Abstract
A multigram-scale robust, efficient, and safe end-to-end continuous-flow process for
the diabetes sulfonylurea drugs gliclazide, chlorpropamide, and tolbutamide is reported.
The drugs were prepared by the treatment of an amine with a haloformate affording
carbamate, which was subsequently treated with a sulfonamide to afford sulfonylurea.
Gliclazide was obtained in 87% yield within 2.5 minutes total residence time with
26 g/h throughput; 0.2 kg of the drug was produced in 8 hours of running the system
continuously. Chlorpropamide and tolbutamide were both obtained in 94% yield within
1 minute residence time with 184–188 g/h throughput; 1.4–1.5 kg of the drugs was produced
in 8 hours of running the system continuously. N-Substituted carbamates were used
as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea
moiety.
Key words
chlorpropamide - gliclazide - diabetes - end-to-end continuous flow - sulfonylurea
- and tolbutamide
