A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C-N Coupling Reaction

作者：Yamashita Yohei^*; Morinaga Yasuhiro; Kasai Makoto; Hashimoto Takao; Takahama Yuji; Ohigashi Atsushi; Yonishi Satoshi; Akazome Motohiro

来源：Organic Process Research & Development, 2017, 21(3): 346-356.

DOI：10.1021/acsoprd.6b00415

• glucokinase activator
• diastereomeric resolution
• epimerization
• palladium-catalyzed C-N coupling

Here we describe the research and development of a process for the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral alpha-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C-N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of (R)-1. Moreover, an epimerization process to obtain (R)-7 from the undesired (S)-7 was developed.

• 出版日期2017-3