Potassium Carbonate → Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate

HRID 350892Notes

Reaction equation

HRID 350892 reaction equation
[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[N:14]=[C:13]1[CH3:20].C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:15]1[N:14]=[C:13]([CH3:20])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:17](=[O:18])[CH:16]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 902971-(Bromomethyl)-2,4-difluorobenzeneHCID 21090223methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate

Product 1

HCID 21089018Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoateYield 83.3%

Reagents, catalysts & solvents 2

HCID 2855718-Crown-6CatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate (0.1 g, 0.00036 mol, from Step 2), K2CO3 (0.075 g, 0.00054 mol) and 2,4 difluorobenzylbromide (0.075 g, 0.00036 mol) in DMF (2.0 mL) containing 18-crown-6 (0.005 g) is stirred at room temperature for 1 h under argon atmosphere. DMF is distilled in vacuo and the residue is 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=401) are combined and concentrated to a small volume (˜20 mL). After cooling, 5% NaHCO3 solution (10 mL) is added and the solution is extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.12 g, 82%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.16 Hz), 7.55 (m, 2H), 7.00 (m, 2H), 5.79 (s, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.14 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 401.1346 (M+H calcd for C21H19N2O4F2 requires 401.1307).

Workup

  1. distillationDMF is distilled in vacuo
  2. customthe residue is purified by reverse-phase
  3. custom10–90% CH3CN/Water gradient (40 min)
  4. concentrationconcentrated to a small volume (˜20 mL)
  5. temperatureAfter cooling
  6. addition5% NaHCO3 solution (10 mL) is added
  7. extractionthe solution is extracted with dichloromethane (3×20 mL)
  8. dry with materialThe combined organic extracts are dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-965f4ae74a374e81a722c177a01330a8
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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