Potassium Carbonate → Ethyl 3-[4-[[5-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-2-thienyl]methoxy]-2-fluoro-phenyl]propanoate

HRID 69094Notes

Reaction equation

HRID 69094 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[S:28][C:27]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:26]([O:38][CH3:39])[CH:25]=1>C(#N)C>[Si:31]([O:30][CH2:29][C:27]1[S:28][C:24]([CH2:23][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:8]([F:14])[CH:9]=2)=[CH:25][C:26]=1[O:38][CH3:39])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 23082888Ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoateHCID 68194046(5-Bromomethyl-3-methoxy-thiophen-2-ylmethoxy)-tert-butyl-dimethyl-silane

Product 1

HCID 67240427Ethyl 3-[4-[[5-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-2-thienyl]methoxy]-2-fluoro-phenyl]propanoateYield 21.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 3-(2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (1.03 g, 4.8 mmol) in acetonitrile (15 mL) is added potassium carbonate (2.31 g, 16.8 mmol) and (5-bromomethyl-3-methoxy-thiophen-2-ylmethoxy)-tert-butyl-dimethyl-silane (1.7 g, 4.8 mmol) at room temperature and the reaction mixture is refluxed for 3 hours. The reaction mixture is concentrated, diluted with water, and extracted with EtOAc (2×30 mL). The combined extracts are washed with water (15 mL) and saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.6:0.4) to give the title compound (0.5 g, 21%). 1H NMR (400 MHz, DMSO d6) δ 7.51 (s, 1H), 7.26-7.2 (t, J=8.4 Hz, 1H), 6.92-6.89 (d, J=12 Hz, 1H), 6.83-6.81 (d, J=7.6 Hz, 2H), 4.92 (s, 2H), 4.82 (s, 2H), 4.10-4.05 (q, J=6.4 Hz, 2H), 3.82 (s, 3H), 2.86-2.82 (t, J=16 Hz, 2H), 2.61-2.55 (m, 2H), 1.21-1.17 (t, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 6H).

Workup

  1. temperaturethe reaction mixture is refluxed for 3 hours
  2. concentrationThe reaction mixture is concentrated
  3. additiondiluted with water
  4. extractionextracted with EtOAc (2×30 mL)
  5. washThe combined extracts are washed with water (15 mL) and saturated brine (15 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude material is purified by silica gel chromatography
  10. washeluting with hexane:ethyl acetate (9.6:0.4)

Sources & evidence

ORD record
ord-1cbae7c373ed4e5693e02d25c8ab2c21
Source dataset
uspto-grants-2014_09
Patent number
US08822486B2

Reaction notes

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