Optimization of the synthesis process for 3‐chloro‐4‐fluoroaniline

Abstract BACKGROUND 3‐Chloro‐4‐fluoroaniline ( 4 ), a key intermediate in synthesizing quinolone drugs and pesticides, is widely used in the fine chemical industry. Existing synthetic methods face challenges such as high raw material costs, toxic reagents, safety hazards from by‐products, high energy consumption, impurities in crude products, and increasing post‐processing expenses. In order to overcome these challenges, the present study focuses on the optimization of the synthetic route utilizing o ‐dichlorobenzene as the primary feedstock, a reagent widely adopted in existing industrial‐scale manufacturing processes. RESULTS This study represents the initial phase, wherein 3,4‐dichloronitrobenzene ( 2 ) is synthesized via the nitration of o ‐dichlorobenzene ( 1 ) employing a mixed acid system consisting of concentrated nitric acid and sulfuric acid. Compared to the initial process, this optimized approach significantly minimizes the formation of dinitrobenzene by‐products, thereby effectively reducing the safety risks associated with industrial‐scale production. In the second step, the reaction utilizes potassium fluoride, tetramethylammonium chloride, and N , N ‐dimethylformamide as key reagents, which effectively lower both the process temperature and reaction time. Additionally, the product can be directly used in subsequent reactions without requiring distillation, thereby significantly improving process efficiency and reducing overall production costs. This optimized procedure produces 3‐chloro‐4‐fluoronitrobenzene ( 3 ) with high purity (98.26%) and an excellent yield (88.34%). In the third step of the process optimization, a reduction in both reaction temperature and dehalogenation byproducts was achieved compared to the initial conditions. This modification not only mitigated potential safety hazards but also enhanced the atom economy of the reaction. In the final step, purified 3 was subjected to catalytic hydrogenation at 40 °C under 0.95 MPa H₂ in ethanol, affording compound 4 with a purity of >99% and a yield of >96%. The overall yield of the process reached approximately 72%. CONCLUSION This study presents an optimized process that enhances yield and simplifies the purification procedure, thereby providing a potential reference for the synthesis of pharmaceutical and agrochemical intermediates. © 2025 Society of Chemical Industry (SCI).