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-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-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-(S)-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).
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