen inlet. The solution was cooled to -5 °C. Phenyl chloroformate (500.0 g, 3.16 mol) was added over 2.5 h maintaining the reaction temperature between -5 and 0 °C. On complete addition the white slurry was stirred for lh at ~0 °C.

The slurry was filtered, washed with water (500 mL) and dried under a nitrogen sweep overnight to afford 465g (96% yield) of the desired product as a white crystalline solid; XH NMR (CDCI3, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).

Step 2

2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide: Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 °C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 °C for 6 h.

Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 °C for 10-12 h. The reaction mixture was initially a clear colorless solution. The mixture was seeded with product (0.5 g) after 4h at 83-85 °C. The slurry was slowly cooled to 20 °C over 2h and aged for lh. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 83-85 °C for 4 hours.

The slurry was filtered and washed with IPA (600 mL). The cake was dried under a nitrogen sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: XH NMR (D20, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).

Step 3

3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide (130 g @ ~95wt%, 0.84 mol), w-propanol (130 mL) and water (130 mL) were charged to a 1 L vessel with jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. Sodium hydroxide (pellets, 16.8 g, 0.42 mol) was added and the slurry warmed to reflux for 3h. The reaction mixture was cooled to 20 °C and the pH adjusted to 6.5 (+/- 0.5) using concentrated hydrochloric acid (28.3 mL, 0.34 mol). Water was

azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content was <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and the filter cake was dried under a nitrogen sweep to provide 125g (85% yield) of an off-white crystalline solid. The solid was -73 wt% due to residual inorganics (NaCl): ¾ NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).

Step 4

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCl2 (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. The reaction progress was monitored by HPLC. On complete reaction (>99.5% by area at 210nm), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to – 10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under a nitrogen sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: XH NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).

EXAMPLE 2

Step 1 – Ethyl Ester Synthesis

Experimental Procedure;

A

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL Η20). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0-5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H20 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temperature at 0-5 °C. Additional H20 (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/H20 ratio is 1 : 1.5. The resulting slurry was aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL), followed by water (200 mL). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C. The cake is considered dry when H20 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield: XH NMR (CDC13, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.

Step 2 – Pyridone Synthesis

Synthetic Scheme;

Experimental Procedures;

Aldol Condensation

(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4-dienoate (C): Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL) and 4-ethoxy-l, l,l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.

The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.

The ester solution was pumped to one flow reactor inlet. Potassium tert-amylate solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel.

The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-amylate solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.

Charged toluene (50 mL) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.

The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 LCAP diene .

The solution of diene (573 mL) was used without purification in the subsequent reaction.

Cyclization

3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical) was charged methanol (25 mL). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased to maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.

The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: XH NMR (DMSO-ifc, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.

Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-‘ dihydro-lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface nitrogen (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).

3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicated <1% 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seeded with anhydrate Form II (134 g)(procedures for making anhydrate Form II are described in WO2014/052171). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried under N2 to give 2.53 kg (85% yield) of a white solid that was confirmed to be crystalline Form II of the title compound by X-ray powder detraction analysis.

EXAMPLE 3

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A):

70%

Step 3

Three step one pot sequence

Steps 1 and 2:

To an oven dried 250mL round bottom flask was added sodium 2-methylpropan-2-olate (12.85 g, 134 mmol) and BHT (0.641 g, 2.91 mmol) then added DMF (30mL). After lOmin, a light yellow solution resulted. 2-Phenylethanol (7.66 ml, 63.9 mmol) was added and the solution exothermed to 35 °C. The light yellow solution was warmed to 55 °C and then a solution of 3,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (15mL) was added over 2h via syringe pump. The resulting red-orange suspension was aged at 55-60 °C. After 2h, HPLC showed >98% conversion to the sodium phenolate.

Step 3:

The suspension was cooled to 10 °C, then ethyl 2-bromoacetate (8.70 ml, 78 mmol) was added over lh while maintaining the temperature <20 °C. The resulting mixture was aged at ambient temperature. After lh, HPLC showed >99% conversion to the title compound.

