(3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid | 930585-94-7

• 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: (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid
• 英文别名: (3R)-5-methyl-3-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethyl]hexanoic acid
• CAS: 930585-94-7
• 化学式: C₁₇H₂₅NO₃
• 分子量: 291.39
• InChiKey: MNEMQQWDPAVARE-ZIAGYGMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 在 硫酸 、 水 、 sodium hydroxide 、 盐酸 作用下， 以 水 为溶剂， 反应 2.0h， 生成 3-丁基戊二酸
  参考文献：
  名称：

  WO2007/35789

  摘要：

  公开号：
• 作为产物：
  描述：

  3-丁基戊二酸 在 4-二甲氨基吡啶 、 乙酸酐 作用下， 以 甲苯 为溶剂， 生成 (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid
  参考文献：
  名称：

  一种异丁加巴的不对称合成方法

  摘要：

  本发明公开了一种异丁加巴的不对称合成方法，其特征在于：合成步骤包括：以3‑异丁基戊二酸为原料依次进行环酐化反应、与(R)‑(+)‑1‑苯乙胺进行不对称开环、氢化反应、霍夫曼重排得到异丁加巴。与现有技术相比，本发明原料价廉易得、反应步骤较少、总收率高达60％，异丁加巴产品纯度大于99％，ee值大于99％，在工业放大生产中具有非常好的应用前景。

  公开号：

  CN108069866A

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。
• Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-Pregabalin
  申请人：Kansal Kumar Vinod

  公开号：US20070191636A1

  公开（公告）日：2007-08-16

  The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.

  该发明涵盖了通过中间体（3R）-5-甲基-3-（2-氧代-2 [（1R）-1-苯乙基]氨基}乙基）己酸合成（S）-（+）-3-（氨甲基）-5-甲基己酸，即（S）-普瑞巴林。
• Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-pregabalin
  申请人：Kansal Kumar Vinod

  公开号：US20080045747A1

  公开（公告）日：2008-02-21

  The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.

  该发明涵盖了通过中间体(3R)-5-甲基-3-(2-氧代-2-[(1R)-1-苯乙基]氨基)乙酸合成(S)-(+)-3-(氨甲基)-5-甲基己酸和(S)-pregabalin的过程。
• 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。
• CHIRAL 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACIDS, KEY INTERMEDIATES FOR THE NEW SYNTHESIS OF (S)-PREGABALIN
  申请人：TEVA PHARMACEUTICAL INDUSTRIES LTD.

  公开号：EP1802568A1

  公开（公告）日：2007-07-04