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

HRID 1930133Notes

Reaction equation

HRID 1930133 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:46]([O:48][CH3:49])=[O:47])[CH2:45][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:46]([O:48][CH3:49])=[O:47])[CH2:45][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 59627692Methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxylate2×HCID 596277294-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate2×

Product 1

HCID 59627699Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylateYield 69%

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; 289 mg, 0.77 mmol) and methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxylate (Intermediate 7-2; 270 mg, 0.77 mmol) and potassium phosphate, tri-basic (196 mg, 0.92 mmol) in DME (10 mL), MeOH (5 mL) and water (2.5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (31.4 mg, 0.04 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours. The reaction mixture was allowed to cool, diluted with EtOAc (40 mL) and water (20 mL). This was passed through a silica pad washing with EtOAc. The filtrate was separated and washed with brine (20 mL) then 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)cyclobutanecarboxylate (239 mg, 69.0%) as a colourless gum.

Workup

  1. customdegassed again
  2. temperatureto cool
  3. additiondiluted with EtOAc (40 mL) and water (20 mL)
  4. washwashing with EtOAc
  5. customThe filtrate was separated
  6. washwashed with brine (20 mL)
  7. customthen evaporated
  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-3ddbb706093c4a8b95f3e3050711c011
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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