N,N-Dimethylaniline → 2-[2-[3-Methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]acetonitrile

HRID 59134Notes

Reaction equation

HRID 59134 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([NH2:25])=O)[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)[NH:15][C:16]1[N:21]=[C:20]([CH2:22][C:23]#[N:25])[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=1

Participants

4

Reactant 3

HCID 949N,N-DimethylanilineHCID 24813Phosphorus oxychlorideHCID 121317228HCID 121317228, compound

Product 1

HCID 863444322-[2-[3-Methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]acetonitrile

Procedure

2-(2-{[3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}-6-[(2,2,2-trifluoroethoxy)-methyl]pyrimidin-4-yl)acetamide (68 mg, 0.15 mmol, 1.0 eq) was added to a solution of Phosphorus oxychloride (4 mL) and dimethylaniline (0.033 mL, 0.26 mmol, 1.75 eq). The reaction mixture was immersed in a pre-heated oil bath at 120° C. for 10 min. The reaction mixture, still hot, was rapidly poured into ice/DCM slurry and stirred for 16 h. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel cartridge eluting with a gradient of methanol, DCM and EtOAc. The residue was further purified on a C18 reverse phase cartridge eluting with 30% to 70% MeOH/H2O containing 0.05% TFA to give the title compound, 8 mg (12%).

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted twice with dichloromethane
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified on a silica gel cartridge
  6. washeluting with a gradient of methanol, DCM and EtOAc
  7. customThe residue was further purified on a C18 reverse phase cartridge
  8. washeluting with 30% to 70% MeOH/H2O containing 0.05% TFA

Sources & evidence

ORD record
ord-6ae0893af4024ddeb622db4bede41b1d
Source dataset
uspto-grants-2016_09
Patent number
US09439904B2

Reaction notes

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