Hg(OAc)2/1,2,3-triazole-mediated efficient synthesis of Tazobactam

A short and simple synthesis of 2 beta-(1,2,3-Triazol-1-yl) methyl-2 alpha-methyl-6,6-dihydropenicillin-3 alpha-carboxylic acid diphenylmethyl ester (7), on multi-gram scale, is described. Compound 7 is the key intermediate for the synthesis of tazobactam. Mercury (II) acetate and azobisisobutyronitrile (AIBN) were used to optimize the direct substitution of 1,2,3-triazole (to avoid hazardous sodium azide and extremely flammable/asphyxiant acetylene gas) to the commercially available starting material benzhydryl 2-((R)-2-(2-(benzo[d]thiazol-2-yl)disulfanyl)-4-oxoaze. Efficient recovery of 1,2,3-triazole was attained. A plausible mechanism for synthesis of 7 is presented. The target tazobactam was obtained with 99.69% purity by HPLC without column chromatographic purification, and with 49% overall yield from 7 as the starting material. [GRAPHICS] .

Automated summary

This article describes a short and simple method for the synthesis of 2 beta-(1,2,3-Triazol-1-yl) methyl-2 alpha-methyl-6,6-dihydropenicillin-3 alpha-carboxylic acid diphenylmethyl ester (7) on a multi-gram scale. The method avoids the use of hazardous sodium azide and extremely flammable/asphyxiant acetylene gas. By optimizing the direct substitution reaction using mercury (II) acetate and azobisisobutyronitrile, the key intermediate 1,2,3-triazole was efficiently recovered. The target compound tazobactam was obtained with high purity and overall yield of 49%.