Methanol → 4-Methyl-2-oxo-4-phenylpentanoic acid-methyl ester

HRID 2215376Notes

Reaction equation

HRID 2215376 reaction equation
[CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:20]O>CN(C)C=O.O>[CH3:20][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][C:2]([CH3:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]

Participants

6

Reactant 3

HCID 887MethanolHCID 24386Thionyl ChlorideHCID 112411954-Methyl-2-oxo-4-phenylpentanoic acid

Product 1

HCID 179892624-Methyl-2-oxo-4-phenylpentanoic acid-methyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 ml of dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chloride and after 15 minutes with 4 ml of methanol. After 15 hours at room temperature, the batch is diluted with water and extracted with ethyl acetate. The organic extracts are washed with water, dried (Na2SO4) and concentrated by evaporation, whereby 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. The latter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate and stirred for 16 hours at room temperature. Water is added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). The intermediate product that is concentrated by evaporation is taken up in 200 ml of THF and 50 ml of a 1 M solution of tetrabutylammonium fluoride in THF is added. It is stirred for 2 hours, water is added, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). After chromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 g of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methyl ester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 ml of THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride is added in small portions over a period of 2.5 hours. After complete conversion, 5 ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of water is carefully added. The formed precipitate is filtered out and washed carefully with ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0–35%), 5.40 g of 4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.6 g (21.35 mmol) of triphenylphosphine and, while being cooled with ice, 4.3 ml (27.31 mmol) of azodicarboxylic acid-diethyl ester are added to diol (5.40 g, 20.59 mmol) in 43 ml of THF. The reaction mixture is refluxed for 3 hours and, after cooling, it is concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0–15%), 4.18 g of product is obtained.

Workup

  1. extractionextracted with ethyl acetate
  2. washThe organic extracts are washed with water
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated by evaporation

Sources & evidence

ORD record
ord-f590bfd426194f26bc1f9e5df9fe1e1d
Source dataset
uspto-grants-2006_09
Patent number
US07109212B2

Reaction notes

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