Obeticholic acid

Uncategorized Comments Off

Jun 032016

Obeticholic acid

Obeticholic acid; 6-ECDCA; INT-747; 459789-99-2; 6-Ethylchenodeoxycholic acid; 6alpha-Ethyl-chenodeoxycholic acid;

(4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid


Molecular Formula:	C₂₆H₄₄O₄
Molecular Weight:	420.62516 g/mol

A farnesoid X receptor (FXR) agonist potentially for treatment of primary biliary cirrhosis and nonalcoholic steatohepatitis.

6-ECDCA; DSP-1747; INT-747

CAS No.459789-99-2

Obeticholic acid.png

Obeticholic acid (abbreviated to OCA), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It has also been known as INT-747. It is undergoing development as a pharmaceutical agent for severalliver diseases and related disorders. Intercept Pharmaceuticals Inc. (NASDAQ symbol ICPT) hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.^[2]

REVIEW
INT-747(Obeticholic acid; 6-ECDCA) is a potent and selective FXR agonist(EC50=99 nM) endowed with anticholestatic activity. IC50 value: 99 nM(EC50) [1] Target: FXR agonist in vitro: The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp) [2]. in vivo: In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha [2]. high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls [3]. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. After INT-747 treatment, natural killer cells and interferon-gamma expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL [4].

REFERENCES FOR ABOVE TEXT ONLY

[1]	Verbeke L, et al. The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats. Am J Pathol. 2015 Feb;185(2):409-19.
[2]	Ghebremariam YT, et al. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One. 2013 Apr 4;8(4):e60653.
[3]	Fiorucci S, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther. 2005 May;313(2):604-12.
[4]	Pellicciari R, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72.

Invention and development

The natural bile acid, chenodeoxycholic acid, was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist.^[3] FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.^[4] Obeticholic acid is the first FXR agonist to be used in human drug studies.

Clinical studies

OCA is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal disorders.^[5]

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasisand eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue.Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation.^[6] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.^[7] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.^[8]^[9] The results of a randomized, double-blind phase 3 study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trial’s primary endpoint of a significant reduction in serum alkaline phosphatase, abiomarker predictive of disease progression, liver transplantation or death.^[10]

Nonalcoholic steatohepatitis (NASH)

Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver, inflammation andfibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH.^[11] A phase 2 trial published in 2013 showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.^[12]

The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls.^[13] However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients.^[14]

Portal hypertension

Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.^[15] An open label phase 2a clinical study is under way.

Bile acid diarrhea

Bile acid diarrhea (also called bile acid malabsorption) can be secondary to Crohn’s disease or be a primary condition. Reduced median levels of FGF19, an ileal hormone that regulates increased hepatic bile acid synthesis, have been found in this condition.^[16] FGF19 is potently stimulated by bile acids and especially by OCA.^[17] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.^[18]

SYNTHESIS

CN 105541953

Take 10g of austempered cholic acid 89.6% purity crude (single hetero greater than 2%), 3 times its weight of acetone and added to their 20% by weight of triethylamine was added, was heated at reflux for 2h, cooled slowly to 10 ° C, the precipitated crystals were filtered to give Obey acid organic amine salt crystals.

Acidification [0020] The organic amine salts Obey acid crystals were dissolved with purified water after 10wt% by mass percentage to the PH value of 2.0 with dilute hydrochloric acid, filtered and dried to give purified Obey acid.

[0021] The purified Obey acid ethyl acetate dissolved by heating and then cooling to 20 ° C, the precipitated crystals were filtered and dried to obtain a purity of 98.7% recrystallization Obey acid (single hetero less than 0.1%), recovery was 84.5%.

PATENT

WO 2016045480

Obey acid (as shown in formula I) is a semi-synthetic chenodeoxycholic acid derivative, for the treatment of high blood pressure, the portal vein and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, non-alcoholic steatohepatitis. Obey acid through activation of FXR receptors play a role, FXR is a nuclear receptor, is expressed mainly in the liver, intestine, kidney, and it can be adjusted with acids fat and carbohydrate metabolism related gene expression in bile, also regulate immune response. FXR activation can inhibit the synthesis of bile acids, bile acids prevent excessive accumulation of toxic reactions caused.

WO2002072598 debuted Obey acid preparation method (shown below), which in strong alkaline conditions to give compound VII by alkylation with ethyl iodide compound VI directly, through reducing compound VII prepared and carboxy deprotection Obey acid. However, due to direct alkylation with ethyl iodide poor selectivity and yield is too low, the synthesis process is difficult to achieve amplification synthesis.

Obey bile acid synthesis (WO2002072598)

WO2006122977 above synthesis process has been improved (see below), the process by the silicon compound IX into protected enol compound X, compound X and acetaldehyde after dehydration condensation to give compound Vb, after compound Vb in alkaline conditions under palladium on carbon hydrogenation to give compound XI, after a carbonyl compound XI reduction system Obey acid.

Obey bile acid synthesis (WO2006122977)

The synthetic process can be achieved, although the enlarged combined, however, the compound Vb produce large amounts of byproducts under strongly alkaline conditions palladium on carbon hydrogenation process for preparing high temperature and strong alkaline compound XI during this step leading to the separation of income a lower rate (about 60%), low yield of this step may be due to compound Vb and XI in unprotected hydroxy dehydration occurs under strongly basic (30% NaOH) and high temperature (95-105 ℃) conditions side effects caused.

synthesis of bile acids Obey,

Obey bile acid synthesis route is as follows:

PATENT

CN 105175473

According to Obey acid 6 was prepared in the form of C Patent Document W02013192097A1 reaction of Example 1, as follows:

The 3 a – hydroxy -6 a – ethyl-7-keto -5 P – 24-oic acid (. 86g, 205 4mmol), water (688mL) and 50% (w / w) hydrogen sodium hydroxide solution (56. 4mL) and the mixture of sodium borohydride (7. 77g, 205. 4mmol) in a mixture of 50% (w / w) sodium hydroxide solution (1.5 mL of) and water (20 mL) in 90 ° in C to 105 ° C reaction. Was heated with stirring under reflux for at least 3 hours, the reaction was completed, the reaction solution was cooled to 80 ° C. Between 30 ° C at 50 ° C of citric acid (320. 2g, anhydrous), a mixture of n-butyl acetate (860 mL of) and water (491mL) to ensure an acidic pH of the aqueous phase was separated. Evaporation of the organic phase was distilled to give the residue was diluted with n-butyl acetate, slowly cooled to 15 ° C to 20 ° C, centrifugation. The crude product was crystallized from n-butyl acetate. After Obey acid isolated by n-butyl acetate (43mL, 4 times), dried samples were dried at 80 ° C under vacuum. To give 67. 34g (77. 9%) crystalline form C Obey acid.

Patent

WO2016107575

Obey acid (Obeticholic acid), developed by Intercept company farnesol X receptor (FXR) agonist, for the treatment of primary biliary cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH). Obey acid is currently in Phase III clinical studies, the Phase III study shows Obey acid treatment of primary biliary cirrhosis have optimistic data, more than 20 years may become the future treatment of primary biliary cirrhosis A new method of choice, and Obey acid on improving nonalcoholic steatohepatitis important role. Obey acid, also known as 6-ethyl-chenodeoxycholic acid, and its structural formula is as follows:

(I)

Pharmaceutical polymorphs (drug polymorphism) refers to the presence of the drug has a different crystalline state of matter of two or more.Polymorphism in drugs is widespread. Different polymorphs of the same drug have significant differences in solubility, melting point, density, stability, etc., which to varying degrees, affect the stability of the drug, uniformity, bioavailability, efficacy and safety. Thus, the pharmaceutical research and development carried out comprehensive polymorph screening system to select the most suitable for the development of the crystalline form, it is one of the important research can not be ignored.

