Water → ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate

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Reaction Conditions

Reaction Steps

Ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 1.32 g of 60% sodium hydride in 120 cm3 of 1,2-dimethoxyethane, 6.57 cm3 of triethyl phosphonoacetate and 12.07 g of 5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 24 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is then treated with 150 cm3 of water and the mixture is then extracted with 3 times 250 cm3 of diethyl ether. The organic extracts are combined, washed with 150 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. A mixture of 2.3 g of the residue is injected onto a column 8 cm in diameter containing 1.2 kg of Whelk OI,SS chiral stationary phase. The elution is performed with a mobile phase composed of a mixture of dichloromethane, ethanol and heptane in proportions of 14.5/0.5/85 v/v. Two additional injections of 2.7 g and 3 g are made under identical conditions. The fractions comprising the first regioisomer are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature in the region of 40° C. 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a white solid (Rf=0.64, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)). The fractions comprising the second regioisomer are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature in the region of 40° C. to give 2.79 g of a white solid. This product is repurified by chromatography under argon pressure (80 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with a mixture of cyclohexane/ethyl acetate (90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.25 g of ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a colorless viscous oil. (Rf=0.46, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).

Provenance & Evidence