4-Methylpyrazole → 4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

HRID 227785Notes

Reaction equation

HRID 227785 reaction equation
[CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1COCC1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[C:38]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=4)=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:27]=2)=[N:17][N:16]=1>O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[C:38]([C:39]5[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=5)=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:28][CH:27]=3)=[N:17][N:16]=2)[CH:6]=1

Participants

6

Reactant 4

HCID 34064-MethylpyrazoleHCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 426043304-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

Product 1

HCID 577562644-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

A dry resealable pressure bottle, under nitrogen, was charged with 4-methylpyrazole (0.086 ml, 1.05 mmol). To this was added THF (1.3 ml, 0.2 M) and reaction mixture cooled to 0° C. 60% wt sodium hydride in mineral oil (44.0 mg, 1.10 mmol) was added slowly. Reaction mixture stirred at 0° C. for 15 minutes and 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.260 mmol) added slowly. Reaction kept at 0° C. for 10 minutes, then warmed up slowly to room temperature and placed in an oil bath. Reaction heated to 65° C. and stirred at this temperature overnight. Reaction mixture was cooled to 0° C. and diluted with water, and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated to afford an orange residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a yellow solid. MS m/z=502 [M+H]+. Calc'd for C28H23N9O: 501.54.

Workup

  1. additionTo this was added
  2. additionwas added slowly
  3. customReaction mixture
  4. customReaction
  5. waitkept at 0° C. for 10 minutes
  6. temperaturewarmed up slowly to room temperature
  7. customplaced in an oil bath
  8. customReaction
  9. temperatureheated to 65° C.
  10. stirringstirred at this temperature overnight
  11. customReaction mixture
  12. temperaturewas cooled to 0° C.
  13. extractionextracted with EtOAc
  14. customThe organic layer was collected
  15. dry with materialdried over Na2SO4
  16. concentrationconcentrated
  17. customto afford an orange residue, which
  18. customwas purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA)
  19. additionbasified by addition of aq. NaHCO3
  20. extractionextracted with ethyl acetate
  21. dry with materialThe organic portion was dried with Na2SO4
  22. filtrationfiltered
  23. concentrationconcentrated

Sources & evidence

ORD record
ord-0c057a1829bd4192af32d4af39513df0
Source dataset
uspto-grants-2009_07
Patent number
US07560551B2

Reaction notes

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