Potassium Phosphate, Tribasic → Tert-butyl 5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

HRID 1849607Notes

Reaction equation

HRID 1849607 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]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:27]1(B(O)O)[CH2:29][CH2:28]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:27]1([C:2]2[C:3]([O:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]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])[CH2:29][CH2:28]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acid2×HCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborate2×HCID 86703462Tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

Product 1

HCID 86703461Tert-butyl 5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoateYield 25.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 22272177Toluene waterSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate (0.681 g, 1.70 mmol) in toluene-water (v/v 20:1, 10.5 mL) was added cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.064 g, 0.17 mmol) and potassium phosphate tribasic (1.658 g, 7.80 mmol). The mixture was sparged with nitrogen gas for 10 minutes and sonicated for an additional 5 minutes. Palladium (II) acetate (0.019 g, 0.082 mmol) was added and the reaction mixture heated at 100° C. under nitrogen for 16 hours. The mixture was then cooled to ambient temperature then charged with additional cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.070 g, 0.19 mmol) and palladium(II) acetate (0.021 g, 0.094 mmol). The mixture was heated to 100° C. and stirred for an additional 24 hours. The solution was then cooled to ambient temperature and filtered through diatomaceous earth with ethyl acetate. The solution was concentrated in vacuo and purified by column chromatography (0% to 20% ethyl acetate in hexanes) to afford the title compound (0.173 g, 25%): 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.7 Hz, 1H), 4.04 (t, J=6.2 Hz, 2H), 2.15-2.07 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.61 (m, 7H), 1.57 (s, 9H), 1.43-1.31 (m, 2H), 0.92-0.86 (m, 2H), 0.66-0.61 (m, 2H).

Workup

  1. customThe mixture was sparged with nitrogen gas for 10 minutes
  2. customsonicated for an additional 5 minutes
  3. temperatureThe mixture was then cooled to ambient temperature
  4. temperatureThe mixture was heated to 100° C.
  5. temperatureThe solution was then cooled to ambient temperature
  6. filtrationfiltered through diatomaceous earth with ethyl acetate
  7. concentrationThe solution was concentrated in vacuo
  8. custompurified by column chromatography (0% to 20% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-83ab23fffb7d40e3ba1b36d765799e27
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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