反应详情

温度

80 °C

A stirred mixture of 4-(3-{5-chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid ethyl ester (415 g, 0.81 mol) and 55% hydrazine solution (141 g, 2.42 mol) in 2-propanol (4 L) is warmed to 80° C. for 3 h-4 h. The reaction is complete when the product/starting material ratio is greater than 99/1 by HPLC. The reaction mixture is cooled to room temperature. The byproduct is removed by filtration. The cake is washed with 2-propanol (400 mL×3). The filtrate and wash are combined and distilled to about half volume. Pyridine (830 mL×2) is added and the remainder of the 2-propanol is removed under reduced pressure. The stirred mixture is cooled to 5° C.-10° C. Acetic anhydride (90.4 g, 1.10 mol) is added dropwise to the reaction mixture at 5° C.-10° C. The reaction is complete when the product/starting material ratio is >99/1 by HPLC analysis. Water (5.0 L) is added to the reaction mixture, maintaining the temperature below 25° C. The reaction mixture is stirred at room temperature for 12 hours. The solid product is collected by filtration, washed with water (500 mL×3) and dried in vacuum oven (70° C.) to give 303 g (87.6%, 95.4% by HPLC) of 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester.

1. temperatureThe reaction mixture is cooled to room temperature
2. customThe byproduct is removed by filtration
3. washThe cake is washed with 2-propanol (400 mL×3)
4. washThe filtrate and wash
5. distillationdistilled to about half volume
6. additionPyridine (830 mL×2) is added
7. customthe remainder of the 2-propanol is removed under reduced pressure
8. temperatureThe stirred mixture is cooled to 5° C.-10° C
9. temperaturemaintaining the temperature below 25° C
10. filtrationThe solid product is collected by filtration
11. washwashed with water (500 mL×3)
12. customdried in vacuum oven (70° C.)