Water → HCID 22025416, compound

Participants

Reaction Conditions

Reaction Steps

3-Hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one and 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one are prepared as described in Example 1, starting with 6.7 g of N-isobutyl-4-methylphthalimide in 65 cm3 of methanol and 1.7 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours, 0.3 g of potassium borohydride is then added, and the reaction mixture is stirred at a temperature in the region of 20° C. for two hours. The mixture is then cooled to a temperature in the region of 0° C., and 40 cm3 of distilled water are added dropwise. The precipitate obtained is filtered off, and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. The residue is purified by chromatography under a pressure of argon (50 kPa), on a column of silica gel (particle size 40-63 μm), eluting successively with mixtures of cyclohexane/ethyl acetate (70/30; 60/40 by volume). The fractions containing a mixture of the two expected products are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 2.27 g of a mixture of 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one and 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white solid (Rf=0.54, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)). A second batch starting with 3.5 g of N-isobutyl-4-methylphthalimide in the same way yields 2.2 g of a mixture of 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one and 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one in the form of a white solid. The two batches are combined and then separated by HPLC chromatography on a system comprising two columns of 60 mm in diameter in series containing, respectively, 700 g and 475 g of CHIRALPAK AS chiral stationary phase with a particle size of 20 μm, eluting with a heptane/isopropanol mixture (90/10 by volume) at a flow rate of 90 ml/min. The first and second isomers eluted correspond to the first pair of regioisomers. The third and fourth isomers eluted correspond to the second pair of regioisomers. Three injections of 1 g, 1.6 g and 1.7 g, respectively, were performed under these conditions. Concentrating the fractions under reduced pressure (1 kPa) at a temperature in the region of 40° C. gives the following: 0.77 g of (+)-3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one in the form of a white solid (αD20=+17.3°±0.8° in methanol, at a concentration of 0.5%), 1.09 g of (+)-3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one in the form of a white solid, (αD20=+23.2°±0.7° in methanol, at a concentration of 0.5%), 1.17 g of (−)-3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one in the form of a white solid (αD20=−20.1°±0.8° in methanol, at a concentration of 0.5%), and 0.85 g of (−)-3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one in the form of a white solid, (αD20=−15.6°±0.6° in dichloromethane, at a concentration of 0.5%).

Provenance & Evidence