Currently, although there are reports of polymorph Obey acid but the reported crystal forms were prepared as amorphous Obey without intermediate acid product, for the purposes of purification of products, rather than as a product . For example WO2013192097 reported the first preparation Obey bile acid Form C, Form C will then be converted to amorphous Obey acid products. It has been reported as an intermediate product purified acid crystalline Obey obviously not suitable as a final product, since these polymorphic purity, and stability are poor, and there may be still other undesirable defects such WO2013192097 reported in Form C, which contains n-heptane.

Example 1

Obey acid Form A preparation method:

The 216.3 mg Obey acid powder was added to 5.0 mL volume ratio of 1: ethyl acetate and n-heptane mixed solvent 9 to prepare a suspension. The suspension was put stirred for 48 hours at room temperature, filtered and the resulting cake was placed in a dry 25 ℃ vacuum oven overnight, the resulting solid was tested as Form A.

Type A crystal obtained in Example X-ray powder diffraction data are shown in Table 1 embodiment. Its XRPD pattern as shown in Figure 1, which is shown in Figure 2 DSC, TGA which is shown in Figure 3.

Also, by evaporative light scattering method Obey acid Form A purity of 99.54%.

The Form A for 90 days at 5 ℃ condition X-ray powder diffraction, FIG. 1 is substantially the same XRPD obtained in FIG.

Table 1

[Table 1]

2theta	d spacing	Relative strength%
4.95	17.87	55.14
5.26	16.79	51.49
6.22	14.20	100.00
7.22	12.24	39.00
7.66	11.54	49.18
8.90	9.93	42.81
9.36	9.44	38.30
9.95	8.89	43.47
10.45	8.46	30.64
10.97	8.06	20.12
12.51	7.08	99.90
14.89	5.95	32.18
15.69	5.65	62.49
15.96	5.55	37.49
16.47	5.38	49.44
17.23	5.15	30.92
17.95	4.94	28.12
18.87	4.70	36.32
19.56	4.54	31.45
20.57	4.32	21.24
21.34	4.16	15.50
22.70	3.92	7.95
23.46	3.79	6.10
24.72	3.60	6.51
25.11	3.55	7.62

References

Gioiello, Antimo; Macchiarulo, Antonio; Carotti, Andrea; Filipponi, Paolo; Costantino, Gabriele; Rizzo, Giovanni; Adorini, Luciano; Pellicciari, Roberto (April 2011). “Extending SAR of bile acids as FXR ligands: Discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine”. Bioorganic & Medicinal Chemistry 19 (8): 2650–2658.doi:10.1016/j.bmc.2011.03.004.
Wall Street Journal. “A $4 Billion Surprise for 45-Person Biotech”. Retrieved10 January 2014.
Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM (August 2002). “6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity”. J. Med. Chem. 45(17): 3569–72. doi:10.1021/jm025529g. PMID 12166927.
Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (September 2005). “Role of FXR in regulating bile acid homeostasis and relevance for human diseases”. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5 (3): 289–303. doi:10.2174/1568008054863781.PMID 16178789.
“ClinicalTrials.gov”.
Hirschfield GM, Gershwin ME (January 2013). “The immunobiology and pathophysiology of primary biliary cirrhosis”. Annu Rev Pathol 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352.
Lindor, KD (May 2011). “Farnesoid X receptor agonists for primary biliary cirrhosis”.Current opinion in gastroenterology 27 (3): 285–8.doi:10.1097/MOG.0b013e32834452c8. PMID 21297469.
Fiorucci S, Cipriani S, Mencarelli A, Baldelli F, Bifulco G, Zampella A (August 2011). “Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA”. Mini Rev Med Chem 11 (9): 753–62. doi:10.2174/138955711796355258.PMID 21707532.
Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC, Parés A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Böhm O, Shapiro D (2015). “Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid”.Gastroenterology 148 (4): 751–61.e8. doi:10.1053/j.gastro.2014.12.005.PMID 25500425.
Intercept Pharma. “Press release: Intercept Announces Positive Pivotal Phase 3 POISE Trial Results”. Retrieved March 27, 2014.
Adorini L, Pruzanski M, Shapiro D (September 2012). “Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis”. Drug Discov. Today 17 (17–18): 988–97.doi:10.1016/j.drudis.2012.05.012. PMID 22652341.
Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D (September 2013). “Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease”. Gastroenterology 145 (3): 574–82.e1.doi:10.1053/j.gastro.2013.05.042. PMID 23727264.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E (2015). “Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial”. Lancet 385 (9972): 956–65.doi:10.1016/S0140-6736(14)61933-4. PMID 25468160.
http://www.thestreet.com/story/12714549/1/intercept-pharma-government-scientists-spar-over-negative-safety-of-liver-drug-emails-show.html?puc=yahoo&cm_ven=YAHOO
Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Vander Elst I, Windmolders P, Vanuytsel T, Nevens F, Laleman W (November 2013). “Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats”. Hepatology 59 (6): :2286–98. doi:10.1002/hep.26939. PMID 24259407.
Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (November 2009). “A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis”. Clin. Gastroenterol. Hepatol. 7 (11): 1189–94.doi:10.1016/j.cgh.2009.04.024. PMID 19426836.
Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (May 2013). “Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids”. Am. J. Physiol. Gastrointest. Liver Physiol. 304 (10): G940–8.doi:10.1152/ajpgi.00398.2012. PMC 3652069. PMID 23518683.
Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA (January 2015). “The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid”. Aliment. Pharmacol. Ther. 41 (1): 54–64.doi:10.1111/apt.12999. PMID 25329562.

External links

“Intercept pharmaceuticals”.
NashBiotechs Several articles on drug candidates in NASH

Patent ID	Date	Patent Title
US8546365	2013-10-01	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US8377916	2013-02-19	Steroids as agonists for FXR
US8058267	2011-11-15	STEROIDS AS AGONISTS FOR FXR
US7994352	2011-08-09	Process for Preparing 3a(Beta)-7a(Beta)-Dihydroxy-6a(Beta)-Alkyl-5Beta-Cholanic Acid
US7932244	2011-04-26	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US7786102	2010-08-31	Steroids as agonists for FXR
US2009062526	2009-03-05	NOVEL METHOD OF SYNTHESIZING ALKYLATED BILE ACID DERIVATIVES
US7138390	2006-11-21	Steroids as agonists for fxr
US2005107475	2005-05-19	Methods of using farnesoid x receptor (frx) agonists

Patent ID	Date	Patent Title
US2016074419	2016-03-17	Preparation and Uses of Obeticholic Acid
US2015359805	2015-12-17	Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2015166598	2015-06-18	Steroids as Agonists for FXR
US2014371190	2014-12-18	Farnesoid X receptor modulators
US2014186438	2014-07-03	COMPOSITIONS COMPRISING EPA AND OBETICHOLIC ACID AND METHODS OF USE THEREOF
US2014148428	2014-05-29	Treatment of Pulmonary Disease
US2014057886	2014-02-27	Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2014024631	2014-01-23	Steroids as Agonists for FXR
US2013345188	2013-12-26	Preparation and Uses of Obeticholic Acid
US8546365	2013-10-01	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions

