Ammonia → (5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl Carbamate

HRID 1867013Notes

Reaction equation

HRID 1867013 reaction equation
[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C1C([N+]([O-])=O)=CC=C([Cl-][C:39]([O-:41])=O)C=1.C([N:44](CC)CC)C.N>C1COCC1.CN(C=O)C.C(O)CC.CC#N.O>[C:39](=[O:41])([O:27][CH2:26][C:23]1[CH:22]=[N:21][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:25][N:24]=1)[NH2:44]

Participants

8

Reactant 3

HCID 222AmmoniaHCID 8471TriethylamineHCID 220506073-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one

Product 1

HCID 22050397(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl CarbamateYield 26.2%

Reagents, catalysts & solvents 4

HCID 10311-PropanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
0 °C

Procedure

To a suspension of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.21 g, 0.00055 mol) in THF (5.0 mL) and DMF (2.0 mL), was added 4-nitrophenylchloroformate (0.1 g, 0.0005 mol) and cooled to 0° C. Triethylamine (0.052 g, 0.0005 mol) was then added, stirred at room temperature for 1 h, and at 65° C. for an additional 1 h. It was cooled in an ice bath and added 2M ammonia in propanol (1.0 mL) and stirred at room temperature for 2 h. After the removal of the solvents under reduced pressure, the residue was partitioned between 5% sod. bicarbonate, and EtOAc (25 mL). The organic phase was washed with 5% sod. bicarbonate, (3×25 mL), water (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting substance was purified by isolated by reverse-phase HPLC using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z=495 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure, to afford the title compound as a white powder (0.065 g):

Workup

  1. waitat 65° C. for an additional 1 h
  2. temperatureIt was cooled in an ice bath
  3. stirringstirred at room temperature for 2 h
  4. customAfter the removal of the solvents under reduced pressure
  5. customthe residue was partitioned between 5% sod
  6. washThe organic phase was washed with 5% sod
  7. dry with materialbicarbonate, (3×25 mL), water (3×25 mL), dried (Na2SO4)
  8. concentrationconcentrated under reduced pressure
  9. customThe resulting substance was purified
  10. customby isolated by reverse-phase
  11. customfreeze-dried
  12. customthe residue was partitioned between 5% sod
  13. washThe organic phase was washed with water
  14. dry with materialdried (Na2SO4)
  15. concentrationconcentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-ba8f32169fdd404e85692189a0c2ef2d
Source dataset
uspto-grants-2009_12
Patent number
US07629363B2

Reaction notes

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