反应详情

N,N'-Carbonyldiimidazole (1.64 g) is added to a solution of (2-dimethylamino-4-fluorophenyl)acetic acid (2 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.3 g) and triethylamine (2.8 g) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.1 g) is obtained in the form of white crystals melting at 164° C.

1. temperaturecooled to +5° C
2. stirringThe reaction mixture is stirred at 20° C. for 16 hours
3. washwashed with water (2×100 cc)
4. dry with materialdried over magnesium sulphate
5. filtrationfiltered
6. concentrationthe filtrate is concentrated to dryness under reduced pressure (2.7 kPa)
7. customThe residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm)
8. washeluting under a nitrogen pressure of 0.4 bar
9. additionwith a mixture of cyclohexane and ethyl acetate (50/50 by volume)
10. customcollecting 50 cc fractions
11. concentrationconcentrated to dryness under reduced pressure
12. customThe residue is triturated in ethyl ether
13. customdried