High yield process study of key intermediate of novel β-lactamase inhibitors in continuous flow microreactors
The continuous flow microreactor is a novel reactor that has gained prominence in recent years due to its notable features of gentleness,exceptional efficiency,and safety.This study aimed to address the issue of bacterial drug resistance and improve the production process of new β-lactamase inhibitors.The key intermediate of β-lactamase inhibitors(S)-5-oxo-2-tert-butoxycarbonylamino-6-dimethylsulfoxide-5-hexenoate benzyl ester(1)was synthesized from N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester(2)by sulfur ylide carburization reaction in a microchannel reactor,and the product was consistent with the target by 1H NMR,13C NMR,and HRMS.In this paper,the effects of base,temperature,flow rate,and equivalent ratio on the reaction were investigated.The results indicated that a yield of up to 95％for the target product could be achieved under the following conditions:using DMSO as the solvent,t-BuONa as the base,and maintaining an equivalent ratio of 1.0∶1.2∶1.2 between compound 2,TMSOI,and t-BuONa.Additionally,the fluoride-propylene coils had an inner diameter of 0.8 mm,while pumps A,B,and C operated at a flow rate of 50 μL·min-1.Furthermore,the total retention time was 26.67 minutes at a constant room temperature.The process conditions were optimized,the reaction rate was significantly accelerated and the reaction yield was increased at the same time for better application in industrial production.
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