Reacción #4149

Ecuación de reacción

maleic acid

1-(4-bromo-2-aminophenyl)indoline

potassium carbonate

4-methyl-1-piperazinecarbonyl chloride hydrochloride

potassium carbonate

carbonyl chloride

→

N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide maleate

Rendimiento 39.8%

Disolventes

ethanol

chloroform

water

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe reaction was refluxed for 6 hours when
2. 2
   workup.ADDITIONwas added
3. 3
   TemperaturaAfter refluxing overnight (about 16 hours)
4. 4
   Temperaturathe reaction was cooled
5. 5
   OtroThe layers were separated
6. 6
   Lavadothe organic phase was washed thrice with water
7. 7
   Secadodried over Na2SO4
8. 8
   Concentraciónconcentrated in vacuo
9. 9
   workup.DISSOLUTIONThe residue was dissolved in 200 ml of toluene
10. 10
    workup.ADDITIONcontaining 1.5 kg of silica gel
11. 11
    LavadoElution first with toluene
12. 12
    workup.DISSOLUTIONThis was dissolved in 100 ml of ethanol
13. 13
    OtroThe maleate salt was collected
14. 14
    Otrodried
15. 15
    OtroRecrystallization from methanol (charcoal)

Procedimiento

To a stirred solution, under nitrogen of 43.5 g (0.15 mole) of 1-(4-bromo-2-aminophenyl)indoline of Example 3b and 82.8 g (0.60 mole) of milled potassium carbonate in 1000 ml of chloroform was added 44.7 g (0.225 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride in portions over 10 minutes. The reaction was refluxed for 6 hours when an additional charge of 10.4 g (0.075 mole) of potassium carbonate and 14.9 g (0.075 mole) of the carbonyl chloride reagent was added. After refluxing overnight (about 16 hours), the reaction was cooled, treated with 500 ml of water, and stirred vigorously for 15 minutes. The layers were separated and the organic phase was washed thrice with water, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in 200 ml of toluene and adsorbed on a tall chromatography column containing 1.5 kg of silica gel packed in toluene. Elution first with toluene, then with increasing percentages of dichloromethane in toluene, (25% per step), followed by dichloromethane alone, and finally with 1% methanol in dichloromethane brought forth 24 g (overall 39% yield) of fairly pure urea. This was dissolved in 100 ml of ethanol and treated with a solution of 6.96 g (0.06 mole) of maleic acid dissolved in 50 ml of ethanol. The maleate salt was collected, dried, and found to weigh 17.3 g (22% overall), m.p. 175°-177° C. dec. Recrystallization from methanol (charcoal) afforded 12.7 g (16% overall yield) of N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide maleate, m.p. 175°-177° C. dec.

Fuente