Chemical Industry and Engineering Progress ›› 2020, Vol. 39 ›› Issue (3): 1129-1136.DOI: 10.16085/j.issn.1000-6613.2019-1075

• Biochemical and pharmaceutical engineering • Previous Articles     Next Articles

Synthesis of meropenem side chain intermediates with high yield

Bin LI1,2,3(),Jixing SHI1,Shuang JIANG1,2(),Tianyong ZHANG1,2,3(),Xiaokang LI1,Minghao ZHOU1,Yiwei LIU1   

  1. 1.Tianjin Key Laboratory of Applied Catalysis Science and Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300354, China
    2.Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Tianjin 300072, China
    3.Tianjin Engineering Research Center of Functional Fine Chemicals, Tianjin 300354, China
  • Received:2019-07-08 Online:2020-04-03 Published:2020-03-05
  • Contact: Shuang JIANG,Tianyong ZHANG

高收率美罗培南侧链中间体的合成

李彬1,2,3(),史继星1,姜爽1,2(),张天永1,2,3(),李小康1,周明浩1,刘艺炜1   

  1. 1.天津大学化工学院,天津市应用催化科学与工程重点实验室,天津 300354
    2.天津化学化工协同创新中心,天津 300072
    3.天津市功能精细化学品技术工程中心,天津 300354
  • 通讯作者: 姜爽,张天永
  • 作者简介:李彬(1982—),男,博士,副教授,博士生导师。E-mail:libin@tju.edu.cn
  • 基金资助:
    天津市自然科学基金(16JCYBJC20800);天津市科技创新平台计划(14TXGCCX00017)

Abstract:

Due to the shortcomings of the present preparation process of meropenem side chain intermediate (thiol lactone), such as high production cost, complex reaction route, many side reactions, low yield and crude product purity, a facile method for preparing thiol lactone was developed. It is prepared with one-pot method by activation of carboxyl group and hydroxyl group in M1 [(2S,4R)-2-carboxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine)], sulfurization to cyclization and phase transfer catalysis. Thiol lactone was subjected to a ring opening reaction to obtain meropenem side chain. Isopropyl chloroformate, MsCl(methylsulfonyl chloride), triethylamine(TEA), Na2S·9H2O and three types of phase transfer catalysts (polyethylene glycols (PEG), quaternary ammonium salts and crown ethers) were used. The effects of the molar ratio of the feed on the yield and product purity of the thiol lactone were studied. The addition of a phase transfer catalyst during the preparation of thiol lactone can both facilitate the reaction and increase the purity and yield of the product. When the molar ratio of M1∶isopropyl chloroformate∶MsCl∶Na2S·9H2O∶CTEA(TEA added during carboxyl activation)∶HTEA(TEA added during hydroxyl activation)∶catalyst was 1∶1∶1.3∶1.3∶1.3∶1.2∶(0.07—0.16), carboxyl activation and hydroxyl activation temperatures were -30—-17℃, the related reaction time was 15 min and 30min, respectively, the reaction temperature of vulcanization into a ring increased from -30—-17℃ to 0℃ in 30min for the reaction time, and then the reflux reaction of the separated organic phase in the temperature of 40℃ with a reaction time of 165min, the yield of thiol lactone was 98.4% with the purity of 98.3%.

Key words: meropenem, intermediate, one-pot method, phase transfer catalysis, thiol lactone

摘要:

针对现有美罗培南侧链中间体(硫醇内酯)制备工艺成本较高、反应路线复杂、副反应多、收率及粗品纯度较低等缺点,研究了一种简便制备硫醇内酯的方法,通过将M1[(2S,4R)-2-羧基-1-(4-硝基苄氧羰基)吡咯烷)]羧基活化、羟基活化和硫化成环合为一锅法以及添加相转移催化剂法制备硫醇内酯,再进行开环反应得到美罗培南侧链。研究了氯甲酸异丙酯、甲基磺酰氯(MsCl)、三乙胺(TEA)、Na2S·9H2O和三类相转移催化剂[聚乙二醇类(PEG)、季铵盐类和冠醚类]的投料摩尔比对制备硫醇内酯收率和纯度的影响。制备硫醇内酯时加入相转移催化剂既可以加快反应的速率,又可以提高产品纯度及收率。nM1n氯甲酸异丙酯nMsClnNa2S·9H2OnCTEA(羧基活化时所加TEA)nHTEA(羟基活化时所加TEA)n催化剂为1∶1∶1.3∶1.3∶1.3∶1.2∶(0.07~0.16),羧基活化和羟基活化反应温度均为-30~-17℃,羧基活化和羟基活化反应时间分别为15min、30min;硫化成环从-30~-17℃升温到0℃,升温反应时间为30min;回流温度为40℃,回流时间165min。硫醇内酯收率为98.4%,纯度为98.3%。

关键词: 美罗培南, 中间体, 一锅法, 相转移催化, 硫醇内酯

CLC Number: 

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