Methyl chloroformate → HCID 21035374, compound

HRID 1832100Notes

Reaction equation

HRID 1832100 reaction equation
[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[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].[CH3:30][O:31][C:32](Cl)=[O:33].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:32](=[O:33])[O:31][CH3:30])=[N:24][CH:25]=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]

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 22050409HCID 22050409, compound

Product 1

HCID 21035374HCID 21035374, compoundYield 57.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
5 °C

Procedure

To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.20 g, 0.4 mmol) in DMF (2.0 ml), was added methylchloroformate (0.049 g, 0.52 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at 5° C. for 30 min and at room temperature for an additional 30 min and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (10.0 mL). The organic extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=523 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.12 g, 53%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (m, 1H), 7.60 (m, 1H), 7.05 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.58 (s, 2H), 3.69 and 3.64 (s, 3H), 2.97 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR(CD3OD/400 MHz) −111.69 (m) and −116.09 (m); ES-HRMS m/z 523.0775(M+H calcd for C22H22BrF2N4O4 requires 523.0787).

Workup

  1. concentrationconcentrated in vacuo
  2. customThe residue was partitioned between water (5.0 mL) and EtOAc (10.0 mL)
  3. extractionThe organic extract
  4. washwas washed with water
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated to dryness
  7. customThe resulting material was purified by reverse-phase
  8. custom10-90% CH3CN/Water gradient (60 min)
  9. customfreeze dried
  10. customto give a white powder
  11. customThis was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL)
  12. washThe organic layer was washed with water
  13. dry with materialdried (Na2SO4)
  14. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-29af51417eee4738b38c6784ff0b484e
Source dataset
uspto-grants-2006_06
Patent number
US07067540B2

Reaction notes

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