Chloroacetone → Ethyl 2-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-YL)acetate

Temperature

20 °C

In reaction vessel 1, potassium hydroxide (11.78 g, 10.0 g corrected for assay, 178 mmol)) was dissolved in water (72 mL) with stirring (highly exothermic) then the solution was cooled back to 20° C. 1,3-cyclohexanedione (20.0 g, 178 mmol) was added (exothermic addition) and the resulting dark red solution was stirred at 20° C. for 5 mins. Redistilled chloroacetone (18.9 g, 17.0 g corrected for assay, 184 mmol) was added in one portion, rinsing in with ethanol (18 mL) and the reaction mixture was stirred overnight at 20° C. The resulting solution of 2-(2-oxopropyl)cyclohexane-1,3-dione, volume 124 mL, was split into 4 equal portions. Glycine ethyl ester hydrochloride (6.85 g, 49.0 mmol), anhydrous sodium acetate (4.02 g, 49.0 mmol), water (26.5 mL) and ethanol (5.0 mL) were charged to reaction vessel 2 and stirring started. One portion of the solution of 2-(2-oxopropyl)cyclohexane-1,3-dione prepared above (31 mL) was then added to the contents of reaction vessel 2 with stirring and the resulting mixture was heated to 75° C., held at this temperature for 2 h, then cooled to 20° C. over 55 mins. After stirring overnight at 20° C., the solid was collected by filtration, washed with water (10 mL), tert-butyl methyl ether (2×10 mL) and then dried in vacuo 40° C. for 20 h to provide (2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid ethyl ester as a beige solid, 5.88 g (56.0% yield). MP 101.2 to 103.5° C. Assay by 1H-NMR 95.3% w/w. Purity by GC 99.25 area %.

1. addition(exothermic addition)
2. stirringthe resulting dark red solution was stirred at 20° C. for 5 mins
3. washrinsing in with ethanol (18 mL)
4. stirringthe reaction mixture was stirred overnight at 20° C
5. customThe resulting solution of 2-(2-oxopropyl)cyclohexane-1,3-dione, volume 124 mL, was split into 4 equal portions
6. stirringstirring
7. additionwas then added to the contents of reaction vessel 2
8. stirringwith stirring
9. temperaturethe resulting mixture was heated to 75° C.
10. temperaturecooled to 20° C. over 55 mins
11. stirringAfter stirring overnight at 20° C.
12. filtrationthe solid was collected by filtration
13. washwashed with water (10 mL), tert-butyl methyl ether (2×10 mL)
14. customdried in vacuo 40° C. for 20 h

ORD record

ord-9386b1b82f4b4d189f4fb2b4bb7c2c93

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08227622B2