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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist from Zydus Cadila


Indian flag
str1
(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
str1
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
 

The compounds of theese type lower blood glucose, regulate peripheral satiety, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density l ipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions.

The compounds of are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. -These compounds  are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non-insulin dependent diabetes mel litus (N I DDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabol ism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, l ike arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.

Diabetes mellitus is a serious disease affl icting over 1 00 mi l lion people worldwide. In the United States, there are more than 12 mill ion diabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. There are many- types of diabetes, but the two most common are Type 1 (also referred to as insulin- dependent diabetes mellitus or IDDM) and Type II (also referred to as non- insulin-dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood, into the cells where it becomes the body’s primary fuel.

People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body. However, people who have diabetes either don’t produce insulin or can’t efficiently use the insulin they produce; therefore, they can’t move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.

Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormal ities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.

About 5% to 10% of the people who have diabetes have IDDM. These individuals don’t produce insulin and therefore must inject insulin to keep their blood glucose levels normal . IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing β cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don’t respond properly to the hormone, so glucose accumulates i n their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insul in levels, whi le other NIDDM patients have inadequate insul in production ( otwein, R. et al. N. Engl. J. Med. 308, 65-71 ( 1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically non-apparent, making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is l ikely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin’s Principles and Practice of Medical Genetics 3rd Ed. 1 : 1401 – 1402 ( 1996)).

Many people with NIDDM have sedentary lifestyles and are obese; they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsul inemia and insul in resistance, a feature shared with NIDDM, hypertension and atherosclerosis.

The G-protein -coupled receptor GPR 40 functions as a receptor for long-chain free fatty acids (FFAs) in the body and as such is impl icated in a large number of metabolic conditions in the body. For example it has been alleged that a GPR 40 agonist promotes insulin secretion whilst a GPR 40 antagonist inhibits insulin secretion and so depending upon the circumstances the agonist and antagonist may be useful as therapeutic agents for the number of insul in related conditions such as type 2 diabetes, obesity, impaired glucose tolerance, insul in resistance, neurodegenerative diseases and the like.

There is increasing evidences that lipids can also serve as extracel lular l igands for a specific class of receptors and thus act as “nutritional sensors” (Nolan CJ et al. J. Clinic. Invest., 2006, 1 1 6, 1 802- 1 812The free fatty acids can regulate cell function. Free fatty acids have demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and have been proposed to play a critical role in physiological glucose homeostasis.

GPR40, GPR 120, GPR41 and GPR43 exemplify a growing number of GPCRs that have been shown to be activated by free fatty acids. GPR40 and GPR 120 are activated by medium to long-chain free fatty acids whereas GPR 41 and GPR 43 are activated by short-chain fatty acid (Brown AJ et al, 2003).

GPR 40 is highly expressed on pancreatic β-cells, and enhances glucose- stimulated insulin secretion {Nature, 2003, 422, 1 73- 1 76, J. Bio. Chem. 2003, 278, 1 1303- 1 13 1 1 , Biochem. Biophys. Res. Commun. 2003, 301, 406-4 10).

Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 is reported {Lett, to Nature 2003, 422, 1 73- 1 76).

GlaxoSmith line Research and Development, US published an article in Bioorg. Med. Chem. Lett. 2006, 16, 1840- 1 845 titled Synthesis and activity of small molecule GPR40 agonists. (Does this describe GW9508?)Another article titled Pharmacological regulation of insul in secretion in ΜΓΝ6 cells through the fatty – acid receptor GPR40: Identification of agonist and antagonist small molecules is reported in

Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKl i ne. USA (Does this describe GW9508?) ‘

GW 9508.

Solid phase synthesis and SAR of small molecule agonists for the. GPR 40 receptor is published in Bioorg. Med. Chem. Lett. 2007, 16, 1 840- 1 845 by Glaxo Smith line Res. 8c Dev. USA, including those with the following structures.

Johnson & Johnson Pharmaceutical Research and development , USA published

Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoic acid as a Novel Series of G-protein -coupled receptor 40 agonists J. Med. Chem. 2007,

76, 2807-2817)

National Institutes of Health, Bethesda, Maryland publ ished “Bidirectional Iterative Approach to the Structural Delineation of the Functional Chemo print in GPR 40 for agonist Recognition (J. Med. Chem. 2007. 50, 298 1 -2990).

Discov roglucinols of the following formula

as a new class of GPR40 (FFAR 1 ) agonists has been publ ished by Piramal Li fe Sciences, Ltd. in Bioorg. Med. Chem. Lett. 2008, 1 8, 6357-6361

Synthesis and SAR of 1 ,2,3,4-tctrahydroisoquinoline- l -ones as novel G-protein coupled receptor40(GPR40) antagonists of the following formula has been published in Bioorg. Med. Chem. Lett. 2009, 79, 2400-2403 by Pfizer

Piramal Life Sciences Ltd. published “Progress in the discovery and development of small molecule modulators of G-protei n coupled receptor 40(GPR40/FFA 1 /FFAR1 ), an emerging target for type 2 diabetes” in Exp. Opin. Therapeutic Patents 2009, 19(2), 237 -264.

There was a report published in Zhonggno Bingli Shengli ^Zazhi 2009, 25(7), 1376- 1380 from Sun Yat. Sen University, Guangzhou, which mentions the role GPR 40 on lipoapoptosis.

A novel class of antagonists for the FFA’s receptor GPR 40 was published in Biochem. Biophy. Res. Commun. 2009 390, 557-563.

N41 (DC260126)

Merck Res. Laboratories published “Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists” having the following formula in Bioorg. Med. Chem. Lett. 2010 20, 1298- 1 301

Discovery of TA -875, a potent, selective, and oral ly bioavai lable G PR 40 agonist is reported by Takeda Pharmaceutical Ltd. ACS Med. Chem. Lett. 2010,

7(6), 290-294

In another report from University of Southern Denmark” Structure -Activity of Dihydrocinnamic acids and discovery of potent FFA l (GPR40) agonist TUG-469″ is reported in ACS Me -349.

The free fatty acid 1 receptor (FFAR 1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insul in secretion, has emerged as an attractive target for the treatment of type 2 diabetes (ACS Med. Chem. Lett. 2010, 1 (6), 290-294).

G-protein coupled receptor (GPR40) expression and its regulation in human pancreatic islets: The role of type 2 diabetes and fatty acids is reported in Nutrition Metabolism & Cardiovascular diseases 2010, 2(9( 1 ), 22-25

Ranbaxy reported “Identification of Berberine as a novel agonist of fatty acid receptor GPR40” in Phytother Res. 2010, 24, 1260-63.

The following substituted 3-(4-aryloxyaryI)-propanoic acids as GPR40 agonists are reported by Merck Res. Lab. in Bioorg. ed. Chem. Lett. 201 1 , 21, 3390-3394

4 EC50=0.970 μΜ 5. EC50=2.484 μΜ

CoMSIA study on substituted aryl alkanoic acid analogs as GPR 40 agonists is reported Chem. Bio. Drug. Des. 201 1 , 77, 361 -372

Takeda further published “Design, Synthesis and biological activity of potential and orally available G-protein coupled receptor 40 agonists” in J. Med. Chem. 201 1 , 54(5), 1365- 1 378.

Amgen disclosed a potent oral ly bioavai lable GPR 40 agonist AMG-837 in Bioorg. Med. Chem. Lett.

Discovery of phenylpropanoic acid derivatives containing polar functional ities as Potent and orally bioavailable G protein-coupled receptor 40 Agonist for the treatment of type 2 Diabetes is reported in J. Med. Chem. 2012, 55, 3756-3776 by Takeda.

Discovery of AM- 1638: A potent and orally bioavailable GPR40/FFA 1 full agonist is reported in ACS Med. Chem. Lett. 2012, 3(9), 726-730.

 

Ranjit Desai

Ranjit Desai

Sr Vice President. Head-Chemistry
Zydus Research Centre, Ahmedabad · Chemistry

Sameer Agarwal

Sameer Agarwal

Cadila Healthcare Ltd., India

Sameer Agarwal has obtained Master’s in Chemistry from IIT, Delhi and was awarded DAAD (German Govt. Scholarship) fellowship to purse research project at Karlsruhe University, Germany. He has received PhD degree from Technical University, Dresden, Germany in the field of Synthetic and bio-organic chemistry under direction of Prof. Dr. Hans-Joachim Knölker, FRSC, a well-known scientist of present times for his contribution towards Alkaloid Chemistry. He worked as Research Scientist (Post-Doc), JADO Technologies, (collaboration with Max Planck Institute (MPI) of Molecular Cell Biology and Genetics and Chemsitry Department, Technical University), Germany. He then decided to return to his home country and working with Zydus Research Centre, Cadila Healthcare Ltd., Ahmedabad as Principal Scientist / Group Leader in the area of basic drug discovery and his research interest includes discovery of cardio metabolic, anti-inflammatory and oncology drugs. He has large number of publications in international journals and patents and is a reviewer of many prestigious journals including American Chemical Society.

Paper

Identification of an Orally Efficacious GPR40/ FFAR1 Receptor Agonist

ArticleinACS Medicinal Chemistry Letters · September 2016
DOI: 10.1021/acsmedchemlett.6b00331
Abstract Image

GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic β-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity

Synthesis of compound 5 is depicted in Scheme 1a.

The reductive amination1 of commercially available 3-thiophene-aldehyde (3) and isopropyl amine using sodium triacetoxyborohydride resulted in secondary amine intermediate 4. Compound 4 on further reductive amination under similar conditions with aldehyde intermediate, (S)-3-(4-((3-formylbenzyl)oxy)phenyl)hex-4-ynoic acid (8), afforded 2d in high yields. The aldehyde intermediate, 8 was obtained from (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (6) as shown in Scheme 1b. Acid 6 was synthesized via 5-step reported procedure using commercially available 4-hydroxybenzaldehyde and Meldrum’s acid.2 Resolution of racemic acid 6 was accomplished via diastereomeric salt formation with (1S,2R)-1-amino-2-indanol followed by salt break with aqueous acid to furnish compound 6. Treatment of 6 with of 40% aqueous tetrabutylphosphonium hydroxide (nBu4POH) in THF, followed by addition of 3-formyl benzyl bromide (7), afforded aldehyde intermediate 8. Compound 2d was further converted to its corresponding calcium salt (5) in two-step sequence with excellent chemical purity.

Scheme 1a. Synthesis of Compounds 2d and 5. Reagent and Conditions: (a) CH(CH3)2NH2, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (b) Comp 8, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (c) NaOH, MeCN/H2O, r.t., 3 h; (d) CaCl2, MeOH/H2O, r.t., 16 h.

BASE

(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1.557 g, 3.34 mmol, 43.0 % yield) as wax solid.

1H NMR (400 MHz, DMSO-d6): δ = 12.35 (br s, 1H), 7.44 (q, J = 3.2 Hz, 2H), 7.32 – 7.24 (m, 6H), 7.04 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.93 (d, J = 2.4 Hz, 1H), 3.51 (d, J = 8.8 Hz, 4H), 2.84 (sept, J = 6.4 Hz, 1H), 2.57 (d, J = 8 Hz, 2H), 1.77 (d, J = 2.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT: DMSO-d6, 100MHz):- δ = 172.35 (C), 157.63 (C), 142.13 (C), 141.44 (C), 137.42 (C), 133.93 (C), 128.73 (CH), 128.64 (CH), 128.43 (CH), 127.99 (CH), 127.73 (CH), 126.28 (CH), 122.21 (CH), 115.10 (CH), 81.16 (C), 78.52 (C), 69.69 (CH2), 52.90 (CH2), 48.64 (CH), 48.49 (CH2), 43.44 (CH2), 33.15 (CH), 17.92 (CH3), 3.66 (CH3);

MS (EI): m/z (%) = 462.35 (100) (M+H) + ;

IR (KBr): ν = 3433, 2960, 2918, 2810, 1712, 1608, 1510, 1383, 1240, 1174, 1109, 1018 cm-1 .

CA SALT

calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate (1.51 g, 1.536 mmol, 46% yield) as white powder. mp: 124.5 o C;

1H NMR (400 MHz, DMSO-d6): δ = 7.43 – 7.42 (m, 2H), 7.28 – 7.24 (m, 6H), 7.04 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.02 (s, 2H), 4.02 (s, 1H), 3.50 (d, J = 7.2 Hz, 4H), 2.84 – 2.77 (sept, J = 6.4 Hz, 1H), 2.43 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 2.28 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 1.73 (s, 3H), 0.99 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT (100 MHz, DMSO-d6): δ = 177.78 (C), 157.23 (C), 142.11 (C), 141.4 (C), 137.46 (C), 135.81 (C), 128.83 (CH), 128.62 (CH), 128.40 (CH), 127.94 (CH), 127.69 (CH), 126.26 (CH), 122.18 (CH), 114.77 (CH), 83.18 (C), 77.32 (C), 69.66 (CH2), 52.89 (CH2), 48.59 (CH), 48.48 (CH2), 46.86 (CH2), 33.52 (CH), 17.88 (CH3), 3.78 (CH3);

MS (EI): m/z (%) = 462.05 (100) (M+H)+ ;

ESI-Q-TOF-MS: m/z [M+H]+ calcd for [C28H31NO3S + H]+ : 462.6280; found: 462.4988;

IR (KBr): ν = 3435, 2960, 2918, 2868, 2818, 1608, 1550, 1508, 1440, 1383, 1359, 1240 cm-1 ;

HPLC (% Purity) = 99.38%; Calcium Content (C56H60CaN2O6S2) Calcd.: 4.17%. Found: 3.99%.

 COMPD Ca salt

Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate

Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist

Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad-382 210, India
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00331
*(S.A.) E-mail: sameeragarwal@zyduscadila.com or sameer_ag@yahoo.com., *(R.C.D.) E-mail: ranjitdesai@zyduscadila.com. Fax:+91-2717-665355. Tel: +91-2717-665555.
Ranjit Desai

Sr Vice President, Head Chemistry

Zydus Cadila

2012 – Present (4 years)Zydus Research Centre, Ahmedabad, India

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd
Dr. Mukul Jain

Senior Vice President at Zydus Research Centre

Prashant Deshmukh

Prashant Deshmukh

Research Officer at Zydus Cadila

Dr. Poonam Giri

Dr. Poonam Giri

Principal Scientist at Zydus Research Centre

Bhadresh Rami

Bhadresh Rami

Debdutta Bandyopadhyay

Debdutta Bandyopadhyay

Senior General manager at Zydus Research Centre

Suresh Giri

Suresh Giri

Research Scientist

 References
1. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem., 1996, 61 (11), 3849–3862.
2. Walker, S. D.; Borths, C. J.; DiVirgilio, E.; Huang, L.; Liu, P.; Morrison, H.; Sugi, K.; Tanaka, M.; Woo, J. C. S.; Faul, M. M. Development of a Scalable Synthesis of a GPR40 Receptor Agonist. Org. Process Res. Dev. 2011, 15, 570–580.
3. Desai, R. C., Agarwal, S. Novel Heterocyclic Compounds, Pharmaceutical Compositions and Uses Thereof. Indian Pat. Appl. 2025/MUM/2015, 25 May 2015.
4. Cheng, Z., Garvin, D., Paguio, A., Stecha, P., Wood, K., & Fan, F. Luciferase Reporter Assay System for Deciphering GPCR Pathways. Current Chemical Genomics, 2010, 4, 84–91. http://doi.org/10.2174/1875397301004010084
5. Arkin, M. R., Connor, P. R., Emkey, R., et al. FLIPR™ Assays for GPCR and Ion Channel Targets. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92012/
6. Garbison, K. E., Heinz, B. A., Lajiness, M. E. IP-3/IP-1 Assays. 2012 May 1. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92004/
7. Milić, A., Mihaljević, V.B., Ralić, J. et al. A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents. Eur J Drug Metab Pharmacokinet, 2014, 39, 263. doi:10.1007/s13318-013-0155-8
8. Bell, R. H.; Hye, R. J. Animal models of diabetes mellitus: physiology and pathology. J. Surg. Res. 1983, 35, 433-460.
9. Shafrir, E. Animal models of non insulin dependent diabetes. Diabetes Metab Rev. 1992, 8, 179- 208.

 

Paper
Development of a Scalable Synthesis of a GPR40 Receptor Agonist
Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320, United States
Org. Process Res. Dev., 2011, 15 (3), pp 570–580
*Tel: 805-313-5152. Fax: 805-375-4532. E-mail: walkers@amgen.com.
Abstract Image

Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (±)-1. An efficient and scalable synthesis of (±)-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum’s acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step Suzuki−Miyaura coupling−bromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.

Image result for AMG 837
CAS [1291087-14-3] AMG 837
 Image result for AMG 837
“Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide” Yazaki, R.; Kumagai, N.; Shibasaki, M. Org. Lett. 2011, 13, 952.   highlighted by Synfacts 2011, 6, 586.
NMR

/////////fatty acids, FFAR1 GPR40, GPR40 agonist, insulin secretion, type 2 diabetes, GPR40/FFAR1 Receptor Agonist, ZYDUS CADILA
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O[Ca]OC(C[C@@H](c4ccc(cc4)OCc5cc(ccc5)CN(Cc6ccsc6)C(C)C)C#CC)=O)C#CC
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O)C#CC
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Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor


Abstract Image

str1

N-(5-amino-2-tert-butyl)-11-fluorbenzol[f]thiazol-[4,5-h]-quinazolin-10-yl)-2,6-difluorbenzolsulfonamide = Dabrafenib_photo (2)

C23H18F3N5O2S2 (Mr = 517.09)

Solution of 5 mg (9.6 μmol) dabrafenib in 2 ml THF was irradiated at 365 nm with 5.4 W for 2 min. This procedure was repeated 18 times at room temperature. The reaction batches were combined. The total initial weight of dabrafenib was 101 mg (190 μmol). The solvent was removed under reduced pressure and the residue was purified by the flash chromatography (SiO2 reversed phase, MeOH/water gradient 50:50 to 100:0) to give compound 2 as a yellowish solid (36.2 mg, 70.0 μmol, yield: 37%).

1H-NMR (DMSO-d6 , 300 MHz): δ = 1.52 (s, 9 H, H-8), 7.28 (m, 2 H, NH2), 7.28 (ddd, 5 J = 0.4 Hz, 4 J = 1.7 Hz, 3 J = 8.5 Hz, 3 J = 8.9 Hz, 2 H, H-18), 7.59 (dd, 3 J = 7.4 Hz, 3 J = 7.8 Hz, 1 H, H-13), 7.71 (tt, 4 J = 6.1 Hz, 3 J = 8.5 Hz, 1 H, H-19), 8.56 (dd, 4 J = 0.9 Hz, 3 J = 9.3 Hz, 1 H, H-14), 9.79 (s, 1 H, H-2), 11.01 (s, 1 H, NH) ppm.

13C-NMR (DMSO-d6 , 300 MHz): δ = 30.4 (s, C-8), 38.3 (s, C-7), 110.9 (d, 4 JCF = 1.6 Hz, C-3), 113.4 (dd, 2 JCF = 22.7 Hz, 2 JCH = 3.5 Hz, C-18), 114.6 (d, 3 JCF = 10.3 Hz, C-9), 117.4 (d, 2 JCF = 16.1 Hz, C-16), 117.6 (dd, 4 JCF = 0.54 Hz, 2 JCH = 4.4 Hz, C-13), 120.8 (d, 2 JCF = 12.3 Hz, C-10), 125.4 (s, C-13), 129.3 (d, 3 JCF = 3.9 Hz, C-15), 130.6 (s, C-5), 135.9 (tt, 3 JCF = 10.9 Hz, 2 JCH = 3.3 Hz, C-19), 148.8 (dd, 2 JCF = 0.54 Hz, 2 JCH = 7.2 Hz, C-12), 149.2 (s, C-4), 150.1 (s, C-11), 157.1 160.5 (dd, 3 JFF = 257.3 Hz, 2 JCF = 3.61 Hz, C-4), 157.9 (s, C-2), 162.1 (s, C-1), 184.0 (s, C-6) ppm.

15N-HMBC (DMSO-d6 , 300 MHz): δ = 9.79/-119.60, 11.01/-268.37 ppm. 19F-NMR (DMSO-d6 , 300 MHz): δ = -121.03 (s, 1 F, F-11), -107.18 (m, 2 F, F-17) ppm.

HRMS (EI, 205 °C, THF): m/z = 517.0849 [M]+ .

LC-MS (ESI, 70 eV, MeOH): tR = 9.3 min; m/z (%) = 518.1 (100) [M+H]+

IR (ATR):  ̃ = 3490 (N-H), 3176 (arom. C-H), 2926 (C-H3), 1696 (N=N), 1613 (N-H), 1587, 1522, 1488, 1469 (arom. C=C), 1342 (sulfonamide), 1277, 1240, 1174 (C-F) cm-1 .

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00340
Publication Date (Web): September 20, 2016
Copyright © 2016 American Chemical Society
*E-mail: cpeifer@pharmazie.uni-kiel.de. Tel: +49-431-880-1137.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/K mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that 2 is still a potent BRAFV600E inhibitor. The intracellular formation of 2 from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications.

////////Photoinduced Conversion, Antimelanoma Agent,  Dabrafenib, Novel Fluorescent BRAFV600E Inhibitor, BRAFV600E; Dabrafenib, fluorescent probe kinase inhibitor photoinduced conversion

Synthesis of 4-Heteroaryl–Quinazoline Derivatives as Potential Anti-breast Cancer Agents


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Figure 1.

Figure 2.

Ethyl 2-[(6,7-dimethoxyquinazolin-4-yl)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (15b)

Yield: 76%; mp: 254–256°C; IR (cm−1): 3200 (NH), 2974, 2854 (CH-aliphatic), 1656 (C=O); 1H NMR (DMSO-d6) δ ppm 1.03 (t, 3H, CH3CH2, J = 7.2 Hz), 1.21 (t, 2H, CH2, J = 6.9 Hz), 2.88 (t, 2H, CH2, J = 6.9 Hz), 3.40 (q, 2H, CH2, J = 6.9 Hz), 3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.96 (m, 4H, 2 CH2), 4.24 (q, 2H, CH3CH2, J = 7.2 Hz), 7.40 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 8.99 (s, 1H, Ar-H), 12.00 (s, 1H, NH, D2O exchangeable); Anal. Calcd for C22H25N3O4S: C, 61.81; H, 5.89; N, 9.83. Found: C, 61.93; H, 5.96; N, 9.98.

General procedure for the synthesis of compounds 15a,15b

A mixture of 4-chloro-6,7-dimethoxyquinazoline (1) (0.22 g, 1 mmol) and ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (14a) or ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (14b) (1 mmol) in isopropanol (15 mL) was heated under reflux for 10 h. The reaction was cooled, and the solid formed was filtered, dried, and crystallized from isopropanol.

Synthesis of 4-Heteroaryl–Quinazoline Derivatives as Potential Anti-breast Cancer Agents

A. E. Kassab, E. M. Gedawy, H. B. El-Nassan+

+Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt

E-mail: hala_bakr@hotmail.com

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Asmaa Elsayed Abd Ellatief Kassab( A. E. Kassab)

4-Heteroaryl or heteroalkyl–quinazoline derivatives were prepared as dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The new compounds were tested for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results indicated that almost all the compounds showed moderate dual inhibition of both enzymes. Compound 3 (methyl piperidine-4-carboxylate derivative) showed the highest inhibitory activity against both enzymes with IC50 97.6 and 64.0 µM against EGFR and VEGFR-2 kinases, respectively. Most of the test compounds showed potent to moderate antitumor activity on MCF7 cell line. Five compounds (3, 9c, 11, 13, and 15b) showed potent cytotoxic activity with IC50values between 10 and 17 µM.

Scheme 4.

Scheme 4.

Scheme 3.

Scheme 3.

Scheme 2.

Scheme 2.

Scheme 1.

Scheme 1.

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Dean of faculty of pharmacy, Cairo University, Dr. Azza Agha during the opening of the first international day at Faculty of Pharmacy.

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//////////4-Heteroaryl–Quinazoline Derivatives,  Anti-breast Cancer Agents

VT 1129, QUILSECONAZOLE


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VT 1129 BENZENE SULFONATE

CAS 1809323-18-9

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VT 1129

QUILSECONAZOLE

1340593-70-5 CAS

MF C22 H14 F7 N5 O2, MW 513.37
2-Pyridineethanol, α-(2,4-difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(trifluoromethoxy)phenyl]-, (αR)-
R ISOMER
ROTATION +
  • Originator Viamet Pharmaceuticals
  • Class Antifungals; Small molecules
  • Mechanism of Action 14-alpha demethylase inhibitors
  • Orphan Drug Status Yes – Cryptococcosis
  • On Fast track Cryptococcosis
  • Phase I Cryptococcosis
  • Most Recent Events

    • 01 Jun 2016 VT 1129 receives Fast Track designation for Cryptococcosis [PO] (In volunteers) in USA
    • 30 May 2016 Viamet Pharmaceuticals plans a phase II trial for Cryptococcal meningitis in USA (Viamet Pharmaceuticals pipeline; May 2016)
    • 27 May 2016 Phase-I clinical trials in Cryptococcosis (In volunteers) in USA (PO) before May 2016 (Viamet Pharmaceuticals pipeline; May 2016)

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William J. Hoekstra, Stephen William Rafferty,Robert J. Schotzinger
Applicant Viamet Pharmaceuticals, Inc.

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Viamet, in collaboration with Therapeutics for Rare and Neglected diseases, is investigating VT-1129, a small-molecule lanosterol demethylase inhibitor, developed using the company’s Metallophile technology, for treating fungal infections, including Cryptococcus neoformans meningitis.

VT-1129 is a novel oral agent that we are developing for the treatment of cryptococcal meningitis, a life-threatening fungal infection of the brain and the spinal cord that occurs most frequently in patients with HIV infection, transplant recipients and oncology patients. Without treatment, the disease is almost always fatal.

VT-1129VT-1129 has shown high potency and selectivity in in vitro studies and is an orally administered inhibitor of fungal CYP51, ametalloenzyme important in fungal cell wall synthesis. In preclinical studies, VT-1129 has demonstrated substantial potency against Cryptococcus species, the fungal pathogens that cause cryptoccocal meningitis, and has also been shown to accumulate to high concentrations within the central nervous system, the primary site of infection.

In in vitro studies, VT-1129 was significantly more potent against Cryptococcus isolates than fluconazole, which is commonly used for maintenance therapy of cryptococcal meningitis in the United States and as a primary therapy in the developing world. Oral VT-1129 has also been studied in a preclinical model of cryptococcal meningitis, where it was compared to fluconazole.  At the conclusion of the study, there was no detectable evidence of Cryptococcus in the brain tissue of the high dose VT-1129 treated groups, in contrast to those groups treated with fluconazole. To our knowledge, this ability to reduce the Cryptococcus pathogen in the central nervous system to undetectable levels in this preclinical model is unique to VT-1129.

Opportunity

An estimated 3,400 hospitalizations related to cryptococcal meningitis occur annually in the United States and the FDA has granted orphan drug designation to VT-1129 for the treatment of this life-threatening disease. In addition, the FDA has granted Qualified Infectious Disease Product designation to VT-1129 for the treatment of Cryptococcus infections, which further underscores the unmet medical need. In developing regions such as Africa, cryptococcal meningitis is a major public health problem, with approximately one million cases and mortality rates estimated to be as high as 55-70%.

Current Status

VT-1129 has received orphan drug and Fast Track designations for the treatment of cryptococcal meningitis and has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Fod and Drug Administration.  We are currently conducting a Phase 1 single-ascending dose study of VT-1129 in healthy volunteers.

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Conclusions

• VT-1129 has robust activity against Cryptococcus isolates with elevated fluconazole MICs and may be a viable option in persons infected with such strains.

• A Phase 1 study of VT-1129 in healthy volunteers is scheduled to begin by the end of 2015. Phase 2 trials in persons with cryptococcal meningitis are targeted to begin by the end of 2016.

