1H-Benzimidazole, 6-(2-chloro-5-fluoro-4-pyrimidinyl)-1-cyclopropyl-4-fluoro-2-methyl- synthesis

Yield:1231930-43-0 4.5 g

Reaction Conditions:

with bis-triphenylphosphine-palladium(II) chloride;sodium carbonate in 1,2-dimethoxyethane;water at 80; for 16 h;Inert atmosphere;Suzuki Coupling;

Steps:

4.5 Step 5

-Cyclopropyl-4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazole (5 g, 15.8 mmol), 2,4-dichloro-5-fluoro-pyrimidine (3 g, 18.0 mmol), sodium carbonate (3 g, 28.3 mmol) and dichlorobis(triphenylphosphine)palladium (550 mg, 0.83 mmol) were dissolved in a mixed solution of ethylene glycol dimethyl ether (70 mL) and water (10 mL), the mixture was stirred under argon atmosphere at 80° C. for 16 hours.
The reaction solution was cooled to room temperature, filtered, and the ethylene glycol dimethyl ether was distilled off under reduced pressure.
The residue was diluted with water and extracted with dichloromethane.
The organic layer was dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was slurried with acetonitrile, filtered and dried to give 4.5 g 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-1-cyclopropyl-4-fluoro-2-methyl-benzimidazole represented by 4-g. LC-MS m/z: (M+H)⁺=321.2.

References:

US2019/10153,2019,A1 Location in patent:Paragraph 0218; 0223