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

HRID 1930170Notes

Reaction equation

HRID 1930170 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]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][C:19]=3[F:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)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]([CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[F:30])=[CH:16][CH:17]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 59627664Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetate2×

Product 1

HCID 596276562-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetic acidYield 56.9%

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Conditions

Temperature
40 °C

Procedure

Powdered potassium hydroxide (0.039 g, 0.70 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetate (Intermediate 24-1; 0.096 g, 0.23 mmol) in tert-butanol (2.00 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 aq 1M HCl (1.4 mL, 1.40 mmol) 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 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. 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)-2,6-difluorobiphenyl-4-yl)acetic acid (0.052 g, 56.0%) as a colourless solid.

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. customThe crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm)
  12. additionFractions containing the desired compound
  13. customwere evaporated to dryness

Sources & evidence

ORD record
ord-b25baa185cff4fd780948b2b357c8b92
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

Loading…