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Living organisms have developed tightly regulated processes that specifically import metals, transport them to intracellular storage sites and ultimately transport them to sites of use. One of the most important functions of metals such as zinc and iron in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme active site and utilize the metal as a part of the catalytic process. More than one-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of the metal ion in the active site of the enzyme. It is well recognized that agents which bind to and inactivate the active site metal ion dramatically decrease the activity of the enzyme. Nature employs this same strategy to decrease the activity of certain metalloenzymes during periods in which the enzymatic activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteases) binds to the zinc ion in the active site of various matrix metalloprotease enzymes and thereby arrests the enzymatic activity. The pharmaceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain a l-(l,2,4-triazole) group that binds to the heme iron present in the active site of the target enzyme lanosterol demethylase and thereby inactivates the enzyme.

In the design of clinically safe and effective metalloenzyme inhibitors, use of the most appropriate metal-binding group for the particular target and clinical indication is critical. If a weakly binding metal-binding group is utilized, potency may be suboptimal. On the other

hand, if a very tightly binding metal-binding group is utilized, selectivity for the target enzyme versus related metalloenzymes may be suboptimal. The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes. One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently- available azole antifungal agents such as fluconazole and voriconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized l-(l,2,4-triazole) to iron in the active site of CYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint pain that has been observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to inhibition of off-target metalloenzymes due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a better balance of potency and selectivity remains an important goal and would be significant in the realization of therapeutic agents and methods to address currently unmet needs in treating and preventing diseases, disorders and symptoms thereof. Similarly, methods of synthesizing such therapeutic agents on the laboratory and, ultimately, commercial scale is needed. Addition of metal-based nucleophiles (Zn, Zr, Ce, Ti, Mg, Mn, Li) to azole-methyl substituted ketones have been effected in the synthesis of voriconazole (M. Butters, Org. Process Res. Dev.2001, 5, 28-36). The nucleophile in these examples was an ethyl-pyrimidine substrate. Similarly, optically active azole-methyl epoxide has been prepared as precursor electrophile toward the synthesis of ravuconazole (A. Tsuruoka, Chem. Pharm. Bull.1998, 46, 623-630). Despite this, the development of methodology with improved efficiency and selectivity is desirable.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011133875

Scheme 1

EXAMPLE 7

2-(2, 4-Difluorophenyl)-l, l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(4- (trifluoromethoxy) phenyl) pyridin-2-yl) propan-2-ol (7)

To a stirred solution of bromo epoxide C (0.5 g, 1.38 mmol) in THF (30 mL) and water (14 mL) were added 4-(trifluoromethoxy) phenylboronic acid (0.22 g, 1.1 mmol), Na2C03 (0.32 g, 3.1 mmol) and Pd(dppf)2Cl2 (0.28 g, 0.34 mmol) at RT under inert atmosphere. After purged with argon for a period of 30 min, the reaction mixture was heated to 75°C and stirring was continued for 4 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and filtered through a pad of celite. The filtrate was concentrated under reduced pressure; obtained residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with water, brine and dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the coupled product (0.45 g, 1.0 mmol, 73%) as solid. 1H NMR (200 MHz, CDC13): δ 8.87 (s, 1 H), 7.90 (dd, / = 8.2, 2.2 Hz, 1 H), 7.66-7.54 (m, 3 H), 7.49-7.34 (m, 3 H), 6.90-6.70 (m, 2 H), 3.49 (d, / = 5.0 Hz, 1 H), 3.02-2.95 (m, 1 H). Mass: m/z 444 [M++l].

To a stirred solution of the coupled product (0.45 g, 1.0 mmol) in DMF (10 mL) was added K2C03 (70 mg, 0.5 mmol) followed by IH-tetrazole (70 mg, 1.0 mmol) at RT under inert atmosphere. The reaction mixture was stirred for 4 h at 80 °C. The volatiles were removed under reduced pressure and obtained residue was dissolved in water (15 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water, brine and dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford 7 (0.19 g, 0.37 mmol, 36 %) as white solid. 1H NMR (500 MHz, CDC13): δ 8.76 (s, 1 H), 8.70 (s, 1 H), 7.97 (dd, / = 8.0, 2.0 Hz, 1 H), 7.68 (d, / = 8.5 Hz, 1 H), 7.60-7.56 (m, 3 H), 7.43-7.36 (m, 3 H), 6.80-6.76 (m, 1 H), 6.70-6.67 (m, 1 H), 5.57 (d, / = 14.5 Hz, 1 H), 5.17 (d, / = 14.5 Hz, 1 H). HPLC: 98.3%. Mass: m/z 513.9 [M++l].

Chiral preparative HPLC of enantiomers:

The enantiomers of 7 (17.8 g, 34.6 mmol) were separated by normal-phase preparative high performance liquid chromatography (Chiralpak AD-H, 250 x 21.2 mm, 5μ; using (A) n-hexane – (B) IPA (A:B : 70:30) as a mobile phase; Flow rate: 15 mL/min) to obtain 7(+) (6.0 g) and 7(-) (5.8 g).

Analytical data for 7 (+):

HPLC: 99.8%.

Chiral HPLC: Rt = 9.88 min (Chiralpak AD-H, 250 x 4.6mm, 5μ; mobile phase (A) n-Hexane (B) IPA (7/3): A: B (70:30); flow Rate: 1.00 mL/min)

Optical rotation [a]D25: + 19° (C = 0.1 % in MeOH).

Patent

WO2015143137,

https://patentscope.wipo.int/search/ko/detail.jsf;jsessionid=61AAA66F887FDBB9CFC3F752AFF04016.wapp2nC?docId=WO2015143137&recNum=303&office=&queryString=&prevFilter=%26fq%3DICF_M%3A%22C07D%22&sortOption=%EA%B3%B5%EA%B0%9C%EC%9D%BC(%EB%82%B4%EB%A6%BC%EC%B0%A8%EC%88%9C)&maxRec=58609

Examples

The present invention will now be demonstrated using specific examples that are not to be construed as limiting.

General Experimental Procedures

Definitions of variables in the structures in schemes herein are commensurate with those of corresponding positions in the formulae delineated herein.

Synthesis of 1 or la

A process to prepare enantiopure compound 1 or la is disclosed. Syntheses of 1 or la may be accomplished using the example syntheses that are shown below (Schemes 1-9). The preparation of precursor ketone 8 is performed starting with reaction of dibromo-pyridine 2-Br with ethyl 2-bromo-difluoroacetate to produce ester 3-Br. This ester is reacted with tetrazole reagent 4 via Claisen reaction to furnish 5-Br. Decarboxylation of 5-Br via a two-step process produces compound 6-Br. Suzukin coupling of 6-Br with boronate 7 furnishes 8.

Scheme 1. Synthesis of ketone 8

Ketone 8 may be prepared in an analogous fashion as described in Scheme 1 starting from corresponding substituted 2-bromo-pyridines, which can be prepared using according to synthetic transformations known in the art and contained in the references cited herein (Scheme 2).

Scheme 2. Synthesis of ketone 8

= halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, – 0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, – 0(S02)-aryl, or -0(S02)-substituted aryl.

Compounds 6 or 8 may be reacted with a series of metallated derivatives of 2,4-difluoro-bromobenzene and chiral catalysts/reagents (e.g. BINOL) to effect enantiofacial-selective addition to the carbonyl group of 6 or 8 (Scheme 3). These additions can be performed on 6 or 8 to furnish 9 (or 9a, the enantiomer of 9, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof), respectively.

Scheme 3. Synthesis of 1 or la

R-i = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

Alternatively, ketone 8 can be synthesized from aldehyde 10 (Scheme 4). Aldehyde 10 is coupled with 7 to produce 11. Compound 11 is then converted to 12 via treatment with diethylaminosulfurtrifluoride (DAST).

Scheme 4. Alternate synthesis of ketone 8

Scheme 5 outlines the synthesis of precursor ketone 15-Br. The ketone is prepared by conversion of 2-Br to 3-Br as described above. Next, ester 3-Br is converted to 15-Br by treatment via lithiation of 2,4-difluoro-bromobenzene.

Scheme 5. Synthesis of ketone 15-Br

Ketone 15 may be prepared in an analogous fashion as described for 15-Br in Scheme 5 starting from corresponding substituted 2-bromo-pyridines, which can be prepared using according to synthetic transformations known in the art and contained in the references cited herein (Scheme 6).

Scheme 6. Synthesis of ketone 15

F = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, – 0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, – 0(S02)-aryl, or -0(S02)-substituted aryl.

Ketone 15 may be used to prepare 9 (or 9a, the enantiomer of 9, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof) by the following three-step process (Scheme 7). In the presence of a chiral catalyst/reagent (e.g. proline derivatives), base-treated nitromethane is added to 15 or 16 to furnish 17 (or 17a, the enantiomer of 17, or mixtures thereof) or 18 (or 18a, the enantiomer of 18, or mixtures thereof), respectively. Reduction of 17 (or 17a, the enantiomer of 17, or mixtures thereof) or 18 (or 18a, the enantiomer of 18, or mixtures thereof) (e.g. lithium aluminum hydride) produces 19 (or 19a, the enantiomer of 19, or mixtures thereof) or 20 (or 20a, the enantiomer of 20, or mixtures thereof). Annulation of 19 (or 19a, the enantiomer of 19, or mixtures thereof) or 20 (or 20a, the enantiomer of 20, or mixtures thereof) by treatment with sodium azide/triethylorthoformate furnishes tetrazoles 9 (or 9a, the enantiomer of 9, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof). Suzuki coupling of 9 (or 9a, the enantiomer of 9, or mixtures thereof) with 4-trifluoromethoxyphenyl-boronic acid produces 1 (or la, the enantiomer of 1, or mixtures thereof).

Scheme 7. Asymmetric Henry reaction

R-ι = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, 0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted a 0(S02)-aryl, or -0(S02)-substituted aryl.

Ketone 21 may be employed to prepare optically-active epoxides via Horner-Emmons reaction of a difluoromethyl substrate to produce 22 or 22a. Ketones related to 21 have been prepared (M. Butters, Org. Process Res. Dev. 2001, 5, 28-36). Nucleophilic addition of metalated 5-(4-trifluoromethoxy)phenyl-2-pyridine (M = metal) to epoxide 22 or 22a may furnish compound

1 or la.

Scheme 8. Enantioselective epoxidation strategy

Ketone 15 or 16 may be used to prepare 9 (or 9a, the enantiomer of 9, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof) by an alternative three-step process to Scheme 7 (Scheme 9). In the presence of a chiral catalyst/reagent, trimethylsilyl-cyanide is added to 15 or 16 to furnish 23 (or 23a, the enantiomer of 23, or mixtures thereof) or 24 (or 24a, the enantiomer of 24, or mixtures thereof), respectively (S.M. Dankwardt, Tetrahedron Lett. 1998, 39, 4971-4974). Reduction of 23 (or 23a, the enantiomer of 23, or mixtures thereof) or 24 (or 24a, the enantiomer of 24, or mixtures thereof) (e.g. lithium aluminum hydride) produces 19 (or 19a, the enantiomer of 19, or mixtures thereof) or 20 (or 20a, the enantiomer of 20, or mixtures thereof). Annulation of 19 (or 19a, the enantiomer of 19, or mixtures thereof) or 20 (or 20a, the enantiomer of 20, or mixtures thereof) by treatment with sodium azide/triethylorthoformate furnishes tetrazoles 9 (or 9a, the enantiomer of 9, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof). Suzuki coupling of 9 (or 9a, the enantiomer of 9, or mixtures thereof) with 4-trifluoromethoxyphenyl-boronic acid produces 1 (or la, the enantiomer of 1, or mixtures thereof).

Scheme 9. Asymmetric cyanohydrin strategy

R’ = H or trimethylsilyl

Suzuki

R-i = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

1

2-(2, 4-Difluorophenyl)-l, l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(4-(trifluoromethoxy) phenyl) pyridin-2-yl) propan-2-ol (1 or la)

White powder: *H NMR (500 MHz, CDC13): δ 8.76 (s, 1 H), 8.70 (s, 1 H), 7.97 (dd, J = 8.0, 2.0 Hz, 1 H), 7.68 (d, / = 8.5 Hz, 1 H), 7.60-7.56 (m, 3 H), 7.43-7.36 (m, 3 H), 6.80-6.76 (m, 1 H), 6.70-6.67 (m, 1 H), 5.57 (d, J = 14.5 Hz, 1 H), 5.17 (d, J = 14.5 Hz, 1 H). HPLC: 98.3%. Mass: m/z 513.9 [M++l]. HPLC: 99.8%. Optical rotation [a]D25: + 19° (C = 0.1 % in MeOH).

INTERMEDIATE 3-Br Ri = Br)

To a clean and dry 100 L jacketed reactor was added copper powder (1375 g, 2.05 equiv, 10 micron, sphereoidal, SAFC Cat # 326453) and DMSO (17.5 L, 7 vol). Next, ethyl bromodifluoroacetate (2.25 kg, 1.05 equiv, Apollo lot # 102956) was added and the resulting slurry stirred at 20-25 °C for 1-2 hours. Then 2,5-dibromopyridine (2-Br, 2.5 kg, 1.0 equiv, Alfa Aesar lot # F14P38) was added to the batch and the mixture was immediately heated (using the glycol jacket) to 35 °C. After 70 hours at 35 °C, the mixture was sampled for CG/MS analysis. A sample of the reaction slurry was diluted with 1/1 CH3CN/water, filtered (0.45 micron), and the filtrate analyzed directly. Ideally, the reaction is deemed complete if <5% (AUC) of 2,5-dibromopyridine remains. In this particular batch, 10% (AUC) of 2,5-dibromopyridine remained. However due to the already lengthy reaction time, we felt that prolonging the batch would not help the conversion any further. The reaction was then deemed complete and diluted with EtOAc (35 L). The reaction mixture was stirred at 20-35 °C for 1 hour and then the solids (copper salts) were removed by filtration through a pad of Celite. The residual solids inside the reactor were rinsed forward using EtOAc (2 x 10 L) and then this was filtered through the Celite. The filter cake was washed with additional EtOAc (3 x 10 L) and the EtOAc filtrates were combined. A buffer solution was prepared by dissolving NH4CI (10 kg) in DI water (100 L), followed by the addition of aqueous 28% NH4OH (2.0 L) to reach pH = 9. Then the combined EtOAc filtrates were added slowly to a pre-cooled (0 to 15 °C) solution of NH4C1 and NH4OH (35 L, pH = 9) buffer while maintaining T<30 °C. The mixture was then stirred for 15-30 minutes and the phases were allowed to separate. The aqueous layer (blue in color) was removed and the organic layer was washed with the buffer solution until no blue color was discernable in the aqueous layer. This experiment required 3 x 17.5 L washes. The organic layer was then washed with a 1/1 mixture of Brine (12.5 L) and the pH = 9 NH4C1 buffer solution (12.5 L), dried over MgS04, filtered, and concentrated to dryness. This provided crude compound 3-Br [2.29 kg, 77% yield, 88% (AUC) by GC/MS] as a yellow oil. The major impurity present in crude 3-Br was unreacted 2,5-dibromopyridine [10% (AUC) by GC/MS]. ‘ll NMR (CDC13) was consistent with previous lots of crude compound 3-Br. Crude compound 3-Br was then combined with similar purity lots and purified by column chromatography (5/95 EtO Ac/heptane on S1O2 gel).

INTERMEDIATE 15-Br (R, = Br)

To a clean and dry 72 L round bottom flask was added l-bromo-2,4-difluorobenzene (1586 g,

1.15 equiv, Oakwood lot # H4460) and MTBE (20 L, 12.6 vol). This solution was cooled to -70 to -75 °C and treated with n-BuLi (3286 mL, 1.15 equiv, 2.5 M in hexanes, SAFC lot # 32799MJ), added as rapidly as possible while maintaining -75 to -55 °C. This addition typically required 35-45 minutes to complete. (NOTE: If the n-BuLi is added slowly, an white slurry will form and this typically gives poor results). After stirring at -70 to -65 °C for 45 minutes, a solution of compound 3-Br (2000 g, 1.0 equiv, AMRI lot # 15CL049A) in MTBE (3 vol) was added rapidly (20-30 min) by addition funnel to the aryl lithium solution while maintaining -75 to -55 °C. After stirring for 30-60 minutes at -75 to -55 °C, the reaction was analyzed by GC/MS and showed only trace (0.5% AUC) l-bromo-2,4-difluorobenzene present. The reaction was slowly quenched with aqueous 2 M HC1 (3.6 L) and allowed to warm to room temperature. The mixture was adjusted to pH = 6.5 to 8.5 using NaHCC>3 (4 L), and the organic layer was separated. The MTBE layer was washed with brine (5% NaCl in water, 4 L), dried over MgS04, filtered, and concentrated. In order to convert the intermediate hemi-acetal to 4-Br, the crude mixture was heated inside the 20 L rotovap flask at 60-65 °C for 3 hours (under vacuum), at this point all the hemi-acetal was converted to the desired ketone 4 by !Η NMR (CDC13). This provided crude compound 4-Br [2.36 kg, 75% (AUC) by HPLC] as a brown oil that solidified upon standing. This material can then be used “as-is” in the next step without further purification.

Image result for VT1129

PATENT FOR VT1161    SIMILAR TO VT 1129

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016149486&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Synthesis of 1 or la

EXAMPLE 1

Preparation of Compound 1 X-Hydrate

Compound 1 and its preparation are described in the art, including in US Patent 8,236,962 (incorporated by reference herein). Compound 1 can then be partitioned between ethanol and water to afford Compound 1 X-hydrate.

EXAMPLE 2

Compound 1 Anhydrous Form Recrystallization

Compound 1 X-hydrate (29.1 g, 28.0 g contained 1) was suspended in 2-propanol (150 ml) and heated to 56 °C. The solution was filtered through a 0.45 μιη Nylon membrane with 2-propanol rinses. The combined filtrate was concentrated to 96.5 g of a light amber solution. The solution was transferred to a 1-L flask equipped with overhead stirring, thermocouple and addition funnel, using 2-propanol (30 ml total) to complete the transfer. The combined solution contained about 116 ml 2-propanol.

The solution was heated to 50 °C and n-heptane (234 ml) was added over 22 minutes. The resulting hazy mixture was seeded with 1 anhydrous form. After about 1 hour a good

suspension had formed. Additional n-heptane (230 ml) was added over 48 minutes. Some granular material separated but most of the suspension was a finely divided pale beige solid. After about ½ hour at 50 °C the suspension was cooled at 10 °C/h to room temperature and stirred overnight. The product was collected at 22 °C on a vacuum filter and washed with 1:4 (v/v) 2-PrOH/ n-heptane (2 x 50 ml). After drying on the filter for 1-2 hours the weight of product was 25.5 g. The material was homogenized in a stainless steel blender to pulverize and blend the more granular solid component. The resulting pale beige powder (25.37 g) was dried in a vacuum oven at 50 °C. The dry weight was 25.34 g. The residual 2-propanol and n- heptane were estimated at <0.05 wt% each by 1H NMR analysis. The yield was 90.5% after correcting the X-hydrate for solvent and water content. Residual Pd was 21 ppm. The water content was 209 ppm by KF titration. The melting point was 100.7 °C by DSC analysis.

Table 1: Data for the isolated and dried Compound 1 – X-hydrate and anhydrous forms

M.P. by DSC; Pd by ICP; Purity by the API HPLC method; Chiral purity by HPLC; water content by KF titration; residual solvent estimated from :H NMR.

Table 2: Characterisation Data for Compounds 1 (X-hydrate) and 1 (anhydrous)

Needle like crystals Needle like crystals and agglomerates

PLM

particle size >100μιη particle size range from 5μπι-100μιη

0.59%w/w water uptake at 90%RH. 0.14%w/w water uptake at 90%RH.

GVS

No sample hysteresis No sample hysteresis

XRPD

No form change after GVS experiment No form change after GVS experiment post GVS

KF 2.4%w/w H20 Not obtained

<0.001mg/ml <0.001mg/ml

Solubility

pH of saturated solution = 8.6 pH of saturated solution = 8.7

Spectral Pattern 1 Spectral Pattern 2

Charcteristic bands/ cm“1: Charcteristic bands/ cm 1:

FT-IR 3499, 3378, 3213, 3172 3162

1612, 1598, 1588, 1522, 1502 1610, 1518, 1501 931, 903, 875, 855, 828, 816 927, 858, 841, 829, 812

The structure solution of Compound 1 anhydrous form was obtained by direct methods, full-matrix least-squares refinement on F 2 with weighting w‘1 = <52{F02) + (0.0474P)2 + (0.3258P), where P = (F02+2F 2)/3, anisotropic displacement parameters, empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Final wR2

= {∑[w(F02-Fc2)2]/∑[w(F02)2]m} = 0.0877 for all data, conventional Ri = 0.0343 on F values of 8390 reflections with F0 > 4a( F0), S = 1.051 for all data and 675 parameters. Final Δ/a (max) 0.001, A/a(mean), 0.000. Final difference map between +0.311 and -0.344 e A“3.

Below shows a view of two molecules of Compound 1 in the asymmetric unit of the anhydrous form showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. The absolute configuration of the molecules has been determined to be R.

EXAMPLE 3

Compound 1 Ethanol Solvate Recrystallization

Compound 1 X-hydrate (50 mg) was suspended in -40 volumes of 15% H20/EtOH. The suspension was then placed in an incubation chamber for maturation. The maturation protocol involved treating the suspension to a two-temperature cycle of 50 °C/ ambient temperature at 8 hours per cycle for 3 days with constant agitation. After maturation, the suspension was cooled in a fridge at 4°C for up to 2 days to encourage the formation of crystals. Then, the solvent was removed at RT and the sample was vacuum dried at 30°C -35°C for up to 1 day. Suitable crystals formed on cooling were harvested and characterized.

Table 4: Single Crystal Structure of 1 Ethanol solvate

Molecular formula C25H22F7N5O3

The structure solution of Compound 1 ethanol solvate was obtained by direct methods, full-matrix least-squares refinement on F 2 with weighting w‘1 = σ2^2) + (0.0450P)2 + (0.5000P), where P = (F02+2F 2)/3, anisotropic displacement parameters, empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Final wR2 = {∑[w(F02-F 2)2]/∑[w(F02)2]m} = 0.0777 for all data, conventional Ri = 0.0272 on F values of 4591 reflections with F0 > 4σ( F0), S = 1.006 for all data and 370 parameters. Final Δ/σ (max) 0.000, A/a(mean), 0.000. Final difference map between +0.217 and -0.199 e A“3.

Below shows a view of the asymmetric unit of the ethanol solvate from the crystal structure showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. The asymmetric unit shows stoichiometry of 1 : 1 for solvent of crystallisation to Compound 1.

EXAMPLE 4

Compound 1 1.5 Hydrate Recrystallization

Compound 1 X-hydrate (50 mg) was suspended in -40 volumes of 15% Η20/ΙΡΑ. The suspension was then placed in an incubation chamber for maturation. The maturation protocol involved treating the suspension to a two-temperature cycle of 50 °C/ ambient temperature at 8 hours per cycle for 3 days with constant agitation. After maturation, the suspension was cooled in a fridge at 4°C for up to 2 days to encourage the formation of crystals. Then, the solvent was removed at RT and the sample was vacuum dried at 30°C -35°C for up to 1 day. Suitable crystals formed on cooling were harvested and characterized.

Table 5: Single Crystal Structure of 1 1.5 Hydrate

The structure solution of Compound 1 1.5 hydrate was obtained by direct methods, full-matrix least-squares refinement on F 2 with weighting w‘1 = ^(F 2) + (0.1269P)2 + (0.0000P), where P = (F02+2F 2)/3, anisotropic displacement parameters, empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Final wR2 = {∑[w(F 2-F 2)2]/∑[w(F 2)2] m} = 0.1574 for all data, conventional Ri = 0.0668 on F values of 2106 reflections with F0 > 4σ( F0), S = 1.106 for all data and 361 parameters. Final Δ/σ (max) 0.000, A/a(mean), 0.000. Final difference map between +0.439 and -0.598 e A“3.

Below shows a view of the asymmetric unit of the 1.5 hydrate from the crystal structure showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. The asymmetric unit shows stoichiometry of 1.5: 1 for water to Compound 1.

EXAMPLE 5

Human Pharmacokinetic Comparison of Compound 1 X-Hydrate and Compound 1 Anhydrous Form

Table 6 compares human multiple-dose pharmacokinetic (PK) parameters between dosing with Compound 1 X-hydrate and Compound 1 Anhydrous form. Compound 1 X-hydrate was dosed at 600 mg twice daily (bid) for three days followed by dosing at 300 mg once daily (qd) for 10 days. Compound 1 Anhydrous form was dosed at 300 mg qd for 14 days. Despite the higher initial dosing amount and frequency (i.e., 600 mg bid) of Compound 1 X-hydrate, Compound 1 Anhydrous form surprisingly displayed higher maximal concentration (Cmax) and higher area-under-the-curve (AUC) than Compound 1 X-hydrate.

Table 6. Comparison of Multiple Dose PK between Compound 1 X-Hydrate and Compound 1

Anhydrous Polymorph

Further characterization of the various polymorph forms of compound 1 are detailed in the accompanying figures.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015143154

Examples

General Experimental Procedures

Definitions of variables in the structures in schemes herein are commensurate with those of corresponding positions in the formulae delineated herein.

Synthesis of 1 or la

la

A process to prepare enantiopure compound 1 or la is disclosed. Syntheses of lor la may be accomplished using the example syntheses that are shown below (Schemes 1-4). The preparation of precursor ketone 3-Br is performed starting with reaction of 2,5-dibromo-pyridine with ethyl 2-bromo-difluoroacetate to produce ester 2-Br. This ester is reacted with morpholine to furnish morpholine amide 2b-Br, followed by arylation to provide ketone 3-Br.

Scheme 1. Synthesis of ketone 3-Br

Ketone 3 may be prepared in an analogous fashion as described in Scheme 1 starting from corresponding substituted 2-bromo-pyridines, which can be prepared using according to synthetic transformations known in the art and contained in the references cited herein (Scheme 2).

Scheme 2. Synthesis of ketone 3

R1 = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, – 0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, 0(S02)-aryl, or -0(S02)-substituted aryl.

Alternatively, compound 1 (or la, the enantiomer of 1, or mixtures thereof) can be prepared according to Scheme 3 utilizing amino-alcohols ±4b or ±1-6. Epoxides 4 and 5 can be prepared by reacting ketones 3 and 1-4 with trimethylsulfoxonium iodide (TMSI) in the presence of a base (e.g., potassium i-butoxide) in a suitable solvent or a mixture of solvents (e.g., DMSO or THF). Also, as indicated in Scheme 3, any of pyridine compounds, 3, 4, ±4b, 4b, or 6, can be converted to the corresponding 4-CF3O-PI1 analogs (e.g., 1-4, 5, ±1-6, 1-6*, or 1 or the corresponding enantiomers, or mixtures thereof) by cross-coupling with (4-trifluoromethoxyphenyl)boronic acid (or the corresponding alkyl boronates or pinnacol boronates or the like), in a suitable solvent system (e.g., an organic-aqueous solvent mixture), in the presence of a transition metal catalyst (e.g., (dppf)PdCl2; dppf = 1,1′-(diphenylphosphino)ferrocene), and in the presence of a base (e.g., KHCO3, K2CO3, CS2CO3, or Na2CC>3, or the like). Epoxides 4 and 5 can then be converted into amino-alcohols ±4b and ±1-6 through ammonia-mediated epoxide opening using ammonia in a suitable solvent (e.g., MeOH, EtOH, or water). Racemic amino-alcohols ±4b and ±1-6 can then be enantio-enriched by exposure to a chiral acid (e.g., tartaric acid, di-benzoyltartaric acid, or di-p-toluoyltartaric acid or the like) in a suitable solvent (e.g., acetonitrile, isopropanol, EtOH, or mixtures thereof, or a mixture of any of these with water or MeOH; preferably acetonitrile or a mixture of acetonitrile and MeOH, such as 90:10, 85: 15, or 80:20 mixture) to afford compounds 4b (or 4c, the enantiomer of 4b, or mixtures thereof) or 1-6* (or 1-7*, the enantiomer of 1-6*, or mixtures thereof). Subsequent treatment with TMS-azide in the presence of trimethylorthoformate and sodium acetate in acetic acid would yield compounds 20 (or 20a, the enantiomer of 20, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof) (US 4,426,531).

