Multi-Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3(rd) step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.

Automated summary

An advanced continuous flow synthesis method was reported for the first time, achieving the synthesis of the Leishmaniasis drug miltefosine from simple starting materials through four chemical transformation steps. In laboratory scale, miltefosine was obtained in 58% overall yield in just 34 minutes, which is sufficient to treat 4800 patients per day.