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

HRID 1930171Notes

Reaction equation

HRID 1930171 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:25]=[C:26]([F:36])[C:27]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)CCC.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:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([F:36])=[CH:25][C:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:22]=3[F:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 59627659Methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate2×HCID 596277414-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid

Product 1

HCID 59627664Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetateYield 26%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8008ButyronitrileSolvent

Conditions

Temperature
150 °C

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (243 mg, 0.90 mmol), methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 24-2; 300 mg, 0.90 mmol) and tripotassium phosphate (286 mg, 1.35 mmol) in butyronitrile (2 mL) was put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (59.1 mg, 0.07 mmol). The reaction mixture was heated in the microwave at 150° C. for 6 hours. The reaction mixture was concentrated and diluted with DCM (25 mL), and washed with water (2×25 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=12 g, flow rate=30 mL/min, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetate (96 mg, 26.0%) as a slightly coloured (purple tinge) solid.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additiondiluted with DCM (25 mL)
  3. washwashed with water (2×25 mL)
  4. customThe organic layer was dried
  5. customseperating cartridge
  6. customevaporated
  7. customto afford crude product
  8. customThe crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=12 g, flow rate=30 mL/min, elution gradient 0 to 50% EtOAc in isohexane
  9. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-d5afd3df650d4f9fa30a3b82f208fd53
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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