Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides

Abstract

The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.

Multistep Continuous Flow Synthesis of Stavudine

“…The precipitate formation presents no challenges in a batch reactor; however on translating this synthesis into a continuous flow process, reactor clogging is bound to be observed, which will lead to pressure buildup, equipment failure, and disruption of the flow process. Nonetheless, a few groups have reported such precipitate-forming reactions in flow albeit with challenges. − In this reaction, we employed ultrasonication − to circumvent any issues that would be caused by the formation of the ammonium chloride salt.…”