(R)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester | 871577-68-3

• 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: (R)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester
• 英文别名: (R)-diethyl 2-(1-cyano-3-methylbutyl)malonate；(R)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester；(R)-2-(1-cyano-3-methylbutyl)malonate diethyl ester；diethyl 2-[(1R)-1-cyano-3-methylbutyl]propanedioate
• CAS: 871577-68-3
• 化学式: C₁₃H₂₁NO₄
• 分子量: 255.314
• InChiKey: PZGIWBPMOSUKEV-JTQLQIEISA-N

物化性质

• 沸点：
  355.7±32.0 °C(Predicted)
• 密度：
  1.043±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  76.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester 在 盐酸 、 sodium ethanolate 、 溶剂黄146 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 乙醇 、 醋酸异丙酯 、 水 、 甲苯 为溶剂， 20.0~110.0 ℃ 、344.75 kPa 条件下， 反应 26.0h， 生成 普瑞巴林
  参考文献：
  名称：

  Development of a Chemoenzymatic Manufacturing Process for Pregabalin

  摘要：

  A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-carboxyethyl-3-eyano-5-methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-methylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-1. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40-45% after one recycle of (R)4), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.

  DOI：

  10.1021/op7002248
• 作为产物：
  描述：

  2-(3-甲基丁亚基)丙二酸二乙酯 在 Thermomyces lanuginosus lipase 、 calcium acetate 、 potassium carbonate 、 sodium hydroxide 作用下， 以 水 、 乙腈 为溶剂， 反应 24.0h， 生成 (R)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester
  参考文献：
  名称：

  在篮式反应器中使用交联酶聚集体 (CLEA) 制备对映体纯普瑞巴林中间体

  摘要：

  摘要 对映体纯的 ( S )-3-氰基-5-甲基己酸乙酯 ( S ) -5（普瑞巴林的关键手性中间体）的合成路线已得到改进。通过明胶催化丙二酸二乙酯与异戊醛的克诺文格尔缩合，然后使用丙酮合氰化氢和 K 2 CO 3对 α,β-不饱和二酯14进行氢氰化，制备了纯度为 98% 的外消旋 β-氰基二酯3。外消旋 2-(1-氰基-3-甲基丁基)丙二酸二乙酯 ( rac - 3 ) 已使用来自疏棉状嗜热丝孢菌 ( Thermomyces lanuginosus)的脂肪酶进行解析以交联酶聚集体 CLEA 的形式固定。CLEA 是通过使用商业豆奶作为额外的蛋白质来源制成的，并在移动篮式反应器中进行反应。研究发现固定化酶在许多有机溶剂和高达 50 °C 的温度下保持稳定。在篮式反应器中，使用 20% w/w 酶负载，在醋酸钙缓冲液（pH 7.5，pH 7.5）中，在篮式反应器中研究拆分反应。表观动力学参数为

  DOI：

  10.1080/10242422.2021.2023507

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。
• PROCESS FOR THE SYNTHESIS OF PREGABALIN
  申请人：RAZZETTI Gabriele

  公开号：US20100292506A1

  公开（公告）日：2010-11-18

  A process for the preparation of a compound of formula (I) is disclosed, which comprises: a) the reaction of a compound of formula (II) with zinc azide of formula (III) Zn(N 3 ) 2 (III) in the presence of a solvent of formula R 1 —OH, wherein R 1 is herein defined, to obtain a compound of formula (IV), b) its conversion into a compound of formula (V); c) its enantiomeric enrichment to obtain the (S) enantiomer of formula (VI); and d) the hydrolysis thereof.

  揭示了一种制备化合物(I)的方法，包括：a)将化合物(II)与化合物(III)Zn(N3)2(III)在溶剂R1—OH的存在下反应，其中R1在此处定义，以获得化合物(IV)；b)将其转化为化合物(V)；c)对其进行对映体富集，以获得化合物(VI)的(S)对映体；和d)对其进行水解。
• Preparation of pregabalin and related compounds
  申请人：Hu Shanghui

  公开号：US20050283023A1

  公开（公告）日：2005-12-22

  Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.

  本发明揭示了通过酶动力学分辨法制备（S）-（+）-3-氨甲基-5-甲基-己酸及其结构相关化合物的材料和方法。
• Process for the Preparation of (S)(+)-3-(Aminomethyl)-5-Methylhexanoic Acid
  申请人：Allegrini Pietro

  公开号：US20090143615A1

  公开（公告）日：2009-06-04

  A process for the preparation of a compound of formula (I), comprising: a) the reaction of a compound of formula (II) with hydrazine to obtain a compound of formula (III), b) the conversion of a compound of formula (III) by rearrangement via formation of nitrene/isocyanate, in a solvent of formula R 1 —OH, wherein R 1 is as herein defined, to obtain a compound of formula (IV); c) the enantiomeric enrichment of a compound of formula (IV) to obtain the enantiomer (S) of a compound of formula (V) d) the hydrolysis of a compound of formula (V).

  一种制备式（I）化合物的方法，包括：a）将式（II）化合物与肼反应，得到式（III）化合物；b）通过在式R1-OH的溶剂中发生亚硝基/异氰酸酯的重排反应，将式（III）化合物转化为式（IV）化合物；c）对式（IV）化合物进行对映体富集，得到式（V）化合物的对映体（S）；d）对式（V）化合物进行水解。其中，R1如本文所定义。
• PROCESS FOR THE PREPARATION OF (S)(+)-3-(AMINOMETHYL)-5-METHYLHEXANOIC ACID
  申请人：Riva Sergio

  公开号：US20080311635A1

  公开（公告）日：2008-12-18

  A process for the preparation of (S)(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) of formula (I) or a salt thereof, comprising the reaction of a compound of formula (II) with an alcohol ROH, in the presence or absence of enzyme, to give a compound of formula (III) as herein defined the transformation of a compound of formula (III) into a compound of formula (VI) or (VIII) as herein defined, and the subsequent hydrolysis of a compound of formula (VI) or (VIII), to give pregabalin.

  一种制备（S）（+）-3-（氨甲基）-5-甲基己酸（pregabalin）的方法，其化学式为（I）或其盐，包括以下步骤：将化合物II与醇ROH在酶的存在或缺席下反应，得到化合物III（如此处所定义）；将化合物III转化为化合物VI或VIII（如此处所定义）；随后水解化合物VI或VIII，得到pregabalin。