TY - JOUR
T1 - Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units
AU - Yamagami, Takafumi
AU - Kobayashi, Ryo
AU - Moriyama, Noriaki
AU - Horiuchi, Hideki
AU - Toyofuku, Eiji
AU - Kadoh, Yoichi
AU - Kawanishi, Eiji
AU - Izumoto, Shinichi
AU - Hiramatsu, Hajime
AU - Nanjo, Takehiro
AU - Sugino, Masuhiro
AU - Utsugi, Masayuki
AU - Moritani, Yasunori
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/19
Y1 - 2019/4/19
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.oprd.9b00068
DO - 10.1021/acs.oprd.9b00068
M3 - Article
AN - SCOPUS:85063129196
SN - 1083-6160
VL - 23
SP - 578
EP - 587
JO - Organic Process Research and Development
JF - Organic Process Research and Development
IS - 4
ER -