CN1802384A - 培哚普利及其可药用盐的新合成方法 - Google Patents
培哚普利及其可药用盐的新合成方法 Download PDFInfo
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- CN1802384A CN1802384A CNA2004800160147A CN200480016014A CN1802384A CN 1802384 A CN1802384 A CN 1802384A CN A2004800160147 A CNA2004800160147 A CN A2004800160147A CN 200480016014 A CN200480016014 A CN 200480016014A CN 1802384 A CN1802384 A CN 1802384A
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- perindopril
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Proteomics, Peptides & Aminoacids (AREA)
- Heart & Thoracic Surgery (AREA)
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- Hospice & Palliative Care (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及式(I)培哚普利及其可药用盐的新合成方法。
Description
本发明涉及式(I)培哚普利及其可药用盐的合成方法:
培哚普利及其可药用盐,更特别是其叔丁胺盐,具有有价值的药理学性质。它们的主要性质是抑制血管紧张素I转化酶(或激肽酶II),这一方面可以阻止十肽血管紧张素I转化为八肽血管紧张素II(一种血管收缩剂),另一方面还可阻止缓激肽(一种血管扩张剂)降解为非活性肽。这两种作用使得培哚普利在心血管病、更特别是动脉高血压与心力衰竭方面具有有益的作用。
培哚普利、其制备及其治疗用途已经在欧洲专利说明书EP 0 049 658中有描述。
由于该化合物具有药用价值,因此能够通过易于实现工业化的有效合成方法来获得该化合物具有重要意义,该方法从价格合理的原料开始,以较高收率和极好的纯度获得培多普利。
专利说明书EP 0 308 341描述了一种培哚普利的合成方法,该方法如下进行:使(2S,3aS,7aS)-八氢吲哚-2-甲酸苄酯与N-[(S)-1-羧丁基]-(S)-丙氨酸乙酯进行肽式偶联,然后催化氢化使杂环的羧基去保护。这种方法的优点是从已经描述其工业化合成的原料开始以较高收率产生培多普利。
然而,该方法还具有与偶联步骤中使用二环己基碳二酰亚胺有关的缺点:偶联杂质和二环己基脲的形成,后者是一种难以除去的副产物。
现在,申请人已经研发了一种合成培哚普利的新方法,该方法可避免那些次要产物的形成。
更具体而言,本发明涉及培哚普利及其药用盐的合成方法,其特征在于使式(II)化合物
与式(III)化合物反应,
其中R1代表咪唑基、苯并咪唑基或四唑基,
得到式(IV)化合物:
该化合物与式(V)化合物或其与无机或有机酸的加成盐反应,
其中R2代表氢原子、苄基、直链或支链(C1-C6)烷基,
经过分离,得到式(VI)化合物:
其中R2如上定义,
式(VI)化合物在催化剂如钯、铂、铑或镍的存在下氢化,氢气压力为1至30巴,优选1至10巴,
当必要时,酸官能团去保护后,得到式(I)培哚普利,
如果希望的话,将式(I)培哚普利转化为可药用盐,如叔丁胺盐。
以下实施例解释而非以任何方式限制本发明。
实施例:(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(乙氧羰基)丁氨基]丙酰基}八氢-1H-吲哚-2-甲酸叔丁胺盐
步骤A:(2S)-2-[(4S)-4-甲基-2-氧化-5-氧代-1,2,3-氧杂噻唑烷-3-基]戊酸乙酯
向反应器中加入200g N-[(S)-乙氧羰基-1-丁基]-(S)-丙氨酸和1.5升二氯甲烷,然后在0℃下加入325g 1H-咪唑-1-亚磺酰氯。然后将反应混合物升至环境温度,搅拌1小时后,滤除所形成的沉淀。蒸发所得滤液至干,得到油形式的所需产物。
步骤B:(2S)-1-{(2S)-2-[(1S)-1-(乙氧羰基)丁氨基]丙酰基}-2,3,4,5,6,7-六氢-1H-吲哚-2-甲酸
向反应器中加入200g(2S)-2,3,4,5,6,7-六氢-1H-吲哚-2-甲酸和1.5升二氯甲烷,然后加入180ml三乙胺。接着,缓慢加入315g上一步骤中所得的化合物在500ml二氯甲烷中的溶液,然后于环境温度另外搅拌1小时。加入水后,将反应混合物冷却至15℃,加入2N盐酸溶液调节pH至4.2。萃取后,洗涤有机相,然后蒸发,得到所需产物。
步骤C:(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(乙氧羰基)丁氨基]丙酰基}八氢-1H-吲哚-2-甲酸
向氢化容器中加入200g步骤B所得化合物的乙酸溶液,然后加入5g10%Pt/C。于5巴压力和环境温度下进行氢化反应,直至已经吸收理论量的氢气。过滤除去催化剂,然后冷却至0至5℃,过滤回收所得固体。洗涤滤饼并干燥至恒重。
步骤D:(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(乙氧羰基)丁氨基]丙酰基}八氢-1H-吲哚-2-甲酸叔丁胺盐
将步骤C所得的化合物(200g)溶于2.8升乙酸乙酯中,然后加入40g叔丁胺和0.4升乙酸乙酯。然后回流该混悬液至全部溶解,接着趁热过滤所得溶液,搅拌冷却至15至20℃。然后将所得沉淀滤出,用乙酸乙酯再次制成糊状,干燥,然后粉碎,得到所需产物,收率95%。
Claims (3)
2.根据权利要求1的合成方法,其中氢化反应的氢气压力为1至10巴。
3.根据权利要求1的方法,用于合成叔丁胺盐形式的培哚普利。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03291601.7 | 2003-06-30 | ||
