Water → HCID 46893125, compound

HRID 1801940Notes

Reaction equation

HRID 1801940 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:37])([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([C:26](OC)=[O:27])=[CH:14][CH:15]=2)[N:10]=1.O.[OH-].[Na+]>C1COCC1>[F:37][C:8]([F:7])([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([CH2:26][OH:27])=[CH:14][CH:15]=2)[N:10]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 21226445Aluminium lithium hydrideHCID 66614322HCID 66614322, compound

Product 1

HCID 46893125HCID 46893125, compoundYield 82.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a suspension of LAH (0.26 g, 6.84 mmol) in THF (50 mL) at 0° C. was slowly added a suspension of methyl 2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carboxylate (1.17 g, 2.74 mmol) in THF (30 mL). The mixture was stirred at 0° C. for 0.5 h and then at rt for 4 h. The mixture was cooled to 0° C., and water (0.26 mL) was added dropwise and the mixture was stirred for 30 min. Then 15% NaOH (0.39 mL) was added and the mixture was stirred for 1 h. Then water (1.3 mL) was added and the mixture was stirred at rt overnight. The mixture was filtered through Celite washing with 20% MeOH/DCM (500 mL), and the filtrate was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and EtOAc (150 mL), and the separated aqueous phase was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to afford a (2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yl)methanol as awhite solid (901 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 4.70 (s, 2H), 5.49 (s, 1H), 6.31 (s, 1H), 7.35 (t, 2H), 7.56 (d, 2H), 7.70 (t, 2H), 7.77 (s, 1H), 8.63 (d, 1H), 10.64 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 400 (M+H)+.

Workup

  1. additionwas slowly added
  2. waitat rt for 4 h
  3. temperatureThe mixture was cooled to 0° C.
  4. stirringthe mixture was stirred for 30 min
  5. stirringthe mixture was stirred for 1 h
  6. stirringthe mixture was stirred at rt overnight
  7. filtrationThe mixture was filtered through Celite
  8. washwashing with 20% MeOH/DCM (500 mL)
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe residue was partitioned between water (200 mL) and EtOAc (150 mL)
  11. extractionthe separated aqueous phase was extracted with EtOAc (2×150 mL)
  12. washThe combined organic layers were washed with brine (200 mL)
  13. dry with materialdried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure
  16. customThe residue was purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-68fdca8740e34e3a88f825bfdd0730f3
Source dataset
uspto-grants-2013_01
Patent number
US08349851B2

Reaction notes

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