Potassium Phosphate, Tribasic → HCID 86703746, compound

HRID 1849859Notes

Reaction equation

HRID 1849859 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH3:24])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([C:2]2[C:3]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:27][CH2:26]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703745HCID 86703745, compound

Product 1

HCID 86703746HCID 86703746, compoundYield 100%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of tert-butyl 5-chloro-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.50 g, 4.30 mmol), cyclopropylboronic acid (0.55 g, 6.41 mmol), potassium phosphate (3.60 g, 17.2 mmol) and tricyclohexylphosphine tetrafluoroborate (0.31 g, 0.86 mmol) in toluene (15 mL) and water (1.5 mL) under a nitrogen atmosphere was added palladium acetate (0.09 g, 0.43 mmol). The reaction mixture was heated at 130° C. for 30 minutes in the microwave, and then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate, the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded tert-butyl 5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.5 g, 4.3 mmol), which was used directly for the next step. To a solution of this compound (1.50 g, 4.30 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo. The residue was triturated in diethyl ether (10 mL), the solid was filtered, rinsed with diethyl ether (2×10 mL) and dried to give the title compound (0.63 g, 48%): 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 1H), 6.58 (d, J=12.9 Hz, 1H), 3.87 (dd, J=6.7, 2.3 Hz, 2H), 2.17-1.91 (m, 3H), 1.76-1.31 (m, 8H), 0.98-0.84 (m, 5H), 0.67-0.58 (m, 2H).

Workup

  1. temperaturecooled to ambient temperature
  2. extractionthe mixture extracted with ethyl acetate
  3. washthe combined organics were washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customPurification of the residue by column chromatography (5% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-9de43e338d214e8dbd1763234311810f
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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