泰比培南酯工艺改进  

Process Improvement of Taibipenem Pivoxil

作　　者：沈华良 邓鸿 陈玉涛 项灵辉 林波 Shen Hualiang;Deng Hong;Chen Yutao;Xian Linghui;Lin Bo(Zhejiang HisoarChuannan Pharmaceutical Co.,Ltd., Zhejiang Linhai 317000)

机构地区：[1]浙江海翔川南药业有限公司,浙江临海317000

出　　处：《化工时刊》2019年第8期13-15,48,共4页Chemical Industry Times

摘　　要：本研究改进了泰比培南酯的合成工艺,开发了各中间体、成品的结晶提纯工艺,突破了文献报道的采用柱色谱分离纯化的方法,建立了更适合产业化生产的合成工艺。以(R)-2-((2S,3S)-3-((R)-1-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-氧代氮杂环丁烷-2-基)丙酸(6)为起始原料,经二步缩合、重氮化,用异丙醇升温溶解降温析晶的方法得到(新戊酰氧基)甲基(R)-4-((2R,3S)-3-((R)-1-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-氧代氮杂环丁烷-2-基)-2-重氮-3-氧代戊酸酯(5);酸性条件下脱保护基,以乙酸乙酯溶解,甲苯析晶的方法得(新戊酰氧基)甲基(R)-4-((2R,3S)-3-((R)-1-羟基乙基)-4-氧代氮杂环丁烷-2-基)-2-重氮-3-氧代戊酸酯(4);然后辛酸铑作用下环合、与二苯氧基磷酰氯缩合,以乙酸乙酯良溶剂,加庚烷析晶的方法得(新戊酰氧基)甲基(4R,5R,6S)-3-((二苯氧基磷酰基)氧基)-6-((R)-1-羟基乙基)-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸酯(3);最后与泰比培南酯侧链缩合,以乙酸乙酯溶解,加庚烷析晶的方法得目标产物泰比培南酯(1)。This study used a new synthetic routeto prepare taibipenem pivoxil, Improved preparation process of taibipenem pivoxil. In particular, the crystallization purification process for each intermediate and finished product has been developed, Avoided the method of chromatographic purification reported in the literature. A preparation process suitable for industrial production has been established.(R)-2-((2S,3S)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-oxoazetidin-2-yl)propanoic acid was used as a starting material. After two steps of condensation and diazotization,(5) was obtained by dissolving and crystallization in isopropanol. Deprotection under acidic conditions,(4) was obtained by dissolved in ethyl acetate and crystallized by toluene. Then, it is cyclized under the action of Rhodium caprylate, condensed with diphenoxyphosphoryl chloride, and then (3) was obtained by dissolved in ethyl acetate and crystallized by heptane. Finally, it is condensed with the side chain of taibipenem, dissolved in ethyl acetate, and crystallized by heptane to obtain the target product (1).

关 键 词：泰比培南酯 碳青霉烯类抗生素 化学合成 结晶提纯 

分 类 号：TQ465[化学工程—制药化工]