EP03291601A EP1367061B1 (fr) | 2003-06-30 | 2003-06-30 | Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables |
PCT/FR2004/001637 WO2005003153A1 (fr) | 2003-06-30 | 2004-06-28 | Nouveau procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1802384A true CN1802384A (zh) | 2006-07-12 |
CN1802384B CN1802384B (zh) | 2010-06-16 |
Family
ID=29414888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2004800160147A Expired - Fee Related CN1802384B (zh) | 2003-06-30 | 2004-06-28 | 培哚普利及其可药用盐的新合成方法 |
Country Status (18)
Country | Link |
---|---|
US (1) | US7179833B2 (zh) |
EP (1) | EP1367061B1 (zh) |
JP (1) | JP4347341B2 (zh) |
CN (1) | CN1802384B (zh) |
AR (1) | AR044944A1 (zh) |
AT (1) | ATE315043T1 (zh) |
AU (1) | AU2004253721B2 (zh) |
DE (1) | DE60303101T2 (zh) |
DK (1) | DK1367061T3 (zh) |
EA (1) | EA008836B1 (zh) |
ES (1) | ES2256689T3 (zh) |
HK (1) | HK1089188A1 (zh) |
MY (1) | MY139159A (zh) |
NZ (1) | NZ544003A (zh) |
PL (1) | PL211161B1 (zh) |
SI (1) | SI1367061T1 (zh) |
WO (1) | WO2005003153A1 (zh) |
ZA (1) | ZA200510330B (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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DE60313391T2 (de) * | 2003-06-30 | 2008-01-17 | Les Laboratoires Servier | Verfahren für die Synthese von Perindopril und seiner pharmazeutisch geeigneten Salze |
DK1380591T3 (da) * | 2003-08-29 | 2006-01-23 | Servier Lab | Fremgangsmåde til syntese af perindopril og farmaceutiske acceptable salte heraf |
SI21800A (sl) * | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nov postopek sinteze perindoprila |
US7615571B2 (en) * | 2004-05-31 | 2009-11-10 | Ipca Laboratories Ltd. | Process for manufacture of pure (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl]amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid and its tert. butyl amine salt |
US9358318B2 (en) * | 2004-10-20 | 2016-06-07 | Ethicon, Inc. | Method of making a reinforced absorbable multilayered hemostatic wound dressing |
JP5191736B2 (ja) * | 2004-10-20 | 2013-05-08 | エシコン・インコーポレイテッド | 吸収性止血材 |
ES2314583T4 (es) | 2005-01-06 | 2009-05-18 | Ipca Laboratories Limited | Proceso para sintesis de los derivados del acido (2s,3as,7as)-1-(s)-alanil-octahidro-1h-indol-2-carboxilico y su utilizacion en la sintesis de perindropil. |
US7291745B2 (en) | 2005-03-21 | 2007-11-06 | Glenmark Pharmaceuticals Limited | Process for the preparation of perindopril |
JP2008019214A (ja) * | 2006-07-13 | 2008-01-31 | Shiono Chemical Co Ltd | ペリンドプリルまたはその誘導体の製造方法 |
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. |
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Publication number | Priority date | Publication date | Assignee | Title |
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FR2503155A2 (fr) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