Scheme 3. Synthesis of 1 or la via TMSI Epoxidation Method

R-ι = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)- substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0- aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, – 0(S02)-aryl, or -0(S02)-substituted aryl.

Compound 1 (or la, the enantiomer of 1, or mixtures thereof) prepared by any of the methods presented herein can be converted to a sulfonic salt of formula IX (or IXa, the enantiomer of

IX, or mixtures thereof), as shown in Scheme 4. This can be accomplished by a) combining compound 1 (or la, the enantiomer of 1, or mixtures thereof), a crystallization solvent or crystallization solvent mixture (e.g., EtOAc, iPrOAc, EtOH, MeOH, or acetonitrile, or o

Z-S-OH

combinations thereof), and a sulfonic acid o (e.g., Z = Ph, p-tolyl, Me, or Et), b) diluting the mixture with an appropriate crystallization co-solvent or crystallization co-solvent mixture (e.g., pentane, methyl i-butylether, hexane, heptane, or toluene, or combinations thereof), and c) filtering the mixture to obtain a sulfonic acid salt of formula IX (or IXa, the enantiomer of IX, or mixtures thereof).

Scheme 4. Synthesis of a Sulfonic Acid Salt of Compound 1 or la

EXAMPLE 1: Preparation of l-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4- (trifluoromethoxy)phenyl)pyridin-2-yl)ethanone (1-4).

la. ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (2)

2-Br
Typical Procedure for Preparing 2-Br

Copper ( 45μιη, 149g, 0.198moles, 2.5 equiv) was placed into a 3L, 3-neck round bottom flask equipped with a condenser, thermocouple, and an overhead stirrer. DMSO (890 mL, 4.7 vol. based on ethyl 2-bromo-2,2-difluoroacetate) and 14mL of concentrated sulfuric acid was added and the mixture stirred for 30 minutes. The mixture self-heated to about 31°C during the stir time. After cooling the contents to 23°C, 2,5-dibromopyridine 1 (277g, 1.17 moles, 1.5 eq) was added to the reaction mixture. The temperature of the contents decreased to 16°C during a 10 minute stir time. 2-bromo-2,2-difluoroacetate (190 g, 0.936 moles, 1.0 eq) was added in one portion and the mixture stirred for 10 min. The flask contents were warmed to 35°C and the internal temperature was maintained between 35-38° for 18 h. In-process HPLC showed 72% desired 2-Br. The warm reaction mixture was filtered through filter paper and the collected solids washed with 300mL of 35°C DMSO. The solids were then washed with 450mL of n-heptane and 450mL of MTBE. The collected filtrate was cooled to about 10°C and was slowly added 900mL of a cold 20% aqueous NH4C1 solution, maintaining an internal temperature of <16°C during the addition. After stirring for 15 minutes, the layers were settled and separated. The aqueous layer was extracted 2 X 450mL of a 1: 1 MTBE: n-heptane mixture. The combined organic layers were washed 2 X 450mL of aqueous 20% NH4CI and with 200mL of aqueous 20% NaCl. The organic layer was dried with 50g MgS04 and the solvent removed to yield 2-Br as a dark oil. Weight of oil = 183g ( 70% yield by weight) HPLC purity ( by area %) = 85%. *H NMR (400 MHz, d6-DMSO) : 58.86 (m, 1H), 8.35 ( dd, J= 8.4, 2.3Hz, 1H), 7.84 (dd, J= 8.3, 0.6Hz, 1H), 4.34 ( q, J= 7.1Hz, 2H), 1.23 ( t, J= 7.1Hz, 3H). MS m/z 280 ( M+H+), 282 (M+2+H+).

lb. 2-(5-bromopyridin-2-yl)-2,2-difluoro-l-morpholinoethanone (2b-Br)

Table 2 illustrates the effects of the relative proportions of each of the reagents and reactants, and the effect of varying the solvent had on the overall performance of the transformation as measured by the overall yield and purity of the reaction.

Table 2. Process Development for the Preparation of compound 2b-Br

Note: All reactions were conducted at 22- 25°C

Typical Procedure for Converting 2-Br to 2b-Br

Crude ester 2-Br (183g, 0.65moles) was dissolved in 1.5L of n-heptane and transferred to a 5L 3-neck round bottom flask equipped with a condenser, an overhead stirrer and a thermocouple. Morpholine ( 248g, 2.85 moles, 4.4 equiv.) was charged to the flask and the mixture warmed to 60°C and stirred for 16 hours. In-process HPLC showed <1 % of ester 2-Br. The reaction mixture was cooled to 22-25 °C and 1.5L of MTBE was added with continued cooling of the mixture to 4°C and slowly added 700mL of a 30%, by weight, aqueous citric acid solution. The temperature of the reaction mixture was kept < 15°C during the addition. The reaction was stirred at about 14°C for one hour and then the layers were separated. The organic layer was washed with 400mL of 30%, by weight, aqueous citric acid solution and then with 400mL of aqueous 9% NaHC03. The solvent was slowly removed until 565g of the reaction mixture

remained. This mixture was stirred with overhead stirring for about 16 hours. The slurry was filtered and the solids washed with 250mL of n-heptane. Weight of 2b-Br = 133g. HPLC purity (by area %) 98%.

This is a 44% overall yield from 2,5-dibromopyridine.

*H NMR (400 MHz, d6-DMSO): 58.86 (d, J= 2.3Hz, 1H), 8.34 (dd, J= 8.5, 2.3Hz, 1H), 7.81 (dd, J = 8.5, 0.5Hz, 1H), 3.63-3.54 ( m, 4H), 3.44-3.39 (m, 2H), 3.34-3.30 ( m, 2H). MS m/z 321 (M+H+), 323 (M+2+H+).

lc. 2-(5-bromopyridin-2-yl)-l-(2,4-difluorophenyl)-2,2-difluoroethanone (3-Br)

Process Development

Table 3 illustrates the effects of the relative proportions of each of the reagents and reactants, and the effect of varying the temperature had on the overall performance of the transformation as measured by the overall yield and purity of the reaction.

Table 3. Process Development for the Preparation of bromo-pyridine 3-Br

Typical Procedure for Converting 2b-Br to 3-Br

Grignard formation:

Magnesium turnings (13.63 g, 0.56 moles) were charged to a 3-neck round bottom flask equipped with a condenser, thermocouple, addition funnel, and a stir bar. 540 mL of anhydrous tetrahydrofuran was added followed by l-Bromo-2,4-difluorobenzene (16.3 mL, 0.144 moles). The contents were stirred at 22-25°C and allowed to self -heat to 44°C. 1- Bromo-2,4-difluorobenzene ( 47mL, 0.416 moles) was added to the reaction mixture at a rate that maintained the internal temperature between 40-44°C during the addition. Once the addition was complete, the mixture was stirred for 2 hours and allowed to cool to about 25° during the stir time.

This mixture was held at 22-25°C and used within 3-4 hours after the addition of l-bromo-2,4-difluorobenzene was completed.

Coupling Reaction

Compound 2b-Br (120 g, 0.0374 moles) was charged to a 3-neck round bottom flask equipped with a condenser, thermocouple, and an overhead stirrer. 600 mL of anhydrous

tetrahydrofuran was added. The flask contents were stirred at 22°C until a clear solution was obtained. The solution was cooled to 0-5°C. The previously prepared solution of the Grignard reagent was then added slowly while maintaining the reaction temperature at 0-2°C. Reaction progress was monitored by HPLC. In-process check after 45 minutes showed <1% amide 2b-Br remaining. 2 N aqueous HC1 (600 mL, 3 vol) was added slowly maintaining the temperature below 18°C during the addition. The reaction was stirred for 30 minutes and the layers were separated. The aqueous layer was extracted with 240mL MTBE. The combined organic layers were washed with 240mL of aqueous 9% NaHCC>3 and 240mL of aqueous 20% NaCl. The organic layer was dried over 28g of MgS04 and removed the solvent to yield 3-Br (137g) as an amber oil.

HPLC purity ( by area %) = -90%; *H NMR (400 MHz, d6-DMSO) : 58.80 (d, J= 2.2Hz, 1H), 8.41 ( dd, J= 8.3, 2.3Hz, 1H), 8.00 (m, 2H), 7.45 ( m, 1H), 7.30 ( m, 1H). MS m/z 348 (M+H+), 350 (M+2+H+).

Id. l-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)ethanone (1-4)

Typical Procedure for Converting 3-Br to 1-4

Into a 250 mL reactor were charged THF (45 mL), water (9.8 mL), bromo-pyridine 3-Br (6.0 g, 17.2 mmoles), 4-(trifluoromethoxy)phenylboronic acid (3.57 g, 17.3 mmoles), and Na2CC>3 (4.55 g, 42.9 mmoles). The stirred mixture was purged with nitrogen for 15 min. The catalyst (Pd(dppf)Cl2 as a CH2C12 adduct, 0.72 g, 0.88 mmoles) was added, and the reaction mixture was heated to 65 °C and held for 2.5 h. The heat was shut off and the reaction mixture was allowed to cool to 20-25 °C and stir overnight. HPLC analysis showed -90% ketone 1-4/hydrate and no unreacted bromo-pyridine 3-Br. MTBE (45 mL) and DI H20 (20 mL) were added, and the quenched reaction was stirred for 45 min. The mixture was passed through a plug of Celite (3 g) to remove solids and was rinsed with MTBE (25 mL). The filtrate was transferred to a separatory funnel, and the aqueous layer drained. The organic layer was washed with 20% brine (25 mL). and split into two portions. Both were concentrated by rotovap to give oils (7.05 g and 1.84 g, 8.89 g total, >100% yield, HPLC purity -90%). The larger aliquot was used to generate hetone 1-4 as is. The smaller aliquot was dissolved in DCM (3.7 g, 2 parts) and placed on a pad of Si02 (5.5 g, 3 parts). The flask was rinsed with DCM (1.8 g), and the rinse added to the pad. The pad was eluted with DCM (90 mL), and the collected filtrate concentrated to give an oil (1.52 g). To this was added heptanes (6 g, 4 parts) and the mixture stirred. The oil crystallized, resulting in a slurry. The slurry was stirred at 20-25 °C overnight. The solid was isolated by vacuum filtration, and the cake washed with heptanes (-1.5 mL). The cake was dried in the vacuum oven (40-45 °C) with a N2 sweep. 0.92 g of ketone 1-4 was obtained, 60.1% yield (corrected for aliquot size), HPLC purity = 99.9%.

TMSI Epoxidation Method

3d. 2-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)-5-(4-(trifluoromethoxy)phenyl)pyridine (5)

Typical Procedure for Converting 1-4 to 5

i-BuOK (2.22 g, 19.9 mmoles), TMSI (4.41 g, 20.0 mmoles), and THF (58.5 mL) were charged to a reaction flask, and the cloudy mixture was stirred. DMSO (35.2 mL) was added, and the clearing mixture was stirred at 20-25°C for 30 min before being cooled to 1-2°C.

Ketone 1-4 (crude, 5.85 g, 13.6 mmoles) was dissolved in THF (7.8 mL), and the 1-4 solution was added to the TMSI mixture over 12.75 min, maintaining the temperature between 1.5 and 2.0°C. The reaction was held at 0-2°C. After 1 h a sample was taken for HPLC analysis, which showed 77.6% epoxide 5, and no unreacted ketone 1-4. The reaction was quenched by the slow addition of 1 N HC1 (17.6 mL), keeping the temperature below 5°C. After 5 min 8% NaHCC>3 (11.8 mL) was added slowly below 5°C to afford a pH of 8. The reaction mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with MTBE (78 mL), and the combined organic layers were washed with 20% NaCl (2 x 20 mL). After concentration, 7.36 g of a dark oil was obtained. HPLC of the crude oil shows it contained 75% epoxide 5. The oil was dissolved in DCM (14.7 g, 2 parts) and the solution placed on a pad of Si02 (22 g, 3 parts). The flask was rinsed with DCM (7.4 g, 1 part) and the rinse placed on the pad. The pad was eluted with DCM (350 mL) to give an amber filtrate. The filtrate was concentrated by rotovap, and when space in the flask allowed, heptane (100 mL) was added. The mixture was concentrated until 39.4 g remained in the flask, causing solid to form. The suspension was stirred for 70 min at 20-25°C. Solid was isolated by vacuum filtration, and the cake washed with heptane (10 mL) and pulled dry on the funnel. After drying in a vacuum oven (40-45 °C) with a N2 sweep, 3.33 g solid was obtained, 55.1% yield from bromo-pyridine 3, HPLC purity = 99.8%.

3e. 3-amino-2-(2,4-difluorophenyl)-l,l-difluoro-l-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (±1-6)

Process Development

Table 8 illustrates the effects of the relative proportions of each of the reagents and reactants, the effect of varying the solvent, and the effect of varying the temperature had on the overall performance of the transformation as measured by the overall yield and purity of the reaction. Table 8. Process Development for the Preparation of ±1-6

Typical Procedure for Converting 5 to +1-6

Epoxide 5 (2.17 g, 4.89 mmoles) was combined in a glass pressure tube with methanol (48 mL) and aqueous ammonia (19.5 mL). The tube was sealed and placed in an oil bath held at 54°C, with stirring. After 15 h the tube was removed from the bath, cooled, and the reaction sampled for HPLC, which showed 93.6% amino-alcohol ±1-6 and 6.0% di-adducts. To the reaction were added MTBE (48 mL) and 20% NaCl (20 mL). The layers were separated and the aqueous layer extracted with MTBE (20 mL). The combined organic layers were washed with H20 (20 mL) and transferred to a rotovap flask. Heptane (20 mL) was added, and the solution was concentrated until 16.9 g remained in the flask. An H20 layer appeared in the flask, and was pipetted out, leaving 12.8 g. Compound 1-6 seed was added, and the crystallizing mixture was stirred at 20-25 °C overnight. The flask was cooled in an ice bath for 2 h prior to filtration, and the isolated solid was washed with cold heptane (5 mL), and pulled dry on the funnel. After drying in a vacuum oven (40-45°C) for several hours 1.37 g of amino-alcohol ±1-6 was obtained, 60.8% yield, HPLC purity = 98.0%.

3f . 3-amino-2-(2,4-difluorophenyl)- 1 , 1-difluoro- 1 -(5-(4-(trifluoromethoxy)phenyl)pyridin-2- yl)propan-2-ol (1-6* or 1-7*)

Process Development

Table 9 illustrates the initial screen performed surveying various chiral acid/solvent combinations. All entries in Table 9 were generated using 0.1 mmoles of amino-alcohol ±1-6, 1 equivalent of the chiral acid, and 1ml of solvent.

Table 9. Resolution of ±1-6 (Initial Screen)

Since the best results from Table 9 were generated using tartaric acid and di-p-toluoyltartaric acid, Table 10 captures the results from a focused screen using these two chiral acids and various solvent combinations. All entries in Table 10 were performed with 0.2 mmoles of amino-alcohol ±1-6, 87 volumes of solvent, and each entry was exposed to heating at 51 °C for lh, cooled to RT, and stirred at RT for 24h.

Table 10. Resolution of ±1-6 (Focused Screen)

Each of the three entries using di-p-toluoyltartaric acid in Table 10 resulted in higher levels of enantio-enrichment when compared to tartaric acid. As such, efforts to further optimize the enantio-enrichment were focusing on conditions using di-p-toluoyltartaric acid (Table 11).

Ό.6 equivalents used

ee sense was opposite from the other entries in the table (i.e., enantiomer of 1-6*)

Typical Procedure for Converting +1-6 to 1-6* or 1-7*

(This experimental procedure describes resolution of ±1-6, but conditions used for DPPTA resolution of 1-6 or 1-7 are essentially the same.)

Amino-alcohol ±1-6 (7.0 g, 15 mmoles) was dissolved in a mixture of acetonitrile (84 mL) and methanol (21 mL). (D)-DPTTA (5.89 g, 15 mmoles) was added, and the reaction was warmed to 50°C and held for 2.5 h. The heat was then removed and the suspension was allowed to cool and stir at 20-25 °C for 65 h. The suspension was cooled in an ice bath and stirred for an additional 2 h. Solid was isolated by vacuum filtration, and the cake was washed with cold 8:2 ACN/MeOH (35 mL). After drying at 50°C, 5.18 g of 1-6* or l-7*/DPPTA salt was isolated, HPLC purity = 99.0, ee = 74.

The 1-6* or l-7*/DPPTA salt (5.18 g) was combined with 8:2 ACN/MeOH (68 mL) and the suspension was heated to 50°C and held for 20 min. After cooling to 20-25 °C the mixture was stirred for 16 h. Solids were isolated by vacuum filtration, and the cake washed with cold 8:2 ACN/MeOH (30 mL), and pulled dry on the funnel. 2.82 g of 1-6* or l-7*/DPPTA salt was obtained, 44.4% yield (from crude ±1-6), ee = 97.5. The resulting solids were freebased to provide 1-6* or 1-7* with the same achiral and chiral purity as the DPPTA salt.

EXAMPLE 4: Preparation of 2-(2.4-difluorophenyl -l.l-difluoro-3-(lH-tetrazol-l-yl -l-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (1 or la).

The procedure used to generate compound 1 or la is as described in US 4,426,531. Table 13 illustrates the efficient and quantitative nature of this procedure as performed on amino- alcohol 1-6* or 1-7* produced from both the TMS-cyanohydrin method and the TMSI- epoxidation method.

Table 13. Formation of Compound 1 or la

EXAMPLE 5: 2-(2.4-difluorophenyl -l.l-difluoro-3-(lH-tetrazol-l-yl -l-(5-(4- (trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol benzenesulfonate (1 or la-BSA).

Typical Procedure for Converting 1 or la to 1 or la-BSA

46.6 g of compound 1 or la was dissolved in ethylacetate (360ml). The solution was filtered through a glass microfiber filter and placed in a 2 L reaction flask equipped with an overhead stirrer, condenser, and a J-Kem thermocouple. Pharma-grade benzenesulfonic acid (BSA, 14.39g, leq) was dissolved in ethyl acetate (100ml). The BSA solution was filtered through a glass microfiber filter and added to the stirred 1 or la solution in one portion. The mixture was warmed to 60-65 °C; precipitation of the 1 or la/BSA salt occurred during the warm up period. The slurry was held for 60 minutes at 60-65 °C. The suspension was allowed to slowly cool to 22 °C and was stirred at 20-25 °C for 16 hours. n-Heptane (920ml) was charged in one portion and the suspension was stirred at 22 °C for an additional 90 minutes. The slurry was filtered and the collected solids washed with n-heptane (250ml). The isolated solids were placed in a vacuum oven at 50 °C for 16 hours. 52.26g (86% yield) of 1 or la

benzenesulfonate was obtained.

*H NMR (400 MHz, DMSO-d6 + D20): 89.16 (s, 1H), 8.95 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 8.2, 2.3 Hz, 1H), 7.96-7.89 (m, 2H), 7.66-7.61 (m, 2H), 7.59 (dd, J = 8.3, 0.4 Hz, 1H), 7.53 (br d, J = 8.0 Hz, 2H), 7.38-7.15 (m, 5H), 6.90 (dt, J = 8.3, 2.5 Hz, 1H), 5.69 (d, J = 14.8 Hz, 1H), 5.15 (d, J = 15.2 Hz, 1H).

Further results are in Table 14.

Table 14. Formation of 1 or la-BSA

( ) (%ee) Yield Purity (%) ee

97.9 95.9 84% 98.2 97.1

Figures 1-2 contain the analytical data for 1 or la-BSA prepared by the TMSI-epoxidation process.

EXAMPLE 6: 5-bromo-2-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridine -Br).

Typical Procedure for Converting 3-Br to 4-Br

KOtBu ( 41.7g, 0.372moles, 1.05 equiv) and trimethylsulfoxonium iodide ( 85.7g,

0.389moles, 1.1 equiv) were charged to a 3L 3-neck round bottom flask equipped with an overhead stirrer, a thermocouple and an addition funnel. 1.2L of anhydrous THF and 740mL of DMSO were added to the flask and stirred at 22-25 °C for 70 minutes. The contents were cooled to 0°C. Crude ketone 3 was dissolved in 250mL of anhydrous THF and slowly added the ketone 3-Br solution to the reaction mixture over 20 minutes while maintaining a reaction temperature at < 3°C during the addition and stirred at 0°C for one hour. In-process HPLC showed <1% ketone 3-Br remaining. 200mL of IN HC1 was slowly added maintaining a reaction temperature of < 6°C during the addition. After stirring for 30 minutes the layers were separated and the aqueous layer was extracted with 375mL of MTBE. The combined organic layers were washed with 375mL of aqueous 9% NaHCC>3 and with 375mL of aqueous 20% NaCl. The solvent was removed to yield 4-Br as a brown waxy solid.

Weight of crude epoxide 4-Br = 124.6g; *H NMR (400 MHz, d6-DMSO) : 58.82 (d, J= 2.3Hz, 1H), 8.21 ( dd, J= 8.3, 2.3Hz, 1H), 7.50 (dd, J= 8.3, 0.5Hz, 1H), 7.41 ( m, 1H), 7.25 ( m, 1H), 7.10 (m,lH), 3.40 ( d, J= 4.5Hz, 1H), 3.14 ( m, 1H). MS m/z 362 (M+H+), 364 (M+2+H+).

EXAMPLE 7: 3-amino-l-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-l,l-difluoropropan-2-ol (4b-Br).

Typical Procedure for Converting 4-Br to 4b-Br

Crude epoxide 4-Br ( 54.4g, 0.15moles) was placed into a Schott autoclave bottle equipped with a stir bar. 550mL of MeOH was added to the bottle and stirred for 90 minutes at 22-25 °C. Concentrated NH4OH ( 550mL, 7.98 moles, 53 equiv) was added to the epoxide 4-Br

solution. The bottle was sealed and placed in an oil bath at 55 °C. The mixture was stirred at 55°C for 17 hours. The bottle was removed from the oil bath and cooled to 22-25°C. In-process HPLC showed <1% epoxide 4-Br remaining. The solvent was removed via rotary evaporation until 362g ( 37%) of the reaction mass remained. 500mL of MTBE was added and cooled the mixture to 8°C. 500mL of 6N HCl was slowly added maintaining the reaction temperature between 8 – 12°C during the addition. After stirring for 10 minutes, the layers were separated. The MTBE layer was extracted with 350mL of 6N HCl. The combined aqueous layers were washed with 250mL MTBE and 2 X 250mL heptane. MTBE, 250mL, was added to the aqueous layer and the mixture was cooled to 2°C. 344g of KOH was dissolved in 500mL of water. The KOH solution was slowly added to the reaction mixture over one hour while maintaining the temperature at <19°C. After stirring for 15 minutes, the layers were separated. The aqueous layer was extracted with 250mL MTBE. The combined organic layers were washed with 250mL of aqueous 20% NaCl and the solvent was removed to yield ±4b-Br as a dark oil. Weight of crude amino alcohol ±4b-Br = 46.0g. HPLC purity ( by area %) = 92%; *H NMR (400 MHz, d6-DMSO) : 58.67 (d, J= 2.2Hz, 1H), 8.15 ( dd, J= 8.6, 2.4Hz, 1H), 7.46 (m, 1H), 7.40 ( dd, J= 8.5, 0.7Hz, 1H), 7.10 ( m, 1H), 7.00 (m,lH), 3.37 (dd, J= 13.7, 2.1Hz, 1H), 3.23 ( dd, J= 13.7, 2.7, 1H). MS m/z 379 (M+H+), 381 (M+2+H+).

EXAMPLE 8: 3-amino-l-(5-bromopyridin-2-yl -2-(2.4-difluorophenyl -l.l-difluoropropan-2-ol (4b-Br or 4c-Br).

Typical Procedure for Converting 4-Br to 4b-Br or 4c-Br

Crude amino alcohol ±4b-Br ( 42.4, O. llmoles) was dissolved in 425mL of 8:2 IPA: CH3CN. The solution was charged to a 1L 3-neck round bottom flask equipped with a condenser, overhead stirrer and a thermocouple. Charged di-p-toluoyl-L-tartaric acid ( 21.6g, 0.056moles, 0.5 equiv) to the flask and warmed the contents to 52°C. The reaction mixture was stirred at 52°C for 5 hours, cooled to 22-25°C and stirred for 12 hours. The slurry was cooled to 5-10°C and stirred for 90 minutes. The mixture was filtered and collected solids washed with 80mL of cold CH3CN. The solids were dried in a vacuum oven 45-50°C. Weight of amino alcohol/ DPTTA salt = 17.4g

Chemical purity by HPLC ( area %) = 98.5%; Chiral HPLC= 98.0% ee.

13.60g of the amino alcohol/ DPTTA salt was placed into a 250mL flask with a stir bar and to this was added lOOmL of MTBE and lOOmL of 10% aqueous K2CO3solution. The reaction was stirred until complete dissolution was observed. The layers were separated and the aqueous layer was extracted with 50mL of MTBE. The combined MTBE layers were washed with 50mL of 20% aqueous NaCl and the solvent removed to yield 8.84 (98%) of 4b-Br or 4c-Br as a light yellow oil.

EXAMPLE 9: 3-amino-2-(2,4-difluorophenyl)-l J-difluoro-l-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (1-6* or 1-7*).

Typical Procedure for Converting 4b-Br or 4c-Br to 1-6* or 1-7*

Amino alcohol 4b-Br or 4c-Br (8.84g, 0.023moles, 1 equiv) was dissolved in 73mL of n-propanol. The solution was transferred to a 250mL 3-neck round bottom flask equipped with a condenser, thermocouple, stir bar and septum. 17mL of water was added and stirred at 22-25°C for 5 minutes. To the reaction was added K2CO3 ( 9.67g, 0.07moles, 3 equiv), 4-(trifluoromethoxy)phenylboronic acid ( 5.76g, 0.028moles, 1.2 equiv.) and Pd(dppf)Cl2 as a CH2Cl2 adduct ( 0.38g, 0.47mmoles, 0.02 equiv) to the flask. After the mixture was purged with nitrogen for 10 minutes, the reaction was then warmed to 85-87°C and stirred at 85-87°C for 16 hours. HPLC analysis showed < 1% of the amino alcohol 4b-Br or 4c-Br remaining. The mixture was cooled to 22-25 °C, then 115mL of MTBE and 115mL of water were added and stirred for 30 minutes. The layers were separated and the organic layer was washed with 2 X 60mL of 20% aqueous NaCl. The solvent was removed to yield 12.96g ( 121% yield) of 1-6* or 1-7* as a crude dark oil. It should be noted that the oil contains residual solvent, Pd and boronic acid impurity.

‘ll NMR (400 MHz, d6-DMSO) : 58.90 (d, J= 2.2Hz, 1H), 8.22 ( dd, J= 8.3, 2.3Hz, 1H), 7.91 (m, 2H), 7.54 ( m, 4H), 7.14 ( m, 1H), 7.02 (m,lH), 3.41 (m, 1H), 3.27 ( dd, J= 14.0, 2.7, 1H). MS m/z 461 (M+H+)

CLIP

Med. Chem. Commun., 2016,7, 1285-1306

DOI: 10.1039/C6MD00222F

Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics. Herein, we provide an overview of the most commonly used antifungals in medicine and agriculture. We also present a summary of the recent progress (from 2010–2016) in the discovery/development of new agents against fungal strains of medical/agricultural relevance, as well as information related to their biological activity, their mode(s) of action, and their mechanism(s) of resistance.

