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

HRID 35099

반응식

HRID 35099 반응식
N[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([N:20](CC)CC)C.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]1.C(Cl)(Cl)=O.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(O)C.O>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[N:9]1([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[CH:2][C:3]=2[NH:20][C:33]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:34])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1

참가 물질

10

반응물 5

HCID 6371PhosgeneHCID 8471Triethylamine2회HCID 444266Maleic AcidHCID 30169344-Methylpiperazine-1-carbonyl chloride monohydrochlorideHCID 212976661-(3-Amino-4-fluorophenyl)indoline

생성물 1

HCID 70406853N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide maleate

시약·촉매·용매 4

HCID 702Ethanol용매HCID 962Water용매HCID 1140Toluene용매2회HCID 6212Chloroform용매

실험 절차

To a stirred solution under nitrogen, of 50.2 g (0.22 mole) of 1-(3-amino-4-fluorophenyl)indoline of Example 2b, and 66.7 g (0.66 mole) of triethylamine in 900 ml of chloroform was added 65.7 g (0.33 mole) of 4-methyl-l-piperazine carbonyl chloride hYdrochloride in portions over 5 minutes. The reaction was refluxed for 6 hours when an additional 22.2 g (22.2 mole) of triethylamine and 43.8 g (0.22 mole) of the carbonyl chloride reagent were added. After refluxing overnight (about 16 hours) the reaction was cooled, treated with 1 liter of water and g stirred vigorously for 15 minutes. The layers were separated, and the organic phase was washed twice with water, dried over Na2SO4, and concentrated in vacuo to leave 50 g. This material was dissolved in 150 ml of toluene and adsorbed on a tall chromatography column containing 1.5 kg of silica gel made up in toluene. Elution first with toluene, then with increasing percentages (25% per step) of dichloromethane (CH2Cl2) in toluene, followed by 100% CH2Cl2, and finally by increasing percentages of methanol (1% per step) in CH2Cl2 brought forth 27.3 g (35% overall yield) of pure urea. 12.7 g (0.036 mole) was converted to the maleate salt in the following manner. The urea was dissolved in 30 ml of ethanol and treated with a solution of 4.64 g (0.04 mole) of maleic acid in 20 ml of warm ethanol. The salt crystals were collected, and found to weigh 13.2 g (78%). Two recrystallizations from ethanol furnished N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide maleate, m.p. 117°14 120° C.

후처리

  1. additionwere added
  2. temperatureAfter refluxing overnight (about 16 hours) the reaction
  3. temperaturewas cooled
  4. customThe layers were separated
  5. washthe organic phase was washed twice with water
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customto leave 50 g
  9. additioncontaining 1.5 kg of silica gel
  10. washElution first with toluene
  11. temperaturefinally by increasing percentages of methanol (1% per step) in CH2Cl2
  12. dissolutionThe urea was dissolved in 30 ml of ethanol
  13. customThe salt crystals were collected
  14. customTwo recrystallizations from ethanol

출처 및 근거

ORD 기록
ord-d1d7d505d5134adf924619288d2e6038
출처 데이터셋
uspto-grants-1988_08
특허 번호
US04764616

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