(R,S)-3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one | 1246853-48-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R,S)-3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one
• 英文别名: 4S-phenyl-3-[(5RS)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3 oxazolidin 2-one；(4S)-3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
• CAS: 1246853-48-4
• 化学式: C₂₀H₂₀FNO₄
• 分子量: 357.382
• InChiKey: AVAZNWOHQJYCEL-QNSVNVJESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R,S)-3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one 在 4-二甲氨基吡啶 、 Candida antarctica B lipase 、 三乙胺 、 磷脂酶B 作用下， 以 aq. phosphate buffer 、 二氯甲烷 、 异丙醚 、 甲苯 为溶剂， 反应 244.0h， 生成 (S)-3-((R)-5-(4-氟苯基)-5-羟基)-4-苯基恶唑烷-2-酮
  参考文献：
  名称：

  Lipase catalyzed kinetic resolution for the production of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one: An intermediate for the synthesis of ezetimibe

  摘要：

  Efficient enzymatic methods were developed for the synthesis of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one, by transesterification of (RS)-3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidin-2-one [(R,S)-FOP alcohol] and hydrolysis of (RS)-1-(4-fluorophenyl)-5-oxo-5-[(S)-2-oxo-4-phenyloxazolidin-3-yl] pentyl acetate [(R,S)-FOP acetate] using lipase as enzyme source. The synthesized S-diastereomer is an intermediate for the potent cholesterol absorption inhibitor, ezetimibe. Among various lipases tried, Candida rugosa lipase in diisopropyl ether was best for both the reactions. Vinyl acetate was found as suitable acyl donor in transesterification reaction. A higher amount of enzyme (500 mg) was required for the transesterification of 10 mM substrate; it may be due to the enzyme denaturation by acetaldehyde formed in the reaction. The ester hydrolysis reaction worked well, excellent conversion and de were obtained at 40 degrees C, pH 7. The 300 mg enzyme hydrolyzed 120 mg (R,S)-FOP acetate with 50% conversion and 99.5% de. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.molcatb.2012.08.014
• 作为产物：
  描述：

  在 磷脂酶B 作用下， 以 aq. phosphate buffer 、 异丙醚 为溶剂， 反应 120.0h， 生成 (R,S)-3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one
  参考文献：
  名称：

  Lipase catalyzed kinetic resolution for the production of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one: An intermediate for the synthesis of ezetimibe

  摘要：

  Efficient enzymatic methods were developed for the synthesis of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one, by transesterification of (RS)-3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidin-2-one [(R,S)-FOP alcohol] and hydrolysis of (RS)-1-(4-fluorophenyl)-5-oxo-5-[(S)-2-oxo-4-phenyloxazolidin-3-yl] pentyl acetate [(R,S)-FOP acetate] using lipase as enzyme source. The synthesized S-diastereomer is an intermediate for the potent cholesterol absorption inhibitor, ezetimibe. Among various lipases tried, Candida rugosa lipase in diisopropyl ether was best for both the reactions. Vinyl acetate was found as suitable acyl donor in transesterification reaction. A higher amount of enzyme (500 mg) was required for the transesterification of 10 mM substrate; it may be due to the enzyme denaturation by acetaldehyde formed in the reaction. The ester hydrolysis reaction worked well, excellent conversion and de were obtained at 40 degrees C, pH 7. The 300 mg enzyme hydrolyzed 120 mg (R,S)-FOP acetate with 50% conversion and 99.5% de. (C) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.molcatb.2012.08.014

文献信息

• Process For Production Of 4-Biphenylyazetidin-2-Ones
  申请人：Lee Peter

  公开号：US20080287663A1

  公开（公告）日：2008-11-20

  The present invention relates to processes for the production of 4-biphenylylazetidin-2-one derivatives of formula

  本发明涉及生产4-联苯基氮杂环己烷-2-酮衍生物的方法。
• [EN] KINETIC RESOLUTION OF (4S)-4-PHENYL-3-[5(RS)-(4-FLUOROPHENYL)-5-HYDROXYPENTANOYL] -1,3 OXAZOLIDIN 2-ONE TO (5S) ISOMER VIA LIPASE CATALYZED ENANTIOSELECTIVE ESTERIFICATION OF THE (5R) ISOMER<br/>[FR] RÉSOLUTION CINÉTIQUE DE (4S)-4-PHÉNYL-3-[5(RS)-(4-FLUOROPHÉNYL)-5-HYDROXYPENTANOYL]-1,3-OXAZOLIDIN-2-ONE EN ISOMÈRE (5S) PAR ESTÉRIFICATION ÉNANTIOSÉLECTIVE CATALYSÉE PAR UNE LIPASE DE L'ISOMÈRE (5R)
  申请人：LUPIN LTD