Obeticholic acid
Systematic (IUPAC) name

(3α,5β,6α,7α)-6-Ethyl-3,7-dihydroxycholan-24-oic acidOR (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
Clinical data
Routes of administration	Oral
Legal status
Legal status	Investigational New Drug
Identifiers
CAS Number	459789-99-2
ATC code	A05AA04 (WHO)
PubChem	CID 447715
IUPHAR/BPS	3435
ChemSpider	394730
UNII	0462Z4S4OZ
KEGG	C15636
ChEMBL	CHEMBL566315
Synonyms	6α-ethyl-chenodeoxycholic acid; INT-747
Chemical data
Formula	C₂₆H₄₄O₄
Molar mass	420.62516 g/mol

/////////6-ECDCA, DSP-1747, INT-747, 459789-99-2, Obeticholic acid

CC[C@@H]1[C@@H]2C[C@@H](CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3[C@@H]1O)CC[C@@H]4[C@H](C)CCC(=O)O)C)C)O

CCC1C2CC(CCC2(C3CCC4(C(C3C1O)CCC4C(C)CCC(=O)O)C)C)O

Flow Chemistry Symposium & Workshop 16-17 June at IICT, Hyderabad, India

flow synthesis Comments Off

Jun 022016

MESSAGE FROM VIJAY KIRPALANI

A 2-day FLOW CHEMISTRY Symposium + Workshop has been organized on 16-17 June 2016 at

IICT Hyderabad, India by Flow Chemistry Society – India Chapter (in collaboration with IICT-Hyderabad & IIT-B)

with speakers from India, UK, Netherlands and Hungary.

Both days have intensive interactive sessions on the theory and industrial applications of Flow Chemistry followed by live demonstrations using 7 different Flow Reactor platforms — from microliters to 10,000 L/day industrial scale.

The Fees are Rs. 5,000 for Industry Delegates and Rs. 2,500 for Academic Delegates (+15% Service Tax) : contact : vk@pi-inc.co or msingh@cipla.com

I have attached a detailed program and look forward to meeting you at the event..

Vijay Kirpalani

Best regards

Vijay Kirpalani
President
Flow Chemistry Society – India Chapter
email : vk@pi-inc.co
Tel: +91-9321342022 // +91-9821342022

ABOUT

IICT, Hyderabad, India

Dr. S. Chandrasekhar,
Director

CSIR-Indian Institute of Chemical Technology (IICT)

Hyderabad, India

SPEAKERS

Vijay Kirpalani

Mr Vijay Kirpalani

President
Flow Chemistry Society – India Chapter, INDIA

Dr Charlotte Wiles , CHEMTRIX

UK &THE NETHERLANDS,UNIV OF HULL

Prof Anil Kumar( IIT-B), INDIA

CIPLA &

Flow Chemistry Society – India Chapter, INDIA

IICT, INDIA

TU EINDHOWEN

GLIMPSE OF HYDERABAD INDIA

OLD MAP

NEW MAP

TAN DOORI CHICKEN IN HYDERABAD

BIRYANI

/////

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

Ladostigil

Uncategorized Comments Off

Jun 022016

Ladostigil, TV-3,326

(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate

(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate; R-CPAI

Carbamic acid, ethylmethyl-, (3R)-2,3-dihydro-3-(2-propynylamino)-1H-inden-5-yl ester

Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 2)
Company: Avraham Pharmaceuticals Ltd

Target Type: Cholinergic System

CAS No:	209349-27-4
Synonyms:	Ladostigil, TV-3326, UNII-SW3H1USR4Q
Molecular Weight:	272.346 g/mol

Chemical Formula:	C16-H20-N2-O2

IUPAC Name:	(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate N-Propargyl-(3R)-aminoindan-5-yl) ethyl methyl carbamate

Ladostigil tartrate Structure

CAS 209394-46-7, Ladostigil tartrate

N-Ethyl-N-methylcarbamic acid 3(R)-(2-propynylamino)-2,3-dihydro-1H-inden-5-yl ester L-tartrate

In 2010, ladostigil tartrate was licensed by Technion Research & Development Foundation and Yissum to Avraham for the treatment of Alzheimer’s disease and other neurogenerative diseases.

Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders likeAlzheimer’s disease, Lewy body disease, and Parkinson’s disease.^[1] It acts as a reversible acetylcholinesterase andbutyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule.^[2]^[3] In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis.^[4] Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.^[5]^[6]

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer’s and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug

LADOSTIGIL

Recently, Yissum Research Development Company associated with the Hebrew University of Jerusalem announced that the University will use a portion of a $9 million dollar grant awarded to Avraham Pharmaceuticals, Pontifax, Clal Biotechnology Industries and Professor Marta Weinstock-Rosin to complete the Phase II efficacy trial in patients afflicted with Alzheimer’s disease.

The trial will be conducted over the course of 52 weeks and will involve the novel drug, Ladostigil. Ladostigil is a new comprehensive drug used to combat symptoms of Alzheimer’s, Parkinson’s, depression, and anxiety. The drug is deemed multi-functional because it addresses a host of neurodegenerative problems. Ladostigil is a brain-selective monoamine oxidase inhibitor (MAOI) that protects the neurons.

PATENT

US 20140243544 http://www.google.co.in/patents/US20140243544

PATENT

WO 2008074816

http://www.google.com/patents/WO2008074816A1?cl=en

Ethylmethyl carbamyl chloride (15.5 g, 127.57 mmol) was added to a stirred suspension of 6-hydroxy-1-indanone (17.2 g, 116.1 mmol) and potassium carbonate (31.8 g, 188 mmol) in acetonitrile (800 mL) at room temperature over a period of 15 minutes. The reaction mixture was heated to reflux and refluxed for 18 hours. The reaction mixture was cooled to ambient temperature, the solvent evaporated and the residue was diluted with water (250 mL) and extracted three times with toluene (250 mL). The combined organic phase was dried on MgSO and toluene was evaporated in a rotary evaporator. The crude crystalline product was purified by crystallization from 2-propanol (200 mL), collected by filtration, and dried under vacuum at 50° C. to afford the title compound (22 g, 81.5%).

1H NMR (300 MHz, CDCl₃) δ ppm 7.47-7.44 (2H, m, Ar), 7.36 (1H, dd, J 8.4 and 2.1, Ar), 3.52-3.37 (2H, m, NCH₂CH₃), 3.14-3.108 [2H, m, OCCH₂CH₂and incl. NCH₃(two rotamers), at 3.08 and 2.99 (3H, s, Me)], 2.74-2.71 (2H, m, OCCH₂CH₂) and 1.25 and 1.19 (two rotamers) (3H,two triplets, J 6.9). Mass Spectrum (FAB+) [MH⁺=234

Example 6(S)-Dimethyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester

Methanesulfonyl anhydride (296 mg, 1.7 mmol) as a solution in dichloromethane (1.5 mL+0.5 mL) was added to a stirred solution of (R)-dimethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (188 mg, 0.8 mmol, product of example 1a) and triethylamine (0.47 mL, 3.4 mmol) in dichloromethane (2 mL) at −78° C. (external) over 10 minutes. The reaction was maintained at this temperature for 1 hour before propargylamine (1.20 mL, 17.0 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (20 mL) and ice-water (20 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 16 mL) before being extracted with ethyl acetate (10 mL). This final organic extract was dried (MgSO₄), filtered and concentrated under reduced pressure to afford the title compound (175 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19 (1H, d, J 8, Ar), 7.09 (1H, d, J 2, Ar), 6.94 (1H, dd, J 8 and 2, Ar), 4.39 (1H, dd, J 6 and 6, CHNH), 3.54 (1H, Dd, J 17 and 3, NCHH), 3.49 (1H, Dd, J 16 and 3, HNCHH), 3.09 (3H, s, Me), 3.03-2.96 [4H, m, NCHCHH and Me incl. at 3.00 (3H, s, Me)], 2.83-2.75 (1H, m, NCHCHH), 2.48-2.39 (1H, m, NCHCH₂CHH), 2.25 (1H, t, J 2, ≡CH) and 1.92-1.83 (1H, m, NCHCH₂CHH). Analysis of this material by chiral LC indicated it to be 70% e.e.