 

Graphical abstract: A complex game of hide and seek: the search for new antifungals
CLIP
Design and optimization of highly-selective fungal CYP51 inhibitors
  • Viamet Pharmaceuticals Inc., Durham, NC 27703, USA

Image for figure Scheme 1

able 3.Antifungal activity of difluoromethyl-pyridyl-benzenes

Antifungal activity of difluoromethyl-pyridyl-benzenes
Compound R C. albicans MICa T. rubrum MICa CYP3A4 IC50b Selectivity indexc
7a Cl ⩽0.001 0.004 36 9000
7b CF3 ⩽0.001 0.002 54 27,000
7c

VT 1129

OCF3 ⩽0.001 ⩽0.001 79 >79,000
7d

VT 1161

OCH2CF3 ⩽0.001 ⩽0.001 65 >65,000
Itraconazole 0.016 0.062 0.07 1.1
aMinimum concentration that achieved 50% inhibition of fungal growth; MIC units in μg/mL.5
bInhibition of CYP3A4 measured in microsomes obtained from pooled human hepatocytes, IC50 units in μM.8
cIn vitro selectivity calculated as CYP3A4 IC50/T. rubrum MIC.
(R)-(+)-Enantiomers (7a7d) were isolated from racemates using chiral chromatography.
16 Hoekstra, W.J.; Schotzinger, R.J.; Rafferty, S.W. U.S. Patent 8,236,962 issued Aug. 7, 2012.

update………….

QUILSECONAZOLE, VT 1129, New Patent, WO, 2017049080, Viamet

str1 Figure imgf000002_0001

<p>Formula (I)</p> <p>Crizotinib is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Enantiomerically pure compound of formula I was first disclosed in US Patent No. 7,858,643. Additionally, the racemate of compound of formula I was disclosed in U.S. patent application 2006/0128724, both of these references discloses similar methods for the synthesis of Compound of Formula I.</p> <p>Conventionally, the compounds of formula I are prepared by reacting Bis(pinacolato)diboron with protected 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine in the presence of Pd catalyst. The obtained product after deprotection is reacted with N- protected 4-(4-bromo-pyrazol-l-yl)-piperidine in the presence of Pd Catalyst. The obtained product is filtered through celite pad and purified by Column Chromatography. The final product of formula I was obtained by deprotection of the purified compound by using HCl/dioxane. US Patent No. 7,858,643 provides enantiomerically pure aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity. More particularly, US 7,858,643 describes process for the preparation of 3-[(lR)-l-(2,6- dichloro-3-fluorophenyl)ethoxy]-5-(l-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine. The Scheme is summarized below in Scheme- 1 :</p>

<p>Scheme-1</p> <p>wherein, “Boc” means tert-butoxycarbonyl; and a) (Boc)<sub>2</sub>, DMF, Dimethylaminopyridine b) Pd(dppf)Cl<sub>2</sub>, KOAc, Dichloromethane; c) HC1, Dioxane, Dichloromethane; d) Pd(PPh<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>, Na<sub>2</sub>C0<sub>3</sub>, DME/H<sub>2</sub>0; e) 4M HCl/Dioxane, Dichloromethane</p> <p>A similar process has been disclosed in the U.S. patent application 2006/0128724 for the preparation of Crizotinib. J. Jean Cui et. al. in J. Med. Chem. 2011, 54, 6342-6363, also provides a similar process for the preparation of Crizotinib and its derivatives.</p> <p>However, above mentioned synthetic process requires stringent operational conditions such as filtration at several steps through celite pad. Also column chromatography is required at various steps which is not only tedious but also results in significant yield loss. Another disadvantage of above process involves extensive use of palladium catalysts, hence metal scavengers are required to remove palladium content from the desired product at various steps which makes this process inefficient for commercial scale.</p> <p>Yet another disadvantage of above process is the cost of Bis(pinacolato)diboron. This reagent is used in excess in the reaction mixture resulting in considerable cost, especially during large-scale syntheses.</p> <p>US Patent No. 7,825,137 also discloses a process for the preparation of Crizotinib where Boc protected 4-(4-iodo-pyrazol-l-yl)-piperidine is first reacted with Bis(pinacolato)diboron in the presence of Pd catalyst. The reaction mixture is filtered through a bed of celite and the obtained filtrate is concentrated and purified by silica gel chromatography to give to form tert-butyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l- carboxylate. To this compound, 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]- pyridin-2-ylamine is added in the presence of a Pd catalyst. The reaction mixture is stirred for 16h at 87°C. The reaction mixture is filtered through celite pad and the concentrated filtrate is purified on silica gel column to obtain (4-{6-amino-5-[(R)-l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-pyri- din-3-yl}-pyrazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester of 95% purity. To the solution of resulting compound in dichloromethane 4N HCl/Dioxane is added and thereby getting the reaction suspension is filtered in Buchner funnel lined with filter paper. The obtained solid is dissolved in HPLC water and pH is adjusted to 10 with the addition of Na<sub>2</sub>C0<sub>3</sub> Compound is extracted using dichloroform and is purified on a silica gel column by eluting with CH<sub>2</sub>Cl<sub>2</sub> MeOH/NEt<sub>3</sub> system to obtain Crizotinib. The scheme is summarized below in scheme 2:</p>

<p>Formula (i) Formula (ii)</p>

<p>Formula (iii) Formula (ii) ula (iv)</p>

<p>Formula (v) Formula (I)</p> <p>Scheme-2</p> <p><span style=”color:#ff0000;”>Preparation of Crizotinib:</span></p> <p>To a stirred solution of Tert-butyl 4-(4-{ 6-amino-5-[(li?)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3 -yl } – lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (material obtained in Example 3) (l.Og, 0.00181 moles) in dichloromethane (-13 ml) at 0°C was added 4.0 M dioxane HQ (6.7 ml, 0.0272 moles). Reaction mixture was stirred at room temperature for 4h. After the completion of reaction monitored by TLC, solid was filtered and washed with dichloromethane (10 ml). The obtained solid was dissolved in water (20 ml); aqueous layer was extracted with dichloromethane (10×2). The pH of aqueous layer was adjusted to 9-10 with Na<sub>2</sub>C03 and compound was extracted with dichloromethane (10 x 3), combined organic layers were washed with water (20 ml), evaporated under vacuum to get solid product. The solid was stirred with ether (10 ml), filtered off, washed well with ether, dried under vacuum to get <span style=”color:#ff0000;”>Crizotinib.</span></p> <p>Yield: 0.45g (55 %)</p> <p>HPLC Purity: 99.35 %</p> <p><span style=”color:#ff0000;”>1HNMR (400 MHz, CDC1<sub>3</sub>) δ: 7.76 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.30 (dd, J = 9.2 Hz), 7.0 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.09 ( q, J= 6.8 Hz, 1H), 4.75 (brs, 1H), 4.19 (m, 1H), 3.25 (m, 2H), 2.76 (m, 2H), 2.16 (m, 2H), 1.92 (m, 2H), 1.85 (d, J= 6.8 Hz, 3H), 1.67 (brs, 1H)</span></p> <p>…………………………</p> <p><a href=”http://www.sciencedirect.com/science/article/pii/S0040403914000872″>http://www.sciencedirect.com/science/article/pii/S0040403914000872</a></p&gt;

Abstract

A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.

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http://www.sciencedirect.com/science/article/pii/S0040403911021745

Abstract

4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.

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</div> </div> </dt> </dl> </div> </div> </div> <p>……………………</p>

Org. Process Res. Dev., 2011, 15 (5), pp 1018–1026
DOI: 10.1021/op200131n
Abstract Image

<p class=”articleBody_abstractText”>A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate <b>6</b>. A highly selective Suzuki reaction between <b>6</b> and pinacol boronate <b>8</b>, followed by Boc deprotection, completed the synthesis of crizotinib <b>1</b>.</p> </div> <p><span id=”d43162769e1806″ class=”title2″>3-[(1<i>R</i>)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1<i>H</i>-pyrazol-4-yl]pyridin-2-amine <b>1</b></span></p> <p><span style=”color:#ff0000;”> <i>crizotinib</i><b>1</b> (20.7 kg, 80%) as a white solid. </span></p> <p><span style=”color:#ff0000;”>Mp 192 °C;</span></p> <p><span style=”color:#ff0000;”><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ: 7.78 (d, <i>J</i> = 1.8 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.31 (dd, <i>J</i> = 9.0, 4.9 Hz, 1H), 7.06 (m, 1H), 6.89 (d, <i>J</i> = 1.7 Hz, 1H), 6.09 (q, 1H), 4.79 (br s, 2H), 4.21 (m, 1H), 3.26 (m, 2H), 2.78 (m, 2H), 2.17 (m, 2H), 1.90 (m, 2H), 1.87 (d, <i>J</i> = 6.7 Hz, 3H), 1.63 (br s, 1H).</span></p> <p><span style=”color:#ff0000;”> <sup>13</sup>C NMR (100.6 MHz, CDCl<sub>3</sub>) δ: 157.5 (d, <i>J</i> = 250.7 Hz), 148.9, 139.8, 137.0, 135.7, 135.6, 129.9, 129.0 (d, <i>J</i> = 3.7 Hz), 122.4, 122.1 (d, <i>J</i> = 19.0 Hz), 119.9, 119.3, 116.7 (d, <i>J</i> = 23.3 Hz), 115.0, 72.4, 59.9, 45.7, 34.0, 18.9.</span></p> <p><span style=”color:#ff0000;”> LC-MS: found <i>m</i>/<i>z</i> 450.0, 451.0, 452.0, 453.0, 454.0, 455.0. </span></p> <p><span style=”color:#ff0000;”>Anal. Calcd for C<sub>21</sub>H<sub>22</sub>Cl<sub>2</sub>FN<sub>5</sub>O: C, 56.01; H, 4.92; N, 15.55. Found: C, 56.08; H, 4.94; N, 15.80.</span></p>

Cui, J. J.; Botrous, I.; Shen, H.; Tran-Dube, M. B.; Nambu, M. D.; Kung, P.-P.; Funk, L. A.; Jia, L.; Meng, J. J.; Pairish, M. A.; McTigue, M.; Grodsky, N.; Ryan, K.; Alton, G.; Yamazaki, S.; Zou, H.; Christensen, J. G.; Mroczkowski, B.Abstracts of Papers; 235th ACS National Meeting, New Orleans, LA, United States, April 6–10, 2008.

</div>

Cui, J. J.; Funk, L. A.; Jia, L.; Kung, P.-P.; Meng, J. J.; Nambu, M. D.; Pairish, M. A.; Shen, H.; Tran-Dube, M. B. U.S. Pat. Appl. U. S. 2006/0046991 A1, 2006.

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WO2010048131A1 * Oct 20, 2009 Apr 29, 2010 Vertex Pharmaceuticals Incorporated C-met protein kinase inhibitors
WO2011042389A2 * Oct 4, 2010 Apr 14, 2011 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles
US7825137 Nov 23, 2006 Nov 2, 2010 Pfizer Inc. Method of treating abnormal cell growth
US7858643 Aug 26, 2005 Dec 28, 2010 Agouron Pharmaceuticals, Inc. Crizotinib, a c-Met protein kinase inhibitor anticancer agent; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine is crizotinib
US20060128724 Aug 26, 2005 Jun 15, 2006 Agouron Pharmaceuticals, Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
1 J. JEAN CUI J. MED. CHEM. vol. 54, 2011, pages 6342 – 6363
2 ORG. PROCESS RES. DEV. vol. 15, 2011, pages 1018 – 1026
3 * PIETER D. DE KONING ET AL: “Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066)“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 5, 16 September 2011 (2011-09-16), pages 1018-1026, XP055078841, ISSN: 1083-6160, DOI: 10.1021/op200131n

 

str1

 

VT 1129 BENZENE SULFONATE

CAS 1809323-18-9

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VT 1129

1340593-70-5 CAS
MF C22 H14 F7 N5 O2, MW 513.37
2-Pyridineethanol, α-(2,4-difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(trifluoromethoxy)phenyl]-, (αR)-
R ISOMER
ROTATION +

QUILSECONAZOLE, VT-1129

Viamet, in collaboration with Therapeutics for Rare and Neglected diseases, is investigating quilseconazole benzenesulfonate (VT-1129), a small-molecule lanosterol demethylase (CYP51) inhibitor, developed using the company’s Metallophile technology, for treating fungal infections, including Cryptococcus neoformans meningitis.

WO-2017049080

 

 

////////VT 1129,  VIAMET, WO 2016149486,  Viamet Pharmaceuticals,  Antifungals,  Small molecules,  14-alpha demethylase inhibitors, Orphan Drug Status, Cryptococcosis, On Fast track, PHASE 1, VT-1129, QUILSECONAZOLE

O[C@@](Cn1cnnn1)(c2ccc(F)cc2F)C(F)(F)c3ccc(cn3)c4ccc(OC(F)(F)F)cc4

WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED


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WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

LINK>>> (WO2016147197) A NOVEL PROCESS FOR PREPARING (2S,3R,4R,5S,6R)-2-[4-CHLORO-3-(4-ETHOXYBENZYL)PHENY 1] -6-(HY DROXY METHYL)TETRAHYDRO-2H-PY RAN-3,4,5-TRIOL AND ITS AMORPHOUS FORM

HARMAN FINOCHEM LIMITED [IN/IN]; 107, Vinay Bhavya Complex 159-A, C.S.T. Road Kalina, Mumbai 400098 Maharashtra (IN)

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KADAM, Vijay Trimbak; (IN).
SAIKRISHNA; (IN).
CHOUDHARE, Tukaram Sarjerao; (IN).
MINHAS, Harpreet Singh; (IN).
MINHAS, Gurpreet Singh; (IN)

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CHAIRMAN

HARPREET SINGH MINHAS

HARPREET SINGH MINHAS

Owner, HARMAN FINOCHEM LIMITED

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(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is sodium dependent glucose transporter (SGLT) which is currently under investigation for the treatment of type-2 diabetes. (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is marketed under the tradename Farxiga or Forxiga.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4ethoxyphenyl)methyl]phenyl]-, (I S). (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5 -triol is a white to off-white powder with a molecular formula of C2iH25C106 and a molecular weight of 408.87

Formula-I

US 6,515,117 B2 discloses (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its pharmaceutically acceptable salts. US 6,515,117 B2 also describes process for preparation of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol which comprises reaction of 5-bromo-2-chloro-4′-ethoxydiphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl- -D-glucolactone in presence of THF/Toluene, methansulfonic acid to yield o-methylglucoside product which further reacts with Et3SiH, BF3Et20 in presence of MDC and acetonitrile to yield yellow solidified foam which is dissolved in MDC, pyridine and followed by acetylation with acetic anhydride, DMAP to yield tetra acetylated- β-C-glucoside as a white solid which is further deprotected with LiOH H20 in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry.

Process for preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenylJ-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is disclosed in US 7,375,213 B2 and J.Med.Chem.2008, 51, 1145-1149. The preparation process is depicted in Scheme-I.

Scheme-1

Prior art US’213 describes reaction of 2-chloro-5-bromo-4′-ethoxy-diphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, n-BuLi in presence of THF and Heptane. After basification with TEA, the oily residue of methyl- l-C-(2-chloro-4′- ethoxy-diphenylmethan-3-yl)-a-D-glucopyranose obtained as solid compound after workup. This compound reacts with acetic anhydride in presence of THF, DIPEA and DMAP to get oily residue of methyl-2,3,4,6 tetra-0-acetyl-l-C-(2-chloro-4′-ethoxydiphenylmethan-3-yl)-a-D-glucopyranose which further undergoes reduction reaction in presence of acetonitirle, t riethylsilane, boron trifluoride etherate to yield 2,3,4,6-tetra-0-acetyl-l-C-(2-chloro-4′-ethoxydi henylmethan-3-yl)-β-D-glucopyranose which is further deprotected by reacting with LiOH monohydrate in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The said prior art describes multiple, time consuming process steps which involves getting the intermediate products as oily residue at various stages of the process, which is difficult to purify and handle for further process step. More over the workup involves multiple evaporation of product which may result in decomposition. Another drawback of the process is that the process describes n-BuLi reaction with two pot reaction. It is very difficult to transfer the material from one reactor to second reactor at -78 °C at industrial level with highly moisture sensitive reaction mass. This makes process uneconomical, cumbersome and commercially not viable. Further when practically the said method followed, a-Isomer of the final product is formed in the range of 6-8% along ith Des-bromo impurity formed in the range of 7-9 %, which increases after addition of n-butyllithium and kept the mass for overnight reaction. Moreover lactone ring cleavage is also observed in the range of 3-4% after addition of Methanesulphonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product.

WO 2008002824 A 1 discloses crystalline forms of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol comprising (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1 :2 L-proline, 1 : 1 L-proline, 1 : 1 L-proline hemihydrate, 1 : 1 L-phenylalanine and its preparation process.

In the light of the above drawbacks, it is necessitated to provide economical, robust, safe and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Accordingly, it is an objective of the present invention to provide a commercially viable process for the preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyb.enzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, prepared via riovel intermediates which gives higher yield and purity and facilitates easy recovery of the final compound. The purification process does not involve any costly technique/equipment, however, carried out with solvents which are industrially feasible. More over the present invention discloses the n-BuLi insitu reaction that makes the present invention cost-effective over the teachings of prior art.

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Scheme-II

Formula-Ill Formula-IV

Formula-V where R1= allyl, prop-2-ynyl,isopropyl

Scheme-Ill

where R = allyl, prop-2-ynyl

Scheme-IV

Scheme-V

Examples:

Example-1: Preparation of 3,4,5-Tris-trimethylsiIanyloxy-6-trimethylsiIanyloxymethyl-tetrahydro-pyran-2-one

To 750 cc of dry THF added 1.12 mole 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one at ambient temperature and stirred for 20 min. To the reaction mass added 9.0 mole N-Methyl morpholine and stirred for another 30.0 min at ambient temperature. Reaction mass was cooled to -5 °C to 0 °C and stirred for 30.0 min. Added 18.0 mole Trimethyl sillyl chloride at the temp -5 °C to 0 °C and stirred for 30.0 min. Temperature was raised to 25 °C to 30 °C and maintained for 18-20hrs. After reaction complies by GC, the reaction mass was cooled to -5 deg to 0 deg. Added Sat.Sodium bicarbonate solution to obtain the pH 7-8 and stirred for 1 hr at 0 °C. Added 500 cc toluene and stirred for lhr. Reaction mass was settled down for 30.0 min and layers were separated. To the Aqueous layer added 250 cc of toluene and stirred for 30.0 min. Layers separated and both the organic layers mixed and back washed with sat.brine solution. Organic layer was distilled under reduced pressure at a temperature of about 40 – 48 deg. Unload the oily mass . Purity: 92-96 %

Example-2: Preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, reaction mass was quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline and stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer was combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 83 % the compound as crystalline solid.

HPLC purity: 88 – 91 %

I R data:

Anomeric C-0 stretching: 1242 cm“1

Allylic C- O stretching: 1 177 cm“1

Allylic C- H stretching: 3010 – 3120 cm“1

Aromatic C- CI stretching: 820 cm“1

Lactones O – H stretching: 3240 – 3380 cm“1

Lactones C – 0 stretching: 1045 – 1092 cm“1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm“1

Alkane C – H stretching: 2877,2866, 2956, 2958, 2962 cm“1

Aromatic C – H stretching: 3050 – 3090 cm“1

Dip-Mass

(M+Na) 487.19 m/z

(M+K) 503.17 m/z

Example 3: Preparation of 2-prop-2ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, the reaction mass was quenched with Methane sulphonic acid and propargyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer were combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75 – 80 % the compound as crystalline solid.

HPLC purity: 88 – 93 %

IR data:

Anomeric C-0 stretching: 1242 cm“1

Propargyl ~c CH stretching: 2125 cm“1

Propargyl C- H stretching : 3010 – 3120 cm“1

Aromatic C- CI stretching: 820 cm“1

Lactones O – H stretching: 3240 – 3380 cm“1

Lactones C – 0 stretching: 1045 – 1092 cm“1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm“1

Alkane C – H stretching: 2877, 2866,2956,2958,2962 cm“1

Aromatic C – H stretching: 3050 – 3090 cm“1

Dip-Mass

(M+Na) 485.25 m/z

(M+K) 501.25 m/z

Example-4: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-trioI

To the mixture of 20 cc (1 : 1 MDC + ACN) added 0.1 1 mole 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon atmosphere, and stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C . and stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and wash with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85 %the light yellow solid.

HPLC purity: 92-95 %

Example 5: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 20 cc (1 :1 MDC + ACN) added 0.11 mole 2-prop-2-ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon

atmosphere. Stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C and Stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and washed with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85%the light yellow solid.

HPLC purity: 90%

Example 6: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 4 charged 500cc of n-heptane and stirred for ½hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs.; cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the, cake with 100 cc n-heptane. Dried at 40-45°C under vacuum to get 85% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 91-93%

Example 7: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 5 charged 500cc of n-heptane and stirred for ½ hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs., cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the cake with 100 cc n-heptane. Dried at 40-45 °C under vacuum to get 85-88% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 89-91%

Example 8: Preparation of L-proline – (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyI]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol co crystal

To the 10 cc of Ethyl acetate charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C and stirred for 1 hr. Slowly added L-proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 92% titled compound.

HPLC purity: 99%

Example 9: Preparation of L-proline – (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolco crystal

To the 10 cc of acetone charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 – 65°C and stirred for 1 hr. Slowly added proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 93-95% titled compound.

HPLC purity: 98-99%

Example 10: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the 15 cc ethyl acetate added (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol at ambient temperature and stirred for 30.0 min. Slowly added 5- 8 cc sat. sodium bicarbonate solution at ambient temperature and stirred for 1.5 hr to get the clear solution. Settled down and separated layers. Extracted the aqueous layer with 25 cc ethyl acetate.

Combined the organic layers and washed the ethyl acetate layer with 50 cc sat. Sodium chloride solution. Distilled out ethyl acetate under reduced pressure at 40 – 45°C to get fluffy solid. Charged 50 cc n-Heptane and stirred for 5 hrs to get 70-78% the title compound as Amorphous soild.

HPLC purity: 99.8-99.95 %

Example 11: Preparation of 2-chloro -4′- ethoxydiphenylmethane (impurity)

To the 20 cc THF and 20 cc Toluene added 0.25 mole 2-ehloro-5-bromo-4′- ethoxydiphenylmethane under argon atmosphere. Cooled the reaction mass to – 78° C. Slowly added n-Butyl lithium (1.9 M in hexane) at – 78° C and stirred for 30 min. Slowly added 20 % Ammonium chloride solution to the reaction mass. Brought the reaction mass to ambient temperature and stirred for 30 min. Settled and separated layers. Extracted the aqueous layer with 50 cc toluene. Washed the combined organic layer with 500 cc brine solution. Distilled out the toluene and charged heptanes, stirred for 2 – 3 hrs at ambient temperature. Filtered the product and dried the product at 45 – 50°C under reduced pressure to get 93 % titled compound.

Mass: (m+1) 247 m/z found 247.1 1

HPLC purity: 96.33 %

SHENDRA AURANGABAD, MAHARASHTRA, INDIA

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Bhupinder Singh Manhas

 

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WO 2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd


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WO-2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

SMILAX LABORATORIES LIMITED [IN/IN]; Plot No. 12/A, Phase – III, I.D.A. Jeedimetla, Hyderabad 500 055 (IN).

The present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula I, with a reduced content of desethyl impurity less than 0.1% and an efficient, commercially viable process for the preparation of pure intermediates of Azilsartan.
KOTAGIRI, Vijaya Kumar; (IN).
YENUMULA, Raghavendra Rao; (IN).
BANDARI, Mohan; (IN).
SURYADEVARA, Murali Krishna; (IN)
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(WO2016147120) AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE AZILSARTAN

Azilsartan (I) is an angiotensin receptor II antagonist used in the treatment of hypertension. Angiotensin II causes vasoconstriction via an angiotensin II receptor on the cell membrane and elevates blood pressure.

Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by USFDA on 25 Feb, 2011 and EMEA on 7 Dec 2011 for the treatment of high blood pressure in adults.

Azilsartan medoxomil and its salts thereof are imbibed with properties such as strong and long lasting angiotensin II antagonistic activity and hypotensive action which has an insulin sensitizing activity useful for the treatment of metabolic diseases such as diabetes and the like., and a useful agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases, nephritis and stroke. Azilsartan medoxomil is the prodrug of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan).

Methods of preparing benzimidazole derivative useful as an angiotensin II receptor antagonist such as Azilsartan Medoxomil and salts thereof are disclosed by Takeda in US 5,243,054 (herein after referred as US ‘054 patent). The US’054 patent describes several synthetic routes for preparing Azilsartan. According to one of the synthetic process, the compound of formula II is reacted with hydroxylamine hydrochloride in a conventional organic solvent and sodium methoxide in methanol to give the amidoxime compound of formula III which on further reaction with ethyl chloroformate in presence of triethylamine base in refluxing xylene undergoes cyclization to provide a compound of formula IV. Azilsartan was prepared by hydrolysis of compound of formula IV in presence of lithium hydroxide by adjusting the pH with HC1. The process is as depicted below in Scheme A:

However, the amidoxime compound of formula III obtained by the above process contains about 50% of amide imputiy along with desired product, owing to the strong reaction conditions which impairs the quality and loss of yield. The pH adjustment with HC1 in the hydrolysis step of compound IV results in the formation of an undesired desethyl impurity of formula V due to acid sensitive nature of the ether linkage in the benzimidazole moiety of Azilsartan.

Formula V

According to another method disclosed in US’054 for the preparation of Azilsartan comprises by reacting ethoxycarboimidoyl biphenyl benzimidazole derivative of compound with ethyl chloroformate to give N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole derivative, which is further converted to compound of formula IV and then to Azilsartan of formula I by hydrolysis.

According to one another embodiment method for the preparation of Azilsartan disclosed in US ‘054, cyanobiphenyl aminobenzoate derivative compound reacts with hydroxylamine hydrochloride in presence of triethylamine subsequently followed by addition of ethyl chlorocarbonate results in the formation of compound of formula IV which is further hydrolyzed to obtain Azilsartan of formula I.

J. Med. Chem. Vol. 39, No. 26, 5230-5237 (1996) describes the use of triethylamine as base during the conversion of compound of formula II to amidoxime compound of formula III and use of 2-ethylhexylchloroformate instead of ethylchloroformate as cyclizing agent.

Processes for the preparation of Azilsartan medoxomil and its potassium salt are described in US 7,157,584 which comprises reacting Azilsartan with 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one in presence of dimethylacetamide, p-toluoyl sulfonylchloride, 4-dimethylaminopyridine and potassium carbonate.

PCT publication WO 2012/107814 discloses process for the preparation of Azilsartan or its esters or salts by reacting amidoxime compound of formula III with carbonyl source such as carbodiimides, dialkyl carbonate and phosgene equivalents in presence of a suitable base to obtain compound of formula IV which is further converted to Azilsartan and its pharmaceutically acceptable salts. The process for the preparation of Azilsartan is as depicted in Scheme B:

Scheme – B

This publication also discloses that use of a carbonyl source reduces the formation of the content of desethyl impurity during cyclization.

Polymorphs of Azilsartan and its salts are disclosed in WO 2013/044816 and WO 2013/186792.

All the above prior art methods for the preparation of Azilsartan have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates as well as Azilsartan having a considerably higher content of desethyl impurity. Accordingly, there remains a need for the industrial preparation of substantially pure Azilsartan which is free of impurities with high yield.

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Examples

Example-1: Preparation of Methyl-2-ethoxy-l-[[2′- ((hydroxycarbamimidoyl)biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylate (Formula-Ill):

To a stirred solution of DMSO (1500.0 mL), Hydroxylamine hydrochloride ( 126.7g 1.83mol) and Dipotassium hydrogen phosphate (634.9g 3.65mol) was added Methyl l-[[2′-cyanobiphenyl-4-yl]methyl]-2-ethoxybenzimidazole-7-carboxylate (lOO.Og 0.243mol) at 25-30°C. The reaction mass temperature was raised to 80-85°C and maintained for 30-40 hours. Reaction completion was monitored by TLC. Upon completion of reaction, reaction mass was cooled to 10- 15°C, and was poured into water (3000.0 mL), stirred for 45min at 20-25°C. and was filtered. The filtered wet solid was washed with water and dried at 65°C to get crude Methyl-2-ethoxy-l-[[(2′-(hydroxycarbarmrmdoyl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate. The wet material was slurried in Acetone (optional) at reflux and filtered at room temperature to obtain pure compound.

Yield: 79.92 g, 74.0%; HPLC Purity: 97.78%; Desethyl impurity: 0.318%; Amide impurity: 1.42%.

