Methanol → Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate

HRID 1930141Notes

Reaction equation

HRID 1930141 reaction equation
FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][CH:8]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:42]2([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]2)[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:32]3[CH:31]=[CH:30][C:29]([C:42]4([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]4)=[CH:28][C:27]=3[Cl:26])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]

Participants

8

Reactant 4

HCID 887MethanolHCID 62657Potassium Phosphate, TribasicHCID 59627717Methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate2×HCID 596277294-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate2×

Product 1

HCID 59627667Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylateYield 49.8%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate (Intermediate 7-4; 245 mg, 0.65 mmol) and methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (Intermediate 10-2; 220 mg, 0.65 mmol) and potassium phosphate, tri-basic (166 mg, 0.78 mmol) in DME (4 mL), methanol (2 mL) and water (1 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (26.7 mg, 0.03 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours in the microwave. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL). 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 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate (141 mg, 49.5%) as a colourless gum.

Workup

  1. customdegassed again
  2. temperatureto cool to room temperature
  3. customevaporated
  4. customThe crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL)
  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 0 to 70% EtOAc in isohexane
  10. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-b3aaec71b9b84addaf4cb48a88887d0b
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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