CN1805972A - 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

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CN1805972A
CN1805972A CNA2004800163249A CN200480016324A CN1805972A CN 1805972 A CN1805972 A CN 1805972A CN A2004800163249 A CNA2004800163249 A CN A2004800163249A CN 200480016324 A CN200480016324 A CN 200480016324A CN 1805972 A CN1805972 A CN 1805972A
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perindopril
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T·迪比费
J-P·勒库夫
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    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
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Abstract

式(I)培哚普利及其可药用盐的合成方法。

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：
Figure A20048001632400041
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，
Figure A20048001632400052
其中X1和X2可以相同或不同，各自代表离去基团，
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，
Figure A20048001632400054
其中R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R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。
不加任何限制可被提及的适宜离去基团X1和X2包括但不限于卤素原子、甲苯磺酸酯基、甲磺酸酯基、直链或支链(C1-C6)烷氧基、直链或支链(C1-C6)烷硫基、咪唑基、苯并咪唑基、四唑基、苯并四唑基、直链或支链三卤代(C1-C6)烷基、直链或支链三卤代(C1-C6)烷氧基和琥珀酰亚氨氧基。
可被提及的优选的离去基团X1和X2包括氯原子、咪唑基和三氯甲氧基。
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-2，5-二氧代-1，3-噁唑烷-3-基]戊酸乙酯
0℃下向反应器中加入200g N-[(S)-乙氧羰基-1-丁基]-(S)-丙氨酸和1.5升甲苯，然后加入184g 1，1，-羰二咪唑，然后将反应混合物的温度升至20℃。于20℃搅拌1小时后，再将混合物冷却至0℃，滤除所得沉淀，然后蒸发滤液，得到标题产物，收率90％。
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290g前一步骤所得的化合物在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，得到预期产物。
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。然后回流所得混悬液至全部溶解，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，得到预期产物，收率95％。

Claims (4)

1.式(I)培哚普利及其可药用盐的合成方法，
其特征在于：使式(II)化合物
Figure A2004800163240002C2
与式(III)化合物反应，
Figure A2004800163240002C3
其中X1和X2可以相同或不同，各自代表离去基团，得到式(IV)化合物：
Figure A2004800163240002C4
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，
Figure A2004800163240003C1
其中R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R如上定义，
式(VI)化合物在催化剂存在下氢化，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，其特征在于氢化反应的氢气压力为1至10巴。
3.根据权利要求1或2中任一项的合成方法，其中X1和X2各自代表氯原子、咪唑基或三氯甲氧基。
4.根据权利要求1至3中任一项的方法，用于合成叔丁胺盐形式的培哚普利。
CNB2004800163249A 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 CN100383159C (zh)

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CN111116709A (zh) * 2019-12-31 2020-05-08 北京鑫开元医药科技有限公司 一种培哚普利制备方法

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ZA200605383B (en) 2003-12-29 2008-06-25 Sepracor Inc Pyrrole and pyrazole daao inhibitors
ATE409036T1 (de) 2005-01-06 2008-10-15 Ipca Lab Ltd Verfahren zur synthese von (2s,3as,7as)-1-(s)- alanyl-octahydro-1h-2-carbonsäurederivaten und verwendung in der synthese von perindopril
WO2007006003A2 (en) 2005-07-06 2007-01-11 Sepracor Inc. Combinations of eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders
WO2007081542A2 (en) 2006-01-06 2007-07-19 Sepracor Inc. Tetralone-based monoamine reuptake inhibitors
RU2430913C2 (ru) 2006-01-06 2011-10-10 Сепракор Инк. Циклоалкиламины в качестве ингибиторов повторного поглощения моноамина
DK2013835T3 (en) 2006-03-31 2015-12-14 Sunovion Pharmaceuticals Inc Preparation of chiral amides and AMINES
US7884124B2 (en) 2006-06-30 2011-02-08 Sepracor Inc. Fluoro-substituted inhibitors of D-amino acid oxidase
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
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
BRPI0811639A2 (pt) 2007-05-31 2014-09-30 Sepracor Inc Cicloaquilaminas fenil substituídas como inibidores da recaptação de monoamina
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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FR2620709B1 (fr) * 1987-09-17 1990-09-07 Adir Procede de synthese industrielle du perindopril et de ses principaux intermediaires de synthese
EP1321471B1 (fr) * 2003-03-12 2005-05-04 Les Laboratoires Servier Nouveau procédé de synthèse du perindopril et de ses sels pharmaceutiquement acceptables
SI1367061T1 (sl) * 2003-06-30 2006-04-30 Servier Lab Nov postopek za sintezo perindoprila in njegovih farmacevtsko sprejemljivih soli

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CN100383159C (zh) 2008-04-23
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