Ethyl Acetate → [3-(2,2-Difluoro-2-phenyl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester

HRID 1016262Notes

Reaction equation

HRID 1016262 reaction equation
Br[C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 1514288Ethyl 2-(3-bromo-6-methyl-2-oxopyrazin-1(2H)-yl)acetateHCID 126355292,2-Difluoro-2-phenylethylamine

Product 1

HCID 22179412[3-(2,2-Difluoro-2-phenyl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl esterYield 76%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a stirred suspension of 3-bromo-1-(ethoxycarbonylmethyl)-6-methylpyrazinone (750 mg, 2.75 mmol), as prepared in step 5 of Example 2, in toluene (30 mL) was added 2,2-difluoro-2-phenylethylamine (900 mg, 5.75 mmol), as prepared in the preceding step. The mixture was refluxed for two days under nitrogen. The solution was allowed to cool to room temperature, and ethyl acetate (50 mL) was added. The diluted reaction mixture was washed with 10% HCl (2×20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (50 mL), brine, and dried over Na2SO4. After evaporating the solvent, the solid was collected and washed with 15% ethyl acetate in hexane to give the title compound as an off-white solid (730 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 (m, 3H), 6.67 (s, 1H ), 6.14 (s(br), 1H), 4.70 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 4.09 (td, 2 H, J=14.3, 6.5 Hz), 2.11 (s, 3H), 1.29 (t, 3H, J=7.1 Hz).

Workup

  1. customas prepared in the preceding step
  2. temperatureThe mixture was refluxed for two days under nitrogen
  3. customThe diluted reaction mixture
  4. washwas washed with 10% HCl (2×20 mL)
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×20 mL)
  6. washThe combined organic layers were washed with 10% citric acid (50 mL), brine
  7. dry with materialdried over Na2SO4
  8. customAfter evaporating the solvent
  9. customthe solid was collected
  10. washwashed with 15% ethyl acetate in hexane

Sources & evidence

ORD record
ord-76b63b06d8834dcabd0d3aeac2cf0441
Source dataset
uspto-grants-2002_11
Patent number
US06476016B2

Reaction notes

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