4-Toluenesulfonyl chloride → Methyl 4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methyl(methylsulfonyl)amino)-5-pyrimidinecarboxylate

Participants

Reaction Conditions

Reaction Steps

In a 200 L-volume glass-lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 17.9 kg (62.0 mol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine prepared as above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol.) of potassium carbonate (available from Asahi Glass Works, Co., Ltd., Lot No. 1111632, particle size distribution: 75-250 μm: 14%, 75 μm pass: 86%), and 12.9 kg (67.7 mol.) of p-toluenesulfonyl chloride. The mixture was heated at 60° C. for 2 hours, to carry out reaction. Subsequently, the reaction mixture was cooled to room temperature. To the cooled mixture were added 8.8 kg (80.6 mol.) of N-methylmethanesulfonamide and 12.9 kg (93.3 mol.) of potassium carbonate, and the resulting mixture was heated at 122-125° C. for 3 hours, for carrying reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture were added acetone and water, and the organic liquid portion was separated. The organic liquid portion was then washed successively with aqueous sodium hydroxide solution (3 wt. %) and a saturated aqueous sodium chloride solution. The washed organic liquid portion was concentrated under reduced pressure. Isopropyl alcohol and water were added to the residue, resulting in precipitation of a crystalline product. The crystalline product was filtered on a filter paper and washed with isopropyl alcohol. The washed crystalline product and 85.7 kg of acetone were placed in a 200 L-volume glass lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser. The mixture was stirred at 50-55° C., to dissolve the crystalline product in acetone. The insoluble was removed with a line filter. Subsequently, 58.3 kg of water was added to the solution, to precipitate a crystalline product. The crystalline product was collected on a filter paper and washed with an acetone/water mixture, to give 19.5 kg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine.

Provenance & Evidence