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

HRID 1433795노트

반응식

HRID 1433795 반응식
[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]

참가 물질

9

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 75806Tricyclohexylphosphine2회HCID 2760897Cyclopropylboronic acid2회HCID 68619655(S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester

생성물 1

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

시약·촉매·용매 4

HCID 167845palladium(II) acetate촉매2회HCID 962Water용매HCID 1140Toluene용매HCID 8857Ethyl Acetate용매

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온도
100 °C

실험 절차

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%).

후처리

  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

출처 및 근거

ORD 기록
ord-e03da0adb421440bbbd46ec13f72546f
출처 데이터셋
uspto-grants-2009_11
특허 번호
US07612212B2

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