Potassium Phosphate, Tribasic → Tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoate

HRID 1849595Notes

Reaction equation

HRID 1849595 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[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:28]1(B(O)O)[CH2:30][CH2:29]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:28]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([C:24]([F:25])([F:26])[F:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[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])[CH2:30][CH2:29]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703448Tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate

Product 1

HCID 86703449Tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoateYield 83.6%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a mixture of tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate (4.37 g, 10.63 mmol), cyclopropylboronic acid (1.37 g, 15.93 mmol), potassium phosphate (10.15 g, 47.81 mmol) and tricyclohexylphosphine tetrafluoroborate (0.39 g, 1.06 mmol) in toluene (60 mL) and water (3 mL) under a nitrogen atmosphere was added palladium acetate (0.12 g, 0.53 mmol). The reaction mixture was heated at 100° C. for 18 hours and then cooled to ambient temperature. Water (20 mL) was added and the mixture, and extracted with ethyl acetate, the combined organic extracts was 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 the title compound (3.70 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.3 Hz, 1H), 4.07 (s, 2H), 1.99-1.88 (m, 4H), 1.76-1.62 (m, 5H), 1.55 (s, 9H), 1.48-1.24 (m, 2H), 0.91-0.82 (m, 2H), 0.62-0.55 (m, 2H).

Workup

  1. temperaturecooled to ambient temperature
  2. extractionthe mixture, and extracted with ethyl acetate
  3. washthe combined organic extracts was 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-e5841c3505d34389ba7c1cfc1df26274
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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