Example 7b(R)-Ethyl-methyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester (ladostigil)

The procedure of example 7a is repeated with (S)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester instead of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester. The R-enantiomer is produced.

PAPER

Tetrahedron: Asymmetry (2012), 23(5), 333-338

http://www.sciencedirect.com/science/article/pii/S0957416612001334

Image for unlabelled figure

(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate

C₁₆H₂₀N₂O₂

ee: 89%

(c 1.46, CHCl₃)

Source of chirality: the precursor

Absolute configuration: (R)

(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate hemi((2R,3R)-2,3-dihydroxysuccinate)

C₃₆H₄₆N₄O₁₀

ee: 99%

(c1.95, CHCl₃)

Source of chirality: the precursor

Absolute configuration: (R,R,R)

Avraham Pharmaceuticals Announces Commencement of a Phase 2 Study of Ladostigil for the Treatment of MCI

Posted on May 17, 2012

Yaacov Michlin appointed Chairman of the Board and Dr. Yona Geffen appointed Chief Executive Officer

Yavne, Israel, May 17, 2012 — Avraham Pharmaceuticals Ltd. announced today the commencement of a Phase 2 clinical trial to evaluate the safety and efficacy of ladostigil in patients diagnosed with mild cognitive impairment (MCI). This 36-month, multi-centre, randomized, double-blind, placebo-controlled trial will include at least 200 patients in 16 centers in Europe and Israel.

In parallel, Avraham Pharmaceuticals has also completed the enrollment of 200 patients in a Phase 2 trial of ladostigil, a novel molecule for the treatment of mild to moderate Alzheimer’s disease. The Phase 2 study is a double-blind, closed-label, placebo-controlled trial taking place at 20 sites in five countries across Europe. In January 2012, the Company performed an interim analysis of this Phase 2 trial, which indicated that the drug is safe and well tolerated, as well as shows a positive trend toward efficacy. Final results of the 26-week trial are expected in the fourth quarter of 2012.

The Company also announced today that it has appointed Yaacov Michlin, CEO of Yissum Research Development Company of the Hebrew University of Jerusalem Ltd., the technology transfer arm of the University, as Chairman of the Board and Yona Geffen, Ph.D., as Chief Executive Officer.

“We strongly believe in ladostigil and are confident that Yona’s background and extensive experience in developing therapies for neurological disorders and neurodegenerative diseases renders her the perfect choice to lead Avraham,” said Yaacov Michlin, Chairman of Avraham Pharmaceuticals and Chief Executive Officer of Yissum. “In further researches performed by Prof. Weinstock-Rosin, ladostigil has showed promise also for the treatment of MCI in addition to Alzheimer’s disease. We are pleased that another Phase 2 clinical trial in patients with MCI has begun in parallel, and look forward to the final results of the Phase 2 study for the treatment of Alzheimer’s disease expected at the end of this year.”

“I am delighted to lead Avraham in these exciting times for the company, as we advance ladostigil in 2 Phase 2 clinical trials simultaneously. We believe that this unique drug candidate has the potential to transform the treatment of various neurodegenerative diseases,” said Dr. Yona Geffen, Avraham Pharmaceuticals Chief Executive Officer.

Dr. Yona Geffen joined Avraham Pharmaceuticals in January 2011 as Senior Vice President of Clinical Affairs and Chief Operating Officer. Dr. Geffen has more than 12 years of experience in the field of drug development in biopharmaceutical companies. Prior to Avraham, she was Executive Drug Development Director at BiolineRx (NASDAQ: BLRX). Before that, Dr. Geffen was a project manager at Proneuron Biotechnologies. Dr. Geffen received her Ph.D. from Ben Gurion University in Beer Sheva, Israel. She also holds an M.Sc. in business management.

Yaacov Michlin has been CEO of Yissum since 2009. Prior to Yissum, Mr. Michlin spent over a decade in leading and assisting pharmaceutical, hi-tech and biomedical companies in various technology commercialization deals, licensing agreements, capital raising activities, partnerships, mergers and acquisitions. Michlin holds a Bachelor of Law and Economics cum laude, and a Master of Law all from Bar-Ilan University, Ramat Gan, Israel. In addition, he has an MBA cum laude from the Technion Israel Institute of Technology, Haifa, Israel.

About Ladostigil

Ladostigil is a novel cholinesterase and brain-selective monoamine oxidase inhibitor, and neuroprotective agent for the treatment of Alzheimer’s disease, mild cognitive impairment and other neurodegenerative diseases. The drug, which was exclusively licensed to Avraham Pharmaceuticals by Yissum Research Development Company Ltd., and by the Technion Research and Development Foundation Ltd. (TRDF), has proven to be safe and well tolerated in Phase 1 and Phase 2 clinical trials. Like other cholinesterase inhibitors currently on the market, ladostigil targets symptomatic relief in Alzheimer’s disease patients. But unlike these drugs, ladostigil, which also causes brain selective inhibition of monoamine oxidase (MAO) provides the potential to improve the behavioral and psychological symptoms of dementia such as depression and anxiety. Moreover, ladostigil has the potential to slow progression of clinical symptoms of Alzheimer’s disease for sustained periods of time and to modify the pathology associated with the disease. In addition, the neuroprotective activity of ladostigil provides a drug candidate that may have the potential to slow progression to Alzheimer’s disease in patients diagnosed with MCI. This potential has been amply demonstrated in animal models, especially in studies of ageing rats.

Ladostigil was designed by Professor Marta Weinstock-Rosin of the Hebrew University of Jerusalem, inventor of Exelon® and Professor Moussa B.H. Youdim of the Technion Israel Institute of Technology, inventor of Azilect®. The drug substance was first synthesized by Professor Michael Chorev of the Hebrew University, who is now based at Harvard University. All three distinguished scientists act as scientific advisors to Avraham Pharmaceuticals.

About Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia worldwide, affecting about one in 20 people 65 years of age or older, accounting for 60-80% of dementia cases. In 2010, 5.4 million people were affected by Alzheimer’s disease in the U.S., where it is the 6th leading cause of death. In Europe, more than 6 million are living with the disease. Approximately half of Alzheimer’s patients also suffer from depression, and up to 40% also exhibit Parkinson-like symptoms.

About Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a syndrome defined as an intermediate stage between the expected cognitive decline of normal aging and the more pronounced decline of dementia. It involves problems with memory, language, thinking and judgment that are greater than typical age-related changes. Although MCI can present with a variety of symptoms, when memory loss is the predominant symptom it is termed “amnestic MCI” and is frequently seen as a prodromal stage of Alzheimer’s disease. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. There is no proven treatment or therapy for MCI.

About Avraham Pharmaceutical

Founded in 2010, Avraham Pharmaceuticals has raised more than $12 million to advance the development of its unique, multi-functional drug substance, ladostigil, currently undergoing two Phase 2 clinical trials for the treatment of Alzheimer’s disease and mild cognitive impairment. The Company has been capitalized by Clal Biotechnology Industries Ltd., the Pontifax Fund and Yissum Research Development Company Ltd., the technology transfer arm of the Hebrew University.

References

Weinstock M, Bejar C, Wang RH, et al. (2000). “TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease”. Journal of Neural Transmission. Supplementum (60): 157–69.PMID 11205137.
Weinreb O, Mandel S, Bar-Am O, et al. (January 2009). “Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer’s disease drugs”. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 6 (1): 163–74.doi:10.1016/j.nurt.2008.10.030. PMID 19110207.
Weinstock M, Luques L, Bejar C, Shoham S (2006). “Ladostigil, a novel multifunctional drug for the treatment of dementia co-morbid with depression”. Journal of Neural Transmission. Supplementum (70): 443–6. PMID 17017566.
Weinreb O, Amit T, Bar-Am O, Youdim MB (December 2007). “Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy”. Annals of the New York Academy of Sciences 1122: 155–68.doi:10.1196/annals.1403.011. PMID 18077571.
Weinstock M, Poltyrev T, Bejar C, Youdim MB (March 2002). “Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression”.Psychopharmacology 160 (3): 318–24. doi:10.1007/s00213-001-0978-x. PMID 11889501.
Weinstock M, Gorodetsky E, Poltyrev T, Gross A, Sagi Y, Youdim M (June 2003). “A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease”. Progress in Neuro-psychopharmacology & Biological Psychiatry 27 (4): 555–61. doi:10.1016/S0278-5846(03)00053-8.PMID 12787840.

Contact Us

Yona Geffen CEO
Avraham Pharmaceuticals Ltd.
42 Hayarkon st.
Northern Industrial Zone
Yavneh, 81227
Israel

WO1998027055A1 *	18 Dec 1997	25 Jun 1998	Teva Pharmaceutical Industries, Ltd.	Aminoindan derivatives
WO2005051371A1	28 Sep 2004	9 Jun 2005	Technion Research & Development Foundation Ltd.	Compositions and methods for treatment of cardiovascular disorders and diseases
WO2006130726A2	31 May 2006	7 Dec 2006	Teva Pharmaceutical Industries, Ltd.	Use of ladostigil for the treatment of multiple sclerosis
WO2007087029A2 *	11 Dec 2006	2 Aug 2007	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Use of low-dose ladostigil for neuroprotection
WO2009022345A1	14 Aug 2008	19 Feb 2009	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Phenyl carbamates for the treatment of multiple sclerosis
WO2009022346A2	14 Aug 2008	19 Feb 2009	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Phenyl carbamates for treating gastrointestinal inflammation
WO2012059920A1	2 Nov 2011	10 May 2012	Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.	Ladostigil dosage regime
US6251938	18 Jun 1999	26 Jun 2001	Teva Pharmaceutical Industries, Ltd.,	Phenylethylamine derivatives
US6303650	18 Jun 1999	16 Oct 2001	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Aminoindan derivatives
US6538025	31 Aug 2001	25 Mar 2003	Teva Pharmaceutical Industries, Ltd.	Aminoindan derivatives
US7335685	22 Feb 2006	26 Feb 2008	Teva Pharmaceutical Industries, Ltd.	Crystals of ladostigil tartrate, methods of production and pharmaceutical compositions thereof
US7375249	21 Feb 2006	20 May 2008	Teva Pharmaceutical Industries Ltd.	Process for the synthesis of enantiomeric indanylamine derivatives
US7476757	15 Apr 2008	13 Jan 2009	Teva Pharmaceutical Industries Ltd.	Process for the synthesis of enantiomeric indanylamine derivatives
US7491847	15 Nov 2006	17 Feb 2009	Teva Pharmaceutical Industries, Ltd.	Methods for isolating propargylated aminoindans
US20050222123	27 Jan 2005	6 Oct 2005	North Shore-Long Island Jewish Research Institute	Cholinesterase inhibitors for treating inflammation
US20060189685	24 Feb 2006	24 Aug 2006	Daniella Licht	Formulations of ladostigil tartrate
US20060189819	22 Feb 2006	24 Aug 2006	Teva Pharmaceutical Industries, Ltd.	Crystals of ladostigil tartrate, methods of production and pharmaceutical compositions thereof
US20060199974	21 Feb 2006	7 Sep 2006	Teva Pharmaceutical Industries Ltd.	Process for the synthesis of enantiomeric indanylamine derivatives
US20070088082	28 Sep 2006	19 Apr 2007	Judith Aronhime	Polymorphic forms of ladostigil tartrate
US20070093549	28 Sep 2006	26 Apr 2007	Judith Aronhime	Methods for preparation of ladostigil tartrate crystalline form A1
US20070112217	15 Nov 2006	17 May 2007	Anton Frenkel	Methods for isolating propargylated aminoindans
US20070135518	8 Dec 2006	14 Jun 2007	Marta Weinstock-Rosin	Use of low-dose ladostigil for neuroprotection
US20070203232	23 Feb 2007	30 Aug 2007	Victor Piryatinsky	Propargylated aminoindans, processes for preparation, and uses thereof
US20070232691	28 Mar 2007	4 Oct 2007	Tamar Goren	Use of ladostigil for the treatment of schizophrenia
US20070293583	11 Dec 2006	20 Dec 2007	Marta Weinstock-Rosin	Use of low-dose ladostigil for neuroprotection

US5532415 *	Mar 28, 1995	Jul 2, 1996	Teva Pharmaceutical Industries Ltd.	R-enantiomer of N-propargyl-1-aminoindan, salts, compositions and uses thereof
US5703059 *	Jan 19, 1994	Dec 30, 1997	British Biotech Pharmaceuticals Ltd.	Disaccharide ligands for selectins
US5936000 *	Jan 16, 1996	Aug 10, 1999	Pharmacia & Upjohn Company	2-aminoindans as selective dopamine D3 ligands
US6271261 *	Jun 24, 1997	Aug 7, 2001	Smithkline Beecham Corporation	IL-8 receptor antagonists
US6271263 *	Mar 2, 1999	Aug 7, 2001	Teva Pharmaceutical Industries, Ltd.	Compositions containing and methods of using 1-aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives
US6303650 *	Jun 18, 1999	Oct 16, 2001	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Aminoindan derivatives
US6462222 *	Aug 31, 2001	Oct 8, 2002	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Aminoindan derivatives
US6538025 *	Aug 31, 2001	Mar 25, 2003	Teva Pharmaceutical Industries, Ltd.	Aminoindan derivatives
US6737547 *	Sep 15, 1999	May 18, 2004	Teva Pharmaceutical Industries, Ltd.	Compositions containing and methods of using N-acyl-1H-aminoindenes
US20040010038 *	Feb 27, 2003	Jan 15, 2004	Eran Blaugrund	Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective MAO inhibitors

