反应详情

1.0 g (4.40 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate was initially charged in 10.0 ml of acetonitrile, and 540 mg (4.40 mmol) of N-chlorosuccinimide were added a little at a time at 0° C. After 30 min, the mixture was warmed to RT and stirred at this temperature overnight. After concentration under reduced pressure, the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase gradient cyclohexane/ethyl acetate 10:1→6:1), 217 mg of a mixed fraction (about 1:1) consisting of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclo-propanecarboxylate and tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate, and also 995.5 mg of tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate, slightly contaminated by the starting material tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, were isolated from the crude product obtained in this manner. The mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]. In this manner, it was possible to isolate 85 mg (7.5% of theory) of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 22A). Starting with 995.5 mg of the slightly contaminated material, 677.6 mg (59.5% of theory) of pure tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 23A) were isolated by preparative RP-HPLC (mobile phase: acetonitrile/water gradient).

1. concentrationAfter concentration under reduced pressure
2. washwashed with saturated sodium bicarbonate solution and saturated sodium chloride solution
3. dry with materialThe organic phase was dried over sodium sulphate
4. concentrationconcentrated under reduced pressure
5. customwere isolated from the crude product
6. customobtained in this manner
7. customThe mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]