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

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)578-587
Number of pages10
JournalOrganic Process Research and Development
Volume23
Issue number4
DOIs
Publication statusPublished - Apr 19 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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