[Synthesis]
General procedure for the synthesis of 4-(trifluoromethyl)-1H-pyrazole from 3,3,3-trifluoropropanal and (methylidene)dimethylammonium chloride: first, 3,3,3-trifluoropropanoic acid (5.64 g, 44.1 mmol) was mixed with methylidene dimethylammonium chloride (11.45 g, 96.6 mmol) in 42 mL of 1,2-dichloroethane and heated to 75 °C and stirred under nitrogen protection for 5 hours. After completion of the reaction, the reaction mixture was cooled and the volatiles were removed overnight under vacuum to give 10.82 g of intermediate. Subsequently, the intermediate was mixed with hydrazine monohydrate (2.72 mL, 1.2 eq.) in 145 mL of acetonitrile and stirred for 1 hour. Trifluoroacetic acid (5.03 mL, 3 eq.) was added to the reaction mixture, which was then heated to 70 °C and stirred under nitrogen protection for 1.5 hours. After the reaction was complete, the reaction mixture was cooled, concentrated under vacuum, and partitioned between 30 mL of water and 30 mL of ethyl acetate. Sodium bicarbonate (3.6 g) was added to the vigorously stirred mixture, the layers were separated and the aqueous layer was washed with ethyl acetate (3 times). The organic layers were combined and the products were separated by chromatography using a hexane solution of 20% ethyl acetate (Biotage 40+S column). The suitable grades were concentrated in vacuum at room temperature to give 1.75 g (29% yield) of 4-(trifluoromethyl)-1H-pyrazol-1-amine as a light yellow solid. Elemental analysis (C4H3F3N2) Calculated values: C, 35.31; H, 2.22; N, 20.59. Measured values: C, 35.34; H, 2.40; N, 20.55. Next, 4-(trifluoromethyl)-1H-pyrazol-1-amine (0.68 g, 5 mmol) was added to stirred hydroxylamine-O-sulfonic acid (0.679 g, 6 mmol ) in 20 mL of 12N sodium hydroxide and stirred overnight. The reaction mixture was extracted with ether and washed (3 times). The organic layers were combined, dried over magnesium sulfate and concentrated to give 0.38 g of 4-(trifluoromethyl)-1H-pyrazol-1-amine as a yellow oil. Finally, 4-(trifluoromethyl)-1H-pyrazol-1-amine (154 mg, 1 mmol) was mixed with 5-chloro-2,4-dimethoxyphenyl isocyanate (213 mg, 1 mmol) in 8 mL of tetrahydrofuran, and 5 mg of DMAP was added.The reaction mixture was stirred at room temperature for 2 days, and then concentrated to a brown solid, which was analyzed using a 50% ethyl acetate solution in hexane for Chromatographic separation (Biotage 25+S column) gave 66 mg (21% yield) of the target product as a white solid. Mass spectrum (EI) m/z: 364 (M)+. |