Reaction Steps
N,N-Diisopropylethylamine (2.32 kg, 17.9 mol) was added via dropping funnel to a mixture of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (2.05 kg, 5.98 mol) and tetrahydrofuran (19.5 L) at 20-25° C. 1,1′-Carbonyldiimidazole (0.94 kg, 5.8 mol) was then added portion-wise, rinsing with tetrahydrofuran (1.03 L), and the mixture was heated to 43-48° C. to dissolve the solids. Methyl 3-(aminomethyl)benzoate hydrochloride (1.39 kg, 6.88 mol) was added, and the reaction mixture was heated to 58-62° C. and was held at that temperature for 3 hours, before being cooled to 20° C. The product mixture was partitioned between aqueous 3M hydrochloric acid solution (8.6 L) and 2-methyltetrahydrofuran (30.8 L). The organic layer was washed sequentially with aqueous 1M hydrochloric acid solution (8.6 L), aqueous 15% ammonium hydroxide solution (2 times with 15 L), and aqueous 2M sodium chloride solution (18 L), and then was concentrated to a low volume under reduced pressure. Methanol (10.27 L) and tetrahydrofuran (20.54 L) were added to the residue and the resulting solution was cooled to 5-10° C. Aqueous 1.5M potassium hydroxide solution (15.9 L, 23.9 mol) was added at a rate maintaining the temperature below 10° C., and the temperature was then held at 15-20° C. for 3 hours. The product mixture was partitioned between aqueous 3M hydrochloric acid solution (8.0 L) and ethyl acetate (30.81 L). The organic layer was washed with aqueous 2M sodium chloride solution (18 L), and then was concentrated under reduced pressure to a volume of approximately 6 L. Ethyl acetate (16.43 L) was added, and the solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (27 L) until the distillation pot temperature was stable at approximately 78° C. The resulting mixture was cooled to 20-25° C. and was held at that temperature for 16 hours. The crystals were collected by filtration, rinsing with ethyl acetate (6.16 L), and then were dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (2.27 kg). 1H NMR (600 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.93 (t, 1H), 8.76 (br s, 2H), 7.89 (s, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 7.44 (t, 1H), 7.01 (d, 1H), 6.89 (m, 2H), 6.84 (m, 1H), 4.50 (d, 2H), 4.29 (m, 1H), 4.14 (dd, 1H), 3.86 (m, 4H), 3.78 (m, 1H), 1.98 (m, 1H), 1.81 (m, 2H), 1.49 (m, 1H), 1.18 (t, 3H). Melting point 151-152° C. Elemental analysis for C26H28N4O5: calculated C, 65.53; H, 5.92; N, 11.76. found C, 65.41; H, 5.58; N, 11.83.
