(4S)-3-[(2R,5S)-5-(4-氟苯基)-2-[(S)-[(4-氟苯基)氨基](4-羟基苯基)甲基]-5-羟基-1-氧代戊基]-4-苯基-2-恶唑烷酮 | 1185883-40-2

• 物质功能分类: 有机原料 - 杂环化合物
• 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
• 中文名称: (4S)-3-[(2R,5S)-5-(4-氟苯基)-2-[(S)-[(4-氟苯基)氨基](4-羟基苯基)甲基]-5-羟基-1-氧代戊基]-4-苯基-2-恶唑烷酮
• 英文名称: (S)-3-((2R,5S)-5-(4-fluorophenyl)-2-((S)-((4-fluorophenyl)amino)(4-hydroxyphenyl)methyl)-5-hydroxypentanoyl)-4-phenyloxazolidin-2-one
• 英文别名: (4S)-3-[(2R,5S)-2-[(S)-(4-fluoroanilino)-(4-hydroxyphenyl)methyl]-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
• CAS: 1185883-40-2
• 化学式: C₃₃H₃₀F₂N₂O₅
• 分子量: 572.608
• InChiKey: WYMDQBFNYMAMNK-LTXXGDHTSA-N

物化性质

• 沸点：
  799.5±60.0 °C(Predicted)
• 密度：
  1.362±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4S)-3-[(2R,5S)-5-(4-氟苯基)-2-[(S)-[(4-氟苯基)氨基](4-羟基苯基)甲基]-5-羟基-1-氧代戊基]-4-苯基-2-恶唑烷酮 在 N,O-双三甲硅基乙酰胺 、 硫酸 、 四丁基氟化铵 作用下， 以 水 、 异丙醇 、 甲苯 为溶剂， 反应 2.0h， 生成 依泽替米贝
  参考文献：
  名称：

  Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe

  摘要：

  A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.

  DOI：

  10.1021/acs.oprd.9b00024
• 作为产物：
  描述：

  (2R)-2-[(S)-(4-fluoroanilino)-(4-hydroxyphenyl)methyl]-5-(4-fluorophenyl)-1-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione 在 dimethyl sulfide borane 、 (R)-2-甲基-CBS-恶唑硼烷 、 甲醇 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.25h， 以75%的产率得到(4S)-3-[(2R,5S)-5-(4-氟苯基)-2-[(S)-[(4-氟苯基)氨基](4-羟基苯基)甲基]-5-羟基-1-氧代戊基]-4-苯基-2-恶唑烷酮
  参考文献：
  名称：

  [EN] INTERMEDIATES FOR THE PREPARATION OF (3INTERMÉDIAIRES POUR LA PRÉPARATION DE (3R,4S)-1-(4-FLUOROPHÉNYL)-3-[(3S)-3-(4-FLUOROPHÉNYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHÉNYL)-2-AZÉTIDINONE20090903WO0034240A1SCHERING CORP [US]20000615WY1-37YWO2006086562A2MICROBIA INC [US], et al20060817293,294,301,308Y1-37YWO2007119106A2MEDICHEM SA [ES], et al20071025WDY1-37DYWO2007120824A2TEVA PHARMA [IL], et al20071025Win particular claim 34DY1-37DY
  [FR] INTERMÉDIAIRES POUR LA PRÉPARATION DE (3R,4S)-1-(4-FLUOROPHÉNYL)-3-[(3S)-3-(4-FLUOROPHÉNYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHÉNYL)-2-AZÉTIDINONE

  摘要：

  一种制备通式II的(S)-醇噁唑烷酮的方法，其中PG代表氢或羟基保护基，如三甲基硅基、叔丁基二甲基硅基、苄氧羰基、叔丁氧羰基、苄基、苄基甲基或三苄基，其中通式III的酮缩噁唑烷醚，其中PG具有与上述相同的含义，R表示具有1-4个碳原子的直链或支链烷基，如甲基、乙基、异丙基或丁基，或R+R一起表示二价烷基，或用1或2个烷基取代，例如1,2-乙烯、1,2-丙烯、1,2-丁烯、1,3-丙烯或2,2-二甲基-1,3-丙烯，通过在0到100°C温度范围内的水和水溶性溶剂混合物中使用酸性试剂脱保护（阶段A），并且在惰性有机溶剂中在-30到+40°C温度范围内用不对称试剂还原通式IV的得到的酮缩噁唑烷醚，其中PG具有与上述相同的含义（阶段B）。

  公开号：

  WO2009106021A1

文献信息

• INTERMEDIATES FOR THE PREPARATION OF (3R, 4S)-1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE
  申请人：Stepankova Hana

  公开号：US20110046389A1

  公开（公告）日：2011-02-24

  A method for the preparation of (S)-alcohol oxazolidides of general formula II, in which PG represents hydrogen or a hydroxyl protecting group, such as trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, benzhydryl or trityl, in which a ketal oxazolidide of general formula III, where PG has the same meaning as above and R means an alkyl with 1-4 carbon atoms, linear or branched, such as methyl, ethyl, isopropyl or butyl, or R+R together represents a divalent alkyl, or substituted with 1 or 2 alkyl groups, e.g. 1,2-ethylene, 1,2-propylene, 1,2-butylene, 1,3-propylene or 2,2-dimethyl-1,3-propylene, is deprotected by the action of acidic reagents in a mixture of water and a water-miscible solvent in the temperature range of 0 to 100° C. (stage A), and the obtained ketone oxazolidide of general IV, in which PG has the same meaning as above, is reduced with asymmetrical reagents in an inert organic solvent in the temperature range of −30 to +40° C. (stage B).

