3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide → 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide

HRID 350904Notes

Reaction equation

HRID 350904 reaction equation
[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[C:5](SC)=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>[Ni].C(O)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[CH:5]=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]

Participants

4

Reactant 1

HCID 210890053-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide

Product 1

HCID 210890063-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamideYield 56%

Reagents, catalysts & solvents 2

HCID 935NickelCatalyst2×HCID 702EthanolSolvent

Procedure

A mixture of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide (0.15 g, 0.00033 mol from step 5), and Raney nickel (0.8 mL, 50% slurry in water) in ethanol (15.0 mL) was refluxed under argon atmosphere. After 12 h, added an additional 0.4 mL of Raney nickel and continued refluxing for another 4 h. The reaction mixture was cooled and the supernatant was decanted off. The catalyst was washed with ethanol, the combined ethanol washings and the supernatant were concentrated under reduced pressure and the resulting residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=406) were combined and concentrated to a small volume (˜20 mL), cooled added 5% sod. bicarbonate (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to dryness to afford the title compound (0.075 g,) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.31 (s, 1H), 7.94 (dd, 1H. J=2.0 Hz & 8.0 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.53 (m, 1H), 7.02 (m, 2H), 5.59 (m, 2H), and 2.19 (s, 3H); ES-HRMS m/z 406.0774 (M+H calcd for C19H15N3O3F2Cl requires 406.0765); 19F NMR(CD3OD/400 MHz) −111.62 (m) and −115.94 (m).

Workup

  1. temperaturewas refluxed under argon atmosphere
  2. temperaturecontinued refluxing for another 4 h
  3. temperatureThe reaction mixture was cooled
  4. customthe supernatant was decanted off
  5. washThe catalyst was washed with ethanol
  6. concentrationthe combined ethanol washings and the supernatant were concentrated under reduced pressure
  7. customthe resulting residue was purified by reverse-phase
  8. custom10–90% CH3CN/Water gradient (40 min)
  9. concentrationconcentrated to a small volume (˜20 mL)
  10. temperaturecooled
  11. additionadded 5% sod
  12. extractionbicarbonate (10 mL) and extracted with dichloromethane (3×20 mL)
  13. dry with materialThe combined organic extracts were dried (Na2SO4)
  14. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-f2d378a418c146c59b2f329d6a581164
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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