CN100383160C - 合成培哚普利及其药学上可接受盐的新方法 - Google Patents
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- 229960002582 perindopril Drugs 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims abstract description 8
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- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
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- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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Abstract
本发明公开合成式(I)培哚普利化合物及其药学可接受的盐的方法。
Description
本发明涉及合成下式(I)的培哚普利及其药学上可接受盐的方法：
培哚普利及其药学上可接受的盐、更具体地说是其叔丁基胺盐具有重要的药理学性质。
所述化合物的主要性质是抑制血管紧张素I转化酶(或激肽酶II)，因此一方面它们能够阻止十肽血管紧张素I转化成八肽血管紧张素II(血管收缩剂)，另一方面它们能够防止缓激肽(血管舒张药)降解成失活肽。
这两种作用有助于培哚普利在心血管疾病、特别是动脉高血压和心脏供血不足中发挥有益的作用。
欧洲专利EP 0 049 658中描述了培哚普利、其制备方法及在治疗中的用途。
考虑到所述化合物的药学价值，重要的是能够采用易转换成工业规模的、竞争力强的合成方法，使用价格合理的原料以高产率和极佳纯度获得培哚普利。
专利EP 0308341描述了通过使(2S，3aS，7aS)-八氢吲哚-2-甲酸苄酯与N-[(S)-1-羧基丁基]-(S)-丙氨酸乙酯偶合，接着采用催化氢化反应使该杂环的羧基去保护，从而工业合成出培哚普利的方法。
本申请人现在已研制一种合成培哚普利的新方法。
更具体地讲，本发明涉及一种合成培哚普利及其药学可接受盐的方法，其特征在于在碱存在下，使下式(II)化合物：
式中Bn代表苄基基团，与具有S构型的下式(III)化合物进行反应：
式中X代表卤素原子，而BOC代表叔丁氧基羰基基团，在氨基官能团去保护后得到下式(IV)化合物：
式中Bn代表苄基基团，然后在氢气压力下，在披钯炭存在下，使式(IV)化合物与2-氧代-戊酸乙酯反应，从而得到式(I)化合物。
在式(II)与(III)化合物反应中，作为非限制性实例，可使用的碱可以列举有机胺，例如三乙胺、吡啶、N-甲基吗啉或二异丙基乙胺，或无机碱，例如NaOH、KOH、Na2CO3、K2CO3、NaHCO3或KHCO3。
优选地，在醇溶剂中、在1-5巴氢气压力与20-60℃温度下进行式(IV)化合物与2-氧代-戊酸乙酯的反应。
实施例：(2S，3aS，7aS)-1-{(2S)-2-[(1S)-1-(乙氧基羰基)-丁基氨基]-丙酰基}-八氢-1H-吲哚-2-甲酸叔丁基胺盐
步骤A：(2S)-1-{(2S)-2-[(叔-丁氧基羰基)-氨基]-丙酰基}-2，3，4，5，6，7-六氢-1H-吲哚-2-甲酸苄酯
向一个反应器中装入200g(2S)-2，3，4，5，6，7-六氢-1H-吲哚-2-甲酸苄酯、1.5升二氯甲烷，然后将反应混合物的温度调到0℃，再添加107ml三乙胺，然后添加162g(2S)-2-[(叔-丁氧基羰基)-氨基]-丙酰氯。然后将该混合物调到室温。在这个温度下搅拌1h后，先用水、再用稀乙酸溶液洗涤混合物。由此得到的(2S)-1-{(2S)-2-[(叔-丁氧基羰基)-氨基]丙酰基}-2，3，4，5，6，7-六氢-1H-吲哚-2-甲酸苄酯溶液可原样用于后续步骤。
步骤B：(2S)-1-{(2S)-2-氨基丙酰基}-2，3，4，5，6，7-六氢-1H-吲哚-2-甲酸苄酯
向一个反应器中装入在前面步骤得到的溶液，然后添加133g三氟乙酸。在室温下搅拌1小时30分钟后，先用水、再用饱和碳酸氢钠溶液洗涤这种混合物，然后蒸去溶剂，得到(2S)-1-{(2S)-2-氨基丙酰基}-2，3，4，5，6，7-六氢-1H-吲哚-2-甲酸苄酯。
步骤C：(2S，3aS，7aS)-1-{(2S)-2-(1S)-1-(乙氧基羰基)-丁基氨基-丙酰基}-八氢-1H-吲哚-2-甲酸
向一个氢化器中装入200g在前面步骤得到的化合物和88g 2-氧代戊酸乙酯在乙醇中的溶液，然后添加5g 10％Pd/C。在大气压下于30℃进行氢化直到吸收理论量的氢。
过滤除去催化剂，再蒸发除去溶剂。
由此得到(2S，3aS，7aS)-1-{(2S)-2-[(1S)-1-(乙氧基羰基)-丁基氨基]-丙酰基}-八氢-1H-吲哚-2-甲酸，其产率是85％。
步骤D：(2S，3aS，7aS)-1-{(2S)-2-[(1S)-1-(乙氧基羰基)-丁基氨基]-丙酰基}-八氢-1H-吲哚-2-甲酸叔丁基胺盐
将前面步骤得到的化合物(200g)溶解在2.8升乙腈中，然后添加40g叔丁胺和0.4升乙酸乙酯。得到的悬浮液升温回流直到完全溶解，然后，得到的溶液趁热过滤，再在搅拌下冷却到15-20℃。过滤沉淀，用乙腈再制浆，干燥，然后在乙酸乙酯中重结晶，得到期望的产物，其产率是95％，对映体纯度是99％。
Claims (7)
1.合成下式(I)的化合物或其药学可接受盐的方法：
其特征在于在碱存在下，使下式(II)化合物：
式中Bn代表苄基基团，与具有S构型的下式(III)化合物进行反应：
式中X代表卤素原子，而BOC代表叔-丁氧基羰基基团，在氨基官能团去保护后得到下式(IV)化合物：
式中Bn代表苄基基团，然后在氢气压力下，在披钯炭存在下，使式(IV)化合物与2-氧代-戊酸乙酯反应，得到式(I)化合物。
2.根据权利要求1所述的合成方法，其特征在于在式(II)与(III)化合物反应中，使用的碱是选自三乙胺、吡啶、N-甲基吗啉和二异丙基乙胺的有机胺，或无机碱。
3.根据权利要求2所述的合成方法，其特征在于所述无机碱为NaOH、KOH、Na2CO3、K2CO3、NaHCO3或KHCO3。
4.根据权利要求1所述的合成方法，其特征在于在醇溶剂中在氢气压力下进行所述式(IV)化合物和2-氧代戊酸乙酯之间的反应。
