1,2-Dimethoxyethane → Ethyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2'-dichlorobiphenyl-4-yl)acetate

HRID 1930165Notes

Reaction equation

HRID 1930165 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([Cl:19])[CH:11]=2)[C:7]([CH3:20])=[N:6][C:5]=1[CH3:21])(=[O:3])[NH2:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:26]=[CH:27][C:28]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:50]OCCOC>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:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:28]3[CH:27]=[CH:26][C:25]([CH2:37][C:38]([O:40][CH2:41][CH3:50])=[O:39])=[CH:24][C:23]=3[Cl:22])=[C:12]([Cl:19])[CH:11]=2)[C:7]([CH3:20])=[N:6][C:5]=1[CH3:21])(=[O:3])[NH2:2]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 62657Potassium Phosphate, TribasicHCID 3564187Methyl 2-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl]acetate2×HCID 672865054-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenylboronic acid2×

Product 1

HCID 59627737Ethyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2'-dichlorobiphenyl-4-yl)acetateYield 19.26%

Reagents, catalysts & solvents 3

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

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenylboronic acid (Intermediate 5-1; 450 mg, 1.47 mmol), methyl 2-(3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 1-2; 490 mg, 1.47 mmol) and tripotassium phosphate (469 mg, 2.21 mmol) in DME (6 mL), ethanol (3 mL) and water (1.5 mL) was put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (97 mg, 0.12 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 (eluted of at 50%). Pure fractions were evaporated to dryness to afford ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-dichlorobiphenyl-4-yl)acetate (130 mg, 19.26%) as a white solid. Trans esterification occurred during the reaction giving the product as an ethyl rather than methyl ester.

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 (eluted of at 50%)
  11. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-099ed71e461e42ebb99d35d4c35407a4
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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