Reacción #4090

Ecuación de reacción

N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide

→

9-fluoro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine

Rendimiento 20.8%

Disolventes

phosphorus oxychloride

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawas refluxed for 6 hours under nitrogen
2. 2
   OtroThe excess phosphorus oxychloride was removed at aspirator pressure with gentle warming
3. 3
   TemperaturaThe residue was chilled in an ice-bath (with exclusion of moisture)
4. 4
   workup.ADDITIONtreated first with 250 ml of ice-cold 2N-NaOH
5. 5
   OtroThe organic phase was separated
6. 6
   Lavadowashed thrice with water
7. 7
   Secadodried over Na2SO4
8. 8
   Concentraciónconcentrated in vacuo to 9.1 g of an oil
9. 9
   workup.ADDITIONcontaining 400 g of alumina
10. 10
    LavadoElution with CH2Cl2
11. 11
    Concentraciónconcentrated
12. 12
    Otroto afford
13. 13
    Otro3.5 g (35% overall yield) of product which
14. 14
    Otrocrystallized
15. 15
    OtroThis was recrystallized from a small volume of acetone

Procedimiento

A stirred mixture of 10.6 g (0.030 mole) of N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide of Example 2c in 250 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, dried over Na2SO4 and concentrated in vacuo to 9.1 g of an oil. This material was adsorbed on a tall chromatography column containing 400 g of alumina made up in CH2Cl2. Elution with CH2Cl2 brought forth fractions of pure tetracycle which were combined and concentrated to afford 3.5 g (35% overall yield) of product which crystallized. This was recrystallized from a small volume of acetone to furnish 2.1 g of 9-fluoro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 151°-153° C.

Fuente