Ethyl Acetate → Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate

HRID 604168Notes

Reaction equation

HRID 604168 reaction equation
[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1Br)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[F:46][C:47]1[C:52]([CH:53]([CH3:55])[CH3:54])=[CH:51][C:50](B(O)O)=[C:49]([O:59][CH3:60])[CH:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:50]1[CH:51]=[C:52]([CH:53]([CH3:55])[CH3:54])[C:47]([F:46])=[CH:48][C:49]=1[O:59][CH3:60])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 53363739(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acidHCID 86626904Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate

Product 1

HCID 86626905Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrateYield 83.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (150 mg) is dissolved in 1,4-dioxane (3 ml) and thereto are added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (128 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32 mg) and cesium carbonate (196 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (140 mg). MS (m/z): 796 [M+H]+

Workup

  1. temperatureThe reaction solution is cooled to room temperature
  2. customthe mixture is separated
  3. washthe organic layer is washed with a saturated brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3)

Sources & evidence

ORD record
ord-cb05ffe716ca4b05ace6c8af878e99dd
Source dataset
uspto-grants-2011_03
Patent number
US07906517B2

Reaction notes

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