  一种制备通式II的(S)-醇噁唑烷二酮的方法，其中PG代表氢或羟基保护基，例如三甲基硅基、叔丁基二甲基硅基、苄氧羰基、叔丁氧羰基、苄基、苄基亚甲基或三苄基，其中通式III的酮缩醛噁唑烷二酮，其中PG具有与上述相同的含义，R表示具有1-4个碳原子的直链或支链烷基，例如甲基、乙基、异丙基或丁基，或者R+R一起表示双价烷基，或被1或2个烷基基团取代，例如1,2-乙烯基、1,2-丙烷基、1,2-丁烷基、1,3-丙烷基或2,2-二甲基-1,3-丙烷基，通过在0至100°C的温度范围内的水和水溶性溶剂混合物中用酸性试剂脱保护（阶段A），并且在惰性有机溶剂中在-30至+40°C的温度范围内用不对称试剂还原得到的通式IV的酮缩醛噁唑烷二酮，其中PG具有与上述相同的含义（阶段B）。
• Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe
  作者：Madhava Rao Mannam、Srimurugan Sankareswaran、Venugopal Reddy Gaddam、Senthilkumar Natarajan、Rajasekhara Prasad Kottapalli、Pramod Kumar

  DOI：10.1021/acs.oprd.9b00024

  日期：2019.5.17

  A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.
• [EN] INTERMEDIATES FOR THE PREPARATION OF (3INTERMÉDIAIRES POUR LA PRÉPARATION DE (3R,4S)-1-(4-FLUOROPHÉNYL)-3-[(3S)-3-(4-FLUOROPHÉNYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHÉNYL)-2-AZÉTIDINONE20090903WO0034240A1SCHERING CORP [US]20000615WY1-37YWO2006086562A2MICROBIA INC [US], et al20060817293,294,301,308Y1-37YWO2007119106A2MEDICHEM SA [ES], et al20071025WDY1-37DYWO2007120824A2TEVA PHARMA [IL], et al20071025Win particular claim 34DY1-37DY<br/>[FR] INTERMÉDIAIRES POUR LA PRÉPARATION DE (3R,4S)-1-(4-FLUOROPHÉNYL)-3-[(3S)-3-(4-FLUOROPHÉNYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHÉNYL)-2-AZÉTIDINONE
  申请人：ZENTIVA KS

  公开号：WO2009106021A1

  公开（公告）日：2009-09-03

  A method for the preparation of (S)-alcohol oxazolidides of general formula II, in which PG represents hydrogen or a hydroxyl protecting group, such as trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, benzhydryl or trityl, in which a ketal oxazolidide of general formula III, where PG has the same meaning as above and R means an alkyl with 1-4 carbon atoms, linear or branched, such as methyl, ethyl, isopropyl or butyl, or R+R together represents a divalent alkyl, or substituted with 1 or 2 alkyl groups, e.g. 1,2-ethylene, 1,2-propylene, 1,2-butylene, 1,3-propylene or 2,2-dimethyl-l,3- propylene, is deprotected by the action of acidic reagents in a mixture of water and a water- miscible solvent in the temperature range of 0 to 100 °C (stage A), and the obtained ketone oxazolidide of general IV, in which PG has the same meaning as above, is reduced with asymmetrical reagents in an inert organic solvent in the temperature range of -30 to +40 °C (stage B).

  一种制备通式II的(S)-醇噁唑烷酮的方法，其中PG代表氢或羟基保护基，如三甲基硅基、叔丁基二甲基硅基、苄氧羰基、叔丁氧羰基、苄基、苄基甲基或三苄基，其中通式III的酮缩噁唑烷醚，其中PG具有与上述相同的含义，R表示具有1-4个碳原子的直链或支链烷基，如甲基、乙基、异丙基或丁基，或R+R一起表示二价烷基，或用1或2个烷基取代，例如1,2-乙烯、1,2-丙烯、1,2-丁烯、1,3-丙烯或2,2-二甲基-1,3-丙烯，通过在0到100°C温度范围内的水和水溶性溶剂混合物中使用酸性试剂脱保护（阶段A），并且在惰性有机溶剂中在-30到+40°C温度范围内用不对称试剂还原通式IV的得到的酮缩噁唑烷醚，其中PG具有与上述相同的含义（阶段B）。