Scalable Synthesis of a Nonracemic 伪-Arylpropionic Acid via Ketene Desymmetrization for a Glucokinase Activator

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• 作者：Takafumi Yamagami ; Noriaki Moriyama ; Masahiro Kyuhara ; Atsushi Moroda ; Takeshi Uemura ; Hiroaki Matsumae ; Yasunori Moritani ; Isao Inoue
• 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：437-445
• 全文大小：402K
• 年卷期：v.18,no.3(March 21, 2014)
• ISSN：1520-586X

文摘

Process research and development for a synthesis of the chiral carboxylic acid (R)-2 as a key intermediate of the glucokinase activator (R)-1 is described. The construction of the stereocenter at the 伪-carbon is a key point for the synthesis of (R)-2. The proposed process utilizes desymmetrization of a ketene in situ generated from the corresponding racemic carboxylic acid Rac-2 with (R)-pantolactone as a chiral auxiliary followed by hydrolysis of the resulting ester. This key step has been successfully scaled up to 20 kg, which demonstrates that this synthetic approach is comparable with a previously reported approach via enantioselective hydrogenation.