Work-up and isolation:

To the suspension was added MTBE (50mL) and H20 (50mL) and the layers were separated. The organic layer was washed with 20% aq brine (25mL). The organic layer was assayed at 12.5g (90% yield). The organic layer was concentrated to -38 mL, diluted with hexanes (12.5mL) and then cooled to 5 °C. The solution was seeded with 0.28g (2 wt%) of crystalline ethyl 2-(3-chloro-5-cyanophenoxy)acetate and aged 0.5h at 5 °C to give a free flowing slurry. Hexane (175mL) was added to the slurry over lh at 0-5 °C. The slurry was filtered at 0-5 °C, washed with hexane (50 mL) and dried under a nitrogen sweep to give 9.8g (70% yield) of the title compound as a white crystalline solid. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.

Paper

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses
Bioorg Med Chem Lett 2014, 24(3): 917

http://www.sciencedirect.com/science/article/pii/S0960894X13014546

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Full-size image (16 K)

Full-size image (10 K)

Scheme 1. 

Reagents and conditions: (a) K2CO3, NMP, 120 °C; (b) KOH, tert-BuOH, 75 °C; (c) Zn(CN)2, Pd(PPh3)4, DMF, 100 °C.

Full-size image (12 K)

Scheme 3.

Reagents and conditions: (a) K2CO3, DMF, −10 °C; (b) MeI or EtI, K2CO3, DMF.

 

36 IS DORAVIRINE

 

PATENT

WO 2011120133

http://www.google.com/patents/WO2011120133A1?cl=en

Scheme I depicts a method for preparing compounds of Formula I in which hydroxypyridine 1-1 is alkylated with chlorotriazolinone 1-2 to provide 1-3 which can be selectively alkylated with an alkyl halide (e.g., methyl iodide, ethyl iodide, etc.) to afford the desired 1-4. Scheme I

Figure imgf000039_0001

Scheme II depicts an alternative route to compounds of the present invention, wherein fluorohydroxypyridine II-l can be alkylated with chlorotriazolinone II-2 to provide the alkylated product II-3 which can be converted to the desired II-5 via nucleophilic aromatic substitution (S] fAr) using a suitable hydroxyarene II-4.

Scheme II

Figure imgf000039_0002

Hydroxypyridines of formula I-l (Scheme 1) can be prepared in accordance with Scheme III, wherein a SNAr reaction between pyridine III-l (such as commercially available 2- chloro-3-fluoro-4-(trifluoromethyl)pyridine) and hydroxyarene H-4 can provide chloropyridine III-2, which can be hydrolyzed under basic conditions to the hydroxypyridine I-l. Scheme III

Figure imgf000040_0001

Another method for preparing hydroxypyridines of formula I-l is exemplified in Scheme IV, wherein S Ar coupling of commercially available 2-chloro-3-fluoro-4- nitropyridone-N-oxide IV-1 with a suitable hydroxyarene II-4 provides N-oxide IV-2, which can first be converted to dihalides IV-3 and then hydro lyzed to hydroxypyridine IV-4. Further derivatization of hydroxypyridine IV-4 is possible through transition metal-catalyzed coupling processes, such as Stille or boronic acid couplings using a PdLn catalyst (wherein L is a ligand such as triphenylphosphine, tri-tert-butylphosphine or xantphos) to form hydroxypyridines IV-5, or amination chemistry to form hydroxypyridines IV-6 in which R2 is N(RA)RB.

Scheme IV

Figure imgf000040_0002

IV-1

Figure imgf000040_0003

– – Scheme V depicts the introduction of substitution at the five-position of the hydroxypyridines via bromination, and subsequent transition metal-catalyzed chemistries, such as Stille or boronic acid couplings using PdLn in which L is as defined in Scheme IV to form hydroxypyridines V-3, or amination chemistry to form hydroxypyridines V-4 in which R3 is N(RA)RB.

Scheme V

Figure imgf000041_0001

As shown in Scheme IV, fiuorohydroxypyridines II-l (Scheme II) are available from the commercially available 3-fluoroypridines VI- 1 through N-oxide formation and rearrangement as described in Konno et al., Heterocycles 1986, vol. 24, p. 2169.

Scheme VI

Figure imgf000041_0002

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.

The term “room temperature” in the examples refers to the ambient temperature which was typically in the range of about 20°C to about 26°C.

