4-Methylmorpholine → 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N,4-dimethylbenzamide

HRID 350895Notes

Reaction equation

HRID 350895 reaction equation
[Br: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](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.[CH3:38][N:39]1CCOCC1>>[Br: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]([NH:39][CH3:38])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]

Participants

4

Reactant 3

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 210892453-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid

Product 1

HCID 98263433-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N,4-dimethylbenzamideYield 98.4%

Procedure

To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.16 g, 0.00034 mol, obtained from Step 5) at 0° C. is added isobutylchloroformate (0.063 g, 0.00046 mol) followed by the addition of N-methylmorpholine (0.064 g, 0.00064 mol). The resulting reaction mixture is stirred for 5 minutes under an argon atmosphere. The ice bath is then removed, the reaction mixture is stirred at room temperature for 20 minutes, then the reaction mixture is recooled to 0° C., and N-methylamine (0.5 mL of 2.0 M soln in THF) is added. The resulting mixture is stirred at room temperature for 10 min, concentrated 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=478) are combined, concentrated to a small volume (˜20 mL), cooled, 5% NaHCO3 solution (10 mL) is added and then the combined fractions are extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.16 g, 96%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.87 (dd 1H, J=8.0 Hz), 7.64 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (m, 2H), 2.89 (s, 3H), 2.16 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 478.0586 (M+H calcd for C21H19N2O4F2 requires 478.0572). 19F NMR(CD3OD/400 MHz) −111.84(m) and −115.91 (m).

Workup

  1. customThe resulting reaction mixture
  2. customThe ice bath is then removed
  3. stirringthe reaction mixture is stirred at room temperature for 20 minutes
  4. customis recooled to 0° C.
  5. additionN-methylamine (0.5 mL of 2.0 M soln in THF) is added
  6. stirringThe resulting mixture is stirred at room temperature for 10 min
  7. concentrationconcentrated in vacuo
  8. customthe residue is purified by reverse-phase
  9. custom10–90% CH3CN/Water gradient (40 min)
  10. concentrationconcentrated to a small volume (˜20 mL)
  11. temperaturecooled
  12. addition5% NaHCO3 solution (10 mL) is added
  13. extractionthe combined fractions are extracted with dichloromethane (3×20 mL)
  14. dry with materialThe combined organic extracts are dried (Na2SO4)
  15. filtrationfiltered
  16. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-5c76beaefe2b4eb1a3210192f1a3870b
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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