ËÄÉ«AV

A more sustainable process for the synthesis of the long-​acting muscarinic acetylcholine antagonist umeclidinium bromide is described.ÌýSpecifically, we report the synthesis of ethyl 1-​(2-​chloroethyl)​-​4-​piperidinecarboxylate, a key intermediate in the preparation of umeclidinium bromide, in good yields using triethylamine, as well as the identification and characterization of the by-​product formed in this reaction.ÌýThis new method of synthesis leads to an improvement in yield over that of previously reported protocols using potassium carbonate as base (65.6 % versus 38.6 %)​.ÌýMoreover, in the final synthetic step of the process to obtain umeclidinium bromide, we were able to replace the use of toxic solvents (acetonitrile​/chloroform) with water. The use of this green solvent allowed precipitation of the active pharmaceutical ingredient (API) from the reaction medium with high purity and in high yield.ÌýOverall, we have developed a more efficient and environmentally friendly process for the synthesis of the umeclidinium bromide API with a higher overall yield (37.8 % versus previously reported overall yield of 9.7 %)​.

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