[Fine Chemicals] Summary of OPRD case studies on aromatic/heteroaromatic nitration processes

Precise optimization of continuous flow parameters achieves both yield and efficiency gains. Systematic optimization of key parameters such as reaction temperature, acid dosage, and residence time determined the optimal process conditions: PPD to sulfuric acid mass ratio 1:5.5, PPD to nitric acid molar flow ratio 1:1.1, reaction temperature 40°C, residence time 290 s. Under these conditions, conversion reached over 99.5%, selectivity remained above 96.8%, and the reaction solution yield was as high as 97.5%. The reaction time was shortened from several hours in the traditional batch to less than 5 minutes, greatly improving production efficiency. Optimized workup and material recycling balance yield and greenness. Given that NPPD contains a hydroxyl group and has some water solubility, the optimal dilution and washing water amounts were selected: dilution water at 10 times the mass of PPD, washing water at 12 times the mass of PPD. This ensures full crystallization of the product while effectively removing residual acid, yielding a qualified product with purity >98%. Meanwhile, a material recycling process was developed: washing water is recovered as dilution water, and waste sulfuric acid is concentrated by distillation and reused to dissolve PPD. This operation has no significant impact on product yield or purity, greatly reducing industrial water use and waste emissions, making the process greener. The process has significant advantages and broad prospects for industrial application. Compared with the traditional batch process, the newly developed continuous flow nitration process shows comprehensive advantages: Substantially higher yield: isolated yield reaches 92.4%, 12.4% higher than the highest reported value in the literature, directly improving economic benefits. Higher reaction efficiency: residence time is only 290 s, far shorter than the 1–2 hours of the traditional process, and continuous production is possible, suitable for scale-up. Better safety: precise temperature and mass transfer control completely solves the local overheating problem of traditional batch reactions and avoids the safety risks of nitro compound decomposition and explosion. Greener: material recycling greatly reduces waste emissions, meeting modern pharmaceutical chemical manufacturing's green requirements. More controllable operation: the continuous flow system enables precise regulation of reaction parameters, higher product quality consistency, and easy automation. The research team also verified the superiority of the new process through comparative experiments. In the traditional AcOH/HNO₃ system, adjusting nitric acid concentration cannot balance nitration ability and oxidative side reactions, and the pyrimidine ring opening problem is difficult to solve. In contrast, the H₂SO₄/HNO₃ system with a low-concentration combination ensures nitration efficiency while maximally suppressing oxidative side reactions, which is the core reason for the high yield of the new process. Significance and application value. This study achieved continuous flow nitration synthesis of NPPD for the first time, providing an efficient, safe, and green new process for the industrial production of ticagrelor, improving the production efficiency and market supply capacity of this antithrombotic drug, and also providing an important technical reference for the nitration of pyrimidine compounds. The successful application of continuous flow technology in the nitration synthesis of pharmaceutical intermediates further confirms its unique advantages in solving strongly exothermic, high-risk organic reactions, and provides new ideas and examples for the continuous, green, and intelligent upgrading of the pharmaceutical chemical industry.