Potassium Phosphate, Tribasic → HCID 86703530, compound

HRID 1849664Notes

Reaction equation

HRID 1849664 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].[CH:26]1(B(O)O)[CH2:28][CH2:27]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:26]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([C:22]([F:24])([F:25])[F:23])[CH2:19][CH2:20][CH2:21]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:28][CH2:27]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703528HCID 86703528, compound

Product 1

HCID 86703530HCID 86703530, compound

Reagents, catalysts & solvents 3

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

Conditions

Temperature
110 °C

Procedure

To a solution of tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate (2.11 g, 5.5 mmol), cyclopropylboronic acid (0.94 g, 11.0 mmol), potassium phosphate (5.25 g, 24.8 mmol) and tricyclohexylphosphine tetrafluoroborate (0.4 g, 1.10 mmol) in toluene (60 mL) and water (3 mL) under a nitrogen atmosphere was added palladium acetate (0.25 g, 1.10 mmol). The reaction mixture was heated to 110° C. for 18 hours 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., the crude product tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate was dissolved in dichloromethane (30 mL) and added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by column chromatography (5% to 60% ethyl acetate contains 0.2% acetic acid in hexanes) afforded the title compound was obtained as colorless solid (0.50, 27%): MS (ES+) m/z 333.1 (M+1); MS (ES−) m/z 331.2 (M−1).

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. dissolution, the crude product tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate was dissolved in dichloromethane (30 mL)
  7. additionadded trifluoroacetic acid (10 ml)
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by column chromatography (5% to 60% ethyl acetate contains 0.2% acetic acid in hexanes)

Sources & evidence

ORD record
ord-a680d6484865435c9567db318f3efa77
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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