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One-Pot Racemization Process of 1‑Phenyl-1,2,3,4-tetrahydroisoquinoline: A Key Intermediate for the Antimuscarinic Agent Solifenacin

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journal contribution
posted on 2016-02-19, 17:54 authored by Cristiano Bolchi, Marco Pallavicini, Laura Fumagalli, Valentina Straniero, Ermanno Valoti
(S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N-chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d-(−)-tartaric acid obtaining (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the R enriched form. This was racemized by the same one-pot process and resolved by d-(−)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4-tetrahydroisoquinoline can be industrially useful to recycle the waste R enantiomer resulting from the classical resolution used to obtain the S enantiomer on a large scale.