反应详情

温度

55 °C

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).

1. temperaturewas cooled to 30° C
2. customThe mixture was then partitioned between water (8.4 L) and 2-methyltetrahydrofuran (16.8 L)
3. washThe organic layer was washed with aqueous 2M sodium chloride solution (6.8 L)
4. concentrationwas concentrated by distillation under reduced pressure
5. additionTetrahydrofuran (12.0 L) and methanol (6.0 L) were added to the residue
6. additionan aqueous 8M potassium hydroxide solution was added at a rate
7. temperatureto maintain the temperature below 55° C
8. waitThe mixture was held at 50-55° C. for 1 hour
9. temperaturewas cooled to 30° C.
10. customwas partitioned between ethyl acetate (18.0 L) and aqueous 3M hydrochloric acid solution (8.86 L)
11. washThe organic layer was washed with aqueous 2M sodium chloride solution (6.8 L)
12. distillationwas then distilled to a low volume
13. additionEthyl acetate (22 L) was added
14. distillationthe resulting solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (25 L)
15. temperatureThe mixture was cooled to and
16. customheld at 57° C. for 2 hours as crystallization
17. additionn-Heptane (8.83 L) was added
18. temperaturewhile maintaining temperature at 55-60° C
19. waitAfter 30 min
20. temperaturethe slurry was cooled to 20-25° C.
21. waitwas held at that temperature for 11 hours
22. filtrationThe crystals were collected by filtration
23. washrinsing with 2:1 ethyl acetate
24. customn-heptane (8.0 L), to afford
25. dry with materialafter drying (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1.69 kg)
26. concentrationThe mother liquors were concentrated
27. customthe resulting residue was recrystallized from ethyl acetate (4.2 L), with the addition of n-heptane (2.1 L)
28. customafter crystallization
29. customto afford
30. filtrationafter filtering
31. dry with materialdrying an additional portion of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (0.370 kg)