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

• Published in: Organic Process Research & Development Vol. 23; no. 4; pp. 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: Journal Article
• Language: English; Japanese
• Published: WASHINGTON American Chemical Society 19.04.2019; American Chemical Society (ACS); Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; scale-up; pyrazolo[1,5-a]pyrimidines; PDE10A inhibitors; quinoxalines; nucleophilic aromatic substitution reactions
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.9b00068

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.