Ethanol → N-[4-(4-Cyano-3,5-difluorophenyl)-2-pyrimidinyl]acetamide

HRID 2367202Notes

Reaction equation

HRID 2367202 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([F:16])[C:11]([CH:12]=O)=[C:10]([F:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:25]O.[CH3:27][CH2:28][OH:29]>O>[C:12]([C:11]1[C:14]([F:16])=[CH:15][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[N:7]=2)=[CH:9][C:10]=1[F:17])#[N:25]

Participants

6

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 443297Hydroxyamine hydrochlorideHCID 58504552HCID 58504552, compound

Product 1

HCID 66990812N-[4-(4-Cyano-3,5-difluorophenyl)-2-pyrimidinyl]acetamideYield 39%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a slurry of 4-(2-amino-4-pyrimidinyl)-2,6-difluorobenzaldehyde (5.37 g, 22.8 mmol) in a mixture of EtOH and water were added sodium carbonate (2.66 g, 25.1 mmol) and hydroxylamine hydrochloride (1.75 g, 25.1 mmol). The resulting mixture was refluxed until the starting material was consumed (˜2 hours). The reaction was allowed to cool to room temperature, and the insoluble oxime was filtered. The filtrate was extracted with EtOAc, and the organic layer was concentrated. The resulting gray solid was combined with the oxime precipitate and treated with excess acetic anhydride (solvent). The reaction mixture was stirred at 100° C. until LCMS confirms complete conversion to the desired nitrile (˜5 days). The mixture was concentrated, and the resulting dark brown solid was co-evaporated with EtOH to removed excess acetic anhydride. The dark brown solid was triturated with CH3OH to afford N-[4-(4-cyano-3,5-difluorophenyl)-2-pyrimidinyl]acetamide (2.44 g 39%) as a tan solid. The filtrate was treated with aqueous sodium bicarbonate and K2CO3 in CH3OH, and the resulting mixture was stirred overnight at room temperature. The CH3OH was evaporated, and the resulting tan solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic layers were concentrated, and the resulting tan solid was triturated with CH3OH to afford the title compound (0.60 g 11%). LC-MS (ES) m/z=245 [M+H]+.

Workup

  1. temperatureThe resulting mixture was refluxed until the starting material
  2. customwas consumed (˜2 hours)
  3. filtrationthe insoluble oxime was filtered
  4. extractionThe filtrate was extracted with EtOAc
  5. concentrationthe organic layer was concentrated
  6. additiontreated with excess acetic anhydride (solvent)
  7. customto the desired nitrile (˜5 days)
  8. concentrationThe mixture was concentrated
  9. customto removed excess acetic anhydride
  10. customThe dark brown solid was triturated with CH3OH

Sources & evidence

ORD record
ord-ddfba556577445b987744098dc2e8101
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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