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,Organic Process Research & Development

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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
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-07-14 , DOI: 10.1021/acs.oprd.2c00150
Shinichi Oda ₁ , Yuki Fukui ₁ , Yasuyuki Hozumi ₁ , Yoshiyuki Takeuchi ₁ , Masahiro Hosoya ₁

Affiliation

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.

中文翻译：

抗肥胖候选药物 (S-234462) 的优化合成工艺开发，具有苯并恶唑酮的轻度氯化和 Mitsunobu 反应的原位 IR 监测

在这里，我们概述了 S-234462 的制造过程历史。优化工艺以6-氟苯并恶唑酮、((1r,4r)-4-氨基环己基)甲醇和(叔丁基磺酰基)氨基甲酸乙酯为起始原料。成功工艺开发的第一个关键是发现了使用五氯化磷和多磷酸的 6-氟苯并恶唑酮的温和氯化条件。第二个关键是通过Mitsunobu反应建立N-烷基化，不需要过量的(叔丁基磺酰基)氨基甲酸乙酯。此外，使用原位 IR 分析对 Mitsunobu 反应的动力学研究能够控制反应转化率。

更新日期：2022-07-14

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