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Astellas Pharma Inc. new Glucokinase Activator, ASP ? for Type 2 Diabetes

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str1

ASP ?

(2R)-2-(4-cyclopropanesulfonyl-3-cyclopropylphenyl)-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(R)-3-oxocyclopentyl]propanamide

CAS 1174229-89-0
MW C25 H29 N3 O5 S
Benzeneacetamide, 3-cyclopropyl-4-(cyclopropylsulfonyl)-N-[5-(hydroxymethyl)-2-pyrazinyl]-α-[[(1R)-3-oxocyclopentyl]methyl]-, (αR)-
Molecular Weight, 483.58
[α]D20 −128.7 (c 1.00, MeOH);
1H NMR (DMSO-d6, 400 MHz) δ 11.07 (s, 1H), 9.20 (d, J = 1.4 Hz, 1H), 8.41 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 5.52 (t, J = 5.7 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.04 (t, J = 7.6 Hz, 1H), 3.03–2.97 (m, 1H), 2.79 (tt, J = 8.4, 5.1 Hz, 1H), 2.25–1.81 (m, 8H), 1.53–1.47 (m, 1H), 1.17–1.12 (m, 2H), 1.08–1.02 (m, 4H), 0.89–0.84 (m, 2H);
13C NMR (DMSO-d6, 101 MHz) δ 218.5, 171.8, 152.1, 147.3, 145.7, 143.2, 140.3, 138.2, 134.8, 129.0, 125.3, 125.1, 62.5, 49.9, 44.4, 38.4, 38.2, 34.8, 32.1, 29.1, 12.4, 10.8, 10.7, 5.8;
FTIR (ATR, cm–1) 3544, 3257, 1727, 1692, 1546, 1507, 1363, 1285, 1149, 719;
HRMS (ESI) m/z [M + Na]+ calcd for C25H29N3O5S 506.1726, found 506.1747.
Anal. Calcd for C25H29N3O5S: C, 62.09; H, 6.04; N, 8.69. Found: C, 61.79; H, 6.19; N, 8.62.

To Astellas Pharma,Inc.

Inventors Masahiko Hayakawa, Yoshiyuki Kido, Takahiro Nigawara, Mitsuaki Okumura, Akira Kanai, Keisuke Maki, Nobuaki Amino
Applicant Astellas Pharma Inc.

Image result for Process Chemistry Labs., Astellas Pharma Inc., 160-2 Akahama, Takahagi-shi, Ibaraki 318-0001, Japan

Synthesis

contd…………………………..

PATENT

WO2009091014

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=56E9927692EF5105140FE1CD1FD14A5D.wapp1nC?docId=WO2009091014&recNum=114&maxRec=374&office=&prevFilter=&sortOption=&queryString=FP%3A%28astellas+pharma%29&tab=FullText

str1

PAPER

A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C–N Coupling Reaction

Process Chemistry Labs., Astellas Pharma Inc., 160-2 Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
Astellas Research Technologies Co., Ltd., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
§ Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00415
 Abstract Image

Here we describe the research and development of a process for the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C–N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of (R)-1. Moreover, an epimerization process to obtain (R)-7 from the undesired (S)-7 was developed.

Hayakawa, M.; Kido, Y.; Nigawara, T.; Okumura, M.; Kanai, A.; Maki, K.; Amino, N. PCT Int. Appl. WO/2009/091014 A1 20090723,2009.

https://www.astellas.com/en/ir/library/pdf/3q2017_rd_en.pdf

///////////1174229-89-0, ASTELLAS, Glucokinase Activator, TYPE 2 DIABETES, PRECLINICAL, ASP ?, WO 2009091014Masahiko Hayakawa, Yoshiyuki Kido, Takahiro Nigawara, Mitsuaki Okumura, Akira Kanai, Keisuke Maki, Nobuaki AminoWO2009091014,

O=C(Nc1cnc(cn1)CO)[C@H](C[C@@H]2CC(=O)CC2)c3ccc(c(c3)C4CC4)S(=O)(=O)C5CC5

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DR ANTHONY CRASTO

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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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