Development of Large-Scale Synthesis using a Palladium-Catalyzed Cross-Coupling Reaction for an Isoquinolone Derivative as a Potent DPP-4 Inhibitor

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• 作者：Misayo Sera ; Makoto Yamashita ; Yuujirou Ono ; Takashi Tabata ; Eigo Muto ; Takashi Ouchi ; Hiroyuki Tawada
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：March 21, 2014
• 年：2014
• 卷：18
• 期：3
• 页码：446-453
• 全文大小：377K
• 年卷期：v.18,no.3(March 21, 2014)
• ISSN：1520-586X

文摘

An efficient large-scale synthesis of a novel DPP-4 inhibitor 1, an isoquinolone derivative bearing an aminomethyl group at the 3-position and carbamoylmethoxy group at the 6-position, is described. We have developed an effective and convenient synthetic method utilizing a key intermediate possessing a cyano group at the 3-position and a halogen atom at the 6-position. The key reaction, the insertion of an oxygen atom at the 6-position of isoquinolone was achieved by a cross-coupling reaction using 6-bromoisoquinolone and sodium tert-butoxide (^tBuONa) in the presence of Pd(OAc)₂ and rac-BINAP as a catalyst to afford 6-tert-butoxyisoquinolone in good yield. The cyano group at the 3-position was hydrogenated in the presence of Raney nickel to give the aminomethyl moiety of compound 1. The synthetic route has been successfully applied to multikilogram-scale preparations in good yield and high quality.