Two-stage one-pot synthetic strategy for the key triazone-triazole intermediate of ensitrelvir (S-217622), an oral clinical candidate for treating COVID-19

• Published in: RSC advances Vol. 12; no. 54; pp. 3488 - 34814
• Main Authors: Hu, Wei, Zhang, Xiang, Liu, Yuanchang, Liu, Teng, Wen, Jiale, Peng, Xiaopeng, Xie, Xin, Chen, Weiming
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 06.12.2022; The Royal Society of Chemistry
• Subjects: Alkylation; Chemistry; R&D; Research & development; Triazoles
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d2ra06841a

Herein, the preparation of the key triazone-triazole intermediate of ensitrelvir (S-217622) via sequential cyclization and alkylation reaction is described. Firstly, chloromethyl triazole was synthesized through a one-pot tandem process (condensation and cyclization reaction) from commercially available chloroacetamide in a 72% yield. Then, the key triazone-triazole intermediate was obtained in a second one-pot process by N -alkylation with triazone followed by highly selective N 1 -methylation with iodomethane in a 54% yield. In addition, two of the main process impurities were synthesized and identified. This novel alternative two-stage one-pot strategy for synthesizing the key triazone-triazole intermediate opens a new avenue for further research and development of ensitrelvir analogs. The key triazone-triazole intermediate of ensitrelvir (S-217622), an oral clinical candidate for treating COVID-19, was synthesized via two-stage one-pot strategy with high efficiency.