Acetic Acid → 3-[(2S)-1-(Difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoic acid

HRID 2425484Notes

Reaction equation

HRID 2425484 reaction equation
[F:1][CH:2]([F:30])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].[OH-].[Na+].C(O)(=O)C.Cl>O.CN1C(=O)CCC1>[F:30][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 59205092Methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate

Product 1

HCID 592050903-[(2S)-1-(Difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoic acidYield 86.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

To methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (76.3 g, 179 mmol) was added NMP (534 mL), water (305 mL) and the solution was stirred at 0° C. 2N sodium hydroxide (152 mL, 305 mmol) was charged dropwise and the reaction stirred for 4 hours. Acetic acid (41 mL, 718 mmol) was charged dropwise followed by water (1068 mL) and 1N HCl (400 mL) was added until pH 3 was reached and some material oiled out. The aqueous layer was extracted with toluene (3×988 mL) and combined with the material that oiled out which was dissolved in ethyl acetate (988 mL) and the combined organic layers were washed with water (988 mL), saturated aqueous brine (988 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 5% MeOH in dichloromethane to afford the title compound (64 g).

Workup

  1. stirringthe reaction stirred for 4 hours
  2. additionwas added until pH 3
  3. extractionThe aqueous layer was extracted with toluene (3×988 mL)
  4. dissolutionwas dissolved in ethyl acetate (988 mL)
  5. washthe combined organic layers were washed with water (988 mL), saturated aqueous brine (988 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated under reduced pressure
  8. customThe residue was purified by flash chromatography
  9. washeluting with 5% MeOH in dichloromethane

Sources & evidence

ORD record
ord-c7f4ae0399d141379a30bcd864ad2295
Source dataset
uspto-grants-2011_06
Patent number
US07964725B2

Reaction notes

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