Example-2: Preparation of Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (Formula-IV) :

To the pre cooled solution of Methylene dichloride (375.0 mL) and Methyl-2-ethoxy-1 -[[2′ -((hydroxycarbamimidoyl)biphenyl)-4-yl] methyl]- lH-benzimidazole-7-carboxylate (75.0g, 0.168mol) was added ethyl chloroformate ( 18.3g 0.168mol)

followed by addition of triethylamine (18.75g 0.185mol). The reaction mass was maintained at 0-5 °C for about 1 hour. Upon completion of the reaction, reaction mass was poured into water (200.0 mL), organic layer was separated and washed with 5% NaHC03 solution (150.0 mL) and then with water (150.0 mL). The organic layer was dried over sodium sulfate and distilled to obtain the crude material (optionally be isolated using cyclohexane solvent). To this obtained crude material, ethyl acetate (750.0mL) and potassium carbonate (112.5g 0.814mol) were added and heated to reflux for 6 to 8 hours. The contents were cooled, filtered and wet solid was slurried in water. Wet material so obtained was slurried in ethyl acetate at reflux and filtered at room temperature and dried at 60-65°C to give Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Yield: 64.27 g, 81.0 %; HPLC Purity: 99.80%; Desethyl impurity: 0.085%.

Example-3: Preparation of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.8 mL) and Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (125.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 5.0 using dilute acetic acid at 0-5 °C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 20.0 g, 82.47%; HPLC Purity : 99.80%; Desethyl impurity: 0.10%.

Example-4: Preparation of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (633.33 mL) and Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (40.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (200.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 4.5 using acetic acid at 10-15°C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 32.35 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.12%.

Example-5: Preparation of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (791.66 mL) and Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (50.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (250.0mL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0 using citric acid at 10-15°C. The obtained solid material was filtered and washed with water (125.0mL). This material was dried to obtain the title product.

Yield: 37.0 g, 76.28%; HPLC Purity: 99.69%; Desethyl impurity: 0.083%.

Example-6: Preparation of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.83 mL) and Methyl 2-ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (lOO.OmL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0

using hydrochloric acid at 10-15°C. The obtained solid material was filtered and washed with water (72.5 mL). This material was dried to obtain the title product. Yield: 20.22 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.217%.

Example-7: Purification of 2-Ethoxy-l-[[2′-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

Charged 2-Ethoxy- 1 – [[2′ -(2,5-dihydro-5-oxo- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (lOO.Og), methanol (600.0ml) and methylene dichloride (600.0ml) and were stirred for 10 min at 25-30°C to get a clear solution. Above solution was treated with Activated carbon (lO.Og) and stirred for 10.0 min at 25-30°C. Reaction mixture was passed through a hyflow bed and washed with a mixture of (1: 1) ratio of 200.0ml methanol and methylene dichloride. The solvent mixture was distilled out at below 50°C till the solid formation was observed. Reaction mixture is stirred for 30.0min at 30°C, then the solid was filtered and washed with 200.0ml of methylene dichloride. To the obtained solid, methanol (450.0 ml) was charged at 25-30°C, heated to 45°C, stirred for 30 min at 45°C and then cooled to 30°C. After cooling, the solid was filtered and washed with methanol (90.0ml) which was further dried at 50-55°C for 12 hours.

Yield: 80.0 g, 80.0%; HPLC Purity: 99.96%; Desethyl impurity : 0.012%.

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Accreditation

Smilax Managing Director, S. Murali Krishna received the award from Hon’ble Chief Minister of Andhra Pradesh Shri. N. Kiran Kumar Reddy.

FDA approves Amjevita, a biosimilar to Humira


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FDA approves Amjevita, a biosimilar to Humira

The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar toHumira (adalimumab) for multiple inflammatory diseases.

Read more.

FDA approves Amjevita, a biosimilar to Humira

For Immediate Release

September 23, 2016

Release

The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar to Humira (adalimumab) for multiple inflammatory diseases.

Amjevita is approved for the following indications in adult patients:

  • moderately to severely active rheumatoid arthritis;
  • active psoriatic arthritis;
  • active ankylosing spondylitis (an arthritis that affects the spine);
  • moderately to severely active Crohn’s disease;
  • moderately to severely active ulcerative colitis; and
  • moderate to severe plaque psoriasis.

Amjevita is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.

Health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“This is the fourth FDA-approved biosimilar. The biosimilar pathway is still a new frontier and one that we expect will enhance access to treatment for patients with serious medical conditions,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

Biological products are generally derived from a living organism and can come from many sources, including humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Amjevita is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Amjevita is biosimilar to Humira. It has been approved as a biosimilar, not as an interchangeableproduct.

The most serious known side effects with Amjevita are infections and malignancies. The most common expected adverse reactions with Amjevita are infections and injection site reactions.

Like Humira, the labeling for Amjevita contains a Boxed Warning to alert health care professionals and patients about an increased risk of serious infections leading to hospitalization or death. The Boxed Warning also notes that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor blockers, including adalimumab products. The drug must be dispensed with a patient Medication Guide that describes important information about its uses and risks.

Amjevita is manufactured by Amgen, Inc., of Thousand Oaks, California. Humira was approved in December 2002 and is manufactured by AbbVie Inc. of North Chicago, Illinois.

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Adalimumab
Adalimumab structure.png
Farmaceutische gegevens
t1/2 10–20 dagen
Databanken
CAS-nummer 331731-18-1
ATC-code L04AB04
DrugBank BTD00049
Farmacotherapeutisch Kompas Adalimumab
Chemische gegevens
Molaire massa 144190.3 g/mol

///////FDA, Amjevita, biosimilar, Humira, FDA 2016

Pimavanserin


ChemSpider 2D Image | Pimavanserin | C25H34FN3O2

Pimavanserin

  • MF C25H34FN3O2
  • MW 427.555

Pimavanserin, ACP 103, ACP-103; BVF-048

N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide,

706779-91-1 (Pimavanserin )
706782-28-7 (Pimavanserin Tartrate)

For treatment of psychotic symptoms in patients with Parkinson’s disease

WATCH OUT AS THIS POST IS UPDATED………..

Trade Name:Nuplazid®

MOA:5-HT2A inverse agonist

Indication:Hallucinations and delusions associated with Parkinson’s disease psychosis

Company:Acadia (Originator)

Mikkel Thygesen, Nathalie Schlienger, Bo-Ragnar Tolf, Fritz Blatter, Jorg Berghausen
Applicant Acadia Pharmaceuticals Inc.

APPROVED US FDA 2016-04-29, ACADIA PHARMS INC, (NDA) 207318

To treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease

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706782-28-7 (tartrate)
Molecular Weight 1005.2
Formula (C25H34FN3O2)2 ● C4H6O6

Urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)

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Pimavanserin Tartrate was approved by the U.S. Food and Drug Administration (FDA) on Apr 29, 2016. It was developed by Acadia, then marketed as Nuplazid® by Acadia in US.

Pimavanserin Tartrate is a 5-HT2A receptor inverse agonists, used to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease.

Nuplazid® is available as tablet for oral use, containing 17 mg of pimavanserin. Recommended dose is 34 mg, taken orally as two tablets once daily.

Pimavanserin (INN), or pimavanserin tartate (USAN), marketed under the trade name Nuplazid, is a non-dopaminergic atypical antipsychotic[2] developed by Acadia Pharmaceuticals for the treatment of Parkinson’s disease psychosis and schizophrenia. Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of theserotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the5-HT2B receptor or dopamine receptors.[1] The drug has met expectations for a Phase III clinical trial for the treatment ofParkinson’s disease psychosis,[3] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside anantipsychotic medication.[4]

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[5][6][7] The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses ofrisperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.[8]

On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia’s New Drug Application for pimavanserin.[9] It was approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease on April 29, 2016.[10]

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Clinical pharmacology

Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki 120 nM) and has no appreciable affinity (Ki >300 nM) to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, oradrenergic receptors, or to calcium channels.[2]

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Pimavanserin tartrate, 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea L-hemi-tartrate, has the following chemical structure:

Pimavanserin tartrate was developed by Acadia Pharmaceuticals and was approved under the trade name NUPLAZID® for use in patients with Parkinson’s disease psychosis.

Pimavanserin free base and its synthesis are disclosed in US 7,601,740 (referred to herein as US ‘740 or the ‘740 patent) and US 7,790,899 (referred to herein as US ‘899 or the ‘899 patent). US ‘740 discloses the synthesis of Pimavanserin free base (also referred to herein as“Compound A”), which includes O-alkylation followed by ester hydrolysis, and then in situ azidation. This process suffers from low process safety, and utilizes the hazardous reagent diphenylphosphoryl azide. The process is illustrated by the following Scheme 1.

Scheme 1:

US ‘899 describes another process, which includes O-alkylation followed by aldehyde reductive amination to obtain an intermediate which is then reacted with the hazardous reagent phosgene. This process is illustrated by the following Scheme 2:

Scheme 2:

Both of the above processes for the preparation of Pimavanserin include a reaction between 1-isobutoxy-4-(isocyanatomethyl)benzene, a benzyl isocyanate intermediate, and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine. Processes for preparing benzyl isocyanate derivatives are generally described in the literature, such as in US ‘740; US ‘899; Bioorganic & Medicinal Chemistry, 21(11), 2960-2967, 2013; JP 2013087107; Synthesis (12), 1955-1958, 2005; and Turkish Journal of Chemistry, 31(1), 35-43, 2007. These processes often use the hazardous reagents like phosgene derivatives or diphenylphosphoryl azide.

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synthetic route:

First, reduction of the ketone and a secondary amine to amine condensation after S-3 . 4- hydroxybenzaldehyde etherification, followed by condensation with hydroxylamine to give the oxime S-. 7 , which is then reduced by hydrogenation to the amine S-. 8 , S.8- light gas reaction to give the isocyanate S-. 9 , S. 9- react with the primary amine can be obtained Nuplazid ( pimavanserin ).Kg product can be obtained by this route.

WO2006036874

https://www.google.com/patents/WO2006036874A1?cl=en

Example 1 : Preparation of N-(4-fluorobenzyl)-N-( 1 -methylpiperidin-4-yl)-N’ -( 4-(2- methylpropyloxy)phenylmethyl)carbamide a) Preparation of

Figure imgf000021_0001

Tπacetoxy borohydπde (6.5 kg) was added over 1.5 h to a solution of N- methylpiperid-4-one (3.17 kg) and 4-fluorobenzylamme (3.50 kg) in methanol (30 1), maintaining the temperature under 27 0C. The reaction mixture was stirred for 15 h at 22 0C. The residual amine was checked by gel chromatography (4-fluorobenzylamine: < 5%). A solution of 30% sodium hydroxide (12.1 kg) in water (13.6 kg) was added in 75 minutes (min) maintaining the temperature under 20 0C. Methanol was distilled off to a residual volume of 26 litters. Ethyl acetate was added (26 L), the solution was stirred for 15 min, the phases were decanted over 15 min and the lower aqueous phase was discarded. Ethyl acetate was distilled under reduced pressure from the organic phase at 73-127 0C. At this stage the residue was mixed with a second crude batch prepared according to this method. The combined products were then distilled at 139-140 0C / 20 mbar to yield 11.2 kg product (> 82%). b) Preparation of

Figure imgf000022_0001

4-Hydroxybenzaldehyde (4.0 kg) and ethanol (20 1) were added to a solution of isobutyl bromide (9.0 kg) in ethanol (15 1). Potassium carbonate (13.6 kg) was added and the suspension was refluxed (74-78 0C) for 5 days. The residual 4- hydroxybenzaldehyde was checked by HPLC (< 10%). The suspension was cooled to 20 0C and used in the next step.

c) Preparation of

Figure imgf000022_0002

] Hydroxylamine (50% in water, 8.7 kg) was added to the product from previous step b)(174 1, 176 kg) and ethanol (54 1). The suspension was refluxed (77 0C) for 3 h. Unreacted residual amounts of the compound of step b was checked by HPLC (< 5%). The suspension was cooled to 30 0C, filtered and the filter was washed with ethanol (54 1). The solution was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 67 litters. The solution was cooled to 25 0C and water (110 1) was added. The suspension was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 102 litters. Petrol ether (60-90 fraction, 96 1) was added and the mixture was heated to reflux (70 0C). The solution Λvas cooled to 40 0C and crystallization was initiated by seeding. The suspension was cooled to 5 0C and stirred for 4h. The product was centrifuged and the cake was washed with petrol ether (60-90 fraction, 32 1). The wet cake was dried at about 40 0C to yield 16kg product (63%).

d) Preparation of

Figure imgf000022_0003

[0105] The product from previous step c) (15.7 kg) was dissolved in ethanol (123 1). Acetic acid (8.2 kg) and palladium on charcoal 5% wet (1.1 kg) were added. The oxime was hydxogenated at 22 0C and 1.5 bar for 4h. Consumption of oxime was checked by HPLC (for information). The catalyst was filtered and the solvent was distilled under reduced pressure at 36 0C to a final volume of 31 1. Ethyl acetate (63 1) was added and the mixture was heated to reflux (75 0C) until dissolution. The solution was cooled to 45 0C and the crystallization was initiated by seeding. The suspension was cooled to 6-10 0C and stirred for 2.5h. The product was centrifuged and the cake was washed with 2 portions of ethyl acetate (2 x 0.8 1). The wet cake was dried at a temperature of about 40 0C to yield 8 kg (41%).

e) Preparation of

Figure imgf000023_0001

Aqueous sodium hydroxide (30%, 5.0 kg) was added to a suspension of the product from previous step d) (7.9 kg) in heptane (41 1). The solution was heated to 47 0C, stirred for 15 mm and decanted o~ver 15 mm. The pH was checked (pH>12) and the aqueous phase was separated. The solvent was removed by distillation under reduced pressure at 47-650C. Heptane was added (15 1) and it was removed by distillation under reduced pressure at 58-65 0C. Heptane was added (7 1), the solution was filtered and the filter was washed with heptane (7 1). The solvent was removed by distillation under reduced pressure at 28-60 0C. Tetrahydrofuran (THF, 107 1) and tπethylamme (TEA, 6.8 kg) were added and the temperature was fixed at 22 0C. In another reactor, phosgene (5.0 kg) was introduced in tetrahydrofuran (88 1) previously cooled to -3 0C. The THF and TEA s olution was added to the solution of phosgene in 3h 50 mm maintaining the temperature at -3 0C. The reactor was washed with tetrahydrofuran (22 1). The mixture was stirred for 45 min at 20 0C and then for 90 min at reflux (65 0C). The solvent was distilled under reduced pressure at 25-30 0C to a residual volume of 149 1. The absence of phosgene was controlled. At this stage, there still was phosgene and the suspension was degassed by bubbling nitrogen through it. After this operation the level of phosgene above the solution was below 0.075 ppm. The suspension was filtered and washed with tetrahydrofuran (30 1). The solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 1. Tetrahydrofuran (51 1) was added and the solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 1. The final volume was adjusted to about 52 litters by addition of tetrahydrofuran (11 1). The solution was analysed and used in the next step. f) Preparation of the title compound of formula I

Figure imgf000024_0001

The product from previous step e) (51 1) was added in 1 h to a solution of the product from step a) (7.3 kg) in tetrahydrofuian (132 1) at 17 0C. The line was washed with tetrahydrofuran (12 1) and the mixture was stirred for 15h. Residual product from the first step was checked by HPLC The solvent was removed by distillation under reduced pressure at 20-38 0C to a residual volume of 165 1. Charcoal (Noπt SXl-G, 0 7 kg) was added, the mixture was stirred for 15 mm and filtered. The lme was washed with tetrahydrofuran (7 1) and the solvent was removed by distillation under reduced pressure at 20-25 0C to a residual volume of 30 1. Isopropyl acetate (96 1) was added to obtain a solution of the title compound of formula I, which contains a small amount of impurities, which were mainly side products from the previous reactions. Removal of the solvent from a sample yields a substantially amorphous solid

g) Preparation of N-(4-fluorobenzyl)-N-(l-methylpipeπdm-4-yl)-N’-(4-(2-methylpropyloxy)phe- nylmethyl)carbamide hemi-tartrate

To the solution of the compound of Formula I in isopropyl acetate (96 1) from step f was added at 23 0C a previously prepared solution of tartaric acid (1 7 kg) in water (1.7 1) and tetrahydrofuran (23 1) The residual suspension was stirred for 2.5 days at 22 0C The tartrate crude product was centrifuged and the cake was washed with 4 portions of isopropyl acetate (4 x 23 1). A total of 107 kg of mother liquors was saved for later use in obtaining the tartrate salt The wet cake was dπed at about 40 0C to yield 8.3 kg (50%) product.

h) First Purification

The tartrate crude product of step g) (8.1 kg) was dissolved m demmeralized water (41 1) at 22 0C. Isopropyl acetate (40 L), 30% aqueous sodium hydroxide (4.3 kg) and sodium chloride (2 kg) were added. The pH was checked (>12) and the solution was stirred for 15 mm. The solution was decanted over 15 mm and the aqueous phase was separated. The aqueous phase was re-extracted with isopropyl acetate (12 1) Demmeralized water (20 1) and sodium chloride (2 0 kg) were added to the combined organic phases, the solution was stirred for 15 mm, decanted over 15 mm and the aqueous phase was discarded. Charcoal (0.4 kg) was added, the mixture was stirred for 20 mm and filtered. After a line wash with isopropyl acetate (12 1), the solvent was removed under reduced pressure at 20-25 0C Heptane (49 1) was added and the suspension was stirred for 15 mm at 40 °C. Then, 8 1 of solvent was removed by distillation under reduced pressure at 38-41 0C The slurry was cooled to 20 0C and stirred for 1 h. The product was centrifuged and the cake was washed with heptane (5 1) The wet compound of Forrnu-la I (5.5 kg) was dissolved m ethanol (28 1) at 45 0C. A solution of tartaric acid (0.72 kg) m ethanol (11 1) was added at 45 0C and the line was washed with ethanol (91). The solution was cooled to 43 0C, seeded with the tartrate salt of the compound o f Formula I, then the slurry was cooled to 350C m 30 mm, stirred at this temperature for 1 h and cooled to -5 0C After 14 h at this temperature the product was centrifuged and washed with two portions of ethanol (2×6 1) The wet cake was dried at about 45 0C for 76 h to yield 4 kg of the herm-tartrate

i) Re -crystallization

150 O g of herm-tartrate obtained m h) was dissolved under stirring at 65 0C m 112 ml absolute ethanol and then cooled under stirring to 48 0C at a cooling rate of 1 °C/mm Crystallization started after a few minutes at this temperature and the suspension turned to a thick paste withm 1 h. The suspension was heated again to 60 0C and then cooled to 480C at a rate of 1 °C/mm The obtained suspension was stirred and was cooled to 15 0C at a cooling rate of 3 °C/h. The crystalline precipitate was separated by filtration and the bottle was washed with 10 ml absolute ethanol cooled to 5 0C. The crystalline residue was dried under vacuum and 40 0C for 50 hours to yield 146 g crystalline pure herm-tartrate.

j) Second purification

15 78 g of the tartrate salt prepared from step i) was dissolved 121 130 ml water 500 ml TBME was added and the pH -was adjusted to 9 8 by addition of 2 ISf NaOH solution. After precipitation of a white solid, the aqueous phase was extracted 5 times by 500 ml TBME The organic phases were concentrated until a volume of about 400 ml remained. The solution was stored at 60C. The precipitate was filtered, washed with TBME and finally dried m vacuum for 5 hours. Yield: 8.24 g of a white poΛvder. The mother liquor was concentrated to a fourth and stored at 60C. The precipitate was filtered and dried m vacuum for 18 hours. Yield: 1.6 g of a white powder.

PXRD revealed a crystalline compound of formula I. No Raman peaks from tartaric acid were found. The first scan of DSC (-500C to 2100C5 10°K/mm) revealed a melting point at 123.6°C. Above about 19O0C, the sample started to decompose. Example 2. Preparation of N-(4-fluoroben2yl)-N-(l-methylpiperidin-4-yl)-N’-(4-(2- methylpropγloxy)phenylmethyl)carbamide citrate of formula FV

a) 90 mg of the product from Example 1 and 40 mg citnc acid were suspended m 5.0 ml ethylacetate. The suspension was stirred at 60 0C for 15 minutes (mm), cooled to 23±2 0C, and then stored for 30 mm at 23±2 0C. The precipitate was filtered off and dried in air for 30 mm to yield 52 mg of a crystalline white powder. Optical microscopy shows that the obtained solid was crystalline

b) 182 mg of the product from Example 2 and 78.4 mg citric acid were suspended m 10.0 ml ethyl acetate The suspension was stirred at 60 0C for 30 mm, then stirred at 40 0C for 90 mm, and finally stirred for 60 mm at 23 0C The suspension was filtered and washed with heptane, yielding 237 mg of a white crystalline powder -with an endothermic peak near 153 0C (enthalpy of fusion of about 87 J/g), determined by differential scanning caloπmetry at a rate of 10K/mm (DSC). Thermogravimetry (TG-FTIR) showed a mass loss of about 0.7% between 60 and 160 0C, which was attributed to absorbed water Decomposition started at about 170 0C Solubility m water was about 14 mg/ml The crystalline powder remained substantially unchanged when stored for 1 week at 60 0C and about 75% r_h. m an open container (HPLC area was 99.4% compared to reference value of 99.9%). Elemental analysis and 1H-NMR complies with an 1 : 1 stoichiometry.

PATENT

http://www.google.im/patents/WO2008144326A2?cl=en

Figure imgf000011_0004

Example 1 : Preparation of N-(4-fluorobenzyl)-N-Cl-methylpiperidin-4-yl)-N’-(4-f2- methylpropyloxy)phenylmethγl)carbamide a) Preparation of

Figure imgf000032_0001

Triacetoxy borohydride (6.5 kg) was added over 1.5 h to a solution of N- methylpiperid-4-one (3.17 kg) and 4-fluorobenzylamine (3.50 kg) in methanol (30 L) maintaining the temperature under 27 0C. The reaction mixture was stirred for 15 h at 22 0C. The residual amine was checked by gel chromatography (4-fluorobenzylamine: < 5%). A solution of 30% sodium hydroxide (12.1 kg) in water (13.6 kg) was added in 75 minutes (min) maintaining the temperature under 20 0C. Methanol was distilled off to a residual volume of 26 litres. Ethyl acetate was added (26 L), the solution was stirred for 15 min, the phases were decanted over 15 min and the lower aqueous phase was discarded. Ethyl acetate was distilled under reduced pressure from the organic phase at 73-127 0C. At this stage the residue was mixed with a second crude batch prepared according to this method. The combined products were then distilled at 139-140 0C / 20 mbar to yield 11.2 kg product (> 82%). b) Preparation of

Figure imgf000033_0001

4-Hydroxybenzaldehyde (4.0 kg) and ethanol (20 L) were added to a solution of isobutyl bromide (9.0 kg) in ethanol (15 L). Potassium carbonate (13.6 kg) was added and the suspension was refluxed (74-78 0C) for 5 days. The residual 4- hydroxybenzaldehyde was checked by HPLC (< 10%). The suspension was cooled to 20 °C and used in the next step.

c) Preparation of

Figure imgf000033_0002

[0117] Hydroxylamine (50% in water, 8.7 kg) was added to the product from previous step b) (174 L5 176 kg) and ethanol (54 L). The suspension was refluxed (77 0C) for 3 h. Unreacted residual was checked by HPLC (< 5%). The suspension was cooled to 30 °C, filtered and the filter was washed with ethanol (54 L). The solution was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 67 litters. The solution was cooled to 25 0C and water (1 10 L) was added. The suspension was concentrated by distillation under reduced pressure at 30 °C to a residual volume of 102 litters. Petrol ether (60-90 fraction, 96 L) was added and the mixture was heated to reflux (70 °C). The solution was cooled to 40 0C and crystallization was initiated by seeding. The suspension was cooled to 5 0C and stirred for 4h. The product was centrifuged and the cake was washed with petrol ether (60-90 fraction, 32 L). The wet cake was dried at about 40 °C to yield 16kg product (63%). d) Preparation of

Figure imgf000034_0001

The product from previous step c) (15.7 kg) was dissolved in ethanol (123 L). Acetic acid (8.2 kg) and palladium on charcoal 5% wet (1.1 kg) were added. The oxime was hydrogenated at 22 0C and 1.5 bar for 4h. Consumption of oxime was checked by HPLC. The catalyst was filtered and the solvent was distilled under reduced pressure at 36 °C to a final volume of 31 L. Ethyl acetate (63 L) was added and the mixture was heated to reflux (75 0C) until dissolution. The solution was cooled to 45 0C and the crystallization was initiated by seeding. The suspension was cooled to 6-10 °C and stirred for 2.5h. The product was centrifuged and the cake was washed with 2 portions of ethyl acetate (2 x 0.8 L). The wet cake was dried at a temperature of about 40 0C to yield 8 kg (41%).

e) Preparation of

Figure imgf000034_0002

Aqueous sodium hydroxide (30%, 5.0 kg) was added to a suspension of the product from previous step d) (7.9 kg) in heptane (41 L). The solution was heated to 47 °C, stirred for 15 min and decanted over 15 min. The pH was checked (pH>12) and the aqueous phase was separated. The solvent was removed by distillation under reduced pressure at 47-65 °C. Heptane was added (15 L) and then removed by distillation under reduced pressure at 58-65 0C. Heptane was added (7 L), the solution was filtered, and the filter was washed with heptane (7 L). The solvent was removed by distillation under reduced pressure at 28-60 0C. Tetrahydrofuran (THF, 107 L) and triethylamine (TEA, 6.8 kg) were added and the temperature was fixed at 22 0C. In another reactor, phosgene (5.0 kg) was introduced in tetrahydrofuran (88 L) previously cooled to -30C. The THF and TEA solution was added to the solution of phosgene in 3h 50 min, maintaining the temperature at – 3 0C. The reactor was washed with tetrahydrofuran (22 L). The mixture was stirred for 45 min at 20 0C and then for 90 min at reflux (65 0C). The solvent was distilled under reduced pressure at 25-30 0C to a residual volume of 149 L. The absence of phosgene was controlled. At this stage, phosgene was still present and the suspension was degassed by bubbling nitrogen through it. After this operation, the level of phosgene above the solution was below 0,075 ppm. The suspension was filtered and washed with tetrahydrofuran (30 L). The solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 L. Tetrahydrofuran (51 L) was added and the solvent was distilled under reduced pressure at 20- 25 0C to a residual volume of 40 L. The final volume was adjusted to about 52 litters by addition of tetrahydrofuran (1 1 L). The solution was analysed and used in the next step.

f) Preparation of the title compound of formula I

Figure imgf000035_0001

The product from previous step e) (51 L) was added in 1 h to a solution of the product from step a) (7.3 kg) in tetrahydrofuran (132 L) at 17 0C. The line was washed with tetrahydrofuran (12 L) and the mixture was stirred for 15h. Residual product from the first step was checked by HPLC. The solvent was removed by distillation under reduced pressure at 20-38 0C to a residual volume of 165 L. Charcoal (Norit SXl-G5 0.7 kg) was added, the mixture was stirred for 15 min and filtered. The line was washed with tetrahydrofuran (7 L) and the solvent was removed by distillation under reduced pressure at 20-25 0C to a residual volume of 30 L. Isopropyl acetate (96 L) was added to obtain a solution of the title compound of formula I, which contains a small amount of impurities (mainly side products from the previous reactions.) Removal of the solvent from a sample yields a substantially amorphous solid.

The solution with the crude product was used for the direct preparation of the hemi-tartrate and simultaneously for the purification of the free base via the hemi-tartrate through crystallization from suitable solvents.

Example 5: Preparation of the hemi-tartrate of formula IV from crude free base of formula I

Crude product according to Example l(f) (4.3 kg) was dissolved at 45 0C in ethanol (23 L). A solution of (+)-L-tartaric acid (0.58 kg) in ethanol was added at 45 0C and the line was washed with 6 L of ethanol. The solution was stirred for 20 min (formation of solid precipitate) and the slurry was cooled to 35 0C over 30 min. The slurry was stirred at this temperature for 1 hour and then cooled to -5 0C. After 14 hours stirring at this temperature, the product was centrifuged and washed with 2 portions of ethanol (2 x 4 L). The wet cake was dried at 45 0C for 80 hours yielding 3.3 kg of product (85%, based on tartaric acid). PXRD of the product revealed that polymorph A was formed.

