Hydrazine hydrate (1:1) → HCID 46214960, compound

HRID 2367547Notes

Reaction equation

HRID 2367547 reaction equation
[CH3:1][CH:2]([CH3:4])[O-].[Na+].[H-].[Na+].[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:22]=[C:21](F)[C:18]([C:19]#[N:20])=[C:17](F)[CH:16]=2)[CH:12]=[C:11]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@H:26]2[CH3:31])[N:10]=1.[OH2:32].[NH2:33][NH2:34].CCN(C(C)C)C(C)C>C(O)(C)C.CN(C=O)C>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:22]=[C:21]3[C:18]([C:19]([NH2:20])=[N:33][NH:34]3)=[C:17]([O:32][CH:2]([CH3:4])[CH3:1])[CH:16]=2)[CH:12]=[C:11]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@H:26]2[CH3:31])[N:10]=1

Participants

8

Reactant 5

HCID 24654Hydrazine hydrate (1:1)HCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 109204432-Propanol, sodium salt (1:1)3×HCID 66991298HCID 66991298, compound

Product 1

HCID 46214960HCID 46214960, compound

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolvent5×HCID 6228DimethylformamideSolvent2×

Procedure

A stock solution of sodium isopropoxide in isopropanol was generated by the addition of isopropanol (40 mL) to NaH (254 mg, 10.56 mmol) at 0° C., followed by stirring at room temperature for 30 minutes, then at 40° C. for 30 minutes. The clear, colorless solution was allowed to cool to room temperature. 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 isopropanol (3 mL). The reaction was cooled to 0° C., and a solution of sodium isopropoxide in isopropanol (8.80 mL, 2.324 mmol) was added dropwise. The reaction was stirred overnight. Then an additional portion of DMF (2 mL) was added, and the reaction was allowed to stir overnight at room temperature. At this time, an additional 0.4 equiv of sodium isopropoxide in isopropanol (3.2 mL) was added, and the reaction was stirred for 3 days over the weekend. The reaction mixture was concentrated, and the resulting residue was dissolved in ethanol (10 mL). Hydrazine hydrate (0.73 mL, 12.7 mmol) and Hunig's base (1.11 mL, 6.34 mmol) were added, and the reaction mixture was heated in a microwave reactor for 90 minutes at 150° C. The reaction was allowed to cool to room temperature, whereupon a precipitate formed. The precipitate was collected by filtration, washed with ethanol and dried in vacuo to afford the title compound (600 mg) as a white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 1.38 (d, J=5.8, 3H), 1.37 (d, J=5.8, 3H), 3.03-3.19 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.65 (m, 1H), 3.66-3.79 (m, 1H), 3.92 (dd, J=11.1, 3.0 Hz, 1H), 4.08 (d, J=12.6 Hz, 1H), 4.45-4.55 (d, J=5.1 Hz, 1H), 4.78-4.94 (m, 1H), 4.99 (s, 2H), 6.09 (s, 2H), 6.47 (s, 1H), 6.94 (s, 1H), 7.45 (s, 1H), 11.50 (s, 1H).

Workup

  1. waitat 40° C. for 30 minutes
  2. temperatureto cool to room temperature
  3. temperatureThe reaction was cooled to 0° C.
  4. stirringThe reaction was stirred overnight
  5. stirringto stir overnight at room temperature
  6. stirringthe reaction was stirred for 3 days over the weekend
  7. concentrationThe reaction mixture was concentrated
  8. dissolutionthe resulting residue was dissolved in ethanol (10 mL)
  9. temperaturethe reaction mixture was heated in a microwave reactor for 90 minutes at 150° C
  10. temperatureto cool to room temperature, whereupon a precipitate
  11. customformed
  12. filtrationThe precipitate was collected by filtration
  13. washwashed with ethanol
  14. customdried in vacuo

Sources & evidence

ORD record
ord-1e7e39b1896b407fbe8d8c27159817d7
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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