Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units

Takafumi Yamagami, Ryo Kobayashi, Noriaki Moriyama, Hideki Horiuchi, Eiji Toyofuku, Yoichi Kadoh, Eiji Kawanishi, Shinichi Izumoto, Hajime Hiramatsu, Takehiro Nanjo, Masuhiro Sugino, Masayuki Utsugi, Yasunori Moritani

研究成果: ジャーナルへの寄稿学術誌査読

4 被引用数 (Scopus)

抄録

In this study, research and development for the synthetic process of a PDE10A inhibitor are described; in particular, an efficient regioselective construction of the quinoxaline unit, a cost-effective pyrazolo[1,5-a]pyrimidine formation, and a cost-saving approach in a nucleophilic aromatic substitution (S N Ar) reaction by introducing oxazolidinone as an electron-withdrawing group to a chloropyrazolo[1,5-a]pyrimidine core are key points. The newly developed process has been successfully scaled up to 40 kg. Furthermore, a one-pot tandem reaction from aminopyrazole to dichloropyrazolo[1,5-a]pyrimidine by activating malonic acid with POCl 3 was discovered. The finding contributed to avoiding isolation of the hygroscopic pyrazolo[1,5-a]pyrimidin-5(4H)-one intermediate, which caused complicated filtration and drying processes observed in the first scale-up campaign.

本文言語英語
ページ(範囲)578-587
ページ数10
ジャーナルOrganic Process Research and Development
23
4
DOI
出版ステータス出版済み - 4月 19 2019
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 物理化学および理論化学
  • 有機化学

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