PATENT

WO2014085362A1.

CN101031548A

CN101035759A

CN102153505A

CN1816524A

US2008280886A1.

WO0144191

PATENT

WO-2016141003

Scheme 4:

The reaction depicted in Scheme 4 can be carried out in a suitable organic solvent such as acetone at rather mild conditions (e.g.40-50°C). If necessary, the R1 substituent may subsequently be converted to an isobutoxy group to obtain Pimavanserin or a salt thereof.

An overview about certain processes for preparation of Pimavanserin is shown in Scheme 5 below.

Scheme 5:

Compound A L-Tartaric acid

Hemi-tartrate salt *Compound A is Pimavanserin

Scheme 10:

Compound 1 Compound 2 Pimavanserin

Scheme 13:

An overview about synthetic routes to Pimavanserin via Compound XVI is shown in the following Scheme 14:

Scheme 14:

Example 16: Preparation of hemi-tartrate salt of Pimavanserin

To a 25 mL seal tube, equipped with a stir bar, was charged 344.4 mg of the above crude PMV (1.0 mmol in theory), 75 mg of L-tartaric acid (FW: 150.09, 0.5 mmol, 0.5 equiv.), and 7 mL (16.4 vol.) of absolute ethanol. The tube was sealed and heated to 70°C to afford a clear solution, then cooled down gradually to room temperature. The product precipitated, and the batch was further cooled down to 0-5°C and stirred at this temperature for 0.5 hour. The product was collected by vacuum filtration, and the filter cake was washed with 2 × 1 mL (2.3 vol.) of EtOH. The product was dried in the Buchner funnel under vacuum overnight, affording 177.6 mg of salt, representing a 35.4% yield in 99.6 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.4 Hz, 6 H), 1.79-1.82 (m, 2H), 2.02-2.19 (m, 3H), 2.63 (brs, 5H), 3.38-3.47 (m, 2H), 3.67 (d, J = 6.4 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.32 (s, 1H), 4.38 (s, 2H), 4.58 (brs, 2H), 6.77 (d, J = 8.0 Hz, 2H), 6.95-6.99 (m, 4H), 7.17 (d, J = 7.2 Hz, 2H).

Example 21: Preparation of Pimavanserin via compound V as dihydrochloride salt

Step 1: Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl)

The reaction was performed in 300 mL reactor. The reactor was purged with N2, then Argon. 4-Fluorobenzylamine (10 g; 80 mmol, 1.0 eq) was dissolved in dry MeCN (100 mL), then 1-methylpiperidin-4-one (10.9 g; 96 mmol, 1.2 eq) was added and the reaction mixture was stirred at ambient temperature for 18h. Then, the reaction mixture was cooled to 0°C and 25.4 g of NaBH(OAc)3 (25.4 g; 120 mmol, 1.5 eq) was added in portions over 20 min and the reaction was allowed to stir to room temperature. After 1h, the reaction was quenched by the addition of 200 ml of water, pH was adjusted to 2 with 5M HCl and then extracted using 3 x 250 mL of DCM. Basification of the aqueous layer to pH 9.5 with 30% sol. NaOH and extraction 3 x 300 ml of DCM followed. The organic layers were collected and dried over anh. Na2SO4, filtered and evaporated to dryness yielding 17.24 g (92%) of oily product, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Compound V).

To a 250 mL, three necked, round bottom flask, equipped with a stir bar and thermometer, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (10 g; 0.045 mol) and DCM (50 mL) were charged and cooled to 10-15 °C. To the resulting solution, 5-6 N HCl in 2-PrOH (3 equiv., 0.135 mmol) was added dropwise over 25 min., white crystals formed, and the solution then cooled to 0-5 °C for 2 hours. Crystals were filtered off, washed with 50 mL of DCM, dried at 50°C/10 mbar for 10 hours yielding 12.8 g (96.4%) of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl).

Step 2: Preparation of 4-isobutoxybenzaldehyde (Compound XIII)

4-Hydroxybenzaldehyde (10 g; 0.082 mol), potassium carbonate (33.95 g; 0.246 mol) and potassium iodide (1.36 g; 0.008 mol) were suspended in N,N-dimethylformamide (50 mL). Isobutyl bromide (26.7 mL; 0.246 mol) was added and the reaction was heated at 70°C under nitrogen for 3 hours. The reaction was cooled down, diluted by using 150 mL of water and extracted by using 300 mL of ethyl acetate. The organic layer was extracted five times by using 150 mL of 10% NaCl solution, dried under Na2SO4, filtered and concentrated which resulted in 14.3 g (98%) of yellow oily product of 4-isobutoxybenzaldehyde

(Compound XIII).

Step 3: Preparation of (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl)

[0142] To a solution of 4-isobutoxybenzaldehyde (Compound XIII) (19.9 g; 0.112 mol) in methanol (90 mL), Raney nickel (6 g) and 7N methanol ammonia solution (90 mL) were added. The reaction mixture was stirred under hydrogen atmosphere (0.5 bar) at 10-15°C for 24 hours. The reaction solution was filtered through Celite to remove the catalyst. Methanol was distilled off and toluene (500 mL) was added. The solution was concentrated to 250 mL and 5-6 N HCl in 2-PrOH (30 mL; 0.15 mol) was added dropwise at ambient temperature. The resulting suspension was then cooled to 5 °C and stirred for additional 2 hours. Crystals were filtered off, washed with 60 mL of toluene, dried at 50°C/10 mbar for 10 hours yielding 20.88 g (86.7%) of (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl). The product was analyzed by PXRD– form I was obtained, the PXRD pattern is shown in Figure 3.

Step 4: Option 1: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin

Part a: Preparation of Compound VI-a:

To a 250 mL, three necked, round bottom flask, equipped with a stir bar, condenser and thermometer, (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl) (5 g, 0.023 mol), CDI (6.01 g; 0.037 mol) and acetonitrile (40 mL) were charged. The resulting solution was stirred for 1 h at 65-70 °C and monitored by HPLC until full conversion to Compound VI-a.

Part b: Preparation of Pimavanserin:

N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Compound V) (7.73 g; 0.035 mol) was added to Compound VI-a obtained above. After 2h, complete conversion was observed. Upon completion, the reaction solution was cooled to 50 °C and water was added dropwise in a 1:3 ratio (120 mL). After addition of a whole amount of water, crystals were formed and suspension was allowed to cool to ambient temperature. The crystals were filtered off, washed with 2 x 40 mL solution of CH3CN:H2O 1:3, then 40 mL of water, dried at 45°C/10 mbar for 10 hours yielding 9.35 g (94.4%) of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin).

Step 4– option 2: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin)

Part a: Preparation of Compound VI-a:

To a 500 mL, three necked, round bottom flask, equipped with a stir bar, condenser and thermometer, (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl) (10 g; 0.046 mol), CDI (11.28 g; 0.07 mol) and acetonitrile (100 mL) were charged. The resulting solution was stirred for 1 h at 65-70 °C and monitored by HPLC until full conversion to Compound VI-a.

Part b: Preparation of Pimavanserin:

[0146] The reaction solution containing Compound VI-a obtained above was cooled to 30°C and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl) (20.53 g; 0.07 mol) and K2CO3 (9.61 g; 0.07 mol) were added. The reaction mixture was heated to 65-70 °C and stirred for next 18 hours. Upon completion, the reaction solution was cooled to 50 °C, pH of solution was adjusted to 10.5 with 6N NaOH solution, and water was added dropwise in ratio 1:3 (300 mL). After addition of a whole amount of water, crystals were formed, and suspension was allowed to cool to ambient temperature, and then cooled on ice-bath (0-5°C) for 1.5 hour. The crystals were filtered off, washed with 2 x 100 mL solution of CH3CN:H2O 1:3, then 100 mL of water, dried at 45°C/10 mbar for 10 hours yielding 18.797 g (95.6%) of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin).

Example 26: One pot preparation of Pimavanserin (without isolation of Compound 1)

Step 1: Preparation of 2-(4-isobutoxyphenyl)acetic acid

To a 250 mL, 3 neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 10 g of 4-hydroxy phenyl acetic acid (Molecular weight (FW): 152.15, 65.7 mmol, 1.0 equiv.), 30 g of potassium carbonate (FW: 138.21, 216.8 mmol, 3.3 equiv.), 1.1 g of potassium iodide (KI, FW: 166, 6.57 mmol, 0.1 equiv.), followed by 100 mL (10 vol.) of DMF. After stirring for 5 minutes at room temperature, 15.7 mL of isobutyl bromide (FW: 137.02, 144.6 mmol, 2.2 equiv.) was charged into the batch. The mixture was then heated to 75°C and kept stirring at the same temperature for 2 days until no limited starting material remaining as determined by HPLC. The reaction was cooled down to room temperature, and quenched by charging with 100 mL of deionized (DI) water. The pH of the reaction mixture was adjusted to less than 1 by charging 100 mL of 2N HCl. The product was extracted with 150 mL of ethyl acetate. After partitioning, the upper organic layer was washed with additional 100 mL of DI water, concentrated to dryness on the rotary evaporator under vacuum. The residue was dissolved in 100 mL each of THF (10 vol) and DI water (10 vol). After charging 20 g of lithium hydroxide, the mixture was heated to reflux for 3 hours until complete reaction. The batch was cooled to room temperature, concentrated on rotary

evaporator to remove THF. The residue was acidified with 300 mL of 2N HCl and 45 mL of 6N HCl aqueous solution until pH <1. The product was extracted with 2×250 mL of methylene chloride, dried over sodium sulfate, and filtered on Buchner funnel. The filtrate was concentrated to dryness on rotary evaporator under vacuum to afford 10.18 g of 2-(4-isobutoxyphenyl)acetic acid, representing a 74.4% yield in 98.5 A% purity. 1H NMR (d6-DMSO, 400 MHz): δ = 0.97 (d, J = 6.8 Hz, 6 H), 1.96-2.02 (m, 1H), 3.47 (s, 2H), 3.71 (d, J = 6.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H).

Step 2: Preparation of Pimavanserin

To a 50 mL, single neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 333.2 mg of 2-(4-isobutoxyphenyl)acetic acid (FW: 208.25, 1.6 mmol, 1.0 equiv.), 311.3 mg of CDI (FW: 162.15, 1.92 mmol, 1.2 equiv.), and 3.3 mL of CH3CN (10 vol.). After stirring at room temperature for 1 hour, this was charged 139 mg (FW: 69.5, 2.0 mmol, 1.25 equiv.) of NH2OH.HCl and stirred for additional 15-18 hours at room temperature. Additional 518.9 mg of CDI (FW: 162.15, 3.2 mmol, 2.0 equiv.) was charged and the batch turned from a slurry to a clear solution again. This was followed by charging a solution of 334 mg of Compound V (FW: 222.3, 1.5 mmol, 0.94 equiv.), and heating up to 60 oC. The reaction was stirred at this temperature for approximately 5 hour before cooling back to room temperature. The reaction was quenched with 20 mL of DI water, and concentrated on rotary evaporator to remove acetonitrile. The aqueous residue was diluted with 40 mL of ethyl acetate, and washed with 2×20 mL of brine. The organic phase was concentrated to dryness on rotary evaporator under vacuum. The residue was purified by chromatography (160 g RediSep Alumina column), eluting with 0-5% of methanol in dichloromethane to afford 305 mg of Pimavanserin, representing a 47.6% yield in 99.3 A% purity.1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.8 Hz, 6 H), 1.62-1.73 (m, 4H), 2.03-2.09 (m, 3H), 2.25 (s, 3H), 2.84-2.87 (m, 2H), 3.68 (d, J = 6.4 Hz, 2H), 4.27-4.34 (m, 5H), 4.45-4.48 (m, 1H), 6.67-6.79 (m, 2H), 6.99-7.02 (m, 4H), 7.16-7.27 (m, 2H). HRMS-ESI (m/z): [M+1]+ Calcd for C25H35F1N3O2: 428.2708; found 428.2723.

Example 27: Preparation of Pimavanserin (with isolation of Compound 1)

Step 1: Preparation of Compound 1

To a 100 mL, single neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 1 g of Compound XV (FW: 208.25, 4.8 mmol, 1.0 equiv.), 934.0 mg of CDI (FW: 162.15, 5.76 mmol, 1.2 equiv.), followed by 10 mL (10 vol.) of acetonitrile. After stirring for 45 minutes at room temperature, 417 mg of NH2OH.HCl (FW: 69.5, 6.0 mmol, 1.25 equiv.) was charged into the batch. The mixture was kept stirring at the ambient temperature overnight and turned into a thick slurry. HPLC determined 1.6 A% of starting material remaining. The batch was diluted with 6 mL of acetonitrile (6 vol.) and 16 mL (16 vol.) of DI water, and cooled down to 0-5 ºC. After stirring at the same temperature for additional 1 hour, the batch was filtered on the Buchner funnel. The filter cake was washed with 2×10 mL (10 vol.) of DI water, and dried in the funnel under vacuum overnight to afford 774.1 mg of hydroxamic acid Compound 1, representing a 72% yield in 99.6 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 0.96 (d, J = 6.8 Hz, 6 H), 1.95-2.02 (m, 1H), 3.19 (s, 2H), 3.70 (d, J = 6.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 8.80 (s, 1H), 10.61 (s, 1H).

Step 2: Synthesis of Pimavanserin

To a 50 mL sealed tube, equipped with nitrogen sweep, was charged 250 mg of compound 1 (FW: 223.27, 1.12 mmol, 1.0 equiv.), 217.9 mg of CDI (FW: 162.15, 1.34 mmol, 1.2 equiv.), and 1.7 mL of acetonitrile (6.8 vol.). After stirring at room temperature for 40 minutes, the batch was heated to 60 oC and kept stirring at the same temperature for additional 10 minutes. This was followed by charging 373.5 mg of Compound 3 (FW: 222.3, 1.68 mmol, 1.5 equiv.). The container of Compound V was rinsed with 0.5 mL (2 vol.) of acetonitrile, and the wash was combined with the batch. The reaction was monitored by HPLC and complete in 2 hours. The batch was cooled down to room temperature, diluted with 5 mL (20 vol.) of ethyl acetate, which was washed with 3×5 mL (20 vol.) of DI water. After partitioning, the upper organic layer was concentrated to dryness on rotary evaporator. The residue was re-dissolved into 3 mL (12 vol.) of ethyl acetate after heating up to reflux to afford a slightly milky solution. This was charged with 12 mL (48 vol.) of heptane, and cooled down to 0-5oC. The batch was kept stirring at the same temperature for 1 hour and filtered on a Buchner funnel. The filter cake was washed with 2×5 mL (20 vol.) of heptane, and dried in the funnel with a nitrogen sweep for 1 hour to afford 270.8 mg of Pimavanserin as a white solid, representing a 56.6% yield in 98.8 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.8 Hz, 6 H), 1.62-1.73 (m, 4H), 2.03-2.09 (m, 3H), 2.25 (s, 3H), 2.84-2.87 (m, 2H), 3.68 (d, J = 6.4 Hz, 2H), 4.27-4.34 (m, 5H), 4.45-4.48 (m, 1H), 6.67-6.79 (m, 2H), 6.99-7.02 (m, 4H), 7.16-7.27 (m, 2H). HRMS-ESI (m/z): [M+1]+ Calcd for C25H35F1N3O2: 428.2708; found 428.2723.

Example 34: Preparation of Pimavanserin from Compound 2

To a 25 mL, three neck, round bottom flask, equipped with a stir bar, condenser and thermocouple, Compound 2, 0.210 g, was charged (FW: 249.26, 0.84 mmol, 1.0 equiv.). This was followed 3 mL of acetonitrile, anhydrous, 99.8%. The mixture was stirred at 60°C for 4 h. Then, to the reaction mixture, Compound V, 0.375 g (FW: 222.30, 1.69 mmol, 2.0 equiv.), was added. After 1h, complete conversion was observed. The reaction was diluted with EtOAc (20 mL) and washed twice with a saturated solution of NH4Cl (2 x 15 mL), then H2O (10 mL) and finally with a saturated NaCl solution (10 mL). The organic layer was dried over anh. sodium sulfate, filtered and concentrated under partial vacuum to about 5 mL of EtOAc. To this solution, n-heptane (10 ml) was added with vigorous stirring, in a dropwise manner, over half an hour. A white precipitate was formed, followed by filtration and drying in vacuum at 45°C for 3h, affording 0.188 g of Pimavanserin. HPLC-MS (m/z) [M+1]+ 428.2; 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.7 Hz, 6 H), 1.68-1.77 (m, 4H), 2.03-2.10 (m, 3H), 2.30 (s, 3H), 2.91-2.97 (m, 2H), 3.67(d, J = 6.7 Hz, 2H), 4.27 (d, J = 5.4 Hz, 2H), 4.31-4.43 (m, 3H), 4.50 (brt, J = 5.5 Hz, 1H), 6.74-6-79 (m, 2H), 6.95-7.05 (m, 4H), 7.14-7.22 (m, 2H).

Example 38: Preparation of Pimavanserin from Compound and Compound V x 2HCl

250 mL reactor was charged with N-hydroxy-2-(4-isobutoxyphenyl)acetamide (Compound 1) (10 g, 0.045 mol), CDI (10.53 g, 0.076 mol) and 100 mL of MeCN, p.a. The resulting solution was stirred for 1.5 h at 60-65 °C and monitored by HPLC. Upon full conversion to the corresponding isocyanate, reaction solution was cooled to 35 °C and N-(4- fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl) (22.48 g, 0.065 mol) and K2CO3 (6.19 g, 0.045 mol) were added. Reaction mixture was heated up to 60-65 °C and stirred for 6 hours and followed by 17 h at ambient temperature.

Upon completion, the reaction solution was cooled to 20 °C and water was added dropwise in ratio 1:3 (300 mL) with adjustment of pH to 11 with 6N NaOH solution. After addition of whole amount of water, crystals were formed and suspension was stirred at 20 °C for 2 h and 0-5°C for next 2 hour. Crystals were filtered off, washed with 2 x 100 mL solution of MeCN:H2O 1:3, then 100 mL of H2O, dried at 30°C/10 mbar for 24 hours yielding 17.56 g (91.7%) of Pimavanserin.

 

PAPER

Bioorg. Med. Chem. Lett. 2015, 25, 1053–1056.

11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand

  • a Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
  • b Center for Integrated Molecular Brain Imaging, University of Copenhagen Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
  • c Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson’s disease. Here, we detail the 11C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [11C]Pimavanserin was obtained by N-methylation of an appropriate precursor using [11C]MeOTf in acetone at 60 °C giving radiochemical yields in the range of 1–1.7 GBq (n = 4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs. However, this binding could not be blocked by either ketanserin or pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [11C]pimavanserin is not selective for the 5-HT2AR in pigs.


Graphical abstract

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THURSDAY Oct. 31, 2013 — Many people living with Parkinson’s disease suffer from hallucinations and delusions, but an experimental drug might offer some relief without debilitating side effects.

READ ALL AT

http://www.drugs.com/news/new-shows-early-promise-treating-parkinson-s-psychosis-48630.html

The drug — pimavanserin — appears to significantly relieve these troubling symptoms, according to the results of a phase 3 trial to test its effectiveness.

Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6]

3-D MODEL OF DRUG PIMAVANSERIN, THE DEVELOPMENT OF WHICH HAS BEEN EXPEDITED BY THE FDA

Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.

“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”

Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.

HERBERT MELTZER, MD, DESIGNED ACADIA PHARMACEUTICAL’S INITIAL PROOF OF CONCEPT TRIAL OF THE DRUG PIMAVANSERIN TO TREAT PARKINSON’S DISEASE PSYCHOSIS.

“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”

Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.

24 YEARS IN THE MAKING

The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.

External links

References

  1.  Friedman, JH (October 2013). “Pimavanserin for the treatment of Parkinson’s disease psychosis”. Expert Opinion on Pharmacotherapy. 14 (14): 1969–1975.doi:10.1517/14656566.2013.819345. PMID 24016069.
  2. ^ Jump up to:a b c “Nuplazid (pimavanserin) Tablets, for Oral Use. U.S. Full Prescribing Information” (PDF). ACADIA Pharmaceuticals Inc. Retrieved 1 May 2016.
  3. Jump up^ ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Archived from the original on February 25, 2009. Retrieved 2009-04-11.
  4. Jump up^ “ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
  5. Jump up^ Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (Aug 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 862–70. doi:10.1124/jpet.107.121715.PMID 17519387.
  6. Jump up^ Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (Oct 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacology, Biochemistry, and Behavior. 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670free to read.PMID 18534670.
  7. Jump up^ Abbas A, Roth BL (Dec 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opinion on Pharmacotherapy. 9 (18): 3251–9.doi:10.1517/14656560802532707. PMID 19040345.
  8. Jump up^ Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (Nov 2012). “Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day”. Schizophrenia Research. 141 (2-3): 144–152. doi:10.1016/j.schres.2012.07.029. PMID 22954754.
  9. Jump up^ “ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for NUPLAZID™ (Pimavanserin) for Parkinson’s Disease Psychosis”. Press Releases. Acadia. 2014-09-02.
  10. Jump up^ “Press Announcements — FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease”. U.S. Food and Drug Administration. Retrieved1 May 2016.

NUPLAZID contains pimavanserin, an atypical antipsychotic, which is present as pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2- methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-dihydroxybutanedioate (2:1). Pimavanserin tartrate is freely soluble in water. Its molecular formula is (C25H34FN3O2)2•C4H6O6 and its molecular weight is 1005.20 (tartrate salt). The chemical structure is:

NUPLAZID™ (pimavanserin) Structural Formula Illustration

The molecular formula of pimavanserin free base is C25H34FN3O2 and its molecular weight is 427.55.

NUPLAZID tablets are intended for oral administration only. Each round, white to off-white, immediaterelease, film-coated tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.

WO2006036874A1 * 26 Sep 2005 6 Apr 2006 Acadia Pharmaceuticals Inc. Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation
WO2006037043A1 * 26 Sep 2005 6 Apr 2006 Acadia Pharmaceuticals Inc. Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
WO2007133802A2 * 15 May 2007 22 Nov 2007 Acadia Pharmaceuticals Inc. Pharmaceutical formulations of pimavanserin
US20060205780 * 3 May 2006 14 Sep 2006 Thygesen Mikkel B Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US20060205781 * 3 May 2006 14 Sep 2006 Thygesen Mikkel B Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US20070260064 * 15 May 2007 8 Nov 2007 Bo-Ragnar Tolf Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
Reference
1 * WANG, Y. ET AL: “ACP-103: 5-HT2A receptor inverse agonist treatment of psychosis treatment of sleep disorders” DRUGS OF THE FUTURE , 31(11), 939-943 CODEN: DRFUD4; ISSN: 0377-8282, 2006, XP002446571
Pimavanserin
Pimavanserin structure.svg
Systematic (IUPAC) name
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide
Clinical data
Trade names Nuplazid
Routes of
administration
Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Protein binding 94–97%[1]
Metabolism Hepatic (CYP3A4, CYP3A5,CYP2J2)[2]
Biological half-life 54–56 hours[1]
Identifiers
CAS Number 706779-91-1 Yes
706782-28-7 (tartrate)
ATC code None
PubChem CID 10071196
DrugBank DB05316 
ChemSpider 8246736 
UNII JZ963P0DIK Yes
KEGG D08969 
ChEBI CHEBI:133017 
ChEMBL CHEMBL2111101 
Synonyms ACP-103
Chemical data
Formula C25H34FN3O2
Molar mass 427.553 g/mol
Jeffrey Cummings, Stuart Isaacson, Roger Mills, Hilde Williams, Kathy Chi-Burris, Anne Corbett, Rohit Dhall, Clive Ballard.
Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial.
The Lancet, Volume 383, Issue 9916, Pages 533 – 540, 8 February 2014.
Findings: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen’s d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.This study is registered with ClinicalTrials.gov, number NCT01174004.Bo-Ragnar Tolf, Nathalie Schlienger, Mikkel Boas Thygesen.
Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms.
US patent number:US7790899 B2
Also published as:CA2692001A1, CN101778821A, EP2146960A2, US20070260064, WO2008144326A2, WO2008144326A3.
Publication date:Sep 7, 2010.
Original Assignee:Acadia Pharmaceuticals, Inc.Tolf, Bo-Ragmar; Schlienger, Nathalie; Thygesen, Mikkel Boas.
Preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-[4-(2-methylpropyloxy)phenylmethyl]carbamide and its tartrate salt and crystalline forms.
PCT Int. Appl. (2008), WO2008144326 A2 20081127.Tolf, Bo-Ragnar; Schlienger, Nathalie; Thygesen, Mikkel Boas.
Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms.
U.S. Pat. Appl. Publ. (2007), US20070260064 A1 20071108.Pyke, Robert; Ceci, Angelo.
Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases.
PCT Int. Appl. (2006), WO2006096439 A2 20060914.Wang, Y.; Bolos, J.; Serradell, N.ACP-103:
5-HT2A receptor inverse agonist treatment of psychosis treatment of sleep disorders.
Drugs of the Future (2006), 31(11), 939-943.Roberts, Claire.
Drug evaluation: ACP-103, a 5-HT2A receptor inverse agonist.
Current Opinion in Investigational Drugs (Thomson Scientific) (2006), 7(7), 653-660.hygesen, Mikkel; Schlienger, Nathalie; Tolf, Bo-Ragnar; Blatter, Fritz; Berghausen, Jorg.
Process for preparation of salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy) phenylmethyl)carbamide.
PCT Int. Appl. (2006), WO2006036874 A1 20060406.Clip

FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease

For Immediate Release

April 29, 2016

Release

The U.S. Food and Drug Administration today approved Nuplazid (pimavanserin) tablets, the first drug approved to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease.

Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson’s disease at some time during the course of their illness. People who experience them see or hear things that are not there (hallucinations) and/or have false beliefs (delusions). The hallucinations and delusions experienced with Parkinson’s disease are serious symptoms, and can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves.

“Hallucinations and delusions can be profoundly disturbing and disabling,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Nuplazid represents an important treatment for people with Parkinson’s disease who experience these symptoms.”

An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement — like eating, writing and shaving. Early symptoms of the disease are subtle and occur gradually. In some people Parkinson’s disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of people with Parkinson’s disease, may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; hallucinations and delusions; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.

The effectiveness of Nuplazid was shown in a six-week clinical trial of 199 participants. Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson’s disease.

As with other atypical antipsychotic drugs, Nuplazid has a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs to treat older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

In clinical trials, the most common side effects reported by participants taking Nuplazid were: swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue (peripheral edema); nausea; and abnormal state of mind (confused state).

Nuplazid was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with Parkinson’s disease. Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The drug was also granted a priority review. The FDA’s priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.

Nuplazid is marketed by Acadia Pharmaceuticals Inc. of San Diego, California.

//////////Pimavanserin, FDA 2016,  Nuplazid®,  Acadia , Breakthrough Therapy, PRIORITY REVIEW, 

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy


Image result for Exondys 51

Image result for eteplirsen

CAS 1173755-55-9
eteplirsen, eteplirsén [Spanish], étéplirsen [French] , eteplirsenum [Latin], этеплирсен [Russian], إيتيبليرسان [Arabic]

Structure credit http://lgmpharma.com/eteplirsen-still-proves-efficacious-duchenne-drug/

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy
New therapy addresses unmet medical need

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

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Image result for Duchenne muscular dystrophy

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

September 19, 2016

Release

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects reported by participants taking Exondys 51 in the clinical trials were balance disorder and vomiting.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

The manufacturer received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.

Exondys 51 is made by Sarepta Therapeutics of Cambridge, Massachusetts.

