回归正交优化头孢菌素中间体7-DTMC合成工艺  

Optimization of Synthetic Technology of Cephalosporins Intermediate 7-DTMC by Orthogonal Regression Design

作　　者：赵德明[1] 余继路[1] 张建庭[1] 金宁人[1] 

机构地区：[1]浙江工业大学化学工程与材料学院,浙江杭州310032

出　　处：《广州化工》2011年第1期6-9,24,共5页GuangZhou Chemical Industry

基　　金：中国博士后科学基金资助项目(No.20100471716);浙江省自然科学基金资助项目(No.Y5100075)

摘　　要：7-对甲苯硫亚氨基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧基酸二苯甲酯(7-DTMC)是合成甲氧头孢菌素关键中间体7β-氨基-7α-甲氧基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧酸二苯甲酯(7-MAC)的重要中间体。采用7β-氨基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧酸二苯酯(7-DAMC)为原料,以对甲基苯硫氯(TSC)为氨基保护试剂,二氯甲烷为溶剂,1,2-环氧丙烷为催化剂和4分子筛为脱水剂剂反应制备得到7-DTMC。本文主要探讨了反应温度、反应时间、物料配比、催化剂用量等因素对反应的影响,并通过二次回归建立了数学模型,确定了合成7-DTMC的最佳工艺条件。在此基础上合成的产品收率89.71%,HPLC纯度99.34%。产品结构经1H-NMR和FT-IR表征确认。Diphenylmethyl 7-（4-tolysulfenylimino）-3-[（1-methyl-1H-tetrazo-5-yl） thiomethyl]-3-cephem-4-carboxylate（7-DTMC） was the important intermediates for the synthesis of 7α-Methoxy-7β-Amino-3-[（1-Methyl-1-H-tetrazo-5-yl） thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester（7-MAC） and 7-MAC was the key intermediate for preapring 7α-methoxycephalosporins.7-DTMC was synthesized by using 7β-amino-3-[（1-methyl-1-H-tetrazo-5-yl） thiomethyl]-3-cephem-4-carboxylate（7-DAMC） and 4-tolysulfenyl chloride（TSC） as the materials,the dichloromethane used as the solvent,the 1,2-propylene oxide as the catalyst.The main four influential factors of nucleophilic substitution reaction such as the molar ratio,the amount of catalysis,the reaction time and temperature were studied.By using orthogonal quadratic regression design,the mathematic model was established and the optimization experimental conditions were obtained.The yield of 7-DTMC was 89.71%,the purity of HPLC was 99.34%,and its molecular structure was exactly identified by 1H-NMR and FT-IR.

关 键 词：7-对甲苯硫亚氨基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧基酸二苯甲酯 7β-氨基-7α-甲氧基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧酸二苯甲酯 7β-氨基-3-(1-甲基-1H-四唑-5-硫甲基)-3-头孢烯-4-羧酸二苯酯 对甲基苯硫氯 二次回归 

分 类 号：TQ465.1[化学工程—制药化工]