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

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• 作者：Milo拧 Ru啪i膷 ; Anica Pe膷avar ; Darja Prudi膷 ; David Kralj ; Corina Scriban ; Antonio Zanotti-Gerosa
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：July 20, 2012
• 年：2012
• 卷：16
• 期：7
• 页码：1293-1300
• 全文大小：327K
• 年卷期：v.16,no.7(July 20, 2012)
• ISSN：1520-586X

文摘

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鈥? equiv of H₃PO₄, 60 掳C, 20 bar H₂, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).