The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin

Abstract

The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-(<i>S</i>)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1<i>S</i>)-(3<i>R</i>)-1-azabicyclo­[2.2.2]­oct-3-yl-3,4-dihydro-1-phenyl-2­(1<i>H</i>)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir­(COD)­Cl]₂-(<i>S</i>)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1–2 equiv of H₃PO₄, 60 °C, 20 bar H₂, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity)