Acetic Acid → 2-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetic acid

HRID 1930174Notes

Reaction equation

HRID 1930174 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[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[F:29])=[CH:14][CH:13]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[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[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[F:29])=[CH:16][CH:17]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[O:5])[NH2:4]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 14797Potassium HydroxideHCID 59627677Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate2×

Product 1

HCID 596276602-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetic acidYield 49%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
40 °C

Procedure

Powdered potassium hydroxide (72.7 mg, 1.30 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate (Intermediate 25-1; 170 mg, 0.43 mmol) in tert-butanol (2.0 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 20 minutes. A thick precipitate formed so the reaction was quenched with acetic acid (0.124 mL, 2.16 mmol) in ethanol (20.0 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was partitioned between water (5 mL) and EtOAc (15 mL). The aqueous layer showed a pH=4˜5. The organic layer was separated and the aqueous re-extracted with EtOAc (2×5 mL). The combined organics were washed with brine (15 mL), dried over MgSO4 and evaporated in vacuo to give product. This was washed with Ether (5 mL) and dried under vacuum at room temperature to give an off white solid. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetic acid (80 mg, 48.8%) as a colourless

Workup

  1. customA thick precipitate formed so the reaction
  2. stirringthe resulting solution stirred for a further 20 minutes
  3. custombefore being evaporated to dryness
  4. customThe resulting solid was partitioned between water (5 mL) and EtOAc (15 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous re-extracted with EtOAc (2×5 mL)
  7. washThe combined organics were washed with brine (15 mL)
  8. dry with materialdried over MgSO4
  9. customevaporated in vacuo
  10. customto give product
  11. washThis was washed with Ether (5 mL)
  12. customdried under vacuum at room temperature
  13. customto give an off white solid
  14. customThe crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm)
  15. additionFractions containing the desired compound
  16. customwere evaporated to dryness

Sources & evidence

ORD record
ord-53e8dfb1844a48e2898701c1c040596a
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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