EXAMPLE 1

3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2-oxo-4- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

 

Figure imgf000042_0001

Step 1(a):

 

Figure imgf000042_0002

A mixture of the 3-bromo-5-chlorophenol (3.74 g; 18.0 mmol), 2-chloro-3-fluoro- 4-(trifluoromethyl)pyridine (3.00 g; 15.0 mmol) and 2CO3 (2.49 g; 18.0 mmol) in NMP (15 mL) was heated to 120°C for one hour, then cooled to room temperature. The mixture was then diluted with 250 mL EtOAc and washed with 3 x 250 mL 1 :1 H20:brine. The organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; load with toluene; 100:0 to 0:100 hexanes:CH2Cl2 over 40 minutes) provided title compound (1-2) as a white solid. Repurification of the mixed fractions provided additional title compound. lH NMR (400 MHz, CDCI3): δ 8.55 (d, J = 5.0 Hz, 1 H); 7.64 (d, J = 5.0 Hz, 1 H);

7.30 (s, 1 H); 6.88 (s, 1 H); 6.77 (s, 1 H).

3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3)

 

Figure imgf000042_0003

To a suspension of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1-2; 3.48 g; 8.99 mmol) in lBuOH (36 mL) was added KOH (1.51 g; 27.0 mmol) and the mixture was heated to 75°C overnight, at which point a yellow oily solid had precipitated from solution, and LCMS analysis indicated complete conversion. The mixture was cooled to room temperature, and neutralized by the addition of -50 mL saturated aqueous NH4CI. The mixture was diluted with 50 mL H2O, then extracted with 2 x 100 mL EtOAc. The combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90: 10 CH2Cl2:MeOH over 40 minutes) provided the title compound (1-3) as a fluffy white solid. lH NMR (400 MHz, DMSO): δ 12.69 (s, 1 H); 7.59 (d, J = 6.9 Hz, 1 H); 7.43 (t, J = 1.7 Hz, 1 H); 7.20 (t, J = 1.9 Hz, 1 H); 7.13 (t, J = 2.0 Hz, 1 H); 6.48 (d, J = 6.9 Hz, 1 H).

3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)

 

Figure imgf000043_0001

To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3; 3.25 g; 8.82 mmol) in NMP (29 mL) was added CuCN (7.90 g; 88 mmol) and the mixture was heated to 175°C for 5 hours, then cooled to room temperature slowly. With increased fumehood ventilation, 100 mL glacial AcOH was added, then 100 mL EtOAc and the mixture was filtered through Celite (EtOAc rinse). The filtrate was washed with 3 x 200 mL 1 : 1 H20:brine, then the organic extracts were dried (Na2S04) and concentrated in vacuo.

Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90:10 CH2Cl2:MeOH over 40 minutes), then trituration of the derived solid with Et20 (to remove residual NMP which had co-eluted with the product) provided the title compound (1-4). lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).

Step 1(d): 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (1-5)

Figure imgf000043_0002

The title compound was prepared as described in the literature: Cowden, C. J.; Wilson, R. D.; Bishop, B. C; Cottrell, I. F.; Davies, A. J.; Dolling, U.-H. Tetrahedron Lett. 2000, 47, 8661.

3 -chloro-5 -( { 2-oxo- 1 – [(5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] – 4- (trifiuoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1-6)

Figure imgf000044_0001

A suspension of the 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3- yl]oxy}benzonitrile (1-4; 2.00 g; 6.36 mmol), 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3- one (1-5; 0.849 g; 6.36 mmol) and K2CO3 (0.878 g; 6.36 mmol) in DMF (32 mL) was stirred for 2 hours at room temperature, at which point LCMS analysis indicated complete conversion. The mixture was diluted with 200 mL Me-THF and washed with 150 mL 1 : 1 : 1 H20:brine:saturated aqueous NH4CI, then further washed with 2 x 150 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 150 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (80 g column; dry load; 100:0 to 90:10 EtOAc:EtOH over 25 minutes) provided the title compound (1-6) as a white solid. lH NMR (400 MHz, DMSO): δ 1 1.46 (s, 1 H); 1 1.39 (s, 1 H); 7.93 (d, J = 7.3 Hz, 1 H); 7.76 (s, 1 H); 7.58 (s, 1 H); 7.51 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.02 (s, 2 H).