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ChemSpider 2D Image | eteplirsen | C364H569N177O122P30

CAS 1173755-55-9 [RN]
eteplirsén [Spanish] [INN]
étéplirsen [French] [INN]
eteplirsenum [Latin] [INN]
этеплирсен [Russian] [INN]
إيتيبليرسان [Arabic] [INN]
Eteplirsen
Systematic (IUPAC) name
(P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),5′-(P-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)carbonyl)-1-piperazinyl)-N,N-dimethylphosphonamidate) RNA
Clinical data
Routes of
administration
Intravenous infusion
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 1173755-55-9
ATC code None
ChemSpider 34983391
UNII AIW6036FAS Yes
Chemical data
Formula C364H569N177O122P30
Molar mass 10305.738

///////////Exondys 51, Sarepta Therapeutics, Cambridge, Massachusetts, eteplirsen,  Orphan drug designationPriority reviewfast track designation, Duchenne muscular dystrophy, этеплирсен ,  إيتيبليرسان ,

Ranolazine, 雷诺嗪


Ranolazine.svgChemSpider 2D Image | Ranolazine | C24H33N3O4

Ranolazine

雷诺嗪

  • MF C24H33N3O4
  • MW 427.536

Approvals FDA 2006, EMA 2008 for chronic angina

Sponsor/Developer: Gilead

Mechanism of action: Late sodium current inhibitor

Indication (Phase): Type 2 diabetes (Phase III)

A Phase 3 Study of Ranolazine in Subjects With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone (currently recruiting participants as of August 2012, ClinicalTrials.gov Identifier: NCT01555164, see the link here)

Chemical Name of Ranolazine: (RS)-N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide

N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide

1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-
CAS 95635-55-5 [RN]

QA-2943

Ranexa®

Ranexa, Ranolazine
Ranexa;CVT 303;RS 43285-003
Solubility (25°C) * In vitro DMSO 86 mg/mL (201.15 mM)
Ethanol 20 mg/mL (46.77 mM)
Water <1 mg/mL (<1 mM)
In vivo

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02829034 Recruiting Pulmonary Hypertension University of Pennsylvania|Brigham and Womens Hospital|Un  …more July 2016
NCT02817932 Recruiting Healthy Male Individuals A.Menarini Asia-Pacific Holdings Pte Ltd March 2016 Phase 1
NCT02687269 Not yet recruiting Myocardial Stunning Policlinico Universitario Agostino Gemelli March 2016 Phase 4
NCT02653833 Recruiting Muscular Dystrophy Cedars-Sinai Medical Center December 2015 Phase 0
NCT02611596 Not yet recruiting Silent Myocardial Ischemia|Type 2 Diabetes Walter Reed National Military Medical Center November 2015

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Active Substance
The chemical name of ranolazine is (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxyphenoxy)propyl] piperazineacetamide. Ranolazine is a white to off-white solid, very slightly soluble in water. It is freely soluble in aqueous buffered solutions at pH levels below 4.4 and soluble in several organic solvents e.g. dichloromethane and methanol. The chemical structure is well characterised by means of elemental analysis, UV, IR, 1 H-NMR, 13C-NMR chemical ionization, electron impact mass spectra and x-ray diffraction. Ranolazine exhibits a chiral center and is obtained as a racemic mixture that consists of a 1:1 ratio of (R) and (S) enantiomers. This is confirmed by demonstrating that ranolazine does not exhibit any optical rotation of plane polarized light in polarimeter measurements. Both enantiomers exhibit pharmacological activity. Regarding polymorphism, crystallisation studies were conducted using different solvents, crystallization conditions and vapor diffusion experiments. In these studies three crystalline forms named as Form I, Form II, Form III and one amorphous form were identified. Form I is the only one that was thermodynamically stable, Form II and Form III are kinetically unstable. The synthetic process used for the synthesis of ranolazine has been shown to produce only Form I. Extreme conditions that are not relevant to the synthetic process are required to convert ranolazine to other solid-state forms (amorphous and two other crystalline forms, Form II and Form III)
Manufacture
Ranolazine is manufactured using a three step synthetic process followed by purification, drying and milling. The starting materials are 2,6-dimethylaniline (2,6-DMA), chloroacetyl chloride (CAC), piperazine dihydrochloride and guaiacol glicydil ether (GGE). The synthetic process has been adequately described the critical process parameters have been identified and are controlled with appropriate in-process controls. Data from four validation batches have been provided that demonstrate that the manufacturing process is capable to consistently produce batches of active substance that comply with the predefined specifications. A detailed discussion about potential impurities and their origin has been provided in line with ICH Guideline Q3A(R). Three specified impurities arising from the route of synthesis and one arising from the staring materials have been identified. There are also eight unspecified potential impurities.
Ranolazine, its enantiomers, and three metabolites (RS-88390, RS-89961, and RS-88772) were shown to have moderate affinity for α1A-and α1B-adrenergic receptors. Ranolazine, its S-enantiomer, and the same three metabolites had a similar affinity for β1-adrenergic receptors, with the R-enantiomer having no significant binding activity. The affinity of ranolazine for β2-adrenergic receptors was slightly lower, with the S-enantiomer and metabolites RS-88390 and RS-88772 having a similar affinity as the racemate. The metabolite RS-89961 had a higher affinity for β2-adrenergic receptors, whereas the R-enantiomer had no significant binding activity.
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also
Ranolazine HCl
N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺盐酸盐
CAS 95635-56-6
Molecular Formula C24H35Cl2N3O4
MW 500.46

Ranolazine, developed by CV Therapeutics whom Gilead Sciences bought in 2009, is also sold under the trade name Ranexa for the treatment of  chronic angina (chest pain).

Ranolazine, a partial fatty acid oxidation inhibitor available that is also a late sodium channel inhibitor as an oral extended-release tablet, has been developed and launched by Gilead Palo Alto (formerly CV Therapeutics; CVT), a wholly owned subsidiary of Gilead Sciences, under license from Roche Bioscience (formerly Syntex)

Ranolazine, sold under the trade name Ranexa by Gilead Sciences, is a drug to treat angina that was first approved in 2006.

Angina also known as Angina pectoris is indication for heart disease caused by lack of blood circulation to the heart. The most widespread reason for the angina is Atherosclerosis. In coronary heart disease patients, arteries become narrow and stiff when compared with the healthy heart arteries. These narrow and stiff arteries cause difficulties to reach oxygen rich blood for heart. About 17 million Americans are suffering with coronary heart diseases and about 9 millions are suffering with chronic angina. Ranolazine is the one of the medicament used to manage chronic angina, developed by Roche Bioscience (formerly Syntex) and marketed by CV Therapeutics. USFDA was approved Ranolazine 2 under brand name of Ranexa® in January 27, 2006. Subsequently European medical agency (EMEA) approved in July 09, 2008. Latter on it was approved in few other developing countries. Ranexa ® is available in market in the form of 500 mg and 1000 mg film coated tablet and the maximum daily dosage should be less than 2.0g. Over dosage of Ranexa ® lead to dizziness, nausea, and vomiting. Worldwide sales of Ranexa® by December 2011 is about 400 millions USD (~2000 crores) with the consumption of 1, 00, 678 kg. Major contribution is from USA i.e. about 300 millions USD. ……..CLICK

(5) (a) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. G.; Whiting, R. United states patent, US 4,567,264, 1986. (b) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. L. European patent, EP 0,126,449, 1987. (c) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. Canadian patent, CA 1256874, 1987.

Amongst the various synthetic routes described for the preparation of Ranolazine, some of the key approaches are discussed here under. Kluge.F.A et al 5 have reported two synthetic approaches for preparation of Ranolazine 2 using commercially available 2-Methoxy phenol 25 and 2, 6-dimethyl aniline 20 as key starting materials. The first synthetic route commenced with the synthesis of methyl oxirane derivative 27. Key intermediate methyl oxirane derivative 27 was synthesized from 25 and epichlorohydrin 26 in presence of NaOH employing Williamson reaction conditions. Thus obtained 27 treated with piperazine 23 in ethanol to obtain hydroxyl piperazine derivative 33. Thereafter, reaction of hydroxyl piperazine derivative 33 with phenyl acetamide derivative 22 in dimethylformamide afforded dihydrochloride salt of ranolazine 2, which was treated with ammonia to furnish ranolazine 2(Scheme 3.1).

Second synthetic path way for the preparation of ranolazine involves the condensation of piperazinyl acetamide intermediate 24 and methyl oxirane 27 in mixture of methanol and toluene (Scheme 3.2).

Mingfieng.S et al reported7 similar approach for the synthesis of Ranolazine 2 utilizing hydroxy propyl halide intermediate 94 instead of methyl oxirane compound 27. The requisite hydroxy propyl halide intermediate 94 prepared by reacting 2-methoxy phenol 25 with 1, 3- dichloropropan-2-ol 93 in presence of NaOH and mixture of ethanol & water as shown in Scheme 3.3.

(7) Lisheng, W.; Xiaoyu, F.; Hong-yuan, Z. Journal of Guangxi University (Natural Science Edition), 2003, 28, 301-303.

Eva.C.A et al.6 discovered an alternative synthetic path way for preparation of Ranolazine. As depicted in Scheme 3.3 reaction of phenyl acetamide derivative 22 with diethanolamine in presence of triethylamine and subsequent chlorination using thionyl chloride furnishes dichloro compound 91. Condensation of dichloro compound 91 with amino isopropanol derivative 92 provided Ranolazine 2. Amino isopropanol derivative 92 is achieved by reaction of methyl oxirane compound 27 with ammonia.

(6) Agai-Csongor, E.; Gizur, T.; Haranyl, K.; Trischler, F.; DemeterSzabo, A.; Csehi, A.; Vajda, E.; Szab-Koml si, G. European patent, EP 483932 A1, 1992.

str1

2 with 99.9% purity.

IR (KBr, cm–1): 3331 (Amine, NH), 3002 (Aromatic, =CH), 2955, 2936 and 2834 (Ali, CH), 1686 (Amide, C=O), 1592 and 1495 (Aromatic, C═C), 1254 and 1022 (Ether, C-O-C) & 1125 (C-N).

1H NMR (500 MHz, DMSO–d6): δH 9.1 (s, 1H, N-H), 6.8-7.1 (m, 6H, ArH), 4.8 (s, 1H, OH), 3.9 (s, 1H, CH), 3.8-3.9 (dd, 2H, J=6.5 Hz, 10.7 Hz, CH2), 3.8 (s, 3H, CH3), 3.1 (s, 2H, CH2), 2.4-2.6 (m, 10H, CH2) 2.1 (s, 6H, CH3).

13C NMR (500 MHz, DMSO–d6): 18.23, 39.16, 39.83, 39.50, 39.76, 39.87, 53.18, 53.31, 55.50, 61.13, 61.44, 66.63, 71.96, 112.37, 113.64, 120.74, 120.03, 126.32, 127.62, 134.97, 135.06, 148.36, 149.17, 167.97.

M/S (m/z): 428.4(M+ + H).

CHN analysis: Anal. Calcd for C24H33N3O4 (427.54): C 67.42, H 7.78, N 9.83.; Found: C 67.62 H 7.47, N 9.68.

Title: Ranolazine
CAS Registry Number: 95635-55-5
CAS Name: N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide
Additional Names: (±)-4-[2-hydroxy-3-(o-methoxyphenoxy)propyl]-1-piperazineaceto-2¢,6¢-xylidide; (±)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl]piperazine
Trademarks: Ranexa (CV Therapeutics)
Molecular Formula: C24H33N3O4
Molecular Weight: 427.54
Percent Composition: C 67.42%, H 7.78%, N 9.83%, O 14.97%
Literature References: Anti-ischemic agent which modulates myocardial metabolism. Prepn: A. F. Kluge et al., EP 126449;eidem, US 4567264 (1984, 1986 both to Syntex). HPLC resolution of enantiomers: E. Delée et al., Chromatographia 24, 357 (1987). Clinical trial in angina: B. R. Chaitman et al., J. Am. Coll. Cardiol. 43, 1375 (2004). Review of pharmacology and clinical development: J. G. McCormack et al., Gen. Pharmacol. 30, 639-645 (1998); R. S. Schofield, J. A. Hill, Expert Opin. Invest. Drugs11, 117-123 (2002).
Derivative Type: Dihydrochloride
CAS Registry Number: 95635-56-6
Manufacturers’ Codes: RS-43285
Molecular Formula: C24H33N3O4.2HCl
Molecular Weight: 500.46
Percent Composition: C 57.60%, H 7.05%, N 8.40%, O 12.79%, Cl 14.17%
Properties: White crystalline powder from methanol/ether, mp 164-166°. Readily sol in water.
Melting point: mp 164-166°
Therap-Cat: Antianginal.

Image result for Ranolazine SYNTHESIS

Image result for ranexa

Medical uses

Ranolazine is used to treat chronic angina.[1] It may be used concomitantly with β blockers, nitrates, calcium channel blockers,antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.[2]

Image result for ranolazine

Contraindications

Some contraindications for ranolazine are related to its metabolism and are described under Drug Interactions. Additionally, in clinical trials ranolazine slightly increased QT interval in some patients[3] and the FDA label contains a warning for doctors to beware of this effect in their patients.[2] The drug’s effect on the QT interval is increased in the setting of liver dysfunction; thus it is contraindicated in persons with mild to severe liver disease.[4]

Image result for ranolazine

Side effects

The most common side effects are dizziness (11.8%) and constipation (10.9%).[1] Other side effects include headache and nausea.[3]

Biological Activity

Description Ranolazine is a calcium uptake inhibitor via the sodium/calcium channel, used to treat chronic angina.
Targets Calcium channel [1]
In vitro Ranolazine is found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL), with apparent dissociation constants K(dr)=7.47 mM and K(di)=1.71 mM, respectively. Ranolazine at 5 mM and 10 mM reversibly shortens the duration of TCs and abolishes the after contraction.[1] Ranolazine inhibits the late component of INa and attenuates prolongation of action potential duration when late INa is increased, both in the absence and presence of IK-blocking drugs. Ranolazine (10 mM) reduces by 89% the 13.6-fold increase in variability of APD caused by 10 nM ATX-II. [2]
In vivo Ranolazine significantly and reversibly shortens the action potential duration (APD) of myocytes stimulated at either 0.5 or 0.25 Hz in a concentration-dependent manner in left ventricular myocytes of dogs. [1] Ranolazine (10 mM) significantly increases glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production is low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate in working heart of rats. Ranolazine (10 mM) similarly increases glucose oxidation in normoxic Langendorff hearts (high Ca, low FA; 15 mL/min) of rats. Ranolazine significantly improves functional outcome in reperfused ischemic working hearts, which is associated with significant increases in glucose oxidation. [3]
Features

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] Undrovinas AI, et al. J Cardiovasc Electrophysiol,?006, 17 Suppl 1, S169-S177.

[2] Song Y, et al. J Cardiovasc Pharmacol,?004, 44(2), 192-199.3]

Baptista T, et al. Circulation,?996, 93(1), 135-142.

Drug interactions

Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.[2] For this reason, the doses of ranolazine and drugs that interact with those enzymes need to be adjusted when they are used by the same patient.

Ranolazine should not be used with drugs like ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A nor with drugs that activate CYP3A like rifampin and phenobarbital.[2]

For drugs that are moderate CYP3A inhibitors like diltiazem, verapamil, erythromycin, the dose of ranolazine should be reduced.[2]

Drugs that are metabolized by CYP2D6 like tricyclic antidepressants may need to be given at reduced doses when administered with ranolazine.[2]

Mechanism of action

Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle[5] in a variety of voltage-gated sodium channels.[6] Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.[3] The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.[2]

Legal status

Ranolazine was approved by the FDA in January 2006, for the treatment of patients with chronic angina as a second-line treatment in addition to other drugs.[3] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.[3] In April 2008 ranolazine was approved by the European EMEA for use in angina.[7]

History

In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from Syntex, a subsidiary of Roche, which had discovered the drug and had developed it through Phase II trials in angina.[8] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.[9] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.[10] In 2009, Gilead acquired CV Therapeutics.[11] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.[12]

Image result for ranolazine

Ranolazine (CAS NO.: 95635-55-5), with its systematic name of 1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride in the presence of triethylamine in dichloromethane affords N-(2,6-dimethylphenyl) chloroacetamide (III), which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV). At last, this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

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Paper

“All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

*Corresponding authors
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India
E-mail: akchakraborti@niper.ac.in,akchakraborti@rediffmail.com
Green Chem., 2013,15, 756-767

DOI: 10.1039/C3GC36997H

A novel strategy of ‘all water chemistry’ is reported for a concise total synthesis of the novel class anti-anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the crucial stages of the synthesis are promoted by water and led to the development of new water-assisted chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection, and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in performing the reactions in water have been demonstrated by performing the respective reactions in organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergistic electrophile and nucleophile dual activation role of water. The new ‘all water’ strategy offers two green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall yields, respectively, and which are devoid of the formation of the impurities that are generally associated with the preparation of ranolazine following the reported processes.

Damodara Naidu Kommi

Damodara Naidu Kommi

Prof. Asit K. Chakraborti

Picture
Graphical abstract: “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazineImage result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

PATENT

https://www.google.com/patents/US20130090475

Ranolazine, chemically known as (±)-N-(2,6-dimethylplenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, is represented by the formula as given below.

Figure US20130090475A1-20130411-C00002

Ranolazine, a novel agent used to treat angina pectoris type coronary heart disease, was developed by American CV Therapeutica Company (now known as Gilead Sciences Company). Ranolazine has firstly been appeared on the market in US in 2006 and could be used to treat myocardial infarction, congestive heart disease, angina and arhythmia etc. The mechanism of action of ranolazine is to inhibit partial fatty acid oxidation, which changes fatty acid oxidation to glucose oxidation in heart, and thereby reduces the cardiac oxygen consumption. Ranolazine is the only antianginal agent without changing heart rate or blood pressure.

The processses for the preparation of ranolazine, which could be roughly divided into two types as shown in FIG. 1 and FIG. 2, were disclosed in International Application Publication No. WO 2010/025370, WO 2010/023687, WO 2009/153651, WO 2008/139492, WO 2008/047388, WO 2006/008753, Chinese patent No. CN101560196, CN101544617, CN1915982, the United States patent No. US2008312247, the publication China Pharmacist, 2007, 10(12), 1176-1177, Chinese Journal of Medicinal Chemistry, 2003, 13(5), 283-285, and Chinese Journal of Pharmaceuticals, 2004, 35(11): 641-642.

The process described in FIG. 1 (method 1) involves reacting [(2,6-dimethylphenyl)-carbamylmethyl]-peperazine with 1-(2-methoxyphenoxy)-2,3-epoxypropane to obtain ranolazine, in which comprises the steps of:

a) condensing 2,6-xylidine with chloroacetyl chloride in the presence of base to get amide, which is further reacted with piperazine by a substitution reaction of N-monoalkylation to get N-(2,6-dimethylphenyl)-1-piperazineacetamide, and

b) condensing guaiacol with epoxy chloropropane to get 1-(2-methoxyphenoxy)-2,3-epoxypropane.

As the condensation is carried out in the alkaline environment, the epoxy ring becomes easy to open loop, and thus the products comprise mixtures of open-looped and looped form, thereby requiring rigorous separation conditions and being difficult to achieve the desired purity in the following reaction.

The process described in FIG. 2 (method 2) involves reacting 2-chloro-N-(2,6-dimethylphenyl)-acetamide with 1-(2-methoxyphenoxy)-3-(N-piperazine)-2-hydroxypropane to get ranolazine, in which comprises the steps of:

a) condensing 2,6-xylidine with chloroacetyl chloride in the presence of base to get 2-chloro-N-(2,6-dimethylphenyl)-acetamide, and

b) condensing guaiacol with epoxy chloropropane to get 1-(2-methoxyphenoxy)-2,3-epoxypropane, which is further reacted with piperazine to get 1-(2-methoxyphenoxy)-3-(N-piperazine)-2-hydroxypropane.

As the condensation is carried out in the alkaline environment, the epoxy ring becomes easy to open loop, and thus the products comprise mixtures of open-looped and looped form, thereby requiring rigorous separation conditions and being difficult to achieve the desired purity in the following reaction. The monosubstitution reaction of N-alkylation reacted with peperazine is further difficult to be controlled to produce the desired products.

Compared with method 2, method 1 could be easier to be industrialized as the quality of intermediates obtained by method 1 could be easier to be controlled and also the method 1 could be easier to be operated. But in the repeated experiments, it was found that it still had a lot of difficulties in realizing the industrialization by method 1 although it could be easier to be operated as there are mixtures including open-looped and looped products rather than single product produced when guaiacol (o-methoxyphenol) was reacted with epoxy chloropropane, so the operation of distillatory separation would still need very high temperature (above 250° C.) and very low vacuum degree (5 mm Hg) with the disadvantages of high energy consumption, high facilities investment and tedious operation. And in the following condensation reaction, there are a lot of products were produced during the reaction so as to make the quality of the products hard to be controlled.

Example 1Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide1.1: Preparation of 2-chloro-N-(2,6-dimethylphenyl)-acetamid

Figure US20130090475A1-20130411-C00006

30.5 g (0.252 mol) of 2,6-xylidine, 100 ml of ethyl acetate, 26.5 g (0.25 mol) of sodium carbonate were successively added into a 250 ml of 3-neck flask and placed in an ice-water bath. 36.5 g (0.323 mol) of chloroacetyl chloride was dissolved in 50 ml of ethyl acetate and then the mixture was dropwise added into the 3-neck flask till completion. The ice-water bath was removed and the reaction was carried out for 3 h at the room temperature. The reaction product was slowly added 100 ml of water in an ice-water bath, stirred for 10 min and filtered. The filter cake as white needle solid was washed and dried under vacuum to get 46.3 g of 2-chloro-N-(2,6-dimethylphenyl)-acetamide having a yield of 93%

1.2: Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide

Figure US20130090475A1-20130411-C00007

58.3 g (0.3 mol) of piperazine hexahydrate was dissolved in 230 ml of ethanol and 50.0 g (0.25 mol) of 2-chloro-N-(2,6-dimethylphenyl)-acetamide was subsquently added. The mixture was heated under reflux for 3 h till completion. The reaction product was cooled to room temperature and filtered. The filter was concentrated under reduced pressure and 80 ml of water was added. The mixture was extracted with dichloromethane and the organic layer was concentrated under vacuum at 60° C. to get 39.4 g of N-(2,6-dimethylphenyl)-1-piperazinylacetamide having a yield of 63%. 1HNMR (CDCl3): 2.23˜2.27,s, 6H, 2.67,s, 4H, 2.96˜2.98,t, 4H, 3.19˜3.21,s, 2H, 7.08˜7.26,m, 3H, 8.69,s, 1H.

Example 2Preparation of Ring-Opening Halide2.1: Preparation of 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol

Figure US20130090475A1-20130411-C00008

26 g (0.65 mol) of sodium hydroxide, 150 ml of water, 150 ml of ethanol, 62 g (0.5 g) of guaiacol were successively added into a reaction flask and 103 g (0.8 mol) of 1,3-dichloro-2-propylalcohol was slowly dropwise added till completion. The mixture was heated up to 45° C. for 24 h. The reaction product was extracted three times with 150 ml of dichloromethane each and the organic layer was combined, dried with anhydrous magnesium chloride and distilled under reduced pressure. The fraction at 160° C. and a pressure of 2 kp was collected to get 73.6 g of faint yellow liquid having a yield of 68%. 1HNMR (CDCl3): 3.44˜3.46,d, 1H, 3.69-3.78,dd, 2H, 3.85,s, 3H, 4.11˜4.12,d, 2H; 4.18˜4.22 μm, 1H, 6.89˜7.00,m, 4H. The result confirmed that the yellow liquid was 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol.

2.2: Preparation of 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol

Figure US20130090475A1-20130411-C00009

26 g (0.65 mol) of sodium hydroxide, 150 ml of water, 150 ml of ethanol, 62 g (0.5 g) of guaiacol were successively added into a reaction flask and 174.4 g (0.8 mol) of 1,3-dibromo-2-propylalcohol was slowly dropwise added till completion. The mixture was heated up to 45° C. for 10 h. The reaction product was extracted three times with 150 ml of dichloromethane each and the organic layer was combined, dried with anhydrous magnesium chloride and distilled under reduced pressure. The fraction at 160° C. and a pressure of 2 kp was collected to get 103 g of faint yellow liquid of 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol having a yield of 79%.

Example 3Preparation of Ranolazine3.1: 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol as a raw material

Figure US20130090475A1-20130411-C00010

2.5 g (0.01 mol) of 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol, 3.1 g (0.012 mol) of N-(2,6-dimethylphenyl)-1-piperazinylacetamide, 4.1 g (0.03 mol) of potassium carbonate, 25 ml of methanol and 50 ml of toluene were successively added into a reaction flask and heated under reflux for 4.5 h till completion.

The fraction whose main ingredient was methanol was collected by atmospheric distillation at boiling point of 62-68° C. and then filtrated. The filtrate was washed with 3N HCl to get 50 ml of liquid having a pH of 1-2 and further treated with 50 ml of saturated sodium carbonate solution to adjust pH to 9-10. The product was extracted three times with 20 ml of dichloromethane each and the lower organic phase was combined. After the dichloromethane was removed by distillation under reduced pressure and rotary evaporation, the yellow viscous liquid was obtained and then further dissolved in about 10 ml of methonal. The tetrahydrofuran was then dropwise added under reflux till turbidity. The product was slowly crystallized with cooling and filtrated to get 3.42 g of white solid having a yield of 80.1% by vacuum drying at 40° C

1HNMR (CDCl3): 2.22,s, 6H, 2.60˜2.62,t, 4H, 2.75,s, 6H, 3.21,s, 2H, 3.45,s, 3H; 3.85,s, 3H, 4.02˜4.04,t, 2H, 4.16,s, 1H, 6.88˜6.90,t, 2H, 6.91˜6.96,m, 2H, 7.08˜7.1,m, 3H, 8.65,s, 1H. The result confirmed that the compound obtained is ranolazine. Purity by HPLC (area normalization method): 99.1%.

PATENT

https://www.google.com/patents/CN102875490A?cl=zh

Ranolazine piperazine derivatives, chemical name: (±) -1- [3- (2_ methoxyphenoxy) -2_-hydroxypropyl] -4- [N- (2, 6- dimethylphenyl) carbamoylmethyl] piperazine. Ranolazine is a novel antianginal drugs, which can provide metabolic myocardial protection at the cellular level by improving myocardial energy, while heart rate, blood pressure and hemodynamic impact, has a good prospect. [0004] Currently, the literature synthetic routes ranolazine can be grouped into three: a route: literature (Wolff HeartFailure Reviews, 2002,7 (2): 187- 203.) Using 2_ [N, N- two – ( 2-chloroethyl) amino] -2,6-dimethyl-acetanilide and 3- (2-methoxyphenoxy) -2-propanol of the -I-, amino cyclization to synthesize the desired product. The advantage of this method is to avoid the use of large amounts of piperazine, but the drawback is six steps required to complete the reaction step is long, the total yield is low, is not applicable to industrial production. Route II: literature (US, 4567264; LI Shu-chun Chinese Journal of Medicinal Chemistry, 2003, 13 (5): 283-285) piperazine used directly as the raw material, the advantage of a four-step reaction process is shorter, but due to the direct use of piperazine N- (2,6- dimethylphenyl) -2-chloro – acetamide (2) the reaction, in order to avoid generating disubstituted compound and increased the yield dropping proportion piperazine, piperazine need to consume a large amount. Route III: Document (Qin Mingli, Xinyang Normal University, 2007,20 (2): 226-229) synthetic routes and route only difference is that two different priorities on the piperazine ring substituted on. After two routes have two places noteworthy: how to avoid the generation of disubstituted compounds and the compound (4), (it) is purified.

Image result for “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Synthesis of Compound (3)

In the synthesis of the compound (3), since piperazine simultaneous introduction of two groups, by changing the reaction conditions, to seek optimal reaction molar ratio, in order to optimize the synthesis process, to improve the yield. Since the formation of crystalline anhydrous piperazine water easily precipitated in the solvent methylene chloride, anhydrous conditions so the need to control and make the feed ratio of I: 2 Avoid disubstituted product formation. Methanol can also be used as solvent to avoid precipitation of piperazine, and generates less disubstituted, but did not significantly increase yield (61.5%), it is still producing less toxic with methylene chloride as the solvent, control anhydrous conditions. Removed by filtration and the compound (3) excess piperazine, after the solvent is evaporated, dissolved in water, filtered off disubstituted extracted with methylene chloride, in high purity in the latter studies, may be mono-substituted piperazine as the raw material, and then and then removing the protecting group, thereby avoiding the generation of double substitution also improves the yield.

