Acetic Acid → 1-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid

HRID 1930178Notes

Reaction equation

HRID 1930178 reaction equation
[OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]4)=[CH:20][C:19]=3[F:32])=[CH:14][CH:13]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[CH:20][C:19]=3[F:32])=[CH:16][CH:17]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 14797Potassium HydroxideHCID 59627671Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate2×

Product 1

HCID 596276721-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylic acidYield 38.4%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
40 °C

Procedure

Powdered potassium hydroxide (91 mg, 1.62 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate (Intermediate 28-1; 142 mg, 0.32 mmol) in tert-butanol (10 mL). The resulting yellow cloudy suspension was stirred at 40° C. for 1 hour. The reaction mixture was quenched with acetic acid (0.149 mL, 2.60 mmol) in ethanol (2 mL) and the resulting solution stirred for a further 10 minutes before being evaporated to dryness. The resulting solid was partitioned between water (20 mL) and ethyl acetate (20 mL). An insoluble solid was filtered off. The organic layer was separated and the aqueous re-extracted with ethyl acetate (20 mL). The combined organics were evaporated in vacuo to give crude product as an off white solid. The crude solid was triturated with mixture of DCM (3 mL) and methanol (3 mL) to give a solid which was collected by filtration and dried under vacuum to give 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid (52.0 mg, 37.8%) as a white solid.

Workup

  1. stirringthe resulting solution stirred for a further 10 minutes
  2. custombefore being evaporated to dryness
  3. customThe resulting solid was partitioned between water (20 mL) and ethyl acetate (20 mL)
  4. filtrationAn insoluble solid was filtered off
  5. customThe organic layer was separated
  6. extractionthe aqueous re-extracted with ethyl acetate (20 mL)
  7. customThe combined organics were evaporated in vacuo
  8. customto give crude product as an off white solid
  9. customThe crude solid was triturated with mixture of DCM (3 mL) and methanol (3 mL)
  10. customto give a solid which
  11. filtrationwas collected by filtration
  12. customdried under vacuum

Sources & evidence

ORD record
ord-4434895ef07d411b9d96a668159226e4
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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