Potassium Phosphate, Tribasic → (S)-[1-(4-cyclopropyl-2-fluoro-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester

HRID 1433795Notes

Reaction equation

HRID 1433795 reaction equation
[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[F:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1(B(O)O)[CH2:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806Tricyclohexylphosphine2×HCID 2760897Cyclopropylboronic acid2×HCID 68619655(S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester

Product 1

HCID 68619453(S)-[1-(4-cyclopropyl-2-fluoro-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl esterYield 53.4%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To (S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.5 g, 9.0 mmol) and cyclopropylboronic acid (1.0 g, 11.7 mmol) in a mixture of toluene (40 mL) and water (2 mL) were added potassium phosphate tribasic (6.68 g, 31.5 mmol), tricyclohexylphosphine (0.50 g, 1.8 mmol) and palladium acetate (0.20 g, 0.89 mmol). The mixture was heated to 100° C. for 3 hours then additional tricyclohexylphosphine (0.25 g, 0.89 mmol) and palladium acetate (0.10 g, 0.45 mmol) were added. Heating at 100° C. was continued for an additional 3 hours before adding cyclopropylboronic acid (0.2 g, 2.33 mmol) and heating at 100° C. for a final period of 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), brine (once), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted with 9:1 v/v dichloromethane in hexanes to afford (S)-[1-(4-cyclopropyl-2-fluoro-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester as a colorless solid (2.0 g, 53%).

Workup

  1. temperatureHeating at 100° C.
  2. temperatureheating at 100° C. for a final period of 3 hours
  3. washwashed with water (twice), brine (once),
  4. dry with materialdried over sodium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by chromatography over silica gel
  8. washeluted with 9:1 v/v dichloromethane in hexanes

Sources & evidence

ORD record
ord-e03da0adb421440bbbd46ec13f72546f
Source dataset
uspto-grants-2009_11
Patent number
US07612212B2

Reaction notes

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