CN1835966A - 合成培哚普利及其药学上可接受盐的新方法 - Google Patents
合成培哚普利及其药学上可接受盐的新方法 Download PDFInfo
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- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 title claims abstract description 13
- 229960002582 perindopril Drugs 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 title claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
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- 238000010189 synthetic method Methods 0.000 claims description 6
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- YERWBBMSDMSDKT-UHFFFAOYSA-N ethyl 2-oxopentanoate Chemical compound CCCC(=O)C(=O)OCC YERWBBMSDMSDKT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims description 2
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
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- -1 amino propionyl Chemical group 0.000 description 2
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- 206010019280 Heart failures Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
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- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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
- 108010021724 tonin Proteins 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 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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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/12—Antihypertensives
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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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 0 308 341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 (6)
1.合成下式(I)的化合物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，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，例如NaOH、KOH、Na2CO3、K2CO3、NaHCO3或KHCO3。
3.根据权利要求1或2所述的合成方法，其特征在于在醇溶剂中进行所述氢化反应。
4.根据权利要求1-3中任一项所述的合成方法，其特征在于所述氢化反应在1-5巴压力下进行。
5.根据权利要求1-4中任一项所述的合成方法，其特征在于所述氢化反应在20-60℃温度下进行。
6.根据权利要求1-5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 |
|---|---|---|---|
| EP03292132A EP1380591B1 (fr) | 2003-08-29 | 2003-08-29 | Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables |
| EP03292132.2 | 2003-08-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1835966A true CN1835966A (zh) | 2006-09-20 |
| CN100383160C CN100383160C (zh) | 2008-04-23 |
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| Application Number | Title | Priority Date | Filing Date |
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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 |
Country Status (18)
| 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) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2250853T3 (es) * | 2003-08-29 | 2006-04-16 | Les Laboratoires Servier | Procedimiento para la sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
| PL1679072T3 (pl) | 2005-01-06 | 2009-03-31 | Ipca Laboratories Ltd | Sposób syntezy pochodnych kwasu (2S, 3aS, 7aS)-1-(S)-alanylo- oktahydro-1H-indolo-2-karboksylowego i zastosowanie w syntezie perindoprilu |
| EP2318365B1 (en) * | 2008-06-24 | 2015-08-12 | Mylan Laboratories Limited | Novel polymorphic forms of perindopril (l)-arginine and process for the 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 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1319668B1 (fr) * | 2003-03-12 | 2004-10-27 | 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 |
| DE60300581T2 (de) | 2003-03-12 | 2006-01-19 | Les Laboratoires Servier | Verfahren für die Synthese von Perindopril und seiner pharmazeutisch annehmba- ren Salzen |
| DK1367061T3 (da) * | 2003-06-30 | 2006-05-15 | Servier Lab | Fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf |
| DK1380590T3 (da) * | 2003-08-29 | 2007-01-08 | Servier Lab | Ny fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf |
| ES2250853T3 (es) * | 2003-08-29 | 2006-04-16 | Les Laboratoires Servier | Procedimiento para la sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
| PT1420028E (pt) * | 2003-11-19 | 2007-05-31 | Servier Lab | Processo de síntese do perindopril e dos seus sais farmacêuticamente aceitáveis. |
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2003
- 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 DK DK03292132T patent/DK1380591T3/da active
- 2003-08-29 ES ES03292132T patent/ES2252633T3/es not_active Expired - Lifetime
- 2003-08-29 SI SI200330124T patent/SI1380591T1/sl unknown
- 2003-08-29 AT AT03292132T patent/ATE310012T1/de active
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2004
- 2004-08-26 MY MYPI20043495A patent/MY136638A/en unknown
- 2004-08-27 PL PL379628A patent/PL211508B1/pl unknown
- 2004-08-27 NZ NZ545336A patent/NZ545336A/en not_active IP Right Cessation
- 2004-08-27 AR ARP040103079A patent/AR045516A1/es not_active Application Discontinuation
- 2004-08-27 US US10/569,537 patent/US7534896B2/en not_active Expired - Fee Related
- 2004-08-27 ZA ZA200601429A patent/ZA200601429B/en unknown
- 2004-08-27 JP JP2006524395A patent/JP4331206B2/ja not_active Expired - Fee Related
- 2004-08-27 AU AU2004270428A patent/AU2004270428B2/en not_active Ceased
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- 2004-08-27 EA EA200600454A patent/EA008668B1/ru not_active IP Right Cessation
- 2004-08-27 WO PCT/FR2004/002197 patent/WO2005023842A1/fr active Application Filing
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Also Published As
| Publication number | Publication date |
|---|---|
| CN100383160C (zh) | 2008-04-23 |
| EP1380591B1 (fr) | 2005-11-16 |
| AR045516A1 (es) | 2005-11-02 |
| HK1096408A1 (en) | 2007-06-01 |
| ES2252633T3 (es) | 2006-05-16 |
| JP4331206B2 (ja) | 2009-09-16 |
| AU2004270428A1 (en) | 2005-03-17 |
| ATE310012T1 (de) | 2005-12-15 |
| SI1380591T1 (sl) | 2006-02-28 |
| PL379628A1 (pl) | 2006-10-30 |
| EA200600454A1 (ru) | 2006-08-25 |
| US20070010572A1 (en) | 2007-01-11 |
| JP2007526902A (ja) | 2007-09-20 |
| EA008668B1 (ru) | 2007-06-29 |
| DE60302287D1 (de) | 2005-12-22 |
| PL211508B1 (pl) | 2012-05-31 |
| MY136638A (en) | 2008-11-28 |
| DE60302287T2 (de) | 2006-08-10 |
| NZ545336A (en) | 2009-03-31 |
| EP1380591A1 (fr) | 2004-01-14 |
| DK1380591T3 (da) | 2006-01-23 |
| ZA200601429B (en) | 2007-05-30 |
| WO2005023842A1 (fr) | 2005-03-17 |
| AU2004270428B2 (en) | 2008-08-21 |
| US7534896B2 (en) | 2009-05-19 |
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