Ethanol → 4-{6-Ethoxy-5-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo [4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazine

HRID 1700135Notes

Reaction equation

HRID 1700135 reaction equation
[O-]CC.[K+].C(O)C.[C:8]([C:11]1[C:15]([NH:16][C:17](=O)[C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[N:20][C:19]=2[O:35][CH2:36][CH3:37])=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[N:12]=1)(=[O:10])[NH2:9]>C(OCC)(=O)C>[CH2:36]([O:35][C:19]1[N:20]=[CH:21][C:22]([S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH2:32]2)(=[O:25])=[O:26])=[CH:23][C:18]=1[C:17]1[NH:9][C:8](=[O:10])[C:11]2[C:15](=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[N:12]=2)[N:16]=1)[CH3:37]

Participants

5

Reactant 3

HCID 702EthanolHCID 12114162N-[3-carbamoyl-5-ethyl-1-(2-Pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamideHCID 23670592Potassium ethoxide

Product 1

HCID 1355816594-{6-Ethoxy-5-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo [4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazineYield 83%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

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).

Workup

  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.

Sources & evidence

ORD record
ord-2ec627104a1e4799afbc88b18e122b37
Source dataset
uspto-grants-2002_02
Patent number
US06350751B1

Reaction notes

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