Development of an Optimized Synthetic Process for an Antiobesity Drug Candidate (S-234462) Featuring Mild Chlorination of Benzoxazolone and In Situ IR Monitoring of a Mitsunobu Reaction

Here, we outline the manufacturing process history of S-234462. For the optimized process, 6-fluorobenzoxazolone, ((1r,4r)-4-aminocyclohexyl)methanol, and ethyl(tert-butylsulfonyl)carbamate were selected as starting materials. The first key to successful process development was the discovery of mild chlorination conditions of 6-fluorobenzoxazolone using phosphorus pentachloride and polyphosphoric acid. The second key was the establishment of N-alkylation by the Mitsunobu reaction, which did not require excess ethyl(tert-butylsulfonyl)carbamate. In addition, kinetic study of the Mitsunobu reaction using in situ IR analysis enabled control of the reaction conversion.