ethyl (E)-3-cyano-5-methylhex-3-enoate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: ethyl (E)-3-cyano-5-methylhex-3-enoate
• 化学式: C₁₀H₁₅NO₂
• 分子量: 181.235
• InChiKey: IFOIXEQWPBMPJK-WEVVVXLNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  13
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  50.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  乙醇 、 一氧化碳 、 carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester 在 palladium diacetate 三苯基膦 作用下， 50.0 ℃ 、2.07 MPa 条件下， 生成 ethyl 3-cyano-5-methylhex-3-enoate 、 ethyl (E)-3-cyano-5-methylhex-3-enoate
  参考文献：
  名称：

  Asymmetric synthesis of pregabalin

  摘要：

  该发明提供了一种通过不对称氢化合成制备(S)-(+)-3-(氨甲基)-5-甲基己酸（盐酸普拉巴林）或其盐的方法。盐酸普拉巴林对于治疗和预防癫痫、疼痛和精神疾病很有用。该发明还提供了在生产盐酸普拉巴林过程中有用的中间体。

  公开号：

  US20030212290A1

文献信息

• PROCESS FOR THE PREPARATION OF PREGABALIN
  申请人：HIKAL LIMITED

  公开号：US20150344919A1

  公开（公告）日：2015-12-03

  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.

  本发明提供了一种改进的制备化合物(I)的方法，包括以下步骤：式(I)，(a)在适当溶剂中，将式(II)异戊醛和式(III)烷基氰乙酸酯在弱酸和弱碱盐或弱碱的存在下反应，得到式(IV)的2-氰基-5-甲基-己-2-烯酸烷基酯；(b)将式(IV)的2-氰基-5-甲基-己-2-烯酸烷基酯与适当的氰化物源在水中或有机溶剂中或二者的混合物中反应，得到式(V)的2-异丁基琥珀酰腈；(c)通过在水中或有机溶剂中或二者的混合物中的单步反应，将式(II)异戊醛和式(III)烷基氰乙酸酯在适当的氰化物源的存在下反应，可选地获得式(V)的2-异丁基琥珀酰腈；(d)通过在水中或适当的pH和温度下，用一种基因改造的腈酶酶(Nit pt 9N_56_2)将式(V)的2-异丁基琥珀酰腈转化为外消旋3-氰基-5-甲基-己酸或其盐的式(VI)；(e)通过在适当溶剂或其混合物中，在碱的存在下，用醇(R3OH)和酸性催化剂或烷基卤化物(R3X)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)的外消旋烷基3-氰基-5-甲基-己酸酯；(f)通过在水或有机溶剂或其混合物中，通过酶选择性立体选择性水解，从式(VII)的外消旋烷基3-氰基-5-甲基-己酸酯获得(S)-烷基3-氰基-5-甲基-己酸酯的式(VIII)和(R)-3-氰基-5-甲基-己酸或其盐的式(X)；(g)通过在有机溶剂或其混合物中，在碱的存在下，将不需要的(R)-3-氰基-5-甲基-己酸或其盐的式(X)或富集的(R)-3-氰基-5-甲基-己酸或其盐的式(X)外消旋化，可选地获得式(VII)的化合物；(h)通过在水或其他有机溶剂或其混合物中，在适当的氢化催化剂的存在下，将(S)-烷基3-氰基-5-甲基-己酸酯转化为式(I)的前列酸，首先用适当的碱或碱土金属碱水解酯基，然后在一个锅中进行氢化。
• [EN] GREENER AND ECONOMIC PROCESS FOR PREPARATION OF PREGABALIN<br/>[FR] PROCÉDÉ ÉCOLOGIQUE ET ÉCONOMIQUE POUR LA PRÉPARATION DE PRÉGABALINE
  申请人：HIKAL LTD

  公开号：WO2020183376A1

  公开（公告）日：2020-09-17

  The present invention relates to an economical, enzyme catalyzed and commercially viable greener process for manufacturing Pregabalin of formula (I) in high yield with highchemical and chiral purity.

  本发明涉及一种经济、酶催化和商业可行的更环保的工艺，用于以高产率、高化学纯度和手性纯度制造化学式（I）的普拉巴林。
• Process for the preparation of pregabalin
  申请人：HIKAL LIMITED

  公开号：US10023885B2

  公开（公告）日：2018-07-17

  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 (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit 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.

  本发明提供了一种制备式(I)化合物的改进工艺，该工艺包括以下步骤：式(I)，(a)使式(II)的异戊醛和式(III)的氰乙酸烷基酯（可选择在弱酸和弱碱或弱碱的盐存在下）在合适的溶剂中反应，得到式(IV)的2-氰基-5-甲基-己-2-烯酸烷基酯；(b) 将式(IV)的 2-氰基-5-甲基-己-2-烯酸烷基酯与合适的氰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) 将式(II)的异戊醛和式(III)的氰乙酸烷基酯在水中或有机溶剂或其混合物中，在适 当氰化物源存在下进行反应，得到式(V)的 2-异丁基琥珀腈；(d) 在适当的 pH 值和温度下，用转基因硝化酶（Nit 9N_56_2）在水中或任选用有机 助溶剂中将式（V）的 2-异丁基琥珀腈转化为式（VI）的外消旋 3-氰基-5-甲基己酸或其盐；(e) 在适当溶剂或其混合物中，在碱存在下，用醇 (R3OH) 和酸性催化剂或烷基卤化物 (R3X) 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) 的外消旋 3-氰基-5-甲基己酸烷基酯；(f) 从式(VII)的外消旋 3-氰基-5-甲基己酸烷基酯在水或有机溶剂或其混合物中通过酶对映 选择性水解得到式(VIII)的(S)-3-氰基-5-甲基己酸烷基酯和式(X)的(R)-3-氰基-5-甲基己酸或其盐；(g) 在有机溶剂或其混合物中，在碱存在下，通过外消旋化不需要的(R)-3-氰基-5-甲基己酸或式(X)的其盐或基本富集的(R)-3-氰基-5-甲基己酸式(X)的其盐，得到可选的式(VII)化合物；(h) 将式(VIII)的(S)-3-氰基-5-甲基己酸烷基酯转化为式(I)的普瑞巴林，方法是先用适当的碱金属或碱土金属碱水解酯基，然后在适当的氢化催化剂存在下，任选在选自水或其他有机溶剂或其混合物的溶剂中一次氢化。
• A PROCESS FOR THE PREPARATION OF PREGABALIN
  申请人：Hikal Limited

  公开号：EP2916832B1

  公开（公告）日：2019-01-16
• [EN] A PROCESS FOR THE PREPARATION OF PREGABALIN<br/>[FR] PROCÉDÉ DE PRÉPARATION DE PRÉGABALINE
  申请人：HIKAL LTD

  公开号：WO2014072785A2

  公开（公告）日：2014-05-15

  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 (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit 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.