Step 1(f): 3 -chloro-5 -( { 1 – [(4-methyl-5-oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2- oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1 -1 )

A solution of 3-chloro-5-({2-oxo-l -[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]- 4-(trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-6; 2.37 g; 5.76 mmol) and K2CO3 (0.796 g; 5.76 mmol) in DMF (58 mL) was cooled to 0°C, then methyl iodide (0.360 mL; 5.76 mmol) was added. The mixture was allowed to warm to room

temperature, and stirred for 90 minutes, at which point LCMS analysis indicated >95%

conversion, and the desired product of -75% LCAP purity, with the remainder being unreacted starting material and 6/s-methylation products. The mixture was diluted with 200 mL Me-THF, and washed with 3 x 200 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 200 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. The resulting white solid was first triturated with 100 mL EtOAc, then with 50 mL THF, which provided (after drying) the title compound (1-1) of >95% LCAP. Purification to >99% LCAP is possible using Prep LCMS (Max-RP, 100 x 30 mm column; 30-60% CH3CN in 0.6% aqueous HCOOH over 8.3 min; 25 mL/min). lH NMR (400 MHz, DMSO): δ 1 1.69 (s, 1 H); 7.88 (d, J = 7.3 Hz, 1 H); 7.75 (s, 1 H); 7.62 (s, 1 H); 7.54 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.17 (s, 2 H); 3.1 1 (s, 3 H). EXAMPLE 1A

3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

 

Figure imgf000045_0001

Step lA(a): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-2)

 

Figure imgf000045_0002

A mixture of the 3-chloro-l-iodophenol (208 g; 816.0 mmol), 2-chloro-3-fluoro-

4-(trifluoromethyl)pyridine (155 g; 777.0 mmol) and K2CO3 (161 g; 1 165.0 mmol) in NMP (1.5 L) was held at 60°C for 2.5 hours, and then left at room temperature for 2 days. The mixture was then re-heated to 60°C for 3 hours, then cooled to room temperature. The mixture was then diluted with 4 L EtOAc and washed with 2 L water + 1 L brine. The combined organics were then washed 2x with 500 mL half brine then 500 mL brine, dried over MgS04 and concentrated to afford crude 1A-2. lH NMR (500 MHz, DMSO) δ 8.67 (d, J = 5.0 Hz, 1 H), 7.98 (d, J = 5.0 Hz, 1 H), 7.63-7.62 (m, 1 H), 7.42-7.40 (m, 1 H), 7.22 (t, J = 2.1 Hz, 1 H).

Step lA(b): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-3)

 

Figure imgf000045_0003

To a suspension of 3-(3-chloro-5-iodophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1A-2; 421 g, 970 mmol) in t-BuOH (1 L) was added KOH (272 g, 4850 mmol) and the mixture was heated to 75°C for 1 hour, at which point HPLC analysis indicated >95% conversion. The t-BuOH was evaporated and the mixture diluted with water (7mL/g, 2.4L) and then cooled to 0°C, after which 12N HC1 (~240mL) was added until pH 5. This mixture was then extracted with EtOAc (20mL/g, 6.5L), back extracted with EtOAc 1 x 5mL/g (1.5L), washed 1 x water:brine 1 : 1 (l OmL/g, 3.2L), 1 x brine (lOmL/g, 3.2L), dried over MgS04, filtered and concentrated to afford a crude proudct. The crude product was suspended in MTBE (2.25 L, 7mL/g), after which hexanes (1 L, 3 mL/g) was added to the suspension over ten minutes, and the mixturen was aged 30minutes at room temperature. The product was filtered on a Buchner, rinsed with MTBE hexanes 1 :2 (2 mL/g = 640 mL), then hexanes

(640mL), and dried on frit to afford 1A-3. lH NMR (400 MHz, acetone-d6): δ 11.52 (s, 1 H); 7.63 (d, J = 7.01 Hz, 1 H); 7.50-7.48 (m, 1 H); 7.34-7.32 (m, 1 H); 7.09-7.07 (m, 1 H); 6.48 (d, J = 7.01 Hz, 1 H).

