Реакция #4095

Уравнение реакции

maleic acid

potassium carbonate

carbonyl chloride

1-(2-amino-4-methylphenyl)indoline

potassium carbonate

4-methyl-1-piperazinecarbonyl chloride hydrochloride

→

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

Растворители

water

dichloromethane

methanol

chloroform

Условия реакции

Обработка

1. 1
   ТемператураThe reaction was refluxed for 7 hours
2. 2
   workup.ADDITIONwas added
3. 3
   ТемператураAfter refluxing overnight (about 16 hours)
4. 4
   Температураthe reaction was cooled
5. 5
   ДругоеThe layers were separated
6. 6
   Промывкаthe organic phase was washed thrice with water
7. 7
   Сушкаdried over NaSO4
8. 8
   Концентрированиеconcentrated in vacuo to a semi-solid
9. 9
   workup.DISSOLUTIONThis was dissolved in 200 ml of methanol
10. 10
    workup.ADDITIONtreated with a solution of 24.4 g of maleic acid in 100 ml of methanol
11. 11
    Другоеyielding 18.1 g
12. 12
    Другоеabsorbed on a tall chromatography column
13. 13
    workup.ADDITIONcontaining 300 g of silica gel
14. 14
    ПромывкаElution first with dichloromethane
15. 15
    workup.DISSOLUTIONThis (0.046 mole) was dissolved in 50 ml of methanol
16. 16
    ДругоеThe resulting maleate salt was recrystallized from methanol

Методика

To a stirred solution, under nitrogen of 43.0 g (0.190 mole) of 1-(2-amino-4-methylphenyl)indoline of Example 5b and 105 g (0.76 mole) of milled potassium carbonate in 1000 ml of chloroform was added 56.7 (0.285 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride in portions over 10 minutes. The reaction was refluxed for 7 hours, when an additional charge of 13.1 g (0.095 mole) of potassium carbonate and 18.9 g (0.095 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 NaSO4, and concentrated in vacuo to a semi-solid weighing 77 g. This was dissolved in 200 ml of methanol and treated with a solution of 24.4 g of maleic acid in 100 ml of methanol. This afforded 37.7 g (43% overall yield) of crystalline maleate salt. This salt was reversed back to the free base urea, yielding 18.1 g. This material was dissolved in 50 ml of dichloromethane and absorbed on a tall chromatography column containing 300 g of silica gel packed in dichloromethane. Elution first with dichloromethane, followed by 25% methanol/75% dichloromethane brought forth 16.2 g (24% overall yield) of pure urea. This (0.046 mole) was dissolved in 50 ml of methanol and treated with a solution of 5.92 g (0.051 mole) of maleic acid dissolved in 25 ml of methanol. The resulting maleate salt was recrystallized from methanol to afford 12.6 g of N-[ 5-methyl-2-(2,3-dihydro-1H-indol-1-yl)-phenyl]-4-methyl-1-piperazinecarboxamide maleate, m.p. 173°-175° C. dec.

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