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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| Published in | Organic Process Research & Development Vol. 23; no. 4; pp. 578 - 587 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English Japanese |
| Published |
WASHINGTON
American Chemical Society
19.04.2019
American Chemical Society (ACS) Amer Chemical Soc |
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| 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 (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. |
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| AbstractList | 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. 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,S-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. |
| Author | Moritani, Yasunori Horiuchi, Hideki Sugino, Masuhiro Kobayashi, Ryo Utsugi, Masayuki Hiramatsu, Hajime Izumoto, Shinichi Toyofuku, Eiji Nanjo, Takehiro Moriyama, Noriaki Kadoh, Yoichi Yamagami, Takafumi Kawanishi, Eiji |
| AuthorAffiliation | Process Development Department, Production Technology & Supply Chain Management Division Global Quality Assurance Department Research Unit/Frontier, Sohyaku Innovative Research Division Technology Management Department, Production Technology & Supply Chain Management Division Research Unit/Immunology & Inflammation, Sohyaku Innovative Research Division Analytical Research Department, Production Technology & Supply Chain Management Division |
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| Keywords | scale-up pyrazolo[1,5-a]pyrimidines PDE10A inhibitors quinoxalines nucleophilic aromatic substitution reactions |
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| Title | Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units |
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