Step lA(c): 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)

 

Figure imgf000046_0001

A solution of 3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1A-3; 190 g; 457 mmol) in DMF (914 mL) was degassed for 20 minutes by bubbling N2, after which CuCN (73.7 g; 823 mmol) was added, and then the mixture was degassed an additional 5 minutes. The mixture was then heated to 120°C for 17 hours, then cooled to room temperature and partitioned between 6 L MeTHF and 2 L ammonium buffer (4:3: 1 = NH4CI

sat/water/NH-iOH 30%). The organic layer washed with 2 L buffer, 1 L buffer and 1 L brine then, dried over MgS04 and concentrated. The crude solid was then stirred in 2.2 L of refluxing

MeCN for 45 minutes, then cooled in a bath to room temperature over 1 hour, aged 30 minutes, then filtered and rinsed with cold MeCN (2 x 400mL). The solid was dried on frit under N2 atm for 60 hours to afford title compound 1-4. lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).

Steps lA(d) and lA(e)

The title compound 1-1 was then prepared from compound 1-4 using procedures similar to those described in Steps 1(d) and 1(e) set forth above in Example 1.

Patent

WO-2014052171

Crystalline anhydrous Form II of doravirine, useful for the treatment of HIV-1 and HIV-2 infections. The compound was originally claimed in WO2008076223. Also see WO2011120133. Merck & Co is developing doravirine (MK-1439), for the oral tablet treatment of HIV-1 infection. As of April 2014, the drug is in Phase 2 trials.

CLIPS

The next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (formerly MK-1439) showed potent antiretroviral activity and good tolerability in combination with tenofovir/FTC (the drugs in Truvada) in a dose-finding study presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) last week in Boston.

NNRTIs are generally well tolerated and well suited for first-line HIV treatment, but as a class they are susceptible to resistance. Pre-clinical studies showed that Merck’s doravirine has a distinct resistance profile and remains active against HIV with common NNRTI resistance mutations including K103N and Y181C.

As reported at last year’s CROI, doravirine reduced HIV viral load by about 1.3 log in a seven-day monotherapy study. Doravirine is processed by the CYP3A4 enzyme, but it is neither a CYP3A4 inducer nor inhibitor, so it is not expected to have major drug interaction concerns.

Javier Morales-Ramirez from Clinical Research Puerto Rico reported late-breaking findings from a phase 2b study evaluating the safety and efficacy of various doses of doravirine versus efavirenz (Sustiva) for initial antiretroviral therapy.

This study included 208 treatment-naive people living with HIV from North America, Europe and Asia. More than 90% were men, 74% were white, 20% were black and the median age was 35 years. At baseline, the median CD4 cell count was approximately 375 cells/mm3 and 13% had received an AIDS diagnosis. Study participants were stratified by whether their viral load was above (about 30%) or below 100,000 copies/ml; median HIV RNA was approximately 4.5 log10.

Morales-Ramirez reported 24-week results from part 1 of the study, which will continue for a total of 96 weeks. In this part, participants were randomly allocated into five equal-sized arms receiving doravirine at doses of 25, 50, 100 or 200mg once daily, or else efavirenz once daily, all in combination with tenofovir/FTC.

At 24 weeks, 76.4% of participants taking doravirine had viral load below 40 copies/ml compared with 64.3% of people taking efavirenz. Response rates were similar across doravirine doses (25mg: 80.0%; 50mg: 76.2%; 100mg: 71.4%; 200mg: 78.0%). More than 80% of participants in all treatment arms reached the less stringent virological response threshold of <200 copies/ml.

Both doravirine and efavirenz worked better for people with lower pre-treatment viral load in an ad hoc analysis. For people with <100,000 copies/ml at baseline, response rates (<40 copies/ml) ranged from 83 to 89% with doravirine compared with 74% with efavirenz. For those with >100,000 copies/ml, response rates ranged from 50 to 91% with doravirine vs 54% with efavirenz.

Median CD4 cell gains were 137 cells/mm3 for all doravirine arms combined and 121 cells/mmfor the efavirenz arm.

Doravirine was generally safe and well tolerated. People taking doravirine were less than half as likely as people taking efavirenz to experience serious adverse events (3.0% across all doravirine arms vs 7.1% with efavirenz) or to stop treatment for this reason (2.4 vs 4.8%). Four people taking doravirine and two people taking efavirenz discontinued due to adverse events considered to be drug-related.

The most common side-effects were dizziness (3.6% with doravirine vs 23.8% with efavirenz), abnormal dreams (9.0 vs 7.1%), diarrhoea (4.8 vs 9.5%), nausea (7.8 vs 2.4%) and fatigue (6.6 vs 4.8%). Other central nervous system (CNS) adverse events of interest included insomnia (5.4 vs 7.1%), nightmares (1.2 vs 9.5%) and hallucinations (0.6 vs 2.4%). Overall, 20.5% of people taking doravirine reported at least one CNS side-effect, compared with 33.3% of people taking efavirenz.

