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

Participants

Reaction Conditions

Reaction Steps

Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 2.9 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 15.2 cm3 of triethyl phosphonoacetate and 9.6 g of a mixture of 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydoxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 110 cm3 of water and then 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of 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. The residue is separated out by HPLC chromatography on a 10 μm WHELK-01SS chiral column, eluting successively with heptane/isopropanol mixtures (90/10 and then 50/50 by volume). The fractions comprising the first regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil (Rf=0.43, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The fractions comprising the second regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil. (Rf=0.38, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).

Provenance & Evidence