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 PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
formula
compound
perindopril
synthesis
hydrogenation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2004800160147A
Other languages
English (en)
Other versions
CN1802384B (zh
Inventor
T·迪比费
J-P·勒库夫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of CN1802384A publication Critical patent/CN1802384A/zh
Application granted granted Critical
Publication of CN1802384B publication Critical patent/CN1802384B/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • 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

培哚普利及其可药用盐的新合成方法
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)

1.式(I)培哚普利及其可药用盐的合成方法，
Figure A2004800160140002C1
其特征在于使式(II)化合物
Figure A2004800160140002C2
与式(III)化合物反应，
Figure A2004800160140002C3
其中R1代表咪唑基、苯并咪唑基或四唑基，
得到式(IV)化合物：
Figure A2004800160140002C4
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：
Figure A2004800160140003C2
其中R2如上定义，
式(VI)化合物在催化剂的存在下氢化，氢气压力为1至30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。
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。
CN2004800160147A 2003-06-30 2004-06-28 培哚普利及其可药用盐的新合成方法 Expired - Fee Related CN1802384B (zh)

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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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

Similar Documents

Publication Publication Date Title
CN1296355C (zh) 合成培哚普利及其药学上可接受的盐的方法
CN1802384B (zh) 培哚普利及其可药用盐的新合成方法
CN1805972A (zh) 培哚普利及其可药用盐的新合成方法
CN1176903C (zh) 合成n-[(s)-1-羧丁基]-s-丙氨酸酯的方法及其用于合成培哚普利的用途
CN100374459C (zh) 合成培哚普利及其药学可接受盐的新方法
CN1839147A (zh) 合成培哚普利及其药学上可接受盐的新方法
KR100825537B1 (ko) 페린도프릴 및 이의 약학적으로 허용되는 염의 합성 방법
CN100439392C (zh) 合成培哚普利及其药学可接受盐的新方法
CN1835966A (zh) 合成培哚普利及其药学上可接受盐的新方法
CN1753906A (zh) 培哚普利和其可药用盐的新合成方法
CN100404548C (zh) 合成培哚普利及其药学可接受盐的新方法
PL211506B1 (pl) Sposób otrzymywania związków kwasu (2S, 3aS, 7aS)-1-[(S)-alanilo]-oktahydro-1H-indolo-2-karboksylowego i ich zastosowanie w syntezie perindoprilu oraz związek przejściowy
CN100469787C (zh) 合成(2s,3as,7as)－1－[(s)－1－丙氨酰基]－八氢－1h－吲哚－2－羧酸衍生物的方法及其用于合成培哚普利的用途

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1089188

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1089188

Country of ref document: HK

CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20100616

Termination date: 20180628