Synthesis [0008] Compound (5)

When the use of trifluoroacetic acid deprotection, since the compound (4) itself has two salt-forming groups, so the need to increase the TFA feeding, paper, compound (4): trifluoroacetic acid = 1: 6 feeding, the reaction was stirred at room temperature for two hours after the end, and then try to solvent evaporated to dryness, a small amount of ethyl acetate was added and then repeatedly evaporated with divisible trifluoroacetic acid. Finally ethanol: petroleum ether = 1: 1.4 was recrystallized to give compound (5).

Synthesis [0009] Compound (I),

Document (Mcaroon, J Med Chem, 1981,24 (11): 1320- 1328) with methanol – toluene system, literature (US, 4567264) with DMF system. Considering the safety, environmental protection, price, cost, industrial production and other factors, we use isopropyl alcohol as a solvent. In this step, less side reaction byproducts concentrated in raw materials, in strict accordance with the reaction so after molar ratio, TLC detection, should be enough to make up the raw materials, to minimize raw material residues, reducing the difficulty of recrystallization.

[0010]

Specific implementation methods

Synthesis below with embodiments of the present invention will be further described in Example a N- (2,6- dimethylphenyl) -2-chloroacetamide (2)

In 3000ml three-neck flask, into 2,6-dimethylaniline (45. 53 g, 0. 375 mol), toluene (750 ml), sodium carbonate (39. 75g, 0. 375 mol), water (750 ml ), with vigorous stirring slowly added dropwise chloroacetyl chloride (50. 90 g, 0. 45mol), temperature 20~35 ° C (ice water bath). During the reaction, TLC detection reaction process. After completion of the reaction, ice-water bath cooling and crystallization, filtration, washed with toluene, recrystallized from 50% ethanol to give the compound (2), white needles (64. 53g, yield of 86. 9%, mp: 148 ~149 ° C).

Synthesis Example Two N-BOC’s [0011] implementation

In three 250ml flask inputs piperazine (3. 07g, 0. 0356mol), dichloromethane 50ml, piperazine with vigorous stirring to dissolve. Was slowly added dropwise while piperazine (2. 99g, 0. 0347mol dissolved in 50ml of methylene chloride), a BOC anhydride (7. 30g, was dissolved in 50ml of methylene chloride), temperature (Γ 5 ° C. After the addition was complete, the reaction was stirred overnight .TLC detection process. after completion of the reaction, a white solid was filtered off. the filtrate was concentrated, dissolved in water IOOml, a white solid was filtered off. the filtrate with dichloromethane (50ml X3 times). the organic layer was dried over anhydrous sodium sulfate , the drying agent was removed by filtration and the filtrate evaporated to give the compound (3), white needle crystals 4. 07g, yield 65. 3%, 1H-NMR (CDCL3):.. 3. 75 (s, 4H), 2 86 ~2. 91 (m, 4H,), I. 99 Cs, 1H), I. 45 (s, 9H).

[0012] Example (2,6-dimethylphenyl) Synthesis of (N-B0C piperazinyl) acetamide (4) of the three N- -1-.

[0013] In 150ml three-necked flask was added N-BOC piperazine (3) (5. 40g, O. 0289mol), the compound (2) (5. 71g, 0.0289mo, potassium carbonate (4. OOgO. 0202mol) in dry ethanol 10ml, was heated 4h, TLC detection progress of the reaction. after completion of the reaction, water was added 10ml, extracted with ethyl acetate (30mlX2). The organic layer was dried over anhydrous sodium sulfate, filtered off and the filtrate was concentrated and dried U. homogeneous, with ethyl .: petroleum ether = 1: 32 recrystallized compound (4) (white solid, 8 Olg, yield 79. 6%, mp: 119~120 ° C; 1H-NMR3 (s, 7. 09, 3H, Ar-H), 3. 50 (q, 4H, J = 4. 8), 3. 22 (s, 2H), 2.64 (q, 4H, J = 4.8), 2. 23 (s, 6H, 2 X CH3), 1.611 (s, 9H, 3X CH3);.. 13CNMR (167.95,154.43,134.78,133.35,128.14,127.08,79.83,61.65,53.40,43.37,26 24,18 47).

[0014] Fourth Embodiment N- (2,6-dimethylphenyl) -1-piperazine acetamide put in 50ml round bottom flask N- (2,6-dimethylphenyl) -1 – (N-BOC piperazine) -acetamide (4) (. 4 30g, O. 121mol), trifluoroacetic acid (8. 24g, 0 0722mol.), ethyl acetate 6ml, was stirred at room temperature under reflux for 2h, TLC detection reaction process . After completion of the reaction, the solvent evaporated to dryness to give a white solid. With ethanol: petroleum ether = 1: 14 recrystallized compound

(5), a white powder (2. 82g, yield 92. 5%, mp:. 130~131 .., 1H-NMR3 9. 573 (s, IN-H), 9 043 (s, 2XN- H), 7 · 187~7. 087 (t, 3X Ar-H), 3. 66 (s, 4H), 3. 27 (s, 2H), 3. 07 (s, 4Η) ^ _

2. 142 (s, 6Η, 2 X CH3).

Four cases of ranolazine dihydrochloride (I) Synthesis of [0015] implementation

In three 150ml round bottom flask was added the compound (3) (5. OOg, O. 02mol), isopropyl alcohol (35. Oml), was slowly added dropwise at the reflux temperature of the compound (5) (4. 14g, 0. 023mol ), continued under reflux conditions I. 5h, TLC detection progress of the reaction, the reaction was complete, cooled and added to the reactor 9. Oml 12mol / L of concentrated hydrochloric acid solution was adjusted to pH 2 and concentrated to near dryness to give bright yellow brown liquid, repeatedly adding ethanol, rotary evaporation to a white solid. Absolute ethanol and recrystallized to give compound (the I), as a white solid (6. 80g, yield 78. 7%, mp: 217 ~219 ° C (Dec) j1H-NMR (DMS0-d6): 10. 17 ( s, 1H, -CONH-), 7.21 ~6.87 (m, 7H, Ar-H), 4. 42 (m, 1H, -OCH2CHCH2-), 4. 23 (s, 2H, -CH2N), 4. 00 ~3.92 (m, 2H, -OCH2CHCH2), 3. 77 (s, 3H, -OCH3), 2. 67~2. 50 (m, 8H, 2 X -NCH2CH2N-), 2. 33 ~I. 91 ( m, 2H, -OCH2CHCH2), 2. 17 (s, 6H, 2 X CH3); MS (m / e): 427. 54).

CLIP

Image result for Ranolazine SYNTHESIS

An in silico modelling based biocatalytic approach for the synthesis of drugs and drug intermediates in enantiopure forms is a rationalized methodology over the organo-chemical routes. In this study, enzyme-ligand based docking was carried out using (RS)-ranolazine, as the model drug for the screening of a suitable biocatalyst for the kinetic resolution of the racemic drug. The differential interaction of the two enantiomers with the lipase was analyzed on the basis of docking score and H-bond interaction with the amino acid residues, which helped to define the trans-esterification mechanism. Ranolazine [N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy)-3-(2-methoxyphenoxy)propylpiperazin-1-yl]acetamide], an anti-anginal drug, significantly reduces the frequency of anginal attack and has also been used for the treatment of ventricular arrhythmias, and bradycardia. Various lipases were examined via computational as well as wet lab screening and Candida antartica lipase in the form of CLEA was the most efficient one for the (S)-selective kinetic resolution of (RS)-ranolazine, with highest conversion and enantiomeric excess. This is the first report of the chemo-enzymatic synthesis of (S)-ranolazine where the whole drug molecule was used for lipase catalysis. The present study showed that the combination of in silico studies and a classical wet lab approach could change the paradigm of biocatalysis.

Graphical abstract: In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drugImage result for Ranolazine SYNTHESISImage result for Ranolazine SYNTHESIS

In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drug

*
Corresponding authors
a
Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research, Sec-67, S. A. S. Nagar-160062, India
E-mail: ucbanerjee@niper.ac.in
RSC Adv., 2016,6, 49150-49157

DOI: 10.1039/C6RA06879K

CLIP

https://www.researchgate.net/publication/259824588_Synthesis_of_Ranolazine_Derivatives_Containing_the_1_S_4_S_-25-Diazabicyclo221Heptane_Moiety_and_Their_Evaluation_as_Vasodilating_Agents

Image result for Ranolazine SYNTHESIS

Image result for Synthesis of Ranolazine Derivatives Containing the (1S,4S)-2,5-Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents

 

OTHER NMR…….http://onlinelibrary.wiley.com/store/10.1111/cbdd.12285/asset/supinfo/cbdd12285-sup-0001-SupplementaryData.pdf?v=1&s=1c11a72432d0627b201f1bd37dab7ef913b0ff1f

OF Epimer (S,S,S)-5, Epimer (S,S,R)-5

PATENT

WO-2016142819

Ranolazine is marketed under the brand name Ranexa® and is indicated for the treatment of chronic angina. Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2, 6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-, (±)- indicated by compound of formula (1).

(1)

U.S. Patent No. 4,567,264 teaches two methods for the preparation process of Ranolazine. Method 1 disclosed reaction of 2-methoxyphenol compound of formula (2) with epichlorohydrin in presence of water, dioxane and NaOH to obtain l-(2-methoxyphenoxy)-2, 3-epoxypropane compound of formula (3) which is condensed with piperazine in presence of ethanol to obtain 2-(2-methoxyphenoxy)-l-(piperazin-l-yl) ethanol compound of formula (4). Reacting 2, 6-Dimethylaniline compound of formula (5) with chloroacetyl chloride in presence of TEA and MDC to obtain 2-chloro-N-(2,6-dimethylphenyl) acetamide compound of formula (6). Compound of formula (4) was condensed with compound of formula (6) in presence of dimethylformamide to obtain Ranolazine compound of formula (1). The method (1) is depicted below as scheme (I).

Scheme (I) (1)

US ‘264 taught another method for preparation of Ranolazine by condensing compound of formula (6) with piperazine in presence of ethanol to obtain N-(2, 6-dimethylphenyl)-2-(piperazin-l-yl) acetamide compound of formula (7). Compound of formula (3) was condensed with compound of formula (7) in presence of mixture of methanol and toluene at reflux temperature. The obtained Ranolazine is purified by column chromatography on silica gel. Excess of hydrochloric acid in methanol was added to get dihydrochloride salt of Ranolazine which was converted into its free base by suspending it in ether and stirred with excess of dilute aqueous potassium carbonate to get Ranolazine free base. The scheme is depicted below by Scheme (II).

Scheme (II) (!)

EP0483932A1 disclosed condensation of condensation of N, N-bis (2-chloro ethyl)-amino]-2,6-dimethyl acetanilide compound of formula (9) with l-[3-(2-methoxyphenoxy)-2-hydroxy]propylamine compound of formula (8) to obtain Ranolazine base. The base was purified by column chromatography; hydrochloride salt was formed by treating with methanolic HCI. The detailed impurity profile study was not reported for Ranolazine. The synthetic scheme is depicted below in scheme (III).

Chinese patent application No.102875490 disclosed condensation of compound of formula (6) with N-Boc-piperazine to obtain compound of formula (10) in the presence of K2CO3 in EtOH, removal of Boc group by means of TFA in EtOAc gives compound of formula (7) which is then converted into Ranolazine. The synthetic scheme is depicted below in scheme (IV).

Scheme (IV)

Organic Process Research & Development 2012, 16, 748-754 disclosed condensation of compound of formula (6) with piperazine in methanol to produce compound of formula (7), in which unwanted solid bis alkylated compound of formula (11) was filtered. The resulting filtrate pH adjusted to 5.0-5.5 with 44% phosphoric acid solution to recover piperazine monophosphate monohydrate salt. The compound of formula (7) was extracted with MDC.

PCT application No. 2008/047388 disclosed a process for the preparation Ranolazine, by reacting 2, 6-dimethyl aniline with Chloroacetyl chloride in the presence of base in water. The resulting amide intermediate is reacted with piperazine, and the resulting piperazine derivative is further condensed with l-(2-methoxyphenoxy)-2,3-epoxypropane in an inert solvent to produce crude Ranolazine, which is further purified by crystallizing from organic solvents selected from alcohols or aromatic hydrocarbons. Ranolazine obtained in the disclosed art does not have satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities are generally formed along with Ranolazine. In addition, the processes involve the additional step of column chromatographic purifications, which are generally undesirable for large-scale operations.

As described above the cited literature processes suffer from many drawbacks like use of excess amount of piperazine during the reaction, which is difficult to handle in large scale; generation of large amount of effluent due to excessive use of piperazine, that is difficult to recover and recycle; Ranolazine obtained as an oil is difficult to handle in large scale production and laborious chromatographic

techniques are used for purification of Ranolazine.

It is observed that pharmaceutically acceptable salts of Ranolazine when prepared from impure Ranolazine do not meet the pharmaceutical acceptable quality. There is therefore, an unfulfilled need to provide industrially feasible process for the preparation of Ranolazine free base and its acid addition salt with high purity. The present invention provides Ranolazine of high purity by using phosphate salt of piperazine to prepare Ranolazine. In this process, excess of unreacted piperazine is easy to recover and recycle in the next reactions. Thus it is easy to avoid the generation of large amount of effluent due to reuse of piperazine, which are generally desirable for large-scale operations thereby making the process commercially feasible.

All the available literature uses unprotected piperazine and protected piperazine leading to formation of dimer impurities which are difficult to remove from the product and also resulting in poor overall yield of the product. The maximum daily dosage of Ranolazine is 2 g; therefore, known and unknown impurities must be controlled below 0.05% in the final drug substance.

From the above known fact our main target is:

1. To study the detailed impurity profile to and to control the formation of all the impurities below the desired limit (NMT 0.05%).

2. To obtained the Cost effective process by utilizing the maximum consumption of piperazine in the form of piperazine monophosphate salt there by reducing formation of unwanted impurities and also reusing recovered piperazine.

All the available literature uses unprotected piperazine and protected piperazine leading to formation of dimer impurities which are difficult to remove from the product and also resulting in poor overall yield of the product.

EXAMPLES

The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.

Example 1 :

Preparation of [(2, 6-Dimethylphenyl)-amino carbonyl methyl) chloride (6)

To 0.74 kg of potassium carbonate and 2.51ml of water, was added. 500 gm of 2,6-Dimethyl aniline in 1.25 L of Acetone at 0-5 °C. 650 gm of Chloroacetyl chloride was added to the reaction mixture below 5 °C and stirred for 3 hrs. 2500 ml of water was added, stirred for 1 hr, filtered the product, washed with water and dried at 75 °C to get [(2,6- Dimethylphenyl)-amino carbonyl methyl] chloride (6). Yield: 95%; purity >98%

Example 2:

Preparation of l-(2-Methoxy phenoxy)-2, 3-epoxy propane (3)

Added 2.5 L of water to R.B Flask, 80 gms of NaOH was added and stirred to dissolve. Added 500 gms of Guaiacol, 1.12 Kg of Epichlorohydrine and stirred at 25-350C for 5-6 h. The organic layer was separated. To the Epichlorohydrine layer charged 160 gms NaOH dissolved in 2.5 L of water and stirred at 25-30°C for 3-4 h. The organic layer was separated and washed with 150 gms NaOH dissolved in 1.5 L of water. Excess Epichlorohydrine was recovered by distillation of the product layer at 90°C under vacuum (600-700 mmHg) to give 650-680 gms of oil. To the crude oil was added 3.0 L of Isopropanol and cooled to 0°C and filtered the product to get l-(2- Methoxy phenoxy)-2,3-epoxy propane (3).

Yield: 80%; purity >98%.

Example 3:

Preparation of piperazine monophosphate monohydrate

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2-h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate.

Example 4:

Preparation of compound of formula (7)

Added 1000 ml of water to R.B Flask. 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride to obtained compound of formula (7).

Example 5:

Preparation of Ranolazine

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid, 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2, 3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 6:

Preparation of Ranolazine from recovered piperazine monophosphate monohydrate

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. Added recovered piperazine monophosphate monohydrate and pH was adjusted to 5.0-5.5 with O-phosphoric acid, 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted pH 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium

hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 7:

Preparation of Ranolazine.

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C, adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml isopropyl alcohol, refluxed for 5-6 h. cooled the reaction mass to 0°C. Filtered the product to get crude Ranolazine. Yield: 80%; purity >98%.

Example 8:

Preparation of Ranolazine

Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with O-phosphoric acid. After stirring for 1-2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30°C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed

with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature, added 500 ml water, cooled to 0°C and filtered the product to get crude Ranolazine. Yield: 80%; purity >99%.

Example 9:

Purification of Ranolazine

Added 300 ml of methanol to R.B Flask, 100 gms of crude ranolazine piperazine and heated to dissolve. Added Activated charcoal and filtered the hot solution through hyflo and washed the hyflo with 100 ml methanol. Reaction mixture was cooled to room temperature. 200 ml water was added and was cooled further to 0-5°C. Filtered to afford pure Ranolazine. Yield: 90%; purity >99.9%.

PATENT

WO2006008753,

https://www.google.com/patents/WO2006008753A1?cl=en

US Patent 4567264 describes the preparation of Ranolazine base from basic stages by condensing [(2,6-dimethyphenyl) amino; carbonyl methyl] – chloride (II) with l-[3-(2-metlioxyphenoxy)-2- hydroxypropyl]piperazine.(III) The base was purified by column chromatography and isolated as oil. The hydrochloride salt was prepared in methanol using hydrochloric acid and the salt was isolated by addition of ether.

Figure imgf000003_0001

Ranolazine Base

EP 0483932 describes the preparation of Ranolazine base by condensation of α-[ N3N -bis (2-cWoroetiiyl)-amino]-2,6-dimetliylacetanilide hydrochloride (IV) with l-[3-(2-methoxy phenoxy)-2-hydroxy]-propylamine (V). The base was purified using column chromatography and hydrochloride was formed by treating with metholic hydrochloric acid and crystallized by addition of diethyl ether as co solvent to obtain a product with melting point 229- 230 0C.

Figure imgf000004_0001

Ranolazine base

It is a long standing need to avoid the formation of oil and obtain the product directly as solid there by eliminating laborious and expensive column chromatographic methods and achieving the higher yields of Ranolazine diliydrochloride. More over the prior art does not teach, any features such as polymorphic forms of the drug which may have varying pharmacological effects

Example-1:

Preparation of l-[3-(2-Metkoxyphenoxy)-2-hydroxypropyl ] piperazine

100 gms l-(2-methoxyphenoxy)-2,3-epoxypropane was added in a 60 min at 0-5 0C to 192 gms of anhydrous piperazine dissolved in 500 ml methanol. Reaction mixture is stirred further for 2 Hrs at 0-5 0C. It is quenched in 400 ml DMW & filtered. The product is obtained by extraction with MDC from the saturated aqueous layer with sodium chloride. 65 gms of acetic acid and 400 ml water is added in the MDC layer. Aqueous layers was separated and basified with 100 ml liquor ammonia. The product was extracted with 500 ml methylene dichloride and isolated by evaporation of solvent. The residue was used as such in the next reaction.

Yield =80 gms. HPLC purity = 96-$k %.

ExampIe-2 r-

Preparation of crude (+)-l-[3~(2-Methoxyphenoxy)-2-hydroxypropyl]-4- [N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride.

A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dimethylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl formamide is stirred at room temperature (30-35 0C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid ( 35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get Ranolazine base. ; Yield = 140 gms ,

The above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is Filtered, is washed with acetone to give the Ranolazine dihydrochloride Yield = 144 gm.

Example-3 :-

Preparation of Crystalline (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-diniethylphenyl)carbamoylmethyl] piperazine dihydrochloride.

100 gms of Crude (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N- (2,6-dimemylplienyl)caitamoyhnetliyl] piperazine dihydrochloride is dissolved to get a clear solution in 500 ml methanol., The solution is cooled to room temperature and further cooled to 100C. The product is filtered, washed with 2 X 50 ml methanol and dried at 75 degree C for 10 Hrs. get crystalline Form -A of Ranolazine diliydrochloride] ;: characterized .by XRD & DSC as shown in Figure |I and II.

Example-4: –

Preparation of Amorphouse (+)-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride

100 gms Ranolazine diliydrochloride is added in 500 ml water and heated to get a clear solution. Water is distilled off under reduced pressure, the residue is cooled to room temperature to obtain, amorphous form characterized by a XRD pattern (Figure III ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.

Example-5: –

Preparation of Amorphouse ,(+)-l-[3-(J2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbampylitnethyl] piperazine dihydrochloride

100 gms Ranolazine dihydrochloride is added ;i| in 2000 ml ethanol containing 10 % water and heated to get a clear: solution. Solvent is distilled off under reduced pressure, the residue is cooled to room temperature to obtain amorphous form characterized by a XRD pattern (Figure m ) and DSC (Figure IV) exhibiting a broad endotherm around 80 and exotherm bet 220-224 and followed by endotherm 150-156 0C.

Example -6:~

Preparation of Ranolazine base from its di hydrochloride salt

20 gms Ranolazine dihydrohloride at room temperature is added to a mixture containing 150 ml water and 50 ml acetone and 20 ml liquor ammonia. It is stirred for two hrs. The precipitated base, was . filtered and dried under vacuum at 70 0C to get crystalline form of Ranolazine base characterized by XRD & DSC as shown in Figure V & VI. Yield = 12 gms.

CLIP

Improved Process for Ranolazine: An Antianginal Agent

Research and Development, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46 and 54, Bachupally, Qutubullapur, Ranga Reddy-500 072, Andhra Pradesh, India
§ Research and Development, Macleods Pharmaceuticals Limited, G-2, Mahakali Caves Road, Shanthi Nagar, Andheri (E), Mumbai-400 093, Maharashtra, India
Department of Chemistry, University College of Science, Osmania University, Hyderabad-500 007, Andhra Pradesh, India
Org. Process Res. Dev., 2012, 16 (5), pp 748–754
DOI: 10.1021/op300026r
Publication Date (Web): April 12, 2012,*E-mail: vummenthalapv@yahoo.co.in. Fax: +91-40-44346285. Telephone: +91-9849210408.
An improved process has been developed for the active pharmaceutical ingredient, ranolazine with 99.9% purity and 47% overall yield (including three chemical reactions and one recrystallization). Formation and control of all the possible impurities is described. All the solvents used in the process were recovered and reused. The unreacted piperazine is recovered as piperazine monophosphate monohydrate salt.
Abstract Image

References

  1. Banon D et al. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82. PMID 24462341
  2.  “Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information”. Gilead Sciences, Inc. Foster City, CA 94404. Retrieved8 September 2016.
  3. ^ Jump up to:a b c d e Kloner RA, et al. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgrad Med. 2013 Nov;125(6):43-52. PMID 24200760
  4. Jump up^ “FDA Approves New Treatment for Chest Pain”. FDA News. 2006-01-31. Retrieved2011-03-02.
  5.  D Noble and P J Noble. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload Heart. Jul 2006; 92(Suppl 4): iv1–iv5.PMID 16775091 PMCID 1861316
  6. Jump up^ Sokolov, S; Peters, CH; Rajamani, S; Ruben, PC (2013). “Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine” (PDF). Frontiers in Pharmacology. 4: 78. doi:10.3389/fphar.2013.00078. PMC 3689222free to read. PMID 23801963. Retrieved8 September 2016.
  7. Jump up^ EMEA Ranolazine page at the EMEA
  8. Jump up^ CV Therapeutics press release. April 1, 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.
  9. Jump up^ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
  10. Thepharmaletter.com 22 September 2008 Italy’s Menarini to pay up to $385 million for rights to CV Thera’s Ranexa
  11. Jump up^ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
  12.  Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries
  13. http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/11/11_chapter%203.pdf

External links

CN1404471A * Feb 22, 2001 Mar 19, 2003 Cv Therapeutics Substituted piperazine compound
Reference
1 * “Green Chemistry” 20,130,131 Damodara N. Kommi ET Al. ” All Water Chemistry ” for A Concise Total Synthesis of Novel, class at The Anti-anginal Drug (the RS), (R & lt), and (S) -ranolazine 756-767 1-9 Vol. 15,
2 * “Tetrahedron Letters” 20080304 Sadula Sunitha et al. An efficient and chemoselective Br nsted acidic ionic liquid-catalyzed N-Boc protection of amines 2527-2532 1-9 Vol. 49,
3 * N. KOMMI the ET AL .: DAMODARA ” ” All Water Chemistry “for A Concise Total Synthesis of Novel, class at The Anti-anginal Drug (the RS), (R & lt), and (S) -ranolazine “, “GREEN CHEMISTRY”, Vol. 15, 31 January 2013 (2013-01-31) , pages 756 – 767
4 * Sunitha the ET AL .: SADULA ” An Efficient and chemoselective Brønsted acidic Ionic Liquid-Catalyzed N of Boc-Protection of Amines “, “TETRAHEDRON LETTERS”, Vol 49, 4 March 2008 (2008-03-04), Pages 2527 -. 2532
5 * Qin Mingli et al: ” Study on the Synthesis of ranolazine ..”, “Xinyang Normal University: Natural Science”, vol 20, no 2, 30 April 2007 (2007-04-30), pages 226 – 229

RANEXA (ranolazine) Extended-release Tablets

Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula:

RANEXA® (ranolazine) Structural Formula Illustration

Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.

RANEXA tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.

Ranolazine
Ranolazine.svg
Systematic (IUPAC) name
(RS)-N-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a606015
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 35 to 50%
Protein binding ~62%
Metabolism Extensive in liver (CYP3A,CYP2D6) and intestine
Biological half-life 7 hours
Excretion Renal (75%) and fecal (25%)
Identifiers
CAS Number 142387-99-3 Yes
ATC code C01EB18 (WHO)
PubChem CID 56959
IUPHAR/BPS 7291
DrugBank DB00243 Yes
ChemSpider 51354 Yes
UNII A6IEZ5M406 Yes
ChEBI CHEBI:87681 
ChEMBL CHEMBL1404 Yes
Chemical data
Formula C24H33N3O4
Molar mass 427.537 g/mol
Chirality Racemic mixture

////////////////////Ranolazine, 盐酸雷诺嗪 ,雷诺嗪 , Antianginal

CLIP

Ranolazine (Ranexa™)
Ranolazine, developed by CV therapeutics after licensing it from Roche (Syntex), is a late stage sodium channel
blocker approved in March 2006 for the treatment of chronic angina. The compounds anti-angina and anti-ischemic affects do not depend on reductions in heart rate or blood pressure.
Because of the potential for QT prolongation, the drug is indicated for treating patients that do not get adequate response with other anti-anginal drugs [6,27].

Two syntheses, one from the inventors at Roche [28] and other from a group in Hungary [29], of Ranolazine have been described in the patent literature.

The original synthesis is highlighted in Scheme 7. Reaction of 2,6-dimethylaniline 46 with chloroacetyl chloride (47) in the presence of triethylamine for 4h at 0ºC gave amide 48 in 82% yield. This chloro amide 48 was reacted with piperazine in refluxing ethanol for 2 h to give piperazinyl amide 50.

Reaction of amide 50 with epoxide intermediate 53, prepared by reacting 2-methoxy phenol 51 with epichlorohydrin, in refluxing isopropanol for 3 h followed by treatment with HCl/methanol gave ranolazine dihydrochloride (VII) in 73% yield.

[6] Graul, A. I.; Prous, J. R. Drug News Perspect, 2007, 20, 17.
[27] Jones, R. IDrugs, 1999, 2, 1353.
[28] Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting,R. L. EP-0126449 A1, 1984.
[29] Agai-Csongor, E.; Gizur, T.; Hasanyl, K.; Trischler, F.; Demeter-Sabo, A.; Csehi, A.; Vajda, E.; Szab-Komi si, G. EP-0483932 A1,1991.

 

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