反应详情

温度

120 °C

Potassium ethoxide solution (86 g, 0.25 mol, 24% w/w in ethanol) was charge to the vessel. To this was added ethanol (235 mL). Ethyl acetate (10.8 g) was added to reaction mixture at ambient. N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl) nicotinamide (70 g, 0.122 mol) was added in one portion to the solvent mixture and the reaction was stirred at ambient. The reaction mixture was warmed in a pressurised vessel to a temperature of 120° C., producing an internal pressure of approximately 50-60 p.s.i., the pressure was then made up to 80 p.s.i. by applying a nitrogen pressure and the reaction was stirred for 8 hours. The reaction was cooled after 8 hours and ethanol is then reduced under atmospheric distillation to a volume of about 720 ml (3 ml/g). Ethyl Acetate (840 ml) was added to the ethanol solution and then reduced under atmospheric distillation to a volume of 1920 ml (8 ml/g). Dilute aqueous hydrochloric acid was added to adjust the pH of the reaction mixture from about pH=13 to pH=8. This was a slow addition over 30 min showing no exotherm. The mixture was stirred for 5 minutes, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. Water (140 mL) was added to ethyl acetate layer (remaining in the vessel), stirred, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. The ethyl acetate phase was slowly cooled from 50° C. to 0-5° C. over two hours, and stirred for a further hour, filtered of the solid, wash with ethyl acetate (3) 0-5° C. and dried under vacuum at 60° C. to afford the title compound (83%) as a white solid. Mpt 178-180° C. (CDCl3): 1.02 (3H, t), 1.30, 3H, t), 1.58 (3H, t), 2.21 (2H, q), 2.55 (4H, m), 3.04 (2H, q), 3.10 (4m), 4.75 (2H, q), 5.69 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1H, d), 8.63 (1H, d), 9.02 (1H, d). m/z (Found:553 [M+H]+, 100%. C26H32N8O4S requires 553.66).

1. customproducing an internal pressure of approximately 50-60 p.s.i
2. stirringthe reaction was stirred for 8 hours
3. temperatureThe reaction was cooled after 8 hours
4. distillationethanol is then reduced under atmospheric distillation to a volume of about 720 ml (3 ml/g)
5. additionEthyl Acetate (840 ml) was added to the ethanol solution
6. distillationreduced under atmospheric distillation to a volume of 1920 ml (8 ml/g)
7. additionDilute aqueous hydrochloric acid was added
8. additiona slow addition over 30 min
9. stirringThe mixture was stirred for 5 minutes
10. temperaturewarmed to 50° C.
11. customthe phases were separated
12. additionWater (140 mL) was added to ethyl acetate layer (
13. stirringstirred
14. temperaturewarmed to 50° C.
15. customthe phases were separated
16. temperatureThe ethyl acetate phase was slowly cooled from 50° C. to 0-5° C. over two hours
17. stirringstirred for a further hour
18. filtrationfiltered of the solid
19. washwash with ethyl acetate (3) 0-5° C.
20. customdried under vacuum at 60° C.