Direct amidation of acids in a screw reactor for the continuous flow synthesis of amides.

A simple and efficient solvent-free protocol for continuous flow synthesis of amides at room temperature is developed using easily available starting materials. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was used as the reagent for the formation of an amide bond without using any metal catalyst or additives. A jacketed screw reactor when operated over a residence time of 30 300 s helped achieve almost complete conversion. This approach is extended for the synthesis of 36 derivatives and 2 bioactive molecules using different substrates having different aliphatic mono and di-acids as well as aromatic acids, including aromatic hetero-acid compounds and phenyl hydrazine. The target amide was scaled up to 100 g with an average 90% yield.

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 3rd 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.