Hydrochloric Acid → {3,5-Dimethyl-1-[4-(4-trifluoromethyl-phenylethynyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid

HRID 1631918Notes

Reaction equation

HRID 1631918 reaction equation
C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+].Cl>O1CCCC1.O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:19][C:6]1[C:5]([CH2:4][C:3]([OH:2])=[O:20])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:30]#[C:29][C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[N:7]=1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 43482951-Ethynyl-4-(trifluoromethyl)benzeneHCID 63276242[1-(4-Bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester2×

Product 1

HCID 58071838{3,5-Dimethyl-1-[4-(4-trifluoromethyl-phenylethynyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

Heck coupling: A solution of [1-(4-bromo-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 12.1.1, 500 mg, 1.5 mmol), 4-trifluoromethyl-phenylacetylene (0.24 ml, 1.5 mmol) and diisopropylethylamine (0.51 ml, 3 mmol) in 15 ml tetrahydrofurane was degassed, and CuI (28 mg, 0.15 mmol) and bis-(triphenylphosphin)-palladium dichloride (104 mg, 0.15 mmol) were added to the solution. The mixture was refluxed for 12 h, the solvent evaporated under reduced pressure, and the residue was purified by MPLC (silica gel, cyclohexane/ethyl acetate 98:2). Saponification: The ester intermediate (170 mg, 0.4 mmol) was dissolved in 1 ml dioxan, 1 ml water and aqueous NaOH solution (0.8 ml, 1 M) was added. After stirring for 1 h, aqueous HCl solution (0.84 ml, 1 M) was added. The mixture was extracted with ethyl acetate, the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 9:1) and preparative reversed phase HPLC (gradient of methanol in water+0.1 NH3).

Workup

  1. temperatureThe mixture was refluxed for 12 h
  2. customthe solvent evaporated under reduced pressure
  3. customthe residue was purified by MPLC (silica gel, cyclohexane/ethyl acetate 98:2)
  4. extractionThe mixture was extracted with ethyl acetate
  5. dry with materialthe organic layer was dried with MgSO4
  6. customevaporated under reduced pressure
  7. customThe residue was purified by MPLC (silica gel, CH2Cl2/methanol 9:1) and preparative reversed phase HPLC (gradient of methanol in water+0.1 NH3)

Sources & evidence

ORD record
ord-dc9349325b644b7ca7cbe92e5e048009
Source dataset
uspto-grants-2014_07
Patent number
US08791272B2

Reaction notes

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