Process Research on the Asymmetric Hydrogenation of a Benzophenone for Developing the Manufacturing Process of the Squalene Synthase Inhibitor TAK-475

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• 作者：Mitsutaka Goto ; Takahiro Konishi ; Shinji Kawaguchi ; Masatoshi Yamada ; Toshiaki Nagata ; Mitsuhisa Yamano
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：September 16, 2011
• 年：2011
• 卷：15
• 期：5
• 页码：1178-1184
• 全文大小：901K
• 年卷期：v.15,no.5(September 16, 2011)
• ISSN：1520-586X

文摘

A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 (1), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori鈥檚 ruthenium precatalyst of the type [RuCl₂(diphosphine)(diamine)]. We focused on tuning of the chiral diphosphine, and have discovered a novel ligand, DADMP-BINAP (18c), for the catalyst that has allowed reduction of the operating pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure (<1 MPa) with sufficient enantioselectivity, and the result enabled us to successfully obtain enantiomerically pure 8 on a multikilogram scale.