5.根据权利要求1-4中任一项所述的合成方法，其特征在于所述式(IV)化合物和2-氧代戊酸乙酯之间的反应在1-5巴的氢气压力下进行。
6.根据权利要求1-4中任一项所述的合成方法，其特征在于在氢气压力下所述式(IV)化合物和2-氧代戊酸乙酯之间的反应在20-60℃温度下进行。
7.根据权利要求1-4中任一项所述的合成方法，其中培哚普利呈叔丁基胺盐形式。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03292132.2 | 2003-08-29 | ||
| EP03292132A EP1380591B1 (fr) | 2003-08-29 | 2003-08-29 | Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables |
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| Publication Number | Publication Date |
|---|---|
| CN1835966A CN1835966A (zh) | 2006-09-20 |
| CN100383160C true CN100383160C (zh) | 2008-04-23 |
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| CNB2004800235355A Expired - Fee Related CN100383160C (zh) | 2003-08-29 | 2004-08-27 | 合成培哚普利及其药学上可接受盐的新方法 |
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| Country | Link |
|---|---|
| US (1) | US7534896B2 (zh) |
| EP (1) | EP1380591B1 (zh) |
| JP (1) | JP4331206B2 (zh) |
| CN (1) | CN100383160C (zh) |
| AR (1) | AR045516A1 (zh) |
| AT (1) | ATE310012T1 (zh) |
| AU (1) | AU2004270428B2 (zh) |
| DE (1) | DE60302287T2 (zh) |
| DK (1) | DK1380591T3 (zh) |
| EA (1) | EA008668B1 (zh) |
| ES (1) | ES2252633T3 (zh) |
| HK (1) | HK1096408A1 (zh) |
| MY (1) | MY136638A (zh) |
| NZ (1) | NZ545336A (zh) |
| PL (1) | PL211508B1 (zh) |
| SI (1) | SI1380591T1 (zh) |
| WO (1) | WO2005023842A1 (zh) |
| ZA (1) | ZA200601429B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1371659T3 (da) * | 2003-08-29 | 2005-11-21 | Servier Lab | Fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf |
| EP1679072B9 (en) | 2005-01-06 | 2009-09-02 | IPCA Laboratories Limited | Process for for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril |
| DK2318365T3 (en) | 2008-06-24 | 2015-11-23 | Mylan Lab Ltd | NOVEL polymorphic forms of perindopril (L) -arginine AND PROCESS FOR PREPARATION THEREOF |
| WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
| FR3050380B1 (fr) | 2016-04-20 | 2020-07-10 | Les Laboratoires Servier | Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains. |
| JP6753699B2 (ja) * | 2016-05-27 | 2020-09-09 | ミネベアミツミ株式会社 | 転がり軸受 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1319668A1 (fr) * | 2003-03-12 | 2003-06-18 | Les Laboratoires Servier | Nouveau procédé de synthèse de dérivés de l'acide (2S, 3aS, 7aS)-1-[(S)]-alanyl]-octahydro-1H-indole-2-carboxylique et application à la synthèse du perindopril |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1321471B1 (fr) | 2003-03-12 | 2005-05-04 | Les Laboratoires Servier | Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables |
| ATE315043T1 (de) * | 2003-06-30 | 2006-02-15 | Servier Lab | Verfahren für die synthese von perindopril und seiner pharmazeutischen annehmbaren salzen |
