Dichloromethane → 5-Amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester

HRID 1929932Notes

Reaction equation

HRID 1929932 reaction equation
Br[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.ClCCl.C(N(CC)CC)C.[C]=O.[C:28]([O:31][CH2:32]C)(=[O:30])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[CH3:32][O:31][C:28]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1)=[O:30]

Participants

8

Reactant 5

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 714639895-Bromo-3-(4-fluorophenyl)pyrazin-2-amineHCID 178418416HCID 178418416, compound

Product 1

HCID 675046415-Amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolvent

Procedure

To a methanol solution (35 ml) of 5-bromo-3-(4-fluoro-phenyl)-pyrazin-2-ylamine (1.87 g, 6.97 mmol, 1.0 eq) was added 15 ml ethyl acetate at room temperature. [1,1′-bis(diphenylphosphino)ferrocen]palladium(II)chloride 1:1 complex with dichloromethane (0.26 g, 0.32 mmol, 0.05 eq) was added portion-wise to the reaction mixture followed by triethylamine (1.95 ml, 13.5 mmol, 2.0 eq) and the solution was heated with stirring to 110° C. under 70 bar carbon monoxide for 18 hours. On cooling and removal of carbon monoxide, the reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1) to afford 5-Amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester as white crystals. Yield=1.26 g (73%). 1H-NMR (400 MHz, DMSO): δ 3.80 (3H, s), 7.11 (2H, br s), 7.33 (2H, t, J=8.87 Hz), 7.67-7.70 (2H, m), 8.56 (1H, s). HPLC-MS=100%; 1.49 min (MW=247; M+1=248.3).

Workup

  1. temperaturethe solution was heated
  2. temperatureOn cooling
  3. customremoval of carbon monoxide
  4. concentrationthe reaction mixture was concentrated in vacuo
  5. customthe residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1)

Sources & evidence

ORD record
ord-b131d861dfb94bd99d2bb380e03a06f4
Source dataset
uspto-grants-2012_05
Patent number
US08188093B2

Reaction notes

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