Citing Patent	Filing date	Publication date	Applicant	Title
US7649115	Jun 1, 2006	Jan 19, 2010	Jenrin Discovery, Inc.	MAO-B inhibitors useful for treating obesity
US8541475	Dec 31, 2009	Sep 24, 2013	Jenrin Discovery, Inc.	MAO-B inhibitors useful for treating obesity
US8569545	Jun 2, 2009	Oct 29, 2013	Generics (Uk) Limited	Process for the preparation of enantiomerically pure amines
US8809589	Jul 18, 2013	Aug 19, 2014	Generics [Uk] Limited	Process for the preparation of enantiomerically pure amines
US20070088004 *	Jun 1, 2006	Apr 19, 2007	Mcelroy John F	MAO-B inhibitors useful for treating obesity
US20100168068 *	Dec 31, 2009	Jul 1, 2010	Jenrin Discovery	Mao-b inhibitors useful for treating obesity
US20110184071 *	Jun 2, 2009	Jul 28, 2011	Vinayak Gore	process for the preparation of amines
US20110218360 *		Sep 8, 2011	Dr. Reddy’s Laboratories Ltd.	Preparation of rasagiline and salts thereof
CN103443111A *	Apr 2, 2012	Dec 11, 2013	高砂香料工业株式会社	Novel ruthenium complex and process for producing optically active alcohol compound using same as catalyst
CN103443111B *	Apr 2, 2012	Mar 2, 2016	高砂香料工业株式会社	钌配合物以及以该配合物作为催化剂的光学活性醇化合物的制备方法
WO2013118126A1	Feb 11, 2013	Aug 15, 2013	Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.	Ladostigil therapy for immunomodulation

Ladostigil
Systematic (IUPAC) name

[(3R)-3-(prop-2-ynylamino)indan-5-yl]-N-propylcarbamate
Clinical data
Routes of administration	Oral
Legal status
Legal status	Uncontrolled
Identifiers
CAS Number	209349-27-4
ATC code	none
PubChem	CID 208907
ChemSpider	181005
UNII	SW3H1USR4Q
Synonyms	[N-propargyl-(3R)-aminoindan-5yl]-N-propylcarbamate
Chemical data
Formula	C₁₆H₂₀N₂O₂
Molar mass	272.34 g/mol

///////////Ladostigil, TV-3,326

c1c(cc2c(c1)CC[C@H]2NCC#C)OC(=O)N(CC)C

Results of a Survey on ICH Q3D “Elemental Impurities”

regulatory Comments Off

Jun 022016

For most companies manufacturing APIs and pharmaceutical products, the implementation of ICH Q3D has a serious impact – as shown in a survey recently carried out by the ECA. Read more about the issues encountered by many companies regarding the assessment and control of elemental impurities and the kind of support they wish.

SEE

http://www.gmp-compliance.org/enews_05395_Results-of-a-Survey-on-ICH-Q3D-%22Elemental-Impurities%22_15499,15332,S-AYL_n.html

One and a half years after the official entry into force of the ICH Q3D Guideline for “Elemental Impurities” and several supporting documents from the ICH (e.g. “Training Package: Modules 0-7“) a number of questions as regards implementation remain.

In a survey recently performed by the ECA, questions were posed about the issues relating to the fulfilling of the requirements laid down in ICH Q3D. The feedback from almost 80 participants from medium and large pharmaceutical companies and API manufacturers located in Germany and other EU Member States shows remarkable results which harsh light on the aspects companies have to struggle against with regard to the implementation of the guideline. Please find an extract of this survey below:

How strong is the impact of the ICH 3D Guideline on your Company?

For more than half of the respondents, ICH Q3D has a strong impact on the company.

Where do you see the main problems for implementation of ICH Q3D?

For most companies, not only the establishment of safety assessment of potential elemental impurities is seen as problematic but also the analytical procedures for elemental impurities testing required for proving elemental impurities as well as the application of the requirements of ICH Q3D to old products.

Application of ICH Q3D to existing products is not expected until 36 months after publication. How do you judge this deadline?

Whereas a quarter of the companies surveyed judge the time for application of ICH Q3D to existing products as too short, half of them consider it nevertheless feasible – with great effort though.

The following question clearly shows what support companies especially wish with regard to the problematic:

What kind of information would you like to receive from ECA in case that ECA would establish an Interest Group?

Examples for risk assessment for elemental impurities would be highly appreciated; besides, also procedure descriptions i.e. SOPs on how to handle the establishment of risk assessment as well as conferences, workshops or forum on that topic have been assessed as very useful.

///////Results, Survey, ICH Q3D, Elemental Impurities

EDQM’s new Guideline on Electronic Submissions for CEP Applications

regulatory Comments Off

Jun 022016

EDQM’s new Guideline on Electronic Submissions for CEP Applications

As of today (June, 1st 2016), the EDQM doesn’t accept any CEP application in paper format. Read more here about the structure of the electronic submission of an application for a Certificate of Suitability and the errors to avoid.

SEE

http://www.gmp-compliance.org/enews_05380_EDQM-s-new-Guideline-on-Electronic-Submissions-for-CEP-Applications_15429,15332,S-WKS_n.html

The EDQM has recently published a document entitled “Guidance for electronic submissions for Certificates of Suitability (CEP) applications” (PA/PH/CEP (09) 108, 3R) in which the authority describes the requirements to be considered for the submission of an application for a CEP. Let us give you the most important message straight away: the EDQM now only accepts CEP applications in the electronic format since June 1st 2016.

Only the following formats are authorised within an application procedure: PDF, NeeS (non-eCTD electronic submission), VNeeS (the respective application format for veterinary purposes) and eCTD. A change of format during an ongoing application procedure is allowed whereas coming back to the original format isn’t. Basically, the EDQM recommends the use of the eCTD with an exception though: CEP applications for the TSE risk of an API have to be submitted in the PDF format.

The guideline extensively describes how a CEP application should look like with regard to its content and structure. This is illustrated by 5 annexes which present the structure and level of granularity (degree of division in subchapters) of the different formats. The sixth annex (“Main issues which may lead to blocking a submission for its format and causing delays”) lists the problems which may lead to delays in the application procedure with the respective reasons and solutions presented in a table. For example, typical errors in the electronic submission are on the one hand those which complicate the navigation through the application (inappropriate level of granularity, annexes not incorporated in the CTD structure, incorrect designation of PDF bookmarks, etc.) and on the other hand those which disrupt the lifecycle of the application in the eCTD format (wrong sequence of the chapters, incorrect attributes, e.g. “New” instead of “Replace” when replacing a leaf).

Generally, the standards applicable for the electronic submission of an application for a marketing authorisation of medicinal products must also be fulfilled in a CEP application. The “Electronic Standards for the Transfer of Regulatory Information” (ESTRI) have been elaborated by ICH’s M2 Expert Working Group and are available on a separate website: the ESTRI webpage.

Now, the electronic submission of a CEP application can be done via the “Common European Submission Platform” (CESP) of the EDQM. First, a registration on the “Common European Submission Portal” is necessary. If it’s not possible, there are other alternatives: secured drop-box (the EDQM provides the access data on request), CD-ROM, DVD and USB stick. Password protection or encodings must be removed first.