  公开号：WO2010113184A1

  公开（公告）日：2010-10-07

  A process for synthesis of 4S-phenyl -3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one comprising resolution of 4S-phenyl -3-[(5RS)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one by selective esterification of 4S-phenyl -3-[(5R)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one using appropriate esterification reagent in an organic solvent in presence of Lipase enzyme at a temperature ranging from 0° to 100°C, and further isolation.

  一种合成4S-苯基-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-1,3-噁唑烷-2-酮的方法，包括通过在有机溶剂中，在0°C至100°C的温度范围内，利用适当的酯化试剂在脂肪酶酶存在下，通过选择性酯化4S-苯基-3-[(5R)-5-(4-氟苯基)-5-羟基戊酰基]-1,3-噁唑烷-2-酮来实现4S-苯基-3-[(5RS)-5-(4-氟苯基)-5-羟基戊酰基]-1,3-噁唑烷-2-酮的分离。
• KETOREDUCTASE POLYPEPTIDES FOR THE STEREOSELECTIVE PRODUCTION OF (4S)-3-[(5S)-5-(4-FLUOROPHENYL)-5-HYDROXYPENTANOYL]-4-PHENYL-1,3-OXAZOLIDIN-2-ONE
  申请人：Mundorff Emily

  公开号：US20100062499A1

  公开（公告）日：2010-03-11

  The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme including the capability of reducing 5-((4S)-2-oxo-4-phenyl(1,3-oxazolidin-3-yl))-1-(4-fluorophenyl)pentane-1,5-dione to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize the intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one in a process for making Ezetimibe.

  本公开提供了经过改良的酮还原酶酶，其性能比自然存在的野生型酮还原酶酶更好，包括还原5-((4S)-2-氧代-4-苯基(1,3-噁唑啉-3-基))-1-(4-氟苯基)戊-1,5-二酮为(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑啉-2-酮的能力。还提供了编码改良的酮还原酶酶的多核苷酸，能够表达改良的酮还原酶酶的宿主细胞，以及使用改良的酮还原酶酶合成中间体(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑啉-2-酮的方法，用于制备依折麦布。
• POLYNUCLEOTIDES ENCODING RECOMBINANT KETOREDUCTASE POLYPEPTIDES
  申请人：Mundorff Emily

  公开号：US20120322136A1

  公开（公告）日：2012-12-20

  The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme including the capability of reducing 5-((4S)-2-oxo-4-phenyl(1,3-oxazolidin-3-yl))-1-(4-fluorophenyl)pentane-1,5-dione to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize the intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one in a process for making Ezetimibe.

  本公开提供了经过改良的酮还原酶酶，其性能优于天然野生型酮还原酶酶，包括能够将5-((4S)-2-氧代-4-苯基(1,3-噁唑啉-3-基))-1-(4-氟苯基)戊-1,5-二酮还原为(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑啉-2-酮的能力。此外，还提供了编码改良的酮还原酶酶的多核苷酸，能够表达改良的酮还原酶酶的宿主细胞，以及使用改良的酮还原酶酶合成中间体(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑啉-2-酮的方法，用于制造依折麦布。
• ENGINEERED KETOREDUCTASE POLYPEPTIDES
  申请人：CODEXIS, INC.

  公开号：US20130210098A1

  公开（公告）日：2013-08-15

  The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme including the capability of reducing 5-((4S)-2-oxo-4-phenyl(1,3-oxazolidin-3-yl))-1-(4-fluorophenyl)pentane-1,5-dione to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize the intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one in a process for making Ezetimibe.

  本公开提供了经过改造的酮还原酶酶，其性能优于自然存在的野生型酮还原酶酶，包括将5-((4S)-2-氧代-4-苯基(1,3-噁唑烷-3-基))-1-(4-氟苯基)戊-1,5-二酮还原为(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑烷-2-酮的能力。还提供了编码经过改造的酮还原酶酶的多核苷酸、能够表达经过改造的酮还原酶酶的宿主细胞，以及使用经过改造的酮还原酶酶合成中间体(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-噁唑烷-2-酮的方法，用于制备依折麦布。