反应详情

温度

-15 °C

A 1 L flask is charged with 2-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 1) (31.2 g, 0.1 mol), sodium borohydride (11.8 g 96%, 0.3 mol), and 250 mL of dimethoxyethanol (DME). The mixture is cooled to −15° C., and to the stirred suspension, BF3-etherate (56.6 g, 0.4 mol) is added dropwise. The temperature is maintained between −15 and −10° C. during the exothermic addition. The mixture is then allowed to warm slowly to ambient temperature (25-27° C.), and left stirring over night. The mixture is cooled with an ice bath and quenched by the addition of 4N NaOH (200 mL). The formed viscous emulsion is heated to 80° C. for 30 minutes, then diazabicyclo[2.2.2]cyclooctane (DABCO) (12.7 g 97%, 0.11 mol) is added, and then the mixture is heated for two additional hours under reflux. After cooling to ambient temperature, the aqueous layer is removed and the organic layer is extracted twice with each 50 mL of a 4 N NaOH.solution. After re-extraction of the combined inorganic layers with toluene (150 mL), the aqueous phase is disposed off, and the toluene layer is added back into the reaction vessel. To the vessel, additional toluene (150 mL) is added and the mixture is then extracted with water (200 mL). The aqueous layer is separated, and extracted twice with each 150 mL of toluene. After disposal of the inorganic the combined toluene layers are extracted for three times with water (300 mL, 2×150 mL), and the aqueous layer is again discarded. The toluene layer is then extracted twice with 4N HCl (100 mL and 50 mL). During the combined acidic extracts, the pH is then adjusted to 14 by the addition of 4 N NaOH. Then the aqueous layer is extracted twice with tert-butyl methyl ether TBME (150 mL and 50 mL), and the combined extracts are washed with brine (50 mL) and then transferred into a 500 mL flask. To the stirred TBME solution, MnO2 (34.8 g, 0.4 mol) is then added, and temporarily the temperature rises to 40° C. After one hour the aniline by-product has been converted completely, and then the MnO2 is filtered off. Removal of the solvent from the filtrate gives the title product as a colourless viscous oil which crystallizes (23.85 g, 85%), mp=95-96° C. 1H-NMR (CDCl3, 300 MHz): δ 2.37 (s, 6H, 2 CH3), 2.27 (m, 2H, CH2CH2NMe2), 2.90 (m, 2H, CH2CH2NMe2), 6.86 (d, 1H, 3J=1.8 Hz, H-2), 7.03 (d, 1H, 3J=8.8 Hz, H-7), 7.21 (dd, 1H, 4J=1.8 Hz, H-6), 7.70 (d, 1H, H-4), 9.36 (br s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 23.60 (CH2CH2NMe2), 45.47 (N(CH3)2), 60.25 (CH2CH2NMe2), 112.42 (C-5), 112.98 (C-7), 113.54 (C-3), 121.39 (C-4), 123.61 (C-2), 124.64 (C-6), 129.43 (C-8), 135.36 (C-9).

1. temperatureThe temperature is maintained between −15 and −10° C. during the exothermic addition
2. temperatureto warm slowly to ambient temperature (25-27° C.)
3. waitleft
4. temperatureThe mixture is cooled with an ice bath
5. customquenched by the addition of 4N NaOH (200 mL)
6. temperatureThe formed viscous emulsion is heated to 80° C. for 30 minutes
7. temperaturethe mixture is heated for two additional hours
8. temperatureunder reflux
9. temperatureAfter cooling to ambient temperature
10. customthe aqueous layer is removed
11. extractionthe organic layer is extracted twice with each 50 mL of a 4 N NaOH
12. extractionAfter re-extraction of the combined inorganic layers with toluene (150 mL)
13. additionthe toluene layer is added back into the reaction vessel
14. additionTo the vessel, additional toluene (150 mL) is added
15. extractionthe mixture is then extracted with water (200 mL)
16. customThe aqueous layer is separated
17. extractionextracted twice with each 150 mL of toluene
18. extractionAfter disposal of the inorganic the combined toluene layers are extracted for three times with water (300 mL, 2×150 mL)
19. extractionThe toluene layer is then extracted twice with 4N HCl (100 mL and 50 mL)
20. additionDuring the combined acidic extracts, the pH is then adjusted to 14 by the addition of 4 N NaOH
21. extractionThen the aqueous layer is extracted twice with tert-butyl methyl ether TBME (150 mL and 50 mL)
22. washthe combined extracts are washed with brine (50 mL)
23. customtransferred into a 500 mL flask
24. customrises to 40° C
25. filtrationthe MnO2 is filtered off
26. customRemoval of the solvent from the filtrate