他唑巴坦合成中1,3-偶极环加成反应的研究

以 6 氨基青霉烷酸为原料 ,经多步化学反应合成了他唑巴坦并重点研究了其中的 1,3 偶极环加成反应。首先由 6 氨基青霉烷酸通过重氮化 -溴化、氧化、保护、还原去溴得到了青霉烷酸二苯甲酯亚砜 ,每步反应的收率都在 90 %以上 ,然后与 2 巯基苯并噻唑反应得双硫开环物 ,收率为 99% ,再分别与无水氯化铜、叠氮化钠、高锰酸钾反应得到 2 β 叠氮甲基青霉烷酸二苯甲酯二氧化物 ,三步总收率为 30 % ,接着以醋酸乙烯作为环合试剂进行 1,3 偶极环加成反应制得 2 β 三唑甲基青霉烷酸二苯甲酯二氧化物 ,收率为 70 % ,最后经间甲酚脱保护得到了他唑巴坦 ,收率为 6 3%。整个反应经中试放大 ,总收率达 8.0 %以上

Study of 1,3-Dipolar Cycloaddition in the Synthesis of Tazobactam

Tazobactam was obtained from 6 aminopenicillanic acid through multistep reactions.The 1,3 dipolar cycloaddition was studied emphatically.Firstly,6 aminopenicillanic acid was converted to benzhydryl penicillanate 1 oxide through diazotization bromination,oxidation,protection and reductive dehalogenation and the yield of each step was over 90%.Then 2 mercaptobenzothiazole was used to form the unsym azetidinone disulfide in 99% yield.Subsequently,anhydrous copper chloride,sodium azide and potassium permanganate were used separately to obtain benzhydryl 2 β azidomethylpenicillanate 1,1 dioxide in 30% overall yield.And then vinyl acetate was employed as reactant in the 1,3 dipolar cycloaddition for producing benzhydryl 2 β triazolmethylpenicillanate 1,1 dioxide in 70% yield.Finally,tazobactam was synthesized after deprotection using m cresol and the yield was 63%.The total yield of pilot scale was up to 8.0%.