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

HRID 1930102Notes

Reaction equation

HRID 1930102 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.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:35][C:36]1[CH:37]=[C:38]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:39]=[CH:40][C:41]=1OS(C(F)(F)F)(=O)=O>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:41]3[CH:40]=[CH:39][C:38]([CH2:50][C:51]([O:53][CH3:54])=[O:52])=[CH:37][C:36]=3[Cl:35])=[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 3564187Methyl 2-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl]acetate2×HCID 596277103,5-Dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide2×

Product 1

HCID 59627714Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetateYield 48.8%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
80 °C

Procedure

To a degassed solution of 3,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (Intermediate 7-6; 196 mg, 0.55 mmol) in DME (6 mL), ethanol (1.5 mL) and water (1.5 mL) was added tripotassium phosphate (141 mg, 0.67 mmol), methyl 2-(3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 1-2; 185 mg, 0.55 mmol) followed by (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (36.5 mg, 0.04 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 4 hours. The reaction mixture was allowed to cool to ambient temperature, evaporated and partitioned between EtOAc (75 mL) and saturated brine (50 mL) then filtered through celite. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetate (110 mg, 48.4%) as a white solid.

Workup

  1. temperatureto cool to ambient temperature
  2. customevaporated
  3. custompartitioned between EtOAc (75 mL) and saturated brine (50 mL)
  4. filtrationthen filtered through celite
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. customto afford crude product
  9. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 80% EtOAc in isohexane
  10. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-0bb3af75685f46449a5ed24318d574e3
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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