Potassium Phosphate, Tribasic → Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate

HRID 1930179Notes

Reaction equation

HRID 1930179 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]([C:37]2([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38]2)[CH:25]=[C:26]([F:36])[C:27]=1OS(C(F)(F)F)(=O)=O.[Cl-].[Li+].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]([C:37]4([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)=[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

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 433294Lithium ChlorideHCID 59627712Methyl 1-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)cyclopropanecarboxylate2×HCID 596277414-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid

Product 1

HCID 59627671Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylateYield 44.1%

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 (226 mg, 0.83 mmol), methyl 1-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)cyclopropanecarboxylate (Intermediate 28-2; 300 mg, 0.83 mmol), lithium chloride (70.6 mg, 1.67 mmol) and tripotassium phosphate (265 mg, 1.25 mmol) in butyronitrile (2 mL) was degassed for 10 minutes then put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (137 mg, 0.17 mmol). The reaction mixture was heated in the microwave at 150° C. for 1 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 90% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate (160 mg, 43.9%)

Workup

  1. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 90% EtOAc in isohexane
  2. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-76b723cdfb3d4b71a772c5d60da4a566
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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