反应详情

A solution of potassium hydroxide (23.58 g, 20.0 g corrected for assay, 357 mmol) in water (36 mL) at r.t. was added to a solution of 1,3-cyclohexanedione (39.97 g, 356 mmol) in ethanol (144 mL) with stirring (exothermic addition). After stirring for 15 mins at 20° C., redistilled chloroacetone (37.62 g, 33.9 g corrected for assay, 366 mmol) was added in one portion and the reaction mixture stirred for 20 h at 20° C. The inorganic by products were removed by filtration, washing the filter cake with ethanol (40 mL) and the filtrates were combined to provide 2-(2-oxo-propyl)cyclohexane-1,3-dione as a solution in aqueous ethanol. To this solution were added glycine ethyl ester hydrochloride (54.73 g, 392 mmol) and anhydrous sodium acetate (32.19 g, 392 mmol). The reaction mixture was heated to reflux (75° C. internal temperature) for 1 h then cooled to 20° C. and stirred for 19 h. The mixture was heated to reflux (internal temperature 75° C.) and water (116 mL) added, then cooled to 20° C. over 30 mins. A small amount of 2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid, ethyl ester was added as a seed (10 mg) and, after a few minutes, crystallization of the product was observed. The slurry was stirred for 30 mins, then cooled to 5° C. and stirred for 18 h. The solid was collected by filtration, washed with water (2×80 mL) followed by tert-butyl methyl ether (2×80 mL) and then dried in vacuo at 40° C. for 20 h to provide ethyl(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetate as a pale yellow crystalline solid, 41.77 g (49.8% yield). MP 105.1 to 105.4° C. Assay by 1H-NMR 99.3% w/w. Purity by GC 100 area %.

1. addition(exothermic addition)
2. stirringAfter stirring for 15 mins at 20° C.
3. additionwas added in one portion
4. stirringthe reaction mixture stirred for 20 h at 20° C
5. customThe inorganic by products were removed by filtration
6. washwashing the filter cake with ethanol (40 mL)