Reaction Steps
To a solution of (R)-ethyl 3-amino-4-(biphenyl-4-yl)butanoate hydrochloride (200 mg, 0.625 mmol), 2,4-pyridinedicarboxylic acid hydrate (151 mg, 0.813 mmol), EDCl (132 mg, 0.688 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.688 mmol) in DMF (6 ml), DIPEA (0.164 ml, 0.938 mmol) is added. The reaction mixture is allowed to stir for 3 hours. Then, the reaction mixture is diluted with H2O. The precipitated solid is collected on a funnel and dried under reduced pressure. To a solution of the crude in THF (8 ml) and MeOH (1 ml), 1 M aqueous NaOH (2.5 ml, 2.5 mmol) is added. After stirring for 1 hour, the reaction is quenched with 5% citric acid and brine, and the products are extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)picolinic acid and (R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic acid as white solids, respectively (Example 13-1: 33 mg; Example 13-2: 36 mg). Example 13-1, HPLC retention time=1.50 minutes (condition D); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.62 (m, 2H) 2.88-2.97 (m, 2H) 4.50-4.59 (m, 1H) 7.31-7.35 (m, 3H) 7.42-7.45 (m, 2H) 7.57-7.64 (m, 4H) 7.89 (dd, J=5, 1.6 Hz, 1H) 8.83 (dd, J=5, 0.8 Hz, 1H) 8.37 (dd, J=1.6, 0.8 Hz) 8.89 (d, J=8.3 Hz, 1H). Example 13-2, HPLC retention time=1.24 minutes (condition A); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.68 (m, 2H) 2.91 (A of ABX, Jab=13.6 Hz, Jax=6.1 Hz, 1H) 3.01 (B of ABX, Jab=13.6 Hz, Jbx=8.1 Hz, 1H) 4.56-4.65 (m, 1H) 7.29-7.34 (m, 3H) 7.41-7.45 (m, 2H) 7.55-7.64 (m, 4H) 7.99 (dd, J=5, 1.6 Hz, 1H) 8.34 (dd, J=1.6, 0.8 Hz, 1H) 8.84 (dd, J=5, 0.8 Hz, 1H) 8.90 (d, J=9.1 Hz, 1H) 12.26 (br s, 1H) 13.87 (br s, 1H).
