Methanol → 4-[6-[(3r)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile

HRID 2367569Notes

Reaction equation

HRID 2367569 reaction equation
[CH3:1][OH:2].[H-].[Na+].[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6].C[O-].[Na+]>CCOC(C)=O.CN(C=O)C>[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27]([O:2][CH3:1])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6]

Participants

7

Reactant 4

HCID 887MethanolHCID 24758Sodium hydrideHCID 10942334Sodium Methoxide2×HCID 585044754-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile

Product 1

HCID 669910904-[6-[(3r)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

CH3OH (10 mL) was added dropwise to a 100 mL RBF at 0° C. charged with sodium hydride (66.8 mg, 2.78 mmol). The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 10 minutes. To a 4 mL vial were added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL) and 1.2 mL of sodium methoxide solution (1.2 eq). The reaction was stirred at room temperature overnight. An extra 0.5 eq of sodium methoxide was added to the reaction and it was heated to 40° C. for 3 hours. The reaction mixture was then poured into EtOAc (10 mL). The organics were washed with H2O (2×) and then dried over Na2SO4 and concentrated to afford 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile. This material was taken up in CH3CN (1 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (10-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (34.8 mg) as a white fluffy powder. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.59-1.82 (m, 2H), 2.82 (d, J=3.8 Hz, 3H), 3.07-3.18 (m, 1H), 3.39-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.82-3.87 (m, 1H), 3.87-3.92 (m, 1H), 3.94 (s, 3H), 4.10-4.23 (m, 1H), 4.27-4.39 (m, 1H), 5.02 (s, 2H), 6.45-6.57 (m, 1H), 6.94 (bs, 1H), 7.52 (bs, 1H), 8.30-8.34 (bs, 1H), 11.53 (bs, 1H).

Workup

  1. stirringThe reaction was stirred at room temperature overnight
  2. temperaturewas heated to 40° C. for 3 hours
  3. washThe organics were washed with H2O (2×)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-a7fc24be38b048f6a70ac88720f77d96
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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