Development of Large-Scale Synthesis using a Palladium-Catalyzed Cross-Coupling Reaction for an Isoquinolone Derivative as a Potent DPP-4 Inhibitor
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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DOI：
10.1021/op5000072
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发表时间：
2014-02
影响因子：
3.4
通讯作者：
Misayo Sera;M. Yamashita;Yuujirou Ono;T. Tabata;Eigo Muto;Takashi Ouchi;H. Tawada
中科院分区：
文献类型：
--
作者：
Misayo Sera;M. Yamashita;Yuujirou Ono;T. Tabata;Eigo Muto;Takashi Ouchi;H. Tawada
本发明描述了一种新型DPP-4抑制剂1的有效大规模合成，所述DPP-4抑制剂1是在3-位上带有氨甲基且在6-位上带有氨基甲酰基甲氧基的异喹诺酮衍生物。我们开发了一种有效和方便的合成方法，利用一个关键的中间体，在3-位上有一个氰基，在6-位上有一个卤素原子。以6-溴异喹啉酮和叔丁醇钠为原料，在Pd（OAc）2和rac-BINAP催化下，通过交叉偶联反应在异喹啉酮的6位插入氧原子，得到6-叔丁氧基异喹啉酮。在阮内镍存在下氢化3-位的氰基，得到化合物1的氨甲基部分。该合成路线已成功地应用于多公斤规模的制剂，产率高，质量好。
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.