Reaction Steps
Step A and B: Cross-coupling and Saponification. To a solution of dimethyl 5-iodoisophthalate (13 g, 40.6 mmol) in 100 mL THF was added 2-cyano-phenyl zinc bromide (97.5 mL, 48.7 mmol, 0.5 M THF) and tetrakis(triphenylphosphine) palladium (214 mg, 0.2 mmol) and the reaction mixture was stirred at room temperature for 2 h. The precipitated solid was filtered, the filtrate was diluted with MeOH to provide after filtration a second crop for a total of 10.1 g of dimethyl 5-(2-cyanophenyl)isophthalate which was hydrolyzed to the corresponding monoacid 2′-cyano-5-(methoxycarbonyl)-1,1′-biphenyl-3-carboxylic acid following a similar procedure as described in intermediate B preparation, step C: 1H NMR (400 MHz, d6-DMSO) δ 13.55 (br s, 1H), 8.60-8.55 (m, 1H), 8.38-8.31 (m, 2H), 8.02 (d, J=8.3 Hz, 1H), 7.85 (td, J=8.3 Hz, 1.5 Hz 1H), 7.75 (d, J=8.3 Hz, 1H), 7.66 (td, J=8.3 Hz, 1.5 Hz 1H), 3.93 (s, 3H). Step C: Amide Coupling. In a 500 mL flask containing 2′-cyano-5-(methoxycarbonyl)-1,1′-biphenyl-3-carboxylic acid (3.0 g, 10.6 mmol) from step B, N-methyl-butylamine (1.39 g, 16.0 mmol), HOAt (1.45 g, 10.6 mamol) in CH2Cl2 was added EDC-HCl (3.06 g, 16.0 mmol) at rt. After stirring overnight the reaction was poured onto 0.1 N HCl, extracted with CH2Cl2 (3×75 mL) and the combined extracts washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (30-40% ethyl acetate/hexanes) gave methyl 5-{[butyl(methyl)amino]carbonyl}-2′-cyano-1,1′-biphenyl-3-carboxylate as an oil: amide rotamers present at rt, 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.14 (d, J=4.0 Hz, 1H), 7.76 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.50 (m, 2H), 3.93 (s, 3H), 3.54 (t, J=7.6 Hz, 1H), 3.32 (t, J=7.2 Hz, 1H), 3.08 (s, 1.5H), 3.00 (s, 1.5H), 1.65 (quint, J=6.8 Hz, 1H), 1.53 (quint, J=7.2 Hz, 1H), 1.40 (sext, J=7.2 Hz, 1H), 1.17 (sext, J=7.2 Hz, 1H), 0.96 (t, J=7.2 Hz, 1.5H), 0.79 (t, J=7.2 Hz, 1.5H) Step D: Hydrolysis. Prepared using a procedure similar to Intermediate B, step E, Methyl 5-{[butyl(methyl)amino]carbonyl}-2′-cyano-1,1′-biphenyl-3-carboxylate (3.4 g, 9.7 mmol) from step C above was hydrolyzed to give 5-{[butyl(methyl)amino]carbonyl}-2′-cyano-1,1′-biphenyl-3-carboxylic acid: amide rotamers present at rt, 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.81 (t, J=1.6 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.67 (t, J=6.4 Hz, 1H), 7.54-7.47 (m, 2H), 3.57 (t, J=7.2 Hz, 1H), 3.34 (t, J=7.2 Hz, 1H), 3.12 (s, 1.5H), 3.04 (s, 1.5H), 1.70 (quint, J=6.4 Hz, 1H), 1.56 (quint, J=6.0 Hz, 1H), 1.42 (sext, J=7.2 Hz, 1H), 1.90 (sext, J=7.2 Hz, 1H), 0.98 (t, J=7.2 Hz, 1.5H), 0.80 (t, J=7.2 Hz, 1.5H); LCMS (M+H)=337.3
