Potassium Phosphate, Tribasic → Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2'-fluorobiphenyl-4-yl)propanoate

HRID 1930177Notes

Reaction equation

HRID 1930177 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][C:8]=1[F:24])(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])[CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1.[Cl-].[Li+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CO>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:33]3[CH:32]=[CH:31][C:30]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])=[CH:29][C:28]=3[Cl:27])=[C:8]([F:24])[CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 433294Lithium ChlorideHCID 59627648Methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate2×HCID 59627655HCID 59627655, compound2×

Product 1

HCID 59627723Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2'-fluorobiphenyl-4-yl)propanoateYield 86.1%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 6-4; 703 mg, 1.79 mmol) and methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (Intermediate 8-2; 580 mg, 1.79 mmol), lithium chloride (133 mg, 3.13 mmol) and potassium phosphate, tri-basic (455 mg, 2.14 mmol) in DME (20 mL), methanol (10 mL) and water (5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (73.0 mg, 0.09 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 85° C. for 17 hours. The reaction mixture was allowed to cool and evaporated, the residue was partitioned between EtOAc (100 mL), and water (75 mL) and the aqueous layer was further extracted with EtOAc (100 mL). The organic layers were combined and washed with saturated brine (100 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)propanoate (681 mg, 86%) as a cream solid.

Workup

  1. customdegassed again
  2. temperatureto cool
  3. customevaporated
  4. customthe residue was partitioned between EtOAc (100 mL), and water (75 mL)
  5. extractionthe aqueous layer was further extracted with EtOAc (100 mL)
  6. washwashed with saturated brine (100 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customto afford crude product
  11. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in isohexane
  12. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-20f34858bb674e5981e987e382bfe19f
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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