반응 #62624

반응 방정식

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

용매

water

dichloromethane

methanol

chloroform

반응 조건

후처리

1. 1
   온도The reaction was refluxed for 7 hours
2. 2
   workup.ADDITIONwas added
3. 3
   온도After refluxing overnight (about 16 hours)
4. 4
   온도the reaction was cooled
5. 5
   기타The layers were separated
6. 6
   세척the organic phase was washed thrice with water
7. 7
   건조dried over NaSO4
8. 8
   농축concentrated 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
    기타yielding 18.1 g
12. 12
    기타absorbed on a tall chromatography column
13. 13
    workup.ADDITIONcontaining 300 g of silica gel
14. 14
    세척Elution first with dichloromethane
15. 15
    workup.DISSOLUTIONThis (0.046 mole) was dissolved in 50 ml of methanol
16. 16
    기타The resulting maleate salt was recrystallized from methanol

실험 절차

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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