β-内酰胺酶抑制剂——他唑巴坦酸的合成

摘要

他唑巴坦是新颍的β-内酰胺酶抑制剂，以6-APA为原料，经重氮化、溴代等反应制得关键中间体青霉烷酸二苯甲酯-1α-氧化物(4)，与2-巯基苯并噻唑缩合后，经氯代得2β-氯甲基-2α-甲基-6,6-二氢青霉烷酸二苯甲酯(6)，该中间体再经缩合、氧化等步骤得到他唑巴坦酸，总收率16.3%。该法原料易得，反应条件温和，后处理方便，适合大量制备他唑巴坦酸。%A convenient synthesis of tazobactam,a new β-lactamase inhibitor,was described starting with 6-aminopenicillanic acid,which was converted to benzhydryl penicillanate 1α-oxide via diazotization,bromination,oxidation with activated magnesium dioxide in the presence of benzophenone hydrazone and reductive debromination.Then heating with 2-mercaptobenzothiazole,chlorination with sulphuryl chloride gave the 2 β-chloromethylpenam.The reaction with 1H-1,2,3-triazole,oxidation with potassium permanganate gave benzhydryl 2β-〔(1,2,3-triazol-1-yl)methyl〕-2α-methylpenam-3α-carboxylic acid 1,1-dioxide.The deprotection by m-cresol gave tazobactam.The process has the advantages of mild reaction,low cast and convenient aftertreatments.The overall yield was 16.3%.