Sodium Bicarbonate → 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester

HRID 541156Notes

Reaction equation

HRID 541156 reaction equation
[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1)[CH3:6])[CH3:2].Cl[C:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:37]([F:40])([F:39])[F:38])([OH:36])[C:27]=2[CH:26]=[C:25]([F:41])[CH:24]=1.C(=O)([O-])O.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[CH:11]=[C:10]([C:23]2[C:35]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([OH:36])([C:37]([F:40])([F:39])[F:38])[C:27]=3[CH:26]=[C:25]([F:41])[CH:24]=2)[CH:9]=[N:8]1)[CH3:6])[CH3:2]

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 59492689(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-olHCID 59492972Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate

Product 1

HCID 594925982-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl esterYield 95.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 22272177Toluene waterSolvent

Conditions

Temperature
115 °C

Procedure

To a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester (29.2 g), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (20.4 g), and sodium hydrogen carbonate (11.1 g) in toluene/water (200 ml/66 ml) were added palladium acetate (743 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.72 g) at room temperature, and the mixture was stirred at 115° C. for 8 hr. To the reaction mixture were added activated carbon (10 g) and Celite (10 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with toluene (100 ml). The filtrate was partitioned, and the aqueous layer was extracted with toluene (60 ml). The combined organic layer was washed 3 times with water (100 ml), and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml) was added silica gel (40 g), and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1) to give the title compound (27.9 g).

Workup

  1. additionTo the reaction mixture were added activated carbon (10 g) and Celite (10 g) at room temperature
  2. stirringthe mixture was stirred for 1 hr
  3. filtrationThe mixture was filtered through celite
  4. washthe solid was washed with toluene (100 ml)
  5. customThe filtrate was partitioned
  6. extractionthe aqueous layer was extracted with toluene (60 ml)
  7. washThe combined organic layer was washed 3 times with water (100 ml)
  8. dry with materialonce with saturated brine (100 ml), dried over anhydrous sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. additionTo a solution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml) was added silica gel (40 g)
  11. stirringthe mixture was stirred at room temperature for 1 hr
  12. filtrationThe mixture was filtered
  13. concentrationconcentrated under reduced pressure
  14. customThe obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1)

Sources & evidence

ORD record
ord-4920c9fae7154fd7bb7c7575a0cad23b
Source dataset
uspto-grants-2014_10
Patent number
US08871934B2

Reaction notes

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