Reaction Steps
[5-(4-Bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (from Example 1, 566 mg, 1.41 mmol), methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (511 mg, 1.69 mmol), X-Phos (134 mg, 0.28 mmol), palladium acetate (31.7 mg, 0.14 mmol) and potassium phosphate (898 mg, 4.23 mmol) were combined in toluene (12 mL) and degassed water (3 mL) was added. The mixture was degassed and sealed. The mixture was stirred at 95° C. for 3 hrs and cooled to room temperature. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by flash column chromatography (40 g silica gel, ethyl acetate in hexanes 10% to 70% in 15 minutes) to give 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester as a pale yellow solid (370 mg, 52.8% yield). LC/MS calcd for C29H28N4O4 (m/e) 496.0, obsd 497.0 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.25 (m, 3H), 1.66 (m, 4H), 3.67 (s, 3H), 3.93 (s, 3H), 5.91 (m, 1H), 6.44 (br, 1H), 7.29-7.40 (m, 5H), 7.44 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.78 (br d, J=6.6 Hz, 2H). 1-{4′-[1-Methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (50 mg) was dissolved in 1 mL of THF and 1 mL of ethanol. To this mixture was added 1N sodium hydroxide solution (1 mL). The clear solution was stirred at room temperature for 12 hrs. Solvents were evaporated and the residue was treated with 2N hydrochloric acid (1.4 mL). The solid was filtered and rinsed with water, dried in the air, to give 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (47.5 mg, 97.8% yield). LC/MS calcd for C28H26N4O4 (m/e) 482.0, obsd 483.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 3H), 1.49 (m, 2H), 1.59 (m, 2H), 3.86 (s, 3H), 5.80 (m, 1H), 7.28-7.50 (m, 7H), 7.63 (d, J=8.1 Hz, 2H), 7.71 (m, 2H), 7.80 (d, J=7.6 Hz, 2H), 9.95 and 9.62 (br s, 1H), 12.35 (s, 1H).
