Hydrochloric Acid → Trifluoroacetic acid

HRID 1255168Notes

Reaction equation

HRID 1255168 reaction equation
[C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.I[C:16]1[CH:49]=[CH:48][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:33]=[C:32]([N:34]3[C:38]([C:39]([F:42])([F:41])[F:40])=[C:37]([C:43]([O:45]CC)=[O:44])[CH:36]=[N:35]3)[CH:31]=[CH:30][CH:29]=2)=[CH:18][CH:17]=1.[OH-].[Li+].Cl>O1CCOCC1.[Cu]Cl>[C:1]([OH:2])([C:39]([F:42])([F:41])[F:40])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:49]=[CH:48][C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:33]=[C:32]([N:34]4[C:38]([C:39]([F:42])([F:41])[F:40])=[C:37]([C:43]([OH:45])=[O:44])[CH:36]=[N:35]4)[CH:31]=[CH:30][CH:29]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 46844-ChlorophenolHCID 10796Cesium carbonateHCID 67159424Ethyl 1-(6-{2-[(4-iodobenzyl)oxy]phenyl}pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

Product 2

HCID 6422Trifluoroacetic acidHCID 252332971-[6-(2-{[4-(4-Chlorophenoxy)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalystHCID 312751,4-DioxaneSolvent2×

Procedure

A vial was charged with copper (I) chloride (1.7 mg, 0.017 mmol), cesium carbonate (55.0 mg, 0.169 mmol), 4-chlorophenol (21.7 mg, 0.169 mmol), and the title compound from Example 5 Step A (50.0 mg, 0.084 mmol). 2,2,6,6-Tetramethyl-3,5-dione (0.007 mL, 0.034 mmol) was added and the mixture was flushed with nitrogen. Degassed N-methylpyrrolidinone (0.170 mL) was added, and the vial was capped and placed in a pre-heated oil bath (120° C.). After 15 h, the mixture was allowed to cool to ambient temperature, then was filtered through a short plug of silica gel with DCM and concentrated in vacuo: LCMS m/z 594.3 [M+H]+. To a solution of the unpurified coupling product in 1,4-dioxane (1 mL) was added lithium hydroxide (0.5 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 564.4 [M−H]−; 1H NMR (500 MHz, d6-DMSO) δ 8.27 (s, 1H), 8.15-8.09 (m, 2H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (dd, J=7.5, 1.0 Hz, 1H), 7.47-7.42 (m, 4H), 7.29 (d, J=8.0 Hz, 2H), 7.12-7.09 (m, 2H), 7.04-7.00 (m, 3H), 5.22 (s, 2H).

Workup

  1. addition2,2,6,6-Tetramethyl-3,5-dione (0.007 mL, 0.034 mmol) was added
  2. customthe mixture was flushed with nitrogen
  3. additionDegassed N-methylpyrrolidinone (0.170 mL) was added
  4. customthe vial was capped
  5. customplaced in a pre-heated oil bath
  6. custom(120° C.)
  7. filtrationwas filtered through a short plug of silica gel with DCM
  8. concentrationconcentrated in vacuo
  9. waitAfter 30 min
  10. filtrationfilter
  11. customPurification by reverse phase HPLC (50 to 100% acetonitrile in water

Sources & evidence

ORD record
ord-64e39c939fe94748ad43929fd6a95abc
Source dataset
uspto-grants-2013_06
Patent number
US08455638B2

Reaction notes

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