Yield:1343498-72-5 75%

Reaction Conditions:

in 1,4-dioxane at 10 - 55; for 2 h;Inert atmosphere;Temperature;

Steps:

2; 4; 6 Example 2 Preparation of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

Add 37.3kg of dioxane into the 100 L reactor,Under nitrogen protection, add 2.5 kg of Intermediate 4,Stir and heat to 55°C.After the intermediate 4 is completely dissolved,Dissolve 2.2 kg of 4-chloro-3-(trifluoromethyl)benzene isocyanate (compound 5) in 6.7 kg of dioxane and pre-cool to 10°C,Add dropwise to 100 L reactor in 1 hour,After dripping, the reaction with intermediate 4 is continued for 1 hour.After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1.Centrifugal filtration, the filter cake was rinsed twice with 6.0 kg ethyl acetate,The weight of the filter cake after drying under reduced pressure was 3.8 kg.Pour 40.0 kg of methanol into the 100 L reactor,Add the above compound 1, heat to reflux, keep for 3.0 hours,Cool down to lower the internal temperature to 34°C for recrystallization.The crystallization was rinsed twice with 4.0 kg methanol,After 72 hours of vacuum drying, 3.5 kg of white crystals were obtained,The yield is about 75%, HPLC purity: ≥99.5%.

References:

CN112159351,2021,A Location in patent:Paragraph 0026; 0028; 0030