4-Chloro-6-trifluoromethylpyrimidine

A solution of 6-(trifluoromethyl)pyrimidin-4-ol (5.0 g, 30.5 mmol), phosphoryl chloride (3.41 mL, 36.6 mmol), and quinoline (2.16 mL, 18.3 mmol) in toluene (50 mL) was stirred at 100° C. for 5 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10percent EtOAc/Hexane) to yield the desired product (1.20 g, 21.6percent). General procedure: 2-Methyl-6-trifluoromethyl-4-hydroxypyrimidine (0.05 mol) and acetonitrile (50 mL) were added to a three-necked flask and stirred in an ice bath.Slowly add phosphorus oxychloride (0.75 mol), After the dropwise addition is completed, the mixture is stirred at room temperature for 0.5 hours.Add acetonitrile to dissolve N, N-isopropylethylamine (0.0005 mol), After the completion of the dropwise addition, the reaction was stopped after heating and refluxing for 10 hours.Spin dry, pour into ice water, adjust the pH to 10 with alkali, extract with dichloromethane, separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, filter, and dissolve.The mass of the brown liquid was 5.37 g (theoretical value 9.83 g) in a yield of 54.6%.General procedure: To a mixture of N-(3-bromobenzyl)-3-(trifluoromethyl)benzenesulfonamide (0.10 g, 0.25 mmol), (3, 5-dimethylisoxazol-4-yl)boronic acid (72 mg, 0.51 mmol), and Na2C03 (54 mg, 0.51 mmol) in dioxane/H20 (1.6 mL/0.4 mL) was added Pd(dppf)Cl2-CH2Cl2 (21 mg, 0.025 mmol). The reaction was degassed with N2 and stirred at 80C for 4 hours. The reaction was cooled to room temperature and DCM was added. The mixture was washed with brine (IX) and water (2X). The organic layer was dried oversodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-35% EtOAc/Hexanes, 2 cycles) to afford the title compound (35 mg, 34%). LCMS(method A): m/z 411.2 (M+H)+. 'H NMR (CDCI3) delta 8.10 (s, 1H), 8.05 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 7.14 (d, 1H), 7.11 (s, 1H), 5.42 (t, 1H), 4.26 (d, 2H), 2.35 (s, 3H), 2.20 (s, 3H). To BE-2 (3.00 g, 14.79 mmol)Add Pd(PPh3)4 (600 mg) to a stirred solution of toluene and DMF, Pd(dppf)Cl2 (600 mg)And Na2CO3 (6.27 g, 59.17 mmol).The mixture was stirred at 90 C for 5 h.The mixture was quenched with water and extracted with EtOAc. The solution was concentrated and purified by SiO2 flash chromatography to yield the residue BE-3.General procedure: 2, 4-Dichloropyrimidine (5 g, 33.2 mmol) was dissolved in 10 ml THF and after addition of neopentylamine (3.48 g, 39.9 mmol) and potassium carbonate (6.96 g, 49.9 mmol) the mixture was stirred at 75 C for 2 h min. The TLC showed 2 products (regioisomers). The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtrated and concentrated under reduced pressure. The crude product was purified by MPLC (silica gel, ethyl acetate/hexanes, 0-50%) to give 2.37 g (35.7%).