反应详情

温度

150 °C

4-Hydroxypiperidine (171.2 g, 1660 mmoles) is added to a solution of methyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (69 g, 207.3 mmoles) in N-methylpyrrolidone (483 mL) and the mixture is stirred at 150° C. for 4 hours. The mixture is cooled to ambient temperature and poured into water (1000 mL). The mixture is washed with methyl t-butyl ether (300 mL). The aqueous layer is then acidified to pH 2 with aqueous 36% HCl. The mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL). The organic layer is evaporated to dryness. Water (500 mL) is added to the residue and the resulting mixture is stirred for 30 minutes, filtered and the filtered material dried in an oven vacuum at 45° C. overnight. The dried light brown solid is dissolved in acetone (500 mL) and heated to 50° C. Water (1000 mL) is slowly added and the mixture is stirred at 50° C. for 2 hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. The dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. overnight to give the title compound as a white solid (50.8 g, 64%). Mass spectrum (m/z): 384.2 (M+1). 1H NMR (300 MHz, DMSO): 12.85 (s, 1H), 9.87 (s, 1H), 7.71 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.68 (d, J=4.1 Hz, 1H), 4.11-4.04 (m, 2H), 3.70 (m, 1H), 3.15-3.07 (m, 2H), 2.41 (s, 3H), 2.27 (s, 6H), 1.81-1.77 (m, 2H), 1.44-1.32 (m, 2H).

1. temperatureThe mixture is cooled to ambient temperature
2. washThe mixture is washed with methyl t-butyl ether (300 mL)
3. extractionThe mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL)
4. customThe organic layer is evaporated to dryness
5. additionWater (500 mL) is added to the residue
6. stirringthe resulting mixture is stirred for 30 minutes
7. filtrationfiltered
8. customthe filtered material dried in an oven vacuum at 45° C. overnight
9. dissolutionThe dried light brown solid is dissolved in acetone (500 mL)
10. temperatureheated to 50° C
11. additionWater (1000 mL) is slowly added
12. stirringthe mixture is stirred at 50° C. for 2 hours
13. temperatureThe mixture is cooled to ambient temperature
14. filtrationfiltered
15. customthe filtered material dried under reduced pressure at 45° C
16. stirringThe dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours
17. temperatureThe mixture is cooled to ambient temperature
18. filtrationfiltered
19. customthe filtered material dried under reduced pressure at 45° C. overnight