Reduction of ethyl benzoylacetate and selective pvotection of 2-(3-hydroxy-l-phenylpropyl)-4-methylphenol: A new and facile synthesis of tolterodine

Abstract

A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel-Crafts alkylation utilizing FeCl3 center dot 6H(2)O as catalyst lead to the known 2-(3-hydroxy1-phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH with p-toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using p-nitrobenzenesulfonyl chloride facilitates direct substitution of diisopropylamine. After simultaneous deprotection of the tosyl group, optically pure (R)-tolterodine center dot L-tartrate was obtained by resolution using L-tartaric acid with 99.99% purity.