Synthesis of difluoro**aldehyde in microchannel reactors – Xi’an Institute of Modern Chemistry

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Public documents from our company, Shandong Nuowei, for attending the Shanghai Microchemicals Conference. Synthesis of difluoro**aldehyde in microchannel reactors Mao Mingzhen, Wang Wei, Wang Lieping, Zhang Jiangong, Zeng**, Ning Binkē* (Xi’an Institute of Modern Chemistry, Key Laboratory for Efficient Development and Utilization of Fluorine-Nitrogen Chemical Resources, Xi’an 710065) Abstract: Difluoro**aldehyde was synthesized in microchannel reactors using difluoro**ring, n-butyl lithium, and N,N-dimethylformamide as raw materials. The effects of factors such as material ratio, reaction temperature, and residence time on the product content were investigated, and the process parameters were optimized. Compared with traditional batch synthesis processes, the continuous flow microreactor process enables the safe and stable synthesis of difluoro**aldehyde, eliminates the effects of reaction scaling and temperature fluctuations, reduces reaction time, and enhances process safety. Keywords: difluoro**aldehyde ； Microchannel reactor ； Continuous flow process. Azoxystrobin, as a new type of non-systemic, highly effective and safe fungicide, is also one of the most widely sold seed treatment agents globally, boasting broad market prospects. Difluoro**aldehyde is a key intermediate in the synthesis of fluzinamid; its structure is shown in Figure 1, and its synthesis process is one of the key factors limiting the industrialization of fluzinamid. file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7752.tmp.png Figure 1. Structural formula of difluoro**aldehyde. Literature reports indicate that the synthesis of difluoro**aldehyde is carried out on an intermittent basis using a reactor: starting from difluoro**ring, it is lithiated using n-BuLi, then reacted with N,N-dimethylformamide (DMF); subsequent acidification yields difluoro**aldehyde. The chemical reaction equation is as follows: file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7753.tmp.png Figure 2. Chemical reaction equation for the synthesis of difluoro**aldehyde. In this method, the temperature of the system must be maintained at around -30°C during the addition of n-BuLi. The reaction process is complex, with a reaction time of over 7 hours, and the actual yield is only about 80%. Furthermore, the traditional batch reactor method for preparing difluoro**aldehyde presents numerous problems: (1) The reactions involving n-butyl lithium are generally highly exothermic, and batch reactors have inaccurate temperature control as well as low efficiency in mass and heat transfer, which easily leads to temperature spikes, an increase in by-products, and a reduction in the yield of the product ； (2) Since n-butyllithium is flammable and explosive when exposed to air, there is a constant risk of safety hazards during the dropping and reaction processes, which can easily lead to safety accidents. file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7754.tmp.pngAuthor profile: Mao Mingzhen (born 1984), male, from Xiangfen, Shanxi Province; holds a doctorate. His research focuses on the synthesis of pesticide active ingredients and intermediates. Email: maomingzhen0303@163.com. Corresponding author: Ning Binkē (born 1968), male, from Qishan, Shaanxi Province; researcher mainly engaged in the research and development of fine chemicals. E-mail: bkning@126.com. As a new type of continuous-flow reaction device, the microchannel reactor offers advantages such as high mass and heat transfer efficiency, precise control over operating conditions, safety and reliability, as well as the absence of amplification effects, making it suitable for such exothermic reactions. To address the issues associated with the traditional batch reactor method for producing difluoro**aldehyde, this paper optimized the production process using a continuous flow microchannel reactor. Optimal process parameters were obtained, which improved reaction efficiency and reduced safety risks; the application of this process makes it possible to carry out the continuous and efficient production of difluoro**aldehyde. 