P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH2:14])=[C:9]([F:15])[CH:8]=1.[CH:16]([NH:19][C:20](=O)[CH3:21])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH:14][C:20](=[N:19][CH:16]([CH3:18])[CH3:17])[CH3:21])=[C:9]([F:15])[CH:8]=1Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES+): m/z=292 (M+H)+.
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