反应详情

To a solution of 3-chlorophthalic anhydride (3.7 g, 20 mmol) ((J. Org. Chem., 1987, 52, 129-134) in 60 mL of anhydrous 1,2-dichloroethane was added 6.6 g (50 mmol) of AlCl3 followed by 4.6 g (20 mmol) of methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (WO 03/023357). The reaction was heated at reflux for 30 min, cooled and concentrated. The resultant gelatinous material was partitioned between cold 2 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to afford an oily material (mixture of 6- and 2-chloroisomers). The oil was dissolved in dichloromethane (˜40 mL) and briefly sonicated (ultrasound bath) to initiate crystallization. The mixture was cooled (ice/water bath) and allowed to crystallize for 30 min (extended crystallization time will result in co-crystallization of undesired 2-chloro isomer). The crystals were collected by filtration washed with cold dichloromethane. Drying under vacuum afforded 4.01 g of desired 6-chloro isomer 32. 1H NMR (DMSO-d6) δ 12.47 (br s, 1H), 10.78 (br s, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 3.46 (s, 3H), 2.27 (m, 2H), 2.41 (t, J=6.6 Hz, 2H).

1. temperatureThe reaction was heated
2. temperatureat reflux for 30 min
3. temperaturecooled
4. concentrationconcentrated
5. customThe resultant gelatinous material was partitioned between cold 2 N HCl (100 mL) and ethyl acetate (100 mL)
6. washThe organic layer was washed with 1 N HCl, brine
7. dry with materialdried over Na2SO4
8. concentrationconcentrated
9. customto afford
10. additionan oily material (mixture of 6- and 2-chloroisomers)
11. custombriefly sonicated (ultrasound bath)
12. customcrystallization
13. temperatureThe mixture was cooled (ice/water bath)
14. customto crystallize for 30 min
15. custom(extended crystallization time will result in co-crystallization of undesired 2-chloro isomer)
16. filtrationThe crystals were collected by filtration
17. washwashed with cold dichloromethane
18. customDrying under vacuum
19. customafforded 4.01 g of desired 6-chloro isomer 32