People taking doravirine had more favourable lipid profiles and less frequent liver enzyme (ALT and AST) elevations compared with people taking efavirenz.

The researchers concluded that doravirine demonstrated potent antiretroviral activity in treatment-naive patients, a favourable safety and tolerability profile, and fewer drug-related adverse events compared with efavirenz.

Based on these findings, the 100mg once-daily dose was selected for future development and will be used in part 2 of this study, a dose-confirmation analysis that will enrol an additional 120 participants.

In the discussion following the presentation, Daniel Kuritzkes from Harvard Medical School noted that sometimes it takes longer for viral load to go down in people who start with a high level, so with further follow-up past 24 weeks doravirine may no longer look less effective in such individuals.

Reference

Morales-Ramirez J et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. 21st Conference on Retroviruses and Opportunistic Infections, Boston, abstract 92LB, 2014.

Merck Moves Doravirine Into Phase 3 Clinical Trials

Wednesday Mar 19 | Posted by: roboblogger | Full story: EDGE

Earlier this month, at the 21st Conference on Retroviruses and Opportunistic Infections , Merck indicated plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.

 

PAPER

A Robust Kilo-Scale Synthesis of Doravirine

Process Research and Development, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, New Jersey 07065,United States
Process Research and Development, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada
WuXi AppTec Co., Ltd., No. 1 Building, No. 288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, China
Org. Process Res. Dev., Article ASAP

 

Abstract Image

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield.

PAPER

Highly Efficient Synthesis of HIV NNRTI Doravirine

Department of Process Chemistry, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States
Org. Lett., 2015, 17 (6), pp 1353–1356
DOI: 10.1021/ol503625z
Publication Date (Web): March 09, 2015
Copyright © 2015 American Chemical Society

Gauthier, D. R., Jr.; Sherry, B. D.; Cao, Y.; Journet, M.; Humphrey, G.; Itoh, T.; Mangion, I.; Tschaen, D. M.Org. Lett. 2015, 17, 1353, DOI: 10.1021/ol503625z………..http://pubs.acs.org/doi/full/10.1021/ol503625z

STR1

US20100034813 * 8 Nov 2007 11 Feb 2010 Yi Xia Substituted pyrazole and triazole compounds as ksp inhibitors
US20100256181 * 14 Nov 2008 7 Oct 2010 Tucker Thomas J Non-nucleoside reverse transcriptase inhibitors
US20110245296 * 6 Oct 2011 Jason Burch Non-nucleoside reverse transcriptase inhibitors
Reference
1 * COWDEN ET AL.: “A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist.“, TETRAHEDRON LETTERS, vol. 41, no. 44, 2000, pages 8661 – 8664, XP004236142
Patent ID Date Patent Title
US2015329521 2015-11-19 PROCESS FOR MAKING REVERSE TRANSCRIPTASE INHIBITORS
US9150539 2015-10-06 Crystalline form of a reverse transcriptase inhibitor
US2015232447 2015-08-20 CRYSTALLINE FORM OF A REVERSE TRANSCRIPTASE INHIBITOR
US2013296382 2013-11-07 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
US2011245296 2011-10-06 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

References

  1.  Collins, Simon; Horn, Tim. “The Antiretroviral Pipeline.” (PDF). Pipeline Report. p. 10. Retrieved 6 December 2015.
  2. Safety and Antiviral Activity of MK-1439, a Novel NNRTI, in Treatment-naïve HIV+ Patients. Gathe, Joseph et al. 20th Conference on Retroviruses and Opportunistic Infections. 3–6 March 2013. Abstract 100.
  3.  CROI 2013: MK-1439, a Novel HIV NNRTI, Shows Promise in Early Clinical Trials. Highleyman, Liz. HIVandHepatitis.com. 6 March 2013.
Doravirine
Doravirine structure.svg
Systematic (IUPAC) name
3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile
Clinical data
Routes of
administration
Oral[1]
Legal status
Legal status
  • Investigational New Drug
Identifiers
CAS Number 1338225-97-0
ATC code none
PubChem CID 58460047
ChemSpider 28424197
UNII 913P6LK81M Yes
KEGG D10624
ChEMBL CHEMBL2364608
Synonyms MK-1439
PDB ligand ID 2KW (PDBe, RCSB PDB)
Chemical data
Formula C17H11ClF3N5O3
Molar mass 425.75 g/mol

