反应详情

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, it is mixed 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 it is stirred for 16 hours at room temperature. Water is added, it is 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, it is 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 over a period of 2.5 hours, 1.52 g (36.20 mmol) of lithium aluminum hydride is added in small portions. After complete conversion, 5 ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of water is carefully added. Formed precipitate is filtered out, and it is 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. 5.7 ml (40.3 mmol) of triethylamine is added to 2.5 g (9.53 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO, and 5 g of pyridine/SO3 complex is added in portions over 20 minutes. It is stirred over 2 hours, and 40 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water, and dried on sodium sulfate. The solvent is removed in a vacuum, and 3 g of product is obtained.

1. waitAfter 15 hours at room temperature
2. extractionextracted with ethyl acetate
3. washThe organic extracts are washed with water
4. dry with materialdried (Na2SO4)
5. concentrationconcentrated by evaporation