1807193-48-1Relevant articles and documents
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
Zhou, Zihong,Wang, Zhongqing,Kou, Jingping,Wu, Shuming,Zhang, Junrong,Yuan, Xi,Wu, Xiwei,Li, Chuan-Hua,Liao, Gaohong
, p. 2716 - 2723 (2019)
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.
Preparation method of key intermediate of baloxavir marboxil
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Paragraph 0033-0044, (2019/05/16)
The invention discloses a preparation method of a key intermediate of baloxavir marboxil. The preparation method comprises the following steps: carrying out a nucleophilic substitution reaction on polysubstituted 2,3-difluoro-6-halogenated benzyl alcohol represented by a formula (I) to synthesize 2,3-difluoro-6-halogenated benzyl halide represented by a formula (II), carrying out a nucleophilic substitution reaction on the polysubstituted benzyl halide represented by the formula (II) to synthesize 2,3-difluoro-6-halogenated benzyl phenylsulfide represented by a formula (III), carrying out a Grignard reaction on the polysubstituted benzyl phenylsulfide represented by the formula (III) to synthesize 3,4-difluoro-2-(phenylthio)methyl)benzoic acid represented by a formula (IV), and carrying out a Friedel-Crafts acylation reaction on the polysubstituted benzoic acid to synthesize 7,8-difluorodibenzo[b,e]thiophene-11(6H)-one represented by a formula (V). In the formula (I), the formula (II)and the formula (III), X and X are separately and independently selected from chlorine, bromine or iodine. According to the preparation method, the polysubstituted benzyl alcohol is used as a starting raw material, and the steps of two-step nucleophilic substitution, Grignard exchange, Friedel-Crafts acylation and the like are carried out to prepare the key intermediate of the anti-influenzadrug baloxavir marboxil, so that original innovation is achieved.
