Development of a Quality Controllable and Scalable Process for the Preparation of 7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol: A Key Intermediate for Baloxavir Marboxil,Organic Process Research & Development

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Development of a Quality Controllable and Scalable Process for the Preparation of 7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol: A Key Intermediate for Baloxavir Marboxil
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-12-09 , DOI: 10.1021/acs.oprd.9b00389
Zihong Zhou _{1,

2} , Zhongqing Wang _{1,

2,

3} , Jingping Kou ₁ , Shuming Wu ₁ , Junrong Zhang ₁ , Xi Yuan ₁ , Xiwei Wu ₁ , Chuan-hua Li ₃ , Gaohong Liao ₁

Affiliation

A novel six-step synthesis of 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (1) is described. Starting with 3,4-difloro-2-methylbenzoic acid and using diphenyl disulfide as an ideal sulfur source effectively solve the problems such as harsh reaction conditions, usage of smelly thiophenol, which might restrict the known process from pilot plant application. Large-scale applicability of this new route has been successfully demonstrated on kilogram-scale production to afford 1 with 98.04% purity in 75% overall yield. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.

中文翻译：

开发质量可控和可扩展的制备7,8-二氟-6,11-二氢二苯并[ b，e ]噻吩-11-ol的方法：Baloxavir Marboxil的关键中间体

描述了新颖的六步合成7,8-二氟-6,11-二氢二苯并[ b，e ]噻吩-11-ol（1）。从3,4-二氟-2-甲基苯甲酸开始，并使用二苯二硫作为理想的硫源，可以有效解决诸如苛刻的反应条件，使用有气味的苯酚等问题，这些问题可能会限制中试工厂的已知工艺。该新路线的大规模适用性已在公斤级生产中成功证明，可提供纯度为98.04％，总收率为75％的1。同时，对相应的杂质分布进行了详细研究并充分记录在案。

更新日期：2019-12-11

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