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 m...

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Published inOrganic process research & development Vol. 26; no. 8; pp. 2483 - 2491
Main Authors Oda, Shinichi, Fukui, Yuki, Hozumi, Yasuyuki, Takeuchi, Yoshiyuki, Hosoya, Masahiro
Format Journal Article
LanguageEnglish
Published American Chemical Society 19.08.2022
Subjects
in situ IR
chlorination of benzoxazolone
Mitsunobu reaction
NPY Y5
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.2c00150