//////////// EDQM, Guideline, Electronic Submissions, CEP Applications

Дапипразол Dapiprazole

Uncategorized Comments Off

Jun 012016

Dapiprazole

CAS 72822-12-9

HCL SALT 72822-13-0

5,6,7,8-Tetrahydro-3-(2-(4-(O-tolyl)-1-piperazinyl)ethyl)-S-triazolo(4,3-a)pyridine

Dapiprazole (Rev-Eyes) is an alpha blocker. It is used to reverse mydriasis after eye examination.^[1]

Used in the treatment of iatrogenically induced mydriasis produced by adrenergic (phenylephrine) or parasympatholytic (tropicamide) agents used in certain eye examinations.

Dapiprazole is an alpha-adrenergic blocking agent. It produces miosis by blocking the alpha-adrenergic receptors on the dilator muscle of the iris. Dapiprazole produces no significant action on ciliary muscle contraction and thus, there are no changes in the depth of the anterior chamber of the thickness of the lens. It does not alter the IOP either in normal eyes or in eyes with elevated IOP. The rate of pupillary constriction may be slightly slower in clients with brown irises than in clients with blue or green irises.

Dapiprazole acts through blocking the alpha1-adrenergic receptors in smooth muscle. It produces miosis through an effect on the dilator muscle of the iris and does not have any significant activity on ciliary muscle contraction and, therefore does not induce a significant change in the anterior chamber depth or the thickness of the lens.

Oral LD₅₀ is 1189-2100 mg/kg in mice, rats and rabbits.

Brief background information

Salt	ATC	formula	MM	CASE
–	N05AX S01EX02	C₁₉H₂₇N₅	325.46 g / mol	72822-12-9
monogïdroxlorïd	N05AX S01EX02	C₁₉H₂₇N₅ · HCl	361.92 g / mol	72822-13-0

Application

antipsihoticheskoe means
in the treatment of glaucoma

Classes substance

Piperazinы
- 1,2,4-triazolo [4,3-a] piridinы

Synthesis

Синтез a)


Scheme illustration:By cyclization of O-methylvalerolactam (I) with 3-(4-o-tolyl-1-piperazinyl) propionic acid hydrazide (II) in refluxing xylene, followed by a treatment with ethanolic HCl.

FR 2423221; GB 2020269; JP 54157576; NL 7902489; US 4252721

Acylation of (1-methylcyclopropyl)guanidine (IV) with 3-bromo-5-chlorothiophene-2-sulfonyl chloride (III) under Schotten-Baumann conditions afforded the sulfonyl guanidine (V). This was cyclized to the desired thienothiadiazine upon treatment with Cs2CO3 and Cu2O in boiling butanol.

In a different method, (1-methylcyclopropyl)guanidine (I) is acylated by 3-bromo-5-chlorothiophene-2-sulfonyl chloride (II) to produce the sulfonyl guanidine (III). Intramolecular cyclization of (III) in the presence of Cu2O and Cs2CO3 leads to the title thienothiadiazine derivative. Similarly, acylation of guanidine (I) with 3,5-dichlorothiophene-2-sulfonyl chloride (IV) provides sulfonyl guanidine (V), which is then cyclized in the presence of Cu2O and Cs2CO3.

In an alternative method, sulfonylation of N-isopropylguanidine (V) with 2,5-dichlorothiophene-3-sulfonyl chloride (IV) produced the sulfonyl guanidine (VI). This was then cyclized to the title compound by treatment with copper bronze and potassium carbonate in boiling DMF……..WO 0102410

Trade names

country	Tradename	Manufacturer
Germany	Remidrial	winegrower
Italy	Glamidolo	Angelini, 1987
Ukraine	no	no

Formulations

eyedrops 50 mg / 10 ml (5%) (hydrochloride)

References

DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
BE 877 161 (Angelini; appl. 21.6.1979).

References

Doughty, Michael J.; Lyle, William M. (May 1992). “A Review of the Clinical Pharmacokinetics of Pilocarpine, Moxisylyte (Thymoxamine), and Dapiprazole in the Reversal of Diagnostic Pupillary Dilation”. Optometry & Vision Science 69 (5).
US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
BE 877 161 (Angelini; appl. 21.6.1979).
DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).

Structural formula

UV- Spectrum

The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH

Conditions : Concentration – 1 mg / 100 ml
maximum absorption	235 nm	235 nm	234 nm	There decay
	212	179	172	–
e	7650	6450	6200	–

IR – spectrum

Wavelength (μm)

Wave number (cm ^-1 )

References

UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
NIST/EPA/NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Dapiprazole
Systematic (IUPAC) name

3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,5-a]pyridine
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a601043
Pregnancy category	B
Routes of administration	Topical (eye drops)
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Negligible when administered topically
Identifiers
CAS Number	72822-12-9
ATC code	S01EX02 (WHO)
PubChem	CID 3033538
IUPHAR/BPS	7155
DrugBank	DB00298
ChemSpider	2298190
UNII	5RNZ8GJO7K
KEGG	D07775
ChEBI	CHEBI:51066
ChEMBL	CHEMBL1201216
Chemical data
Formula	C₁₉H₂₇N₅
Molar mass	325.451 g/mol

//////Дапипразол , Dapiprazole, AF-2139, Remydrial, Rev-Eyes, Reversil, Glamidolo

n1nc(n2c1CCCC2)CCN4CCN(c3ccccc3C)CC4

Activated nanostructured bimetallic catalysts for C-C coupling reactions: recent progress

PROCESS, SYNTHESIS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, 6,3341-3361
DOI: 10.1039/C5CY02225H, Minireview

Rohit Kumar Rai, Deepika Tyagi, Kavita Gupta, Sanjay Kumar Singh
This minireview highlights the recent progress made in the last decade towards the development of activated bimetallic alloy nanoparticle catalysts for C-C coupling reactions, including asymmetric C-C bond coupling reactions.

Minireview

Activated nanostructured bimetallic catalysts for C–C coupling reactions: recent progress

Rohit Kumar Rai,^a Deepika Tyagi,^a Kavita Gupta^a and Sanjay Kumar Singh*^a^b

*Corresponding authors

^aDiscipline of Chemistry, Indian Institute of Technology (IIT) Indore, Simrol, Indore, 452 020 India

^bCentre for Material Science and Engineering, Indian Institute of Technology (IIT) Indore, Simrol, Indore, 452 020 India
E-mail: sksingh@iiti.ac.in
Fax: +91 731 2438 933

Catal. Sci. Technol., 2016,6, 3341-3361

DOI: 10.1039/C5CY02225H

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C5CY02225H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

Catalysts based on bimetallic nanoparticles have received tremendous scientific and industrial attention and are established as an important class of active catalysts. These catalysts displayed improved catalytic activities compared to their monometallic counterparts for several reactions, which is attributed to their highly modified surface structures (electronic and geometrical) due to the synergic cooperation between the two metals of the bimetallic nanoparticle catalyst. Moreover, such synergic interactions are more prominent in alloy nanoparticle catalysts, where the probability of metal-to-metal interactions is higher in comparison with other systems (such as core–shell nanoparticles). This minireview highlights the recent progress made in the last decade towards the development of activated bimetallic alloy nanoparticle catalysts for C–C coupling reactions, including asymmetric C–C bond coupling reactions. Herein, the influence of the modified electronic structures of the newly formed bimetallic alloy nanoparticle catalysts on their activated catalytic performance is also discussed extensively.

