Dimethylformamide → Ammonium Hydroxide

HRID 2367608Notes

Reaction equation

HRID 2367608 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=C(F)[C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH3:24])[N:3]=1.[CH3:25][O-:26].[Na+].[Na].[OH2:29].[NH2:30][NH2:31].[CH3:32]N(C=O)C>CO.C(O)(=O)C>[NH4+:1].[OH-:21].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:30][NH:31]3)=[C:25]([O:26][CH3:32])[CH:15]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:29][CH2:20][C@H:19]2[CH3:24])[N:3]=1

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 24654Hydrazine hydrate (1:1)HCID 5360545SodiumHCID 10942334Sodium MethoxideHCID 66991298HCID 66991298, compound

Product 2

HCID 14923Ammonium HydroxideHCID 58504679HCID 58504679, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 887MethanolSolvent3×

Conditions

Temperature
100 °C

Procedure

4-{2-Amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (500 mg, 1.509 mmol) was suspended in CH3OH (7 mL) with stirring in a 50 mL round bottom flask under nitrogen, and a solution of sodium methoxide in methanol (freshly prepared from sodium (41.6 mg, 1.811 mmol) and methanol (3 mL)) was added. The mixture was stirred at room temperature monitoring it by HPLC. After 4 hours, the reaction was not changing and seemed to stop. Since it was a suspension and solubility was poor, DMF (3 mL) was added to give a clear yellow solution. After another hour (5 hours total), HPLC showed some progression, so the reaction was left of stir overnight. HPLC indicated complete conversion. Acetic acid (5 drops) was added to quench any leftover methoxide, and the mixture was evaporated to dryness. The residue was suspended in ethanol (8 mL), and hydrazine monohydrate (1.464 mL, 30.2 mmol) was added. The mixture was refluxed under nitrogen in a 100° C. oil bath overnight. HPLC showed complete conversion to product. After concentrating to dryness, purification by silica gel chromatograpy (Analogix SF25-40 g cartridge) eluting with a gradient of CHCl3 to 90:10:1 CHCl3:CH3OH: NH4OH gave the title compound (491 mg) as a pale yellow solid. LC-MS (ES) m/z=356 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.6 Hz, 3H), 3.11 (td, J=12.8, 3.7 Hz, 1H), 3.44 (td, J=11.8, 2.9 Hz, 1H), 3.53-3.66 (m, 1H), 3.66-3.79 (m, 1H), 3.84-4.01 (m, 4H), 4.08 (d, J=12.6 Hz, 1H), 4.42-4.55 (m, 1H), 5.03 (s, 2H), 6.11 (s, 2H), 6.50 (s, 1H), 6.92 (s, 1H), 7.49 (s, 1H), 11.54 (s, 1H).

Workup

  1. additionwas added
  2. stirringThe mixture was stirred at room temperature
  3. customto give a clear yellow solution
  4. waitAfter another hour (5 hours total), HPLC showed
  5. waitsome progression, so the reaction was left of stir overnight
  6. customto quench any leftover methoxide
  7. customthe mixture was evaporated to dryness
  8. concentrationAfter concentrating to dryness, purification by silica gel chromatograpy (Analogix SF25-40 g cartridge)
  9. washeluting with a gradient of CHCl3 to 90:10:1 CHCl3

Sources & evidence

ORD record
ord-f5236bc12561446f9d4d78f5cd35ca6b
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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