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

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 substi...

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Bibliographic Details
Published in:Organic process research & development 2019-04, Vol.23 (4), p.578-587
Main Authors: Yamagami, Takafumi, Kobayashi, Ryo, Moriyama, Noriaki, Horiuchi, Hideki, Toyofuku, Eiji, Kadoh, Yoichi, Kawanishi, Eiji, Izumoto, Shinichi, Hiramatsu, Hajime, Nanjo, Takehiro, Sugino, Masuhiro, Utsugi, Masayuki, Moritani, Yasunori
Format: Article
Language:English
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Summary: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 (SNAr) 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 POCl3 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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.9b00068