//////////Doravirine, MK-1439, 1338225-97-0 , Merck Sharp & Dohme Corp, Reverse transcriptase inhibitor, ANTIVIRAL, Non-nucleoside reverse transcriptase, HIV, Triazolinone, Pyridone, Inhibitor,

Supporting Info

AND

Supporting Info

Cn1c(n[nH]c1=O)Cn2ccc(c(c2=O)Oc3cc(cc(c3)Cl)C#N)C(F)(F)F

Share

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

 PATENTS, Uncategorized  Comments Off on New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd
Jul 182016
 

 

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

 

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.


acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

 

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50°C, and the crude mass degassed under vacuum at 50-55°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10°C. Ethyl acetate (60 ml) was added to the reaction mass at 10°C and stirred for 15 minutes at 15-20°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45°C and the obtained crude mass was degassed at 50-55°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85°C till reaction completion. The reaction mass was cooled up to 0-5°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer,  Parasitic infection,  Plasmodium falciparum infection,  Viral infection, artemether artemisinin,  artemotil,  artenimol,  artesunate,

Share

RG 6080

 phase 1, Uncategorized  Comments Off on RG 6080
Jul 152016
 

STR1

RG-6080

Sulfuric acid, mono[(1R,​2S,​5R)​-​2-​[[(2-​aminoethoxy)​amino]​carbonyl]​-​7-​oxo-​1,​6-​diazabicyclo[3.2.1]​oct-​6-​yl] ester

Phase I

A β-lactamase inhibitor potentially for the treatment of bacterial infections.

RG-6080; FPI-1459; OP-0595

CAS No. 1452458-86-4

Molecular Formula C9 H16 N4 O7 S
Formula Weight 324.31
  • Originator Fedora Pharmaceuticals
  • Developer Meiji Seika Pharma
  • Class Antibacterials; Azabicyclo compounds
  • Mechanism of Action Beta lactamase inhibitors
  • Phase IBacterial infections

Most Recent Events

  • 13 Jan 2015 OP 0595 licensed to Roche worldwide, except Japan ,
  • 30 Nov 2014 Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)
  • 01 May 2014 Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)

 

 

SYNTHESIS

WO 2015046207,

STR1

 

CONTD…………………..

 

 

STR1

CONTD………………………………..

STR1

 

Patent

WO 2015053297

The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.
 In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane – 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).
 The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).
Patent Document 1: Japanese Patent No. 4515704 Pat
Patent Document 2: Japanese Patent Publication 2010-138206 Pat
Patent Document 3: Japanese patent publication 2010-539147 Pat
Patent Document 4: International Publication No. WO2011 / 042560 Patent
Patent Document 5: Japanese Patent No. 5038509 Pat
Patent Document 6: Japanese Patent Publication 2011-207900 Pat
Patent Document 7: International Publication No. WO2010 / 126820 Patent
Patent Document 8: Japanese Patent application 2012-122603 Pat.
[Chemical formula 1] (In the formula, R 3 are the same as those described below)

Reference Example
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
Formula 43]
step 1 tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate  (IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; 1 H NMR (400 MHz, CDCl 3 ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] + .
Step 2
tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate
(V-1) tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; 1 H NMR (400 MHz, CD 3 OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] Tasu .
Step 3
Tetrabutylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate
(VI-1) tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide – pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; 1 H NMR (400 MHz, CDCl 3 ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu 4 N + 2H] + .
Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
tetra butylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; 1 H NMR (400 MHz, D 2O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] + .

 

PATENT

WO 2015046207

Example
64 tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1)
[of 124]

tert- butyl {2 – [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.

Example
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)
[of 125]

 

 tert- butyl {2 – [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide – pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 – [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).

 

 The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).

 

 The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.

PATENT

US 20140288051

WO 2014091268

WO 2013180197

US 20130225554

///////////RG-6080, 1452458-86-4, FPI-1459,  OP-0595, Phase I ,  β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, Meiji Seika Pharma

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: