Dimethylformamide → 4-[5-Cyano-7-(2-fluorophenyl)-1,3-benzoxazol-2-yl]-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide

Participants

Reaction Conditions

Reaction Steps

To of 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25, 100 mg) in 4 ml of dichloromethane was slowly added oxalyl chloride (600 μl, 2M in dichloromethane) followed by dimethylformamide (10 □l). The mixture was stirred for 15 min to completely dissolve the carboxylic acid. The solution was then concentrated in vacuo and redissolved in 35 ml of dioxane. To the resultant acyl chloride was added 5-amino-2′-fluoro-6-hydroxybiphenyl-3-carbonitrile (INTERMEDIATE 24, 59 mg). The mixture was heated at 80° C. for 1 h, and then cooled to room temperature. The dioxane was removed in vacuo, and to the residue was added 45 ml of toluene and 46 mg of p-toluenesulfonic acid monohydrate (46 mg). The solution was heated to 140° C. and stirred at this temperature for 15 h. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified via column chromatography using a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 50% ethyl acetate in hexanes over 10 column volumes, followed by 100% ethyl acetate for 4 column volumes to provide the title compound (20 mg, 14%). Mass spectrum (ESI) 601.2 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.48 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.12 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.54 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (t, J=9.7 Hz, 1H), 6.73 (d, J=4.8 Hz, 1H), 6.30 (bs, 1H), 4.87 (d, J=13.5 Hz, 2H), 3.44 (t, J=6.5 Hz, 2H), 2.94 (t, J=13.5 Hz, 2H), 2.01 (m, 1H), 1.90, (d, J=13.0 Hz, 2H), 1.31 (qd, J=12.5 Hz, 3.9 Hz, 2H).

Provenance & Evidence