Reacción #724266

Ecuación de reacción

5-chloropentan-2-one

sodium hydride

5-chloropentan-2-one

sodium hydride

ammonium chloride

1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane

→

1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane

Disolventes

methanol dichloromethane

sodium bicarbonate

tetrahydrofuran

dimethylformamide

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaCool in an ice bath
2. 2
   TemperaturaHeat to reflux
3. 3
   workup.WAITAfter 18 hours
4. 4
   Temperaturacool
5. 5
   Temperaturaagain heat to reflux
6. 6
   workup.WAITAfter 24 hours
7. 7
   Temperaturacool in a dry-ice/acetone bath
8. 8
   TemperaturaWarm to ambient temperature
9. 9
   ConcentraciónConcentrate in vacuo
10. 10
    Otroto remove most to the tetrahydrofuran
11. 11
    Extracciónextract three times with ethyl acetate
12. 12
    ExtracciónExtract the combined organic layers with water
13. 13
    Secadobrine, dry
14. 14
    Filtraciónthe organic layer over Na2SO4, filter
15. 15
    Otroevaporate in vacuo
16. 16
    Otroto give a residue

Procedimiento

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.10 g, 3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in oil, 5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene ketal (0.79 mL, 5.22 mmol) and tetra-n-butylammonium bromide (112 mg, 0.35 mmol) and warm to ambient temperature. Heat to reflux. After 18 hours, cool, add sodium hydride (0.1 g) and 5-chloropentan-2-one, ethylene ketal (0.50 mL) and again heat to reflux. After 24 hours, cool in a dry-ice/acetone bath and add a saturated aqueous solution of ammonium chloride. Warm to ambient temperature and dilute the reaction mixture with a saturated aqueous solution of sodium bicarbonate. Concentrate in vacuo to remove most to the tetrahydrofuran and extract three times with ethyl acetate. Extract the combined organic layers with water and then brine, dry, the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution to give 1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane, ethylene ketal: Rf=0.47 (silica gel, 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution).

Fuente