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

HRID 3999
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HRID 3999 반응식
[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]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.ClCCl.CO.O>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[C:2]([NH:1][C:32]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])[CH:7]=1
참가 물질실험 절차후처리출처 및 근거반응 노트

참가 물질

10

반응물 5

HCID 6371PhosgeneHCID 11430Potassium Carbonate2회HCID 444266Maleic AcidHCID 30169344-Methylpiperazine-1-carbonyl chloride monohydrochlorideHCID 138233242-(2,3-Dihydro-1H-indol-1-YL)-5-methylphenylamine

생성물 1

HCID 70406284
N-[5-methyl-2-(2,3-dihydro-1H-indol-1-yl)-phenyl]-4-methyl-1-piperazinecarboxamide maleate

시약·촉매·용매 4

HCID 887Methanol용매HCID 962Water용매HCID 6212Chloroform용매HCID 6344Dichloromethane용매

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.

후처리

  1. temperatureThe reaction was refluxed for 7 hours
  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 NaSO4
  8. concentrationconcentrated in vacuo to a semi-solid
  9. dissolutionThis was dissolved in 200 ml of methanol
  10. additiontreated with a solution of 24.4 g of maleic acid in 100 ml of methanol
  11. customyielding 18.1 g
  12. customabsorbed on a tall chromatography column
  13. additioncontaining 300 g of silica gel
  14. washElution first with dichloromethane
  15. dissolutionThis (0.046 mole) was dissolved in 50 ml of methanol
  16. customThe resulting maleate salt was recrystallized from methanol

출처 및 근거

ORD 기록
ord-81328b540f06421c8f965823a6923595
출처 데이터셋
uspto-grants-1988_02
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US04723007

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