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

HRID 35101

반응식

HRID 35101 반응식
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[C:4]([NH2:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.C(Cl)(Cl)=O.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43]>C(Cl)(Cl)Cl.C(O)C.O>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[C:4]([NH:17][C:32]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])[CH:3]=1

참가 물질

9

반응물 5

HCID 6371PhosgeneHCID 11430Potassium Carbonate2회HCID 444266Maleic AcidHCID 30169344-Methylpiperazine-1-carbonyl chloride monohydrochlorideHCID 138233205-Bromo-2-(indolin-1-yl)aniline

생성물 1

HCID 70406800N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide maleate수율 39.8%

시약·촉매·용매 3

HCID 702Ethanol용매HCID 962Water용매HCID 6212Chloroform용매

실험 절차

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 absorbed 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 ehtanol 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.

후처리

  1. temperatureThe reaction was refluxed for 6 hours when
  2. additionwas added
  3. temperatureAfter refluxing overnight (about 16 hours)
  4. temperaturethe reaction was cooled
  5. customThe layers were separated
  6. washthe organic phase was washed thrice with water
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in 200 ml of toluene
  10. customabsorbed on a tall chromatography column
  11. additioncontaining 1.5 kg of silica gel
  12. washElution first with toluene
  13. dissolutionThis was dissolved in 100 ml of ehtanol
  14. customThe maleate salt was collected
  15. customdried
  16. customRecrystallization from methanol (charcoal)

출처 및 근거

ORD 기록
ord-4aa14ee132e7488f820590efdf6e6eb8
출처 데이터셋
uspto-grants-1988_08
특허 번호
US04764616

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