SI9500140A (en) * | 1995-04-24 | 1996-10-31 | Genesis Para La Investigacion | Novel n-sulfoxy anhydrides, process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action |
SI1321471T1 (zh) * | 2003-03-12 | 2005-08-31 | Servier Lab | |
US20050171165A1 (en) * | 2003-11-12 | 2005-08-04 | Bhirud Shekhar B. | Process for the preparation of perindopril |
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2003
- 2003-06-30 DE DE60303101T patent/DE60303101T2/de not_active Expired - Lifetime
- 2003-06-30 DK DK03291601T patent/DK1367061T3/da active
- 2003-06-30 AT AT03291601T patent/ATE315043T1/de active
- 2003-06-30 SI SI200330154T patent/SI1367061T1/sl unknown
- 2003-06-30 ES ES03291601T patent/ES2256689T3/es not_active Expired - Lifetime
- 2003-06-30 EP EP03291601A patent/EP1367061B1/fr not_active Expired - Lifetime
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2004
- 2004-06-28 US US10/562,490 patent/US7179833B2/en not_active Expired - Fee Related
- 2004-06-28 WO PCT/FR2004/001637 patent/WO2005003153A1/fr active Application Filing
- 2004-06-28 EA EA200501925A patent/EA008836B1/ru not_active IP Right Cessation
- 2004-06-28 CN CN2004800160147A patent/CN1802384B/zh not_active Expired - Fee Related
- 2004-06-28 AU AU2004253721A patent/AU2004253721B2/en not_active Ceased
- 2004-06-28 PL PL380408A patent/PL211161B1/pl unknown
- 2004-06-28 NZ NZ544003A patent/NZ544003A/en not_active IP Right Cessation
- 2004-06-28 MY MYPI20042540A patent/MY139159A/en unknown
- 2004-06-28 ZA ZA200510330A patent/ZA200510330B/xx unknown
- 2004-06-28 JP JP2006515295A patent/JP4347341B2/ja not_active Expired - Fee Related
- 2004-06-29 AR ARP040102277A patent/AR044944A1/es not_active Application Discontinuation
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2006
- 2006-08-30 HK HK06109654.2A patent/HK1089188A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
EP1367061A1 (fr) | 2003-12-03 |
ATE315043T1 (de) | 2006-02-15 |
HK1089188A1 (en) | 2006-11-24 |
PL211161B1 (pl) | 2012-04-30 |
EA008836B1 (ru) | 2007-08-31 |
EP1367061B1 (fr) | 2006-01-04 |
CN1802384B (zh) | 2010-06-16 |
AU2004253721A1 (en) | 2005-01-13 |
PL380408A1 (pl) | 2007-01-22 |
ZA200510330B (en) | 2007-05-30 |
EA200501925A1 (ru) | 2006-06-30 |
DE60303101T2 (de) | 2006-09-28 |
SI1367061T1 (sl) | 2006-04-30 |
JP2007537974A (ja) | 2007-12-27 |
WO2005003153A1 (fr) | 2005-01-13 |
US7179833B2 (en) | 2007-02-20 |
MY139159A (en) | 2009-08-28 |
DK1367061T3 (da) | 2006-05-15 |
AU2004253721B2 (en) | 2007-12-20 |
AR044944A1 (es) | 2005-10-12 |
ES2256689T3 (es) | 2006-07-16 |
DE60303101D1 (de) | 2006-03-30 |
JP4347341B2 (ja) | 2009-10-21 |
US20060178421A1 (en) | 2006-08-10 |
NZ544003A (en) | 2009-03-31 |
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