Methanol → HCID 59627738, compound

HRID 1930105Notes

Reaction equation

HRID 1930105 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[CH3:12].[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][C:15]=1[C:25]1[C:30]([F:31])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]=1[F:41].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:8]([C:6]1[N:7]=[C:2]([C:28]2[CH:27]=[C:26]([F:41])[C:25]([C:15]3[CH:16]=[CH:17][C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:14]=3[Cl:13])=[C:30]([F:31])[CH:29]=2)[C:3]([CH3:12])=[N:4][C:5]=1[CH3:11])(=[O:9])[NH2:10]

Participants

8

Reactant 4

HCID 887MethanolHCID 62657Potassium Phosphate, TribasicHCID 57992034HCID 57992034, compound2×HCID 59627631HCID 59627631, compound2×

Product 1

HCID 59627738HCID 59627738, compoundYield 53.8%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide (Intermediate A) (228 mg, 1.23 mmol) and methyl 2-(2-chloro-2′,6′-difluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)acetate (Intermediate 2-2; 521 mg, 1.23 mmol) and potassium phosphate, tri-basic (314 mg, 1.48 mmol) in DME (15 mL), MeOH (3.75 mL) and water (3.75 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (50.3 mg, 0.06 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 80° C. for 17 hours. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and 2M HCl (50 mL), the aqueous phase was extracted with a further 80 mL of EtOAc. The organic extracts were combined, dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′,6′-difluorobiphenyl-4-yl)acetate (295 mg, 53.7%) as a white solid.

Workup

  1. customdegassed again
  2. temperatureto cool to room temperature
  3. customevaporated
  4. customThe crude product was partitioned between EtOAc (75 mL), and 2M HCl (50 mL)
  5. extractionthe aqueous phase was extracted with a further 80 mL of EtOAc
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customto afford crude product
  10. customThe crude product was purified by flash silica chromatography, elution gradient 10 to 70% EtOAc in isohexane
  11. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-5130ac02f1204963946ec9218d1679dc
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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