N2-(1-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N2-(1-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine
• 英文别名: N²-(1-ethoxycarbonyl-3-phenylpropyl)-N⁶-trifluoroacetyl-L-lysine；N2-(1-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine；(2S)-2-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]-6-[(2,2,2-trifluoroacetyl)amino]hexanoic acid
• 化学式: C₂₀H₂₇F₃N₂O₅
• 分子量: 432.44
• InChiKey: YNLDFNVDZZGPHE-VYRBHSGPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  30
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N2-(1-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine 、 、 、 乙酸乙酯 、 oxalic acid dihydrate 在 水 、 sodium hydroxide 作用下， 以 1S-isomer 、 正己烷 为溶剂， 反应 27.0h， 以to give 5.8 g of pure N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine的产率得到N2-(1-乙氧羰基-3-苯丙基)-N6-三氟乙酰基-L-赖氨酸
  参考文献：
  名称：

  PREPARATION METHOD OF HIGH-OPTICAL PURITY N2-[1-(S)-ETHOXYCARBONYL-3-PHENYLPROPYL]-N6-TRIFLUOROACETYL-L-LYSINE

  摘要：

  本发明公开了一种高光学纯度N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸的制备方法。该方法包括：将粗N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸加入一个或多个有机溶剂中，然后与有机酸反应形成盐，沉淀，从而达到分离和纯化的目的；接下来，将获得的固体或母液加入去离子水中，然后加入无机碱或有机碱进行碱化，以调节pH值，去除有机酸，过滤，洗涤和干燥，以获得高光学纯度N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸，其中1S-异构体与1R-异构体的摩尔比为99：1或更大。

  公开号：

  US20130178651A1
• 作为产物：
  描述：

  N2-[1-(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine 在 palladium-carbon 盐酸 作用下， 以 乙醇 、 水 为溶剂， 生成 N2-(1-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine
  参考文献：
  名称：

  Process for preparing ethyl-alpha-amino-gamma-oxo-gamma-phenybutyrate

  摘要：

  乙基-β-苯甲基丙烯酸酯与(S)-丙氨酸的碱金属盐或N.sup.6-三氟乙酰-L-赖氨酸的碱金属盐反应，形成相应的迈克尔加成产物，完成迈克尔加成后添加不少于等量的酸以防止产物的(S,S)形式转化为(R,S)形式。

  公开号：

  US04925969A1

文献信息

• [EN] PROCESS FOR THE PRODUCTION OF LISINOPRIL<br/>[FR] PROCEDE DE PRODUCTION DE LISINOPRIL
  申请人：EOS ECZACIBASI OZGUN KIMYASAL

  公开号：WO2004000874A1

  公开（公告）日：2003-12-31

  The present invention provides a process for preparing N2-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine and lisinopril thereof. Lisinopril shows excellent angiotensin converting enzyme inhibitor activity. Friedel-Crafts acylation of benzene with maleic anhydride in the presence of AlCl¿3? affords trans-β-benzoylacrylic acid. Treatment of benzoylacrylic acid with HCl gas in ethanol gives ethyl 2-chloro-4-oxo-4-phenylbutyrate in high yield. The coupling reaction between ethyl 2-chloro-4-oxo-4-phenylbutyrate and trifluoroacetyl-L-lysine benzyl ester in the presence of a base pair and sodium iodide produces alkyl lydine derivative with a good diastereoselectivity. Catalytic hydrogenation of lysine derivative with palladium gives N?2¿-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine. This intermediate is activated to form cyclic N-anhydride by using N,N-carbonyldiimidazole and coupled with L-proline methyl ester hydrochloride to give fully protected lisinopril derivative, which is converted into crude lisinopril by hydrolysis.

  本发明提供了一种制备N2-[1(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸及其琥珀酸二乙酯盐（Lisinopril）的方法。Lisinopril表现出优异的血管紧张素转换酶抑制活性。在AlCl3存在下，苯与马来酸酐进行Friedel-Crafts酰化反应，得到反式-β-苯甲酰丙烯酸。将苯甲酰丙烯酸与HCl气体在乙醇中处理，高收率得到乙酸2-氯-4-氧代-4-苯基丁酯。在碱对和碘化钠存在下，乙酸2-氯-4-氧代-4-苯基丁酯与三氟乙酰-L-赖氨酸苄酯进行偶联反应，产生具有良好对映选择性的烷基赖氨酸衍生物。使用钯进行催化氢化，得到N2-[1(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸。使用N,N-羰基二咪唑激活该中间体形成环状N-酐，并与L-脯氨酸甲酯盐偶联，形成完全保护的Lisinopril衍生物，通过水解转化为粗Lisinopril。
• Process for the production of lisinopril
  申请人：ASLAN TUNCER

  公开号：US20070093664A1

  公开（公告）日：2007-04-26

  The present invention provides a process for preparing N 2 -[1(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine and lisinopril thereof. Lisinopril shows excellent angiotensin converting enzyme inhibitor activity. Friedel-Crafts acylation of benzene with maleic anhydride in the presence of AlCl 3 affords trans-β-benzoylacrylic acid. Treatment of benzoylacrylic acid with HCl gas in ethanol gives ethyl 2-chloro-4-oxo-4-phenylbutyrate in high yield. The coupling reaction between ethyl 2-chloro-4-oxo-4-phenylbutyrate and trifluoroacetyl-L-lysine benzyl ester in the presence of a base pair and sodium iodide produces alkyl lydine derivative with a good diastereoselectivity. Catalytic hydrogenation of lysine derivative with palladium gives N 2 -[1(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine. This intermediate is activated to form cyclic N-anhydride by using N,N-carbonyldiimidazole and coupled with L-proline methyl ester hydrochloride to give fully protected lisinopril derivative, which is converted into crude lisinopril by hydrolysis.

