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标题翻译： VERFAHREN ZUR HERSTELLUNG VON PREGABALIN

公开(公告)号：EP2916832A2

公开(公告)日：2015-09-16

申请号：EP13853048.0

申请日：2013-11-04

申请人： Hikal Limited

发明人： MOHILE, Swapnil, Surendra , YERANDE, Swapnil, Gulabrao , LUNGE, Sarika, Madhukarrao , PATEL, Rameshkumar, Maghabhai , GUGALE, Shivaji, Balbhim , THAKUR, Rajesh, Mataprasad , MOKAL, Ramesh, Ananda , GANGOPADHYAY, Ashok, Kumar , NIGHTINGALE, Peter, David

IPC分类号： A61K31/197 , C07C229/08 , C07C229/24

CPC分类号： C12P13/001 , C07C227/04 , C07C227/30 , C07C253/10 , C07C253/30 , C12P13/002 , C12P41/005 , C07C255/23 , C07C255/09 , C07C255/19 , C07C229/08

摘要： The present invention provides an improved process for the preparation of a compound of formula (I), which comprises the steps of: formula (I), (a) reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) optionally in presence of salts of weak acid and weak base or weak base in a suitable solvent to get 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV); (b) reacting 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV) with a suitable cyanide source in water or in an organic solvent or mixture thereof to get 2-isobutylsuccinonitrile of formula (V); (c) obtaining optionally 2-isobutylsuccinonitrile of formula (V) by reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) in presence of suitable cyanide source in water or in an organic solvent or mixture thereof in single step; (d) converting 2-isobutylsuccinonitrile of formula pa (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit pt 9N_56_2) in water or optionally with an organic co-solvent at appropriate pH and temperature; (e) converting racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) to racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII) by treatment with alcohol (R3OH) and acidic catalyst or alkyl halide (R3X) in presence of a base in a suitable solvent or a mixture of solvents thereof; (f) obtaining (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) and (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) by enzymatic enantioselective hydrolysis in water or organic solvent or a mixture thereof from racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII); (g) obtaining optionally the compound of formula (VII) by racemizing unwanted (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) or substantially enriched (R)-3-cyano-5-methyl-hexanoic acid salt thereof of formula (X) in presence of a base in organic solvent or a mixture thereof; (h) converting (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) to pregabalin of formula (I) by hydrolyzing ester group with suitable alkali or alkaline earth metal base followed by hydrogenation optionally in one pot in a solvent selected from water or other organic solvents or a mixture thereof in presence of a suitable hydrogenation catalyst.

摘要翻译：本发明提供了制备式（I）化合物的改进方法，其包括以下步骤：式（I），（a）使式（II）的异戊醛与式（III）的氰基乙酸烷基酯任选地在在合适的溶剂中存在弱酸和弱碱或弱碱的盐，得到式（IV）的2-氰基-5-甲基 - 己-2-烯酸烷基酯; （b）使式（IV）的2-氰基-5-甲基 - 己-2-烯酸烷基酯与合适的氰化物源在水或有机溶剂或其混合物中反应，得到式（V）的2-异丁基琥珀腈， ; （c）通过使式（II）的异戊醛与式（III）的氰基乙酸烷基酯在合适的氰化物源存在下在水或有机溶剂或其混合物中在单步骤中反应获得式（V）的任选2-异丁基琥珀腈; （d）将式PA（V）的2-异丁基琥珀腈转化成式（VI）的外消旋的3-氰基-5-甲基 - 己酸或其盐与基因修饰的腈水解酶（Nit pt 9N_56_2）在水中或任选与有机溶剂在适当的pH和温度下; （e）通过用醇（R3OH）和酸性催化剂处理将式（Ⅵ）的外消旋3-氰基-5-甲基 - 己酸或其盐转化为式（Ⅶ）的3-氰基-5-甲基 - 己酸外消旋的烷基酯或烷基卤（R3X）在碱的存在下在合适的溶剂或其溶剂的混合物中反应; （f）通过酶学对映选择性水解获得式（Ⅷ）和（R）-3-氰基-5-甲基 - 己酸的3-氰基-5-甲基己酸烷基酯或其盐在式（VII）的3-氰基-5-甲基 - 己酸外消旋烷基酯的水或有机溶剂或其混合物中; （g）通过外消旋化式（X）的不需要的（R）-3-氰基-5-甲基 - 己酸或其盐或基本上富集的（R）-3-氰基-5- （X）的甲基 - 己酸盐在碱的存在下在有机溶剂或其混合物中的存在下反应; （h）通过用合适的碱金属或碱土金属碱水解酯基，然后氢化任选地在一锅中，将式（VIII）的3-氰基-5-甲基 - 己烷酸烷基酯转化成式（I）的普瑞巴林在合适的氢化催化剂存在下，选自水或其它有机溶剂的溶剂或其混合物。

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