| ES2272922T3 (es) * | 2003-08-29 | 2007-05-01 | Les Laboratoires Servier | Nuevo procedimiento de sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
| DK1371659T3 (da) * | 2003-08-29 | 2005-11-21 | Servier Lab | Fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf |
| DK1420028T3 (da) * | 2003-11-19 | 2007-06-18 | Servier Lab | Fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf |
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- 2003-08-29 ES ES03292132T patent/ES2252633T3/es not_active Expired - Lifetime
- 2003-08-29 DK DK03292132T patent/DK1380591T3/da active
- 2003-08-29 DE DE60302287T patent/DE60302287T2/de not_active Expired - Lifetime
- 2003-08-29 EP EP03292132A patent/EP1380591B1/fr not_active Expired - Lifetime
- 2003-08-29 AT AT03292132T patent/ATE310012T1/de active
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- 2004-08-26 MY MYPI20043495A patent/MY136638A/en unknown
- 2004-08-27 US US10/569,537 patent/US7534896B2/en not_active Expired - Fee Related
- 2004-08-27 EA EA200600454A patent/EA008668B1/ru not_active IP Right Cessation
- 2004-08-27 CN CNB2004800235355A patent/CN100383160C/zh not_active Expired - Fee Related
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- 2004-08-27 WO PCT/FR2004/002197 patent/WO2005023842A1/fr active Application Filing
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1319668A1 (fr) * | 2003-03-12 | 2003-06-18 | Les Laboratoires Servier | Nouveau procédé de synthèse de dérivés de l'acide (2S, 3aS, 7aS)-1-[(S)]-alanyl]-octahydro-1H-indole-2-carboxylique et application à la synthèse du perindopril |
Non-Patent Citations (1)
| Title |
|---|
| SYNTHESIS OF SEMISYNTHETIC DIPEPTIDES USINGN-CARBOXYANHYDRIDES ANDCHIRAL INDUCTTION ONRANEY NICKEL. BLACKLOCK T J ET AL.JOURNAL OF ORGANIC CHEMISTRY,Vol.53 No.4. 1988 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2252633T3 (es) | 2006-05-16 |
| SI1380591T1 (sl) | 2006-02-28 |
| PL211508B1 (pl) | 2012-05-31 |
| DE60302287T2 (de) | 2006-08-10 |
| JP2007526902A (ja) | 2007-09-20 |
| DK1380591T3 (da) | 2006-01-23 |
| AU2004270428A1 (en) | 2005-03-17 |
| WO2005023842A1 (fr) | 2005-03-17 |
| EA008668B1 (ru) | 2007-06-29 |
| ATE310012T1 (de) | 2005-12-15 |
| JP4331206B2 (ja) | 2009-09-16 |
| EA200600454A1 (ru) | 2006-08-25 |
| US7534896B2 (en) | 2009-05-19 |
| HK1096408A1 (en) | 2007-06-01 |
| NZ545336A (en) | 2009-03-31 |
| AR045516A1 (es) | 2005-11-02 |
| AU2004270428B2 (en) | 2008-08-21 |
| US20070010572A1 (en) | 2007-01-11 |
| EP1380591B1 (fr) | 2005-11-16 |
| CN1835966A (zh) | 2006-09-20 |
| EP1380591A1 (fr) | 2004-01-14 |
| ZA200601429B (en) | 2007-05-30 |
| DE60302287D1 (de) | 2005-12-22 |
| MY136638A (en) | 2008-11-28 |
| PL379628A1 (pl) | 2006-10-30 |
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