Diisopropylethylamine → (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

N,N-Diisopropylethylamine (2.91 kg, 22.5 mol) was added to a mixture of ethyl 2-chloropyrimidine-5-carboxylate (1.20 kg, 6.43 mol) and (R)-3-(2-ethoxyphenoxy)piperidine D-tartrate (2.63 kg, 7.07 mol) in tetrahydrofuran (12.0 L) at 55° C., at a rate maintaining a temperature of 50-60° C. The mixture was held at that temperature for 1 hour, then was cooled to 30° C. The mixture was then partitioned between water (8.4 L) and 2-methyltetrahydrofuran (16.8 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and then was concentrated by distillation under reduced pressure. Tetrahydrofuran (12.0 L) and methanol (6.0 L) were added to the residue, and then an aqueous 8M potassium hydroxide solution was added at a rate to maintain the temperature below 55° C. The mixture was held at 50-55° C. for 1 hour, then was cooled to 30° C., and was partitioned between ethyl acetate (18.0 L) and aqueous 3M hydrochloric acid solution (8.86 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and was then distilled to a low volume. Ethyl acetate (22 L) was added and the resulting solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (25 L). The mixture was cooled to and held at 57° C. for 2 hours as crystallization initiated. n-Heptane (8.83 L) was added while maintaining temperature at 55-60° C. After 30 min, the slurry was cooled to 20-25° C. and was held at that temperature for 11 hours. The crystals were collected by filtration, rinsing with 2:1 ethyl acetate:n-heptane (8.0 L), to afford after drying (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1.69 kg). MS (ES+) 344.3 (M+H). The mother liquors were concentrated and the resulting residue was recrystallized from ethyl acetate (4.2 L), with the addition of n-heptane (2.1 L) after crystallization initiated, to afford after filtering and drying an additional portion of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (0.370 kg).

Provenance & Evidence