Potassium Phosphate, Tribasic → Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate

HRID 1930175Notes

Reaction equation

HRID 1930175 reaction equation
[CH3:1][C:2]1[C:3]([C:24]([NH2:26])=[O:25])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:31]=[CH:32][C:33]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(O)C.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:24]([C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:33]3[CH:32]=[CH:31][C:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:29][C:28]=3[F:27])=[CH:13][CH:14]=2)[C:6]([CH3:8])=[N:7][C:2]=1[CH3:1])(=[O:25])[NH2:26]

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 59627703Methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate2×HCID 596277103,5-Dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide

Product 1

HCID 59627677Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetateYield 45.8%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

A solution of 3,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (353 mg, 1 mmol), methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 25-2; 411 mg, 1.30 mmol) and tripotassium phosphate (318 mg, 1.50 mmol) in DME (6 mL), ethanol (3.00 mL) and water (1.500 mL) was put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (65.8 mg, 0.08 mmol). The reaction mixture was heated to and left to stir overnight for 16 hrs. The reaction mixture was allowed to cool to room temperature and then evaporated. The residue was partitioned between water (20 mL) and EtOAc (50 mL). The aqueous was re-extracted with EtOAc (2×10 mL) and the combined organics washed with brine (20 mL), dried (MgSO4) and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane on 40 g silicycle column. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate (180 mg, 45.8%) as a white solid.

Workup

  1. temperatureThe reaction mixture was heated to and
  2. waitleft
  3. customevaporated
  4. customThe residue was partitioned between water (20 mL) and EtOAc (50 mL)
  5. extractionThe aqueous was re-extracted with EtOAc (2×10 mL)
  6. washthe combined organics washed with brine (20 mL)
  7. dry with materialdried (MgSO4)
  8. customevaporated
  9. customto give crude product
  10. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane on 40 g silicycle column
  11. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-4d0cc794edd64329b26198b48d5d536a
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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