Potassium Phosphate, Tribasic → Ethyl 2-{4-[(9R)-9-hydroxy-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate

HRID 579394Notes

Reaction equation

HRID 579394 reaction equation
Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH:3]=1.[CH3:28][C:29]([N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1)([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:15][C@@:7]1([C:16]([F:19])([F:17])[F:18])[C:6]2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([C:29]([CH3:28])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:40]=3)[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 58204434ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoateHCID 117599272(9R)-4-chloro-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-9-ol

Product 1

HCID 117599138Ethyl 2-{4-[(9R)-9-hydroxy-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionateYield 94.6%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Under an argon atmosphere, (9R)-4-chloro-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-9-ol (169 mg) was dissolved in 1,4-dioxane (1.5 ml), ethyl 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate (194 mg), water (0.5 ml), tripotassium phosphate (178 mg), palladium acetate (9 mg), and SPhos (33 mg) were added, and the mixture was stirred at 100° C. for 4.5 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (twice). The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate at a mixing ratio 1:1 (hexane:ethyl acetate) was used as an elution solvent) to give the title compound (218 mg).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionthe mixture was extracted with ethyl acetate (twice)
  3. washThe obtained organic layer was washed successively with water (twice) and saturated brine
  4. dry with materialThe obtained organic layer was dried over anhydrous magnesium sulfate
  5. filtrationthe insoluble material was filtered off
  6. customthe solvent in the filtrate was evaporated
  7. customThe obtained residue was purified by silica gel column chromatography (
  8. additiona mixture of hexane and ethyl acetate at a mixing ratio 1:1 (hexane:ethyl acetate)

Sources & evidence

ORD record
ord-869a0d0379ca4cd59257545927629013
Source dataset
uspto-grants-2015_05
Patent number
US09040717B2

Reaction notes

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