3-环外亚甲基头孢烷酸对硝基苄酯合成工艺的改进

以青霉素G钾盐Ⅰ为原料,与对硝基溴化苄反应生成青霉素G的对硝基苄酯Ⅱ。化合物Ⅱ不需纯化,即行氧化,以过氧化氢代替过氧乙酸,得到4-氧化青霉素G对硝基苄酯(Ⅲ)。在开环反应中,实验了多种酸清除剂,发现用分子筛作催化剂最为简便,可使4-氧化青霉素G对硝基苄酯(Ⅲ)顺利开环生成2-(2-氯亚硫酰基-4-氧-3-苯乙酰氨基氮杂环丁-1-基)-3-甲基-丁-3-烯酸对硝基苄酯(Ⅳ)。化合物Ⅳ不需分离,即与SnCl4反应,闭环生成3-环外亚甲基-7-苯乙酰氨基-5-氧-头孢-2-羧酸-4-硝基苄酯(Ⅴ)。再经还原,得到目标化合物3-环外亚甲基头孢烷酸对硝基苄酯(Ⅵ),总产率34·5%。

Some Improvements on the Synthesis of 3-Exomethylenecepham from Penicillin G

Penicillin G potassium salt(Ⅰ) was reacted with p-nitro benzyl bromide to produce the 4-nitrobenzyl ester of penicillin G acid(Ⅱ).Without purification,4-oxo-penicillin 4-nitro-benzyl ester (Ⅲ) was obtained in an oxidation reaction of compound Ⅱ.Hydrogen peroxide was used instead of peroxyacetic acid.Molecular sieve was found as an effective catalyst among many acid scavengers in the ring-opening reaction of compound Ⅲ and 2-(2-chlorosulfinyl-4-oxo-3-phenylacetylamino-azetidin-1-yl)-3-methylbut-3-enoic acid-4-nitrobenzyl ester (Ⅳ)is produced.Without separation,3-exomethylene-7-phenylacetylamino-5-oxo-cepham-2-carboxylic acid-4-nitrobenzyl ester(Ⅴ) was formed in a cyclization reaction of compound Ⅳ with SnC_4.The goal product 3-exomethylenecepham 4-nitrobenzyl ester(Ⅵ) was obtained after reduction of compound Ⅴ in overall yield of 34.6 %.