Water → 1-(1-Methylethyl)-N-[6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide

HRID 244746Notes

Reaction equation

HRID 244746 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][NH:13][C:12]2=[N:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1.CO>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, Tribasic3×HCID 582557371-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamideHCID 178418725HCID 178418725, compound2×

Product 1

HCID 583564271-(1-Methylethyl)-N-[6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (available from ABCR, 24 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The reaction was heated under microwave irradiation at 120° C. for 10 min. Solvias catalyst (8 mg) was added and the reaction heated under microwave irradiation at 120° C. for 10 min. Further Solvias catalyst (8 mg) and tripotassium phosphate (30 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Again further Solvias catalyst (8 mg) and tripotassium phosphate (90 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (12 mg) was added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Addition of catalyst and base was repeated and the reaction was heated under microwave irradiation at 120° C. for 30 min. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fraction was evaporated under a stream of nitrogen. The residue was dissolved in methanol, a few drops of 2M HCl (aq) were added and the mixture was left to stand briefly at room temperature, then evaporated under a stream of nitrogen. Sequential purification was carried out using the following system and the two gradients shown:

Workup

  1. temperaturethe reaction heated under microwave irradiation at 120° C. for 10 min
  2. temperaturethe reaction was heated under microwave irradiation at 120° C. for 30 min
  3. temperaturethe reaction was heated under microwave irradiation at 120° C. for 30 min
  4. temperaturethe reaction was heated under microwave irradiation at 120° C. for 30 min
  5. additionAddition of catalyst and base
  6. temperaturethe reaction was heated under microwave irradiation at 120° C. for 30 min
  7. washwashing with methanol
  8. customdried under a stream of nitrogen
  9. washwash
  10. customdried under a stream of nitrogen
  11. dissolutionThe residue was dissolved in DMSO
  12. custommethanol (1 ml, 1:1, v/v) and purified by MDAP (method A)
  13. customThe appropriate fraction was evaporated under a stream of nitrogen
  14. dissolutionThe residue was dissolved in methanol
  15. additiona few drops of 2M HCl (aq) were added
  16. waitthe mixture was left
  17. customto stand briefly at room temperature
  18. customevaporated under a stream of nitrogen
  19. customSequential purification

Sources & evidence

ORD record
ord-7fa49a1f4fb14ad6874954bfab70a2ac
Source dataset
uspto-grants-2014_02
Patent number
US08658635B2

Reaction notes

Loading…