发明授权
- 专利标题: Process for preparation of duloxetine hydrochloride
- 专利标题(中): 盐酸度洛西汀的制备方法
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申请号: US12530214申请日: 2008-03-05
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公开(公告)号: US08269023B2公开(公告)日: 2012-09-18
- 发明人: Rajinder Singh Siyan , Sunil Kumar Vinubhai Gohel , Girij Pal Singh
- 申请人: Rajinder Singh Siyan , Sunil Kumar Vinubhai Gohel , Girij Pal Singh
- 申请人地址: IN Mumbai
- 专利权人: Lupin Ltd.
- 当前专利权人: Lupin Ltd.
- 当前专利权人地址: IN Mumbai
- 代理机构: Akerman Senterfitt
- 代理商 Peter A. Chiabotti
- 优先权: IN312/KOL/2007 20070305; IN1172/KOL/2007 20070827; IN1343/KOL/2007 20070827
- 国际申请: PCT/IN2008/000125 WO 20080305
- 国际公布: WO2008/107911 WO 20080912
- 主分类号: C07D333/16
- IPC分类号: C07D333/16
摘要:
An improved process for synthesis of duloxetine hydrochloride (1) having chiral purity greater than 99.9% that is characterized by the following: (i) preparation of racemic condensed compound (RS)—N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (4) by reaction of racemic hydroxy compound (2) with 1-fluoronaphthalene (3) in presence of a base such as sodamide, potassium amide or potassium bis(trimethylsilyl)amide (KHDMS) in polar aprotic solvent, (ii) optical resolution of racemic condensed compound (5a+5b) with di-benzoyl-L-tartaric acid (7, DBTA, R=H) or di-para-anisoyl-L-tartaric acid (7, DATA, R=OCH3) to obtain crude (S)—N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)—N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a) respectively, (iii) optionally purification of crude tartarate salts (8a or 9a) by crystallization, (iv) optionally purification of duloxetine hydrochloride (1) by crystallization and (v) racemization of undesired (R)—N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by treatment with base potassium bis(trimethylsilyl)amide (KHDMS) to obtain racemic mixture of condensed compounds (5a and 5b).
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