反応 #594546

反応方程式

BF3

2-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

sodium borohydride

dimethoxyethanol

aniline

cyclooctane

→

title product

[2-(5-Bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine

溶媒

TBME

反応条件

後処理

1. 1
   温度The temperature is maintained between −15 and −10° C. during the exothermic addition
2. 2
   温度to warm slowly to ambient temperature (25-27° C.)
3. 3
   workup.WAITleft
4. 4
   温度The mixture is cooled with an ice bath
5. 5
   その他quenched by the addition of 4N NaOH (200 mL)
6. 6
   温度The formed viscous emulsion is heated to 80° C. for 30 minutes
7. 7
   温度the mixture is heated for two additional hours
8. 8
   温度under reflux
9. 9
   温度After cooling to ambient temperature
10. 10
    その他the aqueous layer is removed
11. 11
    抽出the organic layer is extracted twice with each 50 mL of a 4 N NaOH
12. 12
    抽出After re-extraction of the combined inorganic layers with toluene (150 mL)
13. 13
    workup.ADDITIONthe toluene layer is added back into the reaction vessel
14. 14
    workup.ADDITIONTo the vessel, additional toluene (150 mL) is added
15. 15
    抽出the mixture is then extracted with water (200 mL)
16. 16
    その他The aqueous layer is separated
17. 17
    抽出extracted twice with each 150 mL of toluene
18. 18
    抽出After disposal of the inorganic the combined toluene layers are extracted for three times with water (300 mL, 2×150 mL)
19. 19
    抽出The toluene layer is then extracted twice with 4N HCl (100 mL and 50 mL)
20. 20
    workup.ADDITIONthe pH is then adjusted to 14 by the addition of 4 N NaOH
21. 21
    抽出Then the aqueous layer is extracted twice with tert-butyl methyl ether TBME (150 mL and 50 mL)
22. 22
    洗浄the combined extracts are washed with brine (50 mL)
23. 23
    その他transferred into a 500 mL flask
24. 24
    その他rises to 40° C
25. 25
    ろ過the MnO2 is filtered off
26. 26
    その他Removal of the solvent from the filtrate

実験手順

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 (Reference 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). Using 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.

出典