Rapid multigram scale end-to-end continuous flow synthesis of sulfonylurea anti-diabetes drugs: Gliclazide, chlorpropamide and tolbutamide

Herein we report multigram scale robust, efficient, and safe end-to-end continuous flow processes for the diabetes sulfonylurea drugs gliclazide, chlorpropamide and tolbutamide. The drugs were prepared via the treatment of an amine with a haloformate affording carbamate which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was afforded in 87 % yield within 2.5 min total residence time with 26 g/h throughput; 0.2 Kg of the drug was produced in 8 h of running the system continuously. Chlorpropamide and tolbutamide were both afforded in 94 % yield within 1 min residence time with 184-188 g/h throughput; 1.4-1.5 Kg of the drugs was produced in 8 h of running the system continuously. N-substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.