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Takeda’s Peripherally selective noradrenaline reuptake inhibitor

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ChemSpider 2D Image | 1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid | C18H18ClFN2O4

1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid

  • Molecular Formula C18H18ClFN2O4
  • Average mass 380.798 Da

CAS 1372185-97-1

CAS 1372180-09-0 hydrochloride

Peripherally selective noradrenaline reuptake inhibitor

Image result for takeda pharmaceuticals1-([(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid monohydrochloride

3-Pyridinecarboxylic acid, 1-[[(6S,7R)-7-(4-chloro-3-fluorophenyl)hexahydro-1,4-oxazepin-6-yl]methyl]-1,2-dihydro-2-oxo-, hydrochloride (1:1)

1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic Acid Hydrochloride (1:1) (1·HCl)

TAKEDA PHARMACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP)

ISHICHI, Yuji; (JP).
YAMADA, Masami; (US).
KAMEI, Taku; (JP).
FUJIMORI, Ikuo; (US).
NAKADA, Yoshihisa; (JP).
YUKAWA, Tomoya; (JP).
SAKAUCHI, Nobuki; (JP).
OHBA, Yusuke; (JP).
TSUKAMOTO, Tetsuya; (JP)

Paper

Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-trans-Disubstituted-1,4-oxazepane as a Scaffold

Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00313

Abstract

Abstract Image

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-trans-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita–Baylis–Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-trans-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of N,O-selectivity in SN2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, column chromatograph-free synthesis of the drug candidate with excellent chemical and optical purities in a higher overall yield.

Mp 261–262 °C;
1H NMR (600 MHz, DMSO-d6) δ 3.09–3.18 (m, 1H), 3.20–3.43 (m, 4H), 3.77–3.88 (m, 1H), 3.96 (br dd, J = 13.2, 5.7 Hz, 1H), 4.04 (dt, J = 13.8, 4.2 Hz, 1H), 4.17 (br dd, J = 13.6, 7.6 Hz, 1H), 4.59 (br d, J = 9.1 Hz, 1H), 6.66 (t, J = 7.0 Hz, 1H), 7.27 (br dd, J = 8.3, 1.1 Hz, 1H), 7.47 (br dd, J = 10.4, 1.3 Hz, 1H), 7.54 (br t, J = 8.1 Hz, 1H), 8.10 (dd, J = 6.4, 1.9 Hz, 1H), 8.26 (dd, J = 7.2, 1.9 Hz, 1H), 9.59 (br s, 2H), 14.2 (br s, 1H);
 13C NMR (151 MHz, DMSO-d6) δ 40.5, 44.9, 46.5, 50.0, 63.9, 82.1, 108.4, 116.0 (2JCF = 21.1 Hz), 116.7, 119.3 (2JCF = 18.1 Hz), 125.1 (3JCF = 4.5 Hz), 130.4, 140.9 (3JCF = 7.6 Hz), 145.1, 145.2, 156.8 (1JCF = 247.6 Hz), 163.6, 164.4;
IR (ATR) 2925, 2693, 1725, 1625, 1563, 1484, 1445, 1379, 1293, 1206, 1126, 1097, 1064, 1003, 934, 868, 856, 820, 783, 771, 627, 538, 521, 459, 411 cm–1;
HRMS (ESI): [M + H]+ calcd for C18H19ClFN2O4 (1), 381.1017; found, 381.1009.

PATENT

https://www.google.com/patents/WO2012046882A1?cl=zh

PAPER

Volume 24, Issue 16, 15 August 2016, Pages 3716–3726

http://www.sciencedirect.com/science/article/pii/S0968089616304382

Abstract

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.


Graphical abstract

Image for unlabelled figure

REFERNCES

(a) IshichiY.YamadaM.KameiT.FujimoriI.NakadaY.YukawaT.SakauchiN.OhbaY.TsukamotoT. WO 2012/046882 A1, Apr 12, 2012.

(b) FujimoriI.YukawaT.KameiT.NakadaY.SakauchiN.YamadaM.OhbaY.TakiguchiM.KunoM.KamoI.NakagawaH.HamadaT.IgariT.OkudaT.YamamotoS.TsukamotoT.IshichiY.UenoH. Bioorg. Med. Chem. 2015235000– 5014 DOI: 10.1016/j.bmc.2015.05.017

(c) YukawaT.FujimoriI.KameiT.NakadaY.SakauchiN.YamadaM.OhbaY.UenoH.TakiguchiM.KunoM.KamoI.NakagawaH.FujiokaY.IgariT.IshichiY.TsukamotoT. Bioorg. Med. Chem. 2016243207– 3217 DOI: 10.1016/j.bmc.2016.05.038

(d) YukawaT.NakadaY.SakauchiN.KameiT.YamadaM.OhbaY.FujimoriI.UenoH.TakiguchiM.KunoM.KamoI.NakagawaH.FujiokaY.IgariT.IshichiY.TsukamotoT. Bioorg. Med. Chem. 2016243716– 3726 DOI: 10.1016/j.bmc.2016.06.014

//////////////////1372185-97-1, 1372180-09-0, Peripherally selective,  noradrenaline reuptake inhibitor,  TAKEDA

O=C(O)C3=CC=CN(C[C@@H]1CNCCO[C@H]1c2ccc(Cl)c(F)c2)C3=O

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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 30 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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