Reaktion #444703

Reaktionsgleichung

7-bromo-9-bromomethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester hydrobromic acid salt

diisobutylaluminum hydride

triethylamine

N-methylpiperazine

potassium sodium tartrate tetrahydrate

→

[7-bromo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol

Ausbeute 86.0%

Lösungsmittel

dichloromethane

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGthe mixture is stirred 10 min
2. 2
   SonstigeThe layers are separated
3. 3
   Extraktionthe aqueous phase is extracted with dichloromethane (50 mL)
4. 4
   Waschenwashed with water (2×50 mL)
5. 5
   EinengenThe organic solution is then concentrated to an oil
6. 6
   workup.ADDITIONThe oil is diluted with dichloromethane (50 mL)
7. 7
   workup.ADDITIONis added slowly
8. 8
   Sonstigethe reaction temperature below 30° C.
9. 9
   workup.STIRRINGThe reaction is stirred for 10 min
10. 10
    workup.ADDITIONThe temperature is kept <30° C. with an ice bath during the addition
11. 11
    workup.STIRRINGThe mixture gels and is stirred overnight at room temperature
12. 12
    SonstigeThe layers are separated
13. 13
    Extraktionthe aqueous phase is extracted with dichloromethane (2×75 mL)
14. 14
    Waschenwashed with water (2×50 mL)
15. 15
    EinengenThe organic phase is then concentrated under vacuum (crystallization occurs during concentration) to about 20 mL
16. 16
    Sonstigethe rest of the product crystallized out
17. 17
    workup.ADDITIONby adding tert-butyl methyl ether
18. 18
    FiltrationThe slurry is filtered
19. 19
    Sonstigedried on high vacuum at room temperature overnight

Vorschrift

To a mixture of 7-bromo-9-bromomethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester hydrobromic acid salt, prepared as in example 17 (10 g, 19.6 mmol) in dichloromethane (100 mL) is added triethylamine (5.4 mL. 39.2 mmol) followed by N-methylpiperazine (2.79 mL, 25.5 mmol). After stirring 30 min, water (50 mL) is added and the mixture is stirred 10 min. The layers are separated and the aqueous phase is extracted with dichloromethane (50 mL). The organic phases are combined and washed with water (2×50 mL). The organic solution is then concentrated to an oil. The oil is diluted with dichloromethane (50 mL) and stirred while diisobutylaluminum hydride (1.0M in dichloromethane, 53 mL. 53 mmol) is added slowly while keeping the reaction temperature below 30° C. using an ice bath. The reaction is stirred for 10 min and then slowly poured into an aqueous solution (75 mL) saturated with potassium sodium tartrate tetrahydrate (Rochelle's salt). The temperature is kept <30° C. with an ice bath during the addition. The mixture gels and is stirred overnight at room temperature. The layers are separated and the aqueous phase is extracted with dichloromethane (2×75 mL). The organics are combined and washed with water (2×50 mL). The organic phase is then concentrated under vacuum (crystallization occurs during concentration) to about 20 mL and the rest of the product crystallized out by adding tert-butyl methyl ether. The slurry is filtered and dried on high vacuum at room temperature overnight to provide 6.87 g (86%) of [7-bromo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as a tan solid. MP (184°-186° C.), HRMS calc for C18H22N3O3Br: 407.0841, Found: 407.0827.

Quelle