Continuous-flow double diazotization for the synthesis of m- difluorobenzene via Balz-Schiemann reaction
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Continuous-flow double diazotization for the synthesis of m-difluorobenzene via Balz-Schiemann reaction Jiming Liu 1 & Duoheng Wang 1 & Qilin Xu 2 & Hangwei Yu 1 & Jiadi Zhou 1 & Zhiqun Yu 1
&
Weike Su 1,2
Received: 8 July 2020 / Revised: 31 August 2020 / Accepted: 7 September 2020 # Akadémiai Kiadó 2020
Abstract m-Difluorobenzene is an important structural in many pharmaceutical agents and nature products. However, the conventional method of preparing m-difluorobenzene, which was adopts double diazotization from m-phenylenediamine, is very tricky with potential hazards associated with the strongly exothermic and thermal instability of the diazonium intermediate, and has severe coupled side reactions. Here, we report the continuous-flow methodology, which effectively addresses this series of process challenges by an extra inert solvent flow. The protocol rapidly synthesize m-Difluorobenzene with 85% total yield (the traditional method has 65% total yield). The molar ratio of hydrochloric acid used in the process deduce to 3.6 equivalent (traditional method requires 12 equivalent). Furthermore, the reaction time can be decreased from hours to within 40 s. Above all, the method has potential industrial application value.
Keywords Double diazotization . continuous-flow . Balz − Schiemann . m-difluorobenzene
Introduction The target compound m-Difluorobenzene (MDFB) is a building block or intermediate of several well-established drugs compounds (Fig. 1), such as Diflunisal, Fluconazole, etc. [1–4]. Until now, various MDFB synthesis methods have been reported (Scheme 1). The first method was the Halex process, where treatment of dichlorobenzene with a metal fluoride (KF and, AgF) leads to the replacement of the halogen via an SN2 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s41981-020-00115-4) contains supplementary material, which is available to authorized users. * Zhiqun Yu [email protected] * Weike Su [email protected] 1
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014 People’s Republic of China
2
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014 People’s Republic of China
reaction [5, 6]. This method has a short route, but it is limited to highly activated substrates and low selectivity. The second method was diazotization and hydro-dediazotization from the corresponding difluoroaniline [7, 8]. The main shortcoming of this method is the high cost of raw materials. The third method is the Balz–Schiemann reaction from m-(MPDA) [9, 10]. Since the process is simple and the raw materials are abundant, it is widely employed. However, this process has some deficiencies, such as modest yields and a low reaction temperature requirem
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