भारतीय प्रौद्योगिकी संस्थान इंदौर
INDIAN INSTITUTE OF TECHNOLOGY INDORE

School of Basic Sciences

Discipline of Chemistry

Dr. Sanjay Kumar Singh

Assistant Professor

Chemistry

Organometallics and Nanotech Catalysis Group

Discipline of Chemistry, School of Basic Sciences

Indian Institute of Technology Indore, Simrol, Indore 452 020

Dr. Sanjay Kumar Singh

Assistant Professor

Chemistry

sksingh[at]iiti.ac.in

Mr. Rohit Rai

Ph.D. Student (CSIR-SRF), Since Jan. 2013

He obtained his Masters degree in Organic Chemistry from BHU Varanasi in the year 2012. He is presently engaged in the development of nanoparticle based heterogeneous catalysts for important organic reactions.

rohitrai47[at]gmail.com; phd12123108[at]iiti.ac.in

Rohit Kumar Rai
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd12123108[at]iiti.ac.in

Research Topic: Development of nanoparticle based heterogeneous catalysts for important organic reactions

Ms. Deepika Tyagi

Ph.D. Student (UGC-SRF), Since Jan. 2013

She obtained her Masters degree in Organic Chemistry from C.C.S. Meerut University in the year 2011. She is presently engaged in the development of homogeneous catalysts based on organometallic and coordination complexes for important organic reactions.

tyagi.deepika30[at]gmail.com; phd12123112[at]iiti.ac.in

Deepika Tyagi
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd12123112[at]iiti.ac.in

Research Topic: Development of homogeneous catalysts based on metal complexes for important organic reactions

Ms. Kavita Gupta

Ph.D. Student (CSIR-SRF), Since Jul., 2013

She obtained her Masters degree in Organic Chemistry from Dr. B.R.A. University, Agra in the year 2010. She is presently engaged in the development of catalytic systems for the conversion of bioderived molecules to bio-fuel components and other important products.

phd1301131005[at]iiti.ac.in

Kavita Gupta
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd1301131005[at]iiti.ac.in

Research Topic: Development of catalysts for important catalytic reactions

ALL AUTHORS

//////Activated nanostructured, bimetallic catalysts, C-C coupling reactions, recent progress

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

PROCESS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, 6,3378-3385
DOI: 10.1039/C6CY00033A, Paper

Gang Yang, Lijun Zhou
Several key issues regarding the mechanisms of proline catalysis are unravelled by first-principles calculations that can guide future catalyst design.

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

Gang Yang*^a and Lijun Zhou^a

*Corresponding authors

^aCollege of Resource and Environment & Chongqing Key Laboratory of Soil Multi-scale Interfacial Process, Southwest University, Chongqing, PR China
E-mail: theobiochem@gmail.com
Fax: +86 023 68250444
Tel: +86 023 68251545

Catal. Sci. Technol., 2016,6, 3378-3385

DOI: 10.1039/C6CY00033A

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C6CY00033A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

Proline is an efficient and versatile catalyst for organic reactions while a number of issues remain controversial. Here, ab initio and density functional calculations were used to unravel a few key issues of catalytic mechanisms in water and organic solvents. Zwitterionic proline that predominates in water and DMSO is assumed to be the active conformation for catalysis, and reactivity differences in two solvents are revealed. Meanwhile, an abundance of experimental observations can be finely interpreted by the present computational results, including those seemingly contradictory. Although bearing lower activation barriers than that in DMSO, the production of enamines and further aldol products in water will be blocked at an early stage (J. Am. Chem. Soc., 2006, 128, 734) because the reaction in water is significantly driven towards acetyl formation that is kinetically and thermodynamically preferred. Due to significant promotion of the rate-determining proton transfer step, aldol reactions in organic solvents can be obviously initiated by the addition of some water (Angew. Chem., Int. Ed., 2004, 43, 1983). In order to show catalytic effects in water (an obviously environmentally benign solvent), proline has to be structurally modified so that canonical structures can be the principal (or sole) conformations, which is in line with the analyses of all proline-based catalysts available in water (e.g., J. Am. Chem. Soc., 2006, 128, 734, Catal. Commun., 2012, 26, 6). Thus, the present results provide insightful clues to mechanisms of proline-mediated catalysis as well as future design of more efficient catalysts.

IF YOU HAVE ENJOYED IT ………EMAIL ME amcrasto@gmail.com, +919323115463, India

INDIA FLAG

DR ANTHONY CRASTO , WORLDDRUGTRACKER, HELPING MILLIONS, MAKING INDIA AND INDIANS PROUD

//////Mechanisms, reactivity, differences, proline-mediated catalysis, water , organic solvents

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C6CY00855K, Communication

Nicholas J. Weise, Syed T. Ahmed, Fabio Parmeggiani, Elina Siirola, Ahir Pushpanath, Ursula Schell, Nicholas J. Turner
An industrial-scale method employing a phenylalanine ammonia lyase enzyme

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

Nicholas J. Weise,^a Syed T. Ahmed,^a Fabio Parmeggiani,^a Elina Siirola,^b Ahir Pushpanath,^b Ursula Schell^b and Nicholas J. Turner*^a

*Corresponding authors

^aManchester Institute of Biotechnology & School of Chemistry, University of Manchester, 131 Princess Street, Manchester, UK
E-mail: nicholas.turner@manchester.ac.uk

^bJohnson Matthey Catalysts and Chiral Technologies, 28 Cambridge Science Park, Milton Road, Cambridge, UK

Catal. Sci. Technol., 2016, Advance Article

DOI: 10.1039/C6CY00855K

SEE

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C6CY00855K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

An intensified, industrially-relevant strategy for the production of enantiopure halophenylalanines has been developed using the novel combination of a cyanobacterial phenylalanine ammonia lyase (PAL) and ammonium carbamate reaction buffer. The process boasts STYs up to >200 g L⁻¹ d⁻¹, ees ≥ 98% and simplified catalyst/reaction buffer preparation and work up.

///////Intensified, biocatalytic production, enantiomerically pure, halophenylalanines, acrylic acids, ammonium carbamate, ammonia source

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

flow synthesis Comments Off

May 312016

React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B, Paper

Open Access

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows, Richard A. Bourne
Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.

Paper

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Nicholas Holmes,^a Geoffrey R. Akien,^a^b A. John Blacker,^a^c Robert L. Woodward,^d Rebecca E. Meadows^d and Richard A. Bourne*^a^c^d

*Corresponding authors

^aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: r.a.bourne@leeds.ac.uk

^bDepartment of Chemistry, Faraday Building, Lancaster University, Lancaster, UK

^cSchool of Chemical and Process Engineering, University of Leeds, Leeds, UK

^dAstraZeneca Pharmaceutical Development, Silk Road Business Park, Macclesfield, UK

React. Chem. Eng., 2016, Advance Article

DOI: 10.1039/C6RE00059B

http://pubs.rsc.org/en/Content/ArticleLanding/2016/RE/C6RE00059B#!divAbstract

Scheme 1 Synthesis of the model acrylamide 6 via the β-chloroamide 5 intermediate.

image file: c6re00059b-s1.tif

Scheme 2 Proposed mechanisms to dimers 8a and 8b. The observation of a peak corresponding to 7suggested a Rauhut–Currier mechanism to 8b but subsequent LC-MS-MS analysis showed the major dimer to most likely be 8a. All observed peaks from offline LC-MS are displayed.

image file: c6re00059b-s2.tif