Hydrochloric Acid → (3,5-Dimethyl-1-{4-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-benzyl}-1H-pyrazol-4-yl)-acetic acid

HRID 1631919

Reaction equation

HRID 1631919 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:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[OH-].[Na+].Cl>CN(C)C=O.O1CCOCC1.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](/[CH:28]=[CH:27]/[C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[N:7]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 27827981-Ethenyl-4-(trifluoromethyl)benzeneHCID 63276242[1-(4-Bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester2×

Product 1

HCID 58071668(3,5-Dimethyl-1-{4-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-benzyl}-1H-pyrazol-4-yl)-acetic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

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)styrene (0.24 ml, 1.6 mmol) and diisopropylethylamine (0.38 ml, 2.2 mmol) in 10 ml dimethylformamide was degassed, and Pd(II) acetate (33 mg, 0.15 mmol) and tri(o-tolyl)phosphine (45 mg, 0.15 mmol) were added to the solution under argon. The mixture was heated for 4 h at 90° C. and stirred for 12 h at room temperature. The mixture was poured into water and extracted twice with ethyl acetate. The organic layer was separated, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1). Saponification: The ester intermediate (530 mg, 1.24 mmol) was dissolved in 5 ml dioxane and aqueous NaOH solution (2.5 ml, 1 M). After stirring for 1 h and dilution with water, aqueous HCl solution (2.6 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 91:9) and preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).

Workup

  1. extractionextracted twice with ethyl acetate
  2. customThe organic layer was separated
  3. dry with materialdried over MgSO4
  4. customthe solvent was evaporated under reduced pressure
  5. customThe residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1)
  6. stirringAfter stirring for 1 h
  7. extractionThe mixture was extracted with ethyl acetate
  8. dry with materialthe organic layer was dried with MgSO4
  9. customevaporated under reduced pressure
  10. customThe residue was purified by MPLC (silica gel, CH2Cl2/methanol 91:9) and preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3)

Sources & evidence

ORD record
ord-61f109f97b6849609f42a5a10438203e
Source dataset
uspto-grants-2014_07
Patent number
US08791272B2

Linked notes

Loading…