Water → 2-{5-cyclopropyl-1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-4-methyl-1H-pyrazol-3-yl}-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine

HRID 1484698Notes

Reaction equation

HRID 1484698 reaction equation
[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:37]([F:39])[F:38])=[CH:31][C:30]=1[F:40].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:28][C:29]3[C:30]([F:40])=[CH:31][C:32]([O:36][CH:37]([F:38])[F:39])=[CH:33][C:34]=3[F:35])[N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydride2×HCID 867324312-(Bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene2×HCID 896490232-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine

Product 1

HCID 716122672-{5-cyclopropyl-1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-4-methyl-1H-pyrazol-3-yl}-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

70 mg 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0-217 mmol, 1.0 eq) were dissolved in 0.52 mL THF and cooled to 0° C. 10.4 mg sodiumhydride (60%, 0.261 mmol, 1.2 eq) were added. The mixture stirred for 5 minutes, then the ice bath was removed and 65.2 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.239 mmol, 1.1 eq) were added. The reaction stirred at rt for 4 days. Again 5 mg sodiumhydride (60%, 0.130 mmol, 0.6 eq) and 33 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.120 mmol, 0.55 eq) were added. The reaction stirred at rt for 2 hours. Water was added and the aqueous layer was extracted by ethylacetate twice. The collected organic layers were washed with brine, dried with a silicon filter and concentrated in vacuo The crude product was purified by flashcromatography and HPLC to provide 10 mg (0.02 mmol, 8%) of the analytically pure target compound.

Workup

  1. customthe ice bath was removed
  2. stirringThe reaction stirred at rt for 4 days
  3. stirringThe reaction stirred at rt for 2 hours
  4. extractionthe aqueous layer was extracted by ethylacetate twice
  5. washThe collected organic layers were washed with brine
  6. customdried with a silicon
  7. filtrationfilter
  8. concentrationconcentrated in vacuo The crude product
  9. customwas purified by flashcromatography and HPLC
  10. customto provide 10 mg (0.02 mmol, 8%) of the analytically pure target compound

Sources & evidence

ORD record
ord-bf0c9cb607714c3da57a999c118cde1f
Source dataset
uspto-grants-2016_08
Patent number
US09422268B2

Reaction notes

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