1 Experimental Section 1.1 Reagents, Instruments, and Analysis Methods 1.1.1 Reagents and Instruments Instruments: Microchannel reactor (Type G-1), Corning ； Refrigeration/Heating Temperature Control System (HC-G1-8), Corning ； Metering pump (NP7000C), Jiangsu Hanbang Technology Co., Ltd ； High-performance liquid chromatograph (1260), Agilent. Reagent: Difluoro** ring, home-made, 99% purity ； n-Butyllithium (2.4M), Bailingwei Technology Co., Ltd ； The rest are all AR. 1.1.2 The analytical method employed was high-performance liquid chromatography (HPLC) to determine the content of difluoro**aldehyde in the reaction solution. The measurement conditions were as follows: C18 column; mobile phase: V(acetonitrile)/V(water) = 60:40; wavelength: 230 nm; flow rate: 1.0 mL/min; injection volume: 5 μL. 1.2 Experimental Methods 1.2.1 Batch Experiment: Follow the procedures described in the literature. 1.2.2 The experimental procedure for continuous-flow experiments in microreactors is as follows: (1) The flow rates of each reagent are set according to the molar ratio of the materials (n-butyl lithium/difluoro**cyclohexane), and then the solution of difluoro**cyclohexane in **furane, as well as the n-butyl lithium solution in n-hexane, are fed into the pre-cooling module of the microchannel reactor using metering pumps for pre-cooling; (2) After the pre-cooling process is complete, the solution of difluoro**cyclohexane and the n-butyl lithium solution proceed to the first mixing module for reaction ； (3) The reaction solution from the first mixing module reacts with DMF in the second mixing module ； (4) The effluent from the outlet of the microchannel reactor was acidified to neutrality using concentrated hydrochloric acid; the aqueous layer was extracted with ethyl acetate. After combining the organic layers and drying them over anhydrous sodium sulfate, the solvent was evaporated to yield the product, difluoro**aldehyde. 2 Results and Discussion 2.1 Influence of reaction conditions 2.1.1 Influence of the molar ratio of reactants on product yield file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7755.tmp.jpg Figure 3. Influence of the molar ratio of butyllithium/difluoro**cyclic compound on product yield 2.1.2 Influence of reaction temperature on product yield file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7766.tmp.jpg Figure 4. Influence of reaction temperature on product yield 2.1.3 Influence of residence time on product yield file:///C:\Users\ADMINI~1\AppData\Local\Temp\ksohtml\wps7767.tmp.jpg Figure 5. Influence of residence time on product yield 2.2 Comparison of parameters between batch reaction process and continuous microchannel reaction process To compare batch and continuous reaction conditions, reactions with a product yield of around 98% were selected, and their reaction conditions are presented in the table below for comparison. Table 1 Comparison of results between batch reaction and continuous flow experiments Product content/% Reaction temperature/°C Material ratio/n Residence time Batch reaction 97.8 –30 1.27–8 h Continuous flow reaction 99 –71.05 13.8 s As can be seen from Table 1, when using the same precursor to obtain the same product content, the continuous flow reaction in a microreactor has the following advantages: it reduces the amount of n-butyl lithium required, thereby saving on raw material costs ； Reduced reaction time and improved production efficiency ； Raising the reaction temperature reduces energy consumption, which helps to lower costs. 3 Conclusions In this paper, difluoro** ring and DMF were used as raw materials, with n-butyl lithium as the lithiation reagent, to continuously prepare difluoro** aldehyde in a microreactor. Compared with traditional batch reactions, the use of microreactors for the preparation of difluoro**aldehyde allows for higher reaction temperatures, reduced energy consumption, less use of n-butyllithium, shorter reaction times, improved process safety, and makes the reaction process more in line with the requirements of green chemistry. References: Li Chao, Liao Daohua, Zeng Zhongwu, et al. Synthesis of fludioxonil. Modern Pesticides, 2009, 28(3): 20-24. Ling Jing, Zhang Dongdong. A new synthesis method for a intermediate of the pesticide fludioxonil: CN 103896906A. July 2, 2014. Li Bin. Application of microreactor technology in fine chemical industry. Fine Chemicals, 2006, 23(1): 1-7. Luo Guangsheng, Wang Kai, Lü Yangcheng, et al. Recent advances in microreactor research. Modern Chemical Industry, 2009, 5: 27-30. He Wei, Fang Zheng, Chen Ketao, et al. Application of microreactors in synthetic chemistry. Applied Chemistry, 2013, 30(12): 1376-1381. 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