新酶抑制剂他唑巴坦的合成  

SYNTHESIS OF A NOVEL β-LACTAMASE INHIBITOR TAZOBACTAM

作　　者：陆导仁[1] 崔峰波[1] 庞丹梅 徐月爱 褚敏[1] 王枫 单达先[1] 

机构地区：[1]浙江医科大学有机化学教研室

出　　处：《浙江医科大学学报》1997年第2期52-56,共5页

基　　金：浙江省分析测试基金;江西江中制药厂资助

摘　　要：以6-氨基青霉烷酸为原料，经10步反应合成了他唑巴坦钠。6－APA经重氮化、溴化转变为6α－溴代青霉烷酸（1），在二苯腙存在下用过氧醋酸氧化一步生成6－α溴代青霉亚砜酸二苯甲酯（2），再以锌粉还原得6，6-二氢青霉亚砜酸二苯甲酯（3），（3）与2-巯基苯骈噻唑共热得氮杂环丁酮二硫化物（4），（4）用无水氯化铜反应得2β-氯甲基青霉烷酸二苯甲酯（5），（5）在DMF中与叠氮化钠作用得混合物（6），（6）以高锰酸钾氧化后生成物用分级结晶分离出2β-叠氮甲基青霉砜酸二苯甲酯（7a），后者与乙炔环加成生成他唑巴坦二苯甲酯（8），接着用间-甲酚脱羧基保护基而得到他唑巴坦（9），最后以异辛酸钠成盐处理而得目的物（10）他唑巴坦钠。A method of synthesizing of tazobactam is described in the paper. 6-aminopenicillanic acid (6-APA)was c0nverted to 6a-bromopenicillanic acid which was oxidized with peracetic acid in the presence of benzophenone hydrazone and gave benzhydryl(BH) 6α- bromopenicillanate-1-oxide in one step, and reduction with zinc gave the 6, 6 -dihydropenicillanate-1-oxide. The unsymmetrical azetidinone disulfide was obtained by heating with 2-mercaptobenzothiazole, and reaction with anhydrous cupric chloride gave 2β-chloromet hylpenam. Reaction with sodium azide in aqueous DMF gave a mixture of 2β-azidomethylpenam and 3β-azidocepham. Oxidation with potassium permanganate gave a mixture of 2β-azidomethylpenam-1, 1-dioxide, and 3β-azidocepham-1, 1-dioxide, which was easily separated by fractional crystallization. Benzhydryl ester of 2β-azidomethylpenam-1, 1-dioxide was reacted with acetylene at 80~ 85℃ and gave tazobactam diphenylmethyl ester (8). The deprotection of the BH ester(8) in m-cresol afforded tazobactam (9) which was treated with sodium 2-ethylhexanoate to obtain sodium tazobactam (10) as a white powder.

关 键 词：酶抑制剂 他唑巴坦钠 化学全成 抗生素 合成 

分 类 号：TQ465.1[化学工程—制药化工]