Hydrazine hydrate (1:1) → HCID 58504643, compound

HRID 2367546Notes

Reaction equation

HRID 2367546 reaction equation
[O-:1][CH2:2][CH3:3].[Na+].[H-].[Na+].[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:21]=[C:20](F)[C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=2)[CH:11]=[C:10]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@H:25]2[CH3:30])[N:9]=1.[NH4+:31].[Cl-].O.[NH2:34]N.CCN(C(C)C)C(C)C>C(O)C.O.CN(C=O)C>[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:21]=[C:20]3[C:17]([C:18]([NH2:34])=[N:19][NH:31]3)=[C:16]([O:1][CH2:2][CH3:3])[CH:15]=2)[CH:11]=[C:10]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@H:25]2[CH3:30])[N:9]=1

Participants

10

Reactant 6

HCID 24654Hydrazine hydrate (1:1)HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 2723922Sodium ethoxide3×HCID 66991298HCID 66991298, compound

Product 1

HCID 58504643HCID 58504643, compound

Reagents, catalysts & solvents 3

HCID 702EthanolSolvent5×HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

A stock solution of sodium ethoxide in ethanol was generated by the addition of ethanol (20 mL) to NaH (254 mg, 10.56 mmol), followed by stirring at room temperature for 30 minutes. To a 20-mL microwave vial was added 4-{2-amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (700 mg, 2.11 mmol), DMF (2 mL), and ethanol (3 mL). The reaction was cooled to 0° C., and a solution of sodium ethoxide in ethanol (4.40 mL, 2.324 mmol) was added. The reaction was stirred overnight, and an additional portion of DMF was added, and the reaction was allowed to stir overnight at room temperature. An additional 0.25 equiv of sodium ethoxide in ethanol (1 mL) was added and the reaction was stirred for 8 hours. The reaction mixture was poured into NH4Cl (sat.) and water (1:1, 30 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was dissolved in ethanol (10 mL), and hydrazine hydrate (0.73 mL, 12.7 mmol) and Hunig's base (1.11 mL, 6.34 mmol) were added. The reaction was heated in a microwave reactor for 90 minutes at 150° C. The reaction was allowed to cool to room temperature, concentrated, and the resulting precipitate collected by filtration, washed with ethanol and dried in vacuo to afford the title compound (400 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.6 Hz, 3H), 1.45 (t, J=7.0 Hz, 3H), 3.05-3.15 (m, 1H), 3.38-3.49 (m, 1H), 3.54-3.65 (m, 1H), 3.66-3.78 (m, 1H), 3.88-3.96 (m, 1H), 4.08 (d, J=12.6 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 4.50 (d, J=4.8 Hz, 1H), 5.00 (s, 2H), 6.10 (s, 2H), 6.49 (s, 1H), 6.91 (s, 1H), 7.49 (s, 1H), 11.53 (s, 1H).

Workup

  1. temperatureThe reaction was cooled to 0° C.
  2. stirringThe reaction was stirred overnight
  3. stirringto stir overnight at room temperature
  4. stirringthe reaction was stirred for 8 hours
  5. extractionextracted with EtOAc (3×100 mL)
  6. dry with materialThe combined organics were dried over Na2SO4
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in ethanol (10 mL)
  9. temperatureThe reaction was heated in a microwave reactor for 90 minutes at 150° C
  10. temperatureto cool to room temperature
  11. concentrationconcentrated
  12. filtrationthe resulting precipitate collected by filtration
  13. washwashed with ethanol
  14. customdried in vacuo

Sources & evidence

ORD record
ord-1c45530e6b694493819ca6bdff1131a2
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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