Water → (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid

Participants

Reaction Conditions

Reaction Steps

A solution of (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (21.3 g, 43.5 mmol) in THF (100 mL) was cooled to 5° C. Aqueous 1.9M lithium hydroxide solution (50 mL, 96 mmol) was added via addition funnel, maintaining the temperature below 14° C., followed by a 30-mL water rinse of the addition funnel. The reaction mixture was warmed to 20-25° C. and was stirred at that temperature for 72 hours. The mixture was concentrated to remove THF, and then was cooled to 8° C. Hydrochloric acid (1N, 80 mL) was added dropwise, and a precipitate began to form. Ethyl acetate (200 mL) was added to dissolve the solids, and the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organics were washed with brine (4 times with 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (20.4 g) was slurried in ethanol (250 mL) and heated to 75° C., resulting in a yellow solution. Water (250 mL) was added slowly, forming a precipitate, and the mixture was heated to 90° C. to dissolve the solids. The solution was then cooled to 30° C. and was held at that temperature for 16 hours. The mixture was further cooled to −1.5° C. for 3 hours. The resulting crystals were collected by filtration, rinsed with water (50 mL), and then dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (19.2 g). 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 2H), 8.03 (s, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.01 (dd, 1H), 6.92 (m, 2H), 6.86 (m, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 3.92 (m, 4H), 2.07 (m, 1H), 1.97 (m, 2H), 1.58 (m, 1H), 1.29 (t, 3H). Chiral SFC: Chiralcel OJ-H, 4.6 mm×25 cm, 70:30 CO2:methanol, 0.2% isopropylamine, 2.5 mL/min, 210/254 nM; retention time (R)-enantiomer (Example 1) 4.13 min, (S)-enantiomer 2.35 min. MS (ES+) 477.3 (M+H).

Provenance & Evidence