Telescoped Approach to Aryl Hydroxymethylation in the Synthesis of a Key Pharmaceutical Intermediate

Abstract

An efficient synthetic approach leading to introduction of the hydroxymethyl group to an aryl moiety via combination of the Bouveault formylation and hydride reduction has been optimized using a rational, mechanistic-based approach. This approach enabled telescoping of the two steps into a single efficient process, readily amenable to scaleup.

Ru-Catalyzed Regioselective Direct Hydroxymethylation of (Hetero)Arenes via C–H Activation

“…Furthermore, the CH 2 OH group can be readily manipulated and converted into other functional groups allowing for the use of numerous synthetic protocols. Therefore, over the past few decades, hydroxymethylation has been a prominent research topic in drug discovery, material science, and the chemical industry . Among the various hydroxy­methylation reactions, a radical pathway has displayed encouraging versatility for the preparation of benzylalcohol and pyridylalcohol.…”

Leveraging an Industrial–Academic Partnership To Optimize Small Molecule Process Development within the Pharmaceutical Industry

“…Telescoped Approach to Aryl Hydroxymethylation in the Synthesis of a Key Pharmaceutical Intermediate. 2 The synthetic route to produce benzyl alcohol 1, an important pharmaceutical intermediate for production of edivoxetine hydrochloride has been developed by UCC using a rational, mechanistic-based approach (Scheme 1). This approach enabled telescoping of two synthetic steps, a Bouveault formylation and hydride reduction, into a single efficient process which is readily amenable to large scale manufacture.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…Heating of either one gives the monomeric species, but this can quickly repolymerize giving rise to blockages. There are also thermal issues (215).…”