  本发明提供了一种制备N2-[1（S）-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸及其L-赖氨酸普利类的方法。L-赖氨酸普利类表现出优异的血管紧张素转换酶抑制剂活性。苯基与马来酸酐在AlCl3存在下的Friedel-Crafts酰化反应得到顺式-β-苯甲酰丙烯酸。将苯甲酰丙烯酸与乙醇中的HCl气体处理，可以高产率得到乙酸2-氯-4-氧代-4-苯基丁酯。在碱对和碘化钠存在下，乙酸2-氯-4-氧代-4-苯基丁酯与三氟乙酰-L-赖氨酸苄酯进行偶联反应，产生具有良好对映选择性的烷基赖氨酸衍生物。用钯进行催化氢化，得到N2-[1（S）-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸。使用N，N-碳酰亚咪唑激活该中间体形成环状N-酐，并与L-脯氨酸甲酯盐酸盐偶联，得到完全保护的L-赖氨酸普利类衍生物，通过水解转化为粗制L-赖氨酸普利类。
• Process for purifying n2-(1(s)-ethoxycarbonyl -3-phenylpropyl)-n6-thifluoroacetyl-l-lysine
  申请人：——

  公开号：US20040147773A1

  公开（公告）日：2004-07-29

  A process for purifying N 2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N 6 -trifluoroacetyl-L-lysine which comprises subjecting N 2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N 6 -trifluoroacetyl-L-lysine contaminated with impurities to crystallization from a solvent comprising a water-soluble non-protic organic solvent, thereby removing the impurities into the mother liquor and giving crystals of N 2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N 6 -trifluoroacetyl-L-lysine, according to which N 2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N 6 -trifluoroacetyl-L-lysine having a high quality can be obtained in a high yield and a high productivity and which is suitable for practice on an industrial scale.

  一种纯化N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸的方法，包括将受杂质污染的N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸经过结晶，使用一种水溶性非质子有机溶剂作为溶剂，将杂质移入母液并得到N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸的晶体。这种方法可获得高质量的N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸，且产量和生产率高，适合在工业规模上实践。
• Process for purifying n2-(1(s)-ethoxycarbonyl-3-phenylpropyl)-n6-thifluoroacetyl-l-lysine
  申请人：Kaneka Corporation

  公开号：US07253299B2

  公开（公告）日：2007-08-07

  A process for purifying N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine which comprises subjecting N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine contaminated with impurities to crystallization from a solvent comprising a water-soluble non-protic organic solvent, thereby removing the impurities into the mother liquor and giving crystals of N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine, according to which N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine having a high quality can be obtained in a high yield and a high productivity and which is suitable for practice on an industrial scale.

  一种用于纯化N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸的方法，包括将杂质污染的N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸经过结晶处理，使用一种水溶性非质子有机溶剂作为溶剂，将杂质移入母液中，得到N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸的晶体。该方法适用于工业生产，可以高产高效地获得高质量的N2-(1(S)-乙氧羰基-3-苯基丙基)-N6-三氟乙酰-L-赖氨酸。
• PREPARATION METHOD OF HIGH-OPTICAL PURITY N2-[1-(S)-ETHOXYCARBONYL-3-PHENYLPROPYL]-N6-TRIFLUOROACETYL-L-LYSINE
  申请人：Que Limin

  公开号：US20130178651A1

  公开（公告）日：2013-07-11

  Disclosed is a preparation method of high-optical purity N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine. The method includes: adding crude N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine to one or more organic solvents, and then reacting with an organic acid to form a salt, which is precipitated, thereby achieving the purpose of separation and purification; next, adding the obtained solid or mother concentrate into deionized water, and then adding an inorganic base or an organic base for basification, so as to adjust the pH value, removing the organic acid, filtering, washing and drying, to obtain the high-optical purity N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine, where the molar ratio of 1S-isomer to 1R-isomer is equal to or greater than 99:1.

  本发明公开了一种高光学纯度N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸的制备方法。该方法包括：将粗N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸加入一个或多个有机溶剂中，然后与有机酸反应形成盐，沉淀，从而达到分离和纯化的目的；接下来，将获得的固体或母液加入去离子水中，然后加入无机碱或有机碱进行碱化，以调节pH值，去除有机酸，过滤，洗涤和干燥，以获得高光学纯度N2-[1-(S)-乙氧羰基-3-苯基丙基]-N6-三氟乙酰-L-赖氨酸，其中1S-异构体与1R-异构体的摩尔比为99：1或更大。