Pyridine → (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal

Participants

Reaction Steps

23.6 g (119 mmol) of 2,3-difluoro-6-(1-methylenepropyl)anisole, 31.4 ml (238 mmol) of ethyl trifluorpyruvate and 10 g of molecular sieve are added dropwise at 0° C. over 30 minutes to 2.58 g (2.98 mmol) of [Cu(R,R)bis-tert-butyl-oxazoline)(H2O)2]((SbF6)2 in 85 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 16 hours and the reaction mixture is purified by means of column chromatography on silica gel (hexane/ethyl acetate 0-10%). This gives 16.7 g of ethyl (R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate as an E/Z mixture with an enantiomeric excess of greater than 80%. 16.7 g (45.3 mmol) of ethyl E/Z-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-hex-4-enoate in 600 ml of diethyl ether are cooled to −5° C. and over 10 minutes 3.44 mg (90.7 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at room temperature for 2 hours and poured into saturated ammonium chloride solution. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 13.9 of crude E/Z-4-(3,4-difluoro-2-methoxyphenyl)-2-(trifluoromethyl)-hex-4-ene-1,2-diol. 16 g (49 mmol) of (E/Z-4-(3,4-difluoro-2-methoxyphenyl)-2-(trifluoromethyl)-hex-4-ene-1,2-diol are dissolved in 680 ml of methanol and 9.4 ml of acetic acid, and 1.07 g of palladium on carbon (10%) are added. The suspension is shaken under a hydrogen atmosphere at atmospheric pressure until reaction is complete. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 16.1 g of crude 4-(3,4-difluoro-2-methoxyphenyl)-2-(trifluoromethyl)-hexane-1,2-diol as a mixture of the diastereomers. 16.1 g (49 mmol) of 4-(3,4-difluoro-2-methoxyphenyl)-2-(trifluoromethyl)-hexane-1,2-diol in 600 ml of dichloromethane and 220 ml of DMSO are admixed with 33.5 ml (242 mmol) of triethylamine and in portions over 10 minutes with 29.8 g (188 mmol) of pyridine SO3 complex. The mixture is stirred for 3 hours and saturated ammonium chloride solution is added. The mixture is stirred for a further 5 minutes, the phases are separated and extraction is carried out with dichloromethane. The extracts are washed with water and dried over sodium sulphate. The solvent is removed in vacuo, then column chromatography on silica gel (hexane/diisopropyl ether 0-30%) gives 2.7 g of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal

Provenance & Evidence