P-Xylene → ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate

HRID 2361395Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2361395
[NH2:1][CH:2]([CH3:36])[CH:3]([C:18]1[C:19]([CH3:35])=[C:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1.CC1C=CC(C)=CC=1>O1CCOCC1.[Pd].CCOC(C)=O>[CH2:27]([O:26][C:25]([NH:24][C:20]1[C:19]([CH3:35])=[C:18]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][C:2]=2[CH3:36])[CH:23]=[CH:22][CH:21]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Komponenten

8

Edukt 4

HCID 7809P-XyleneHCID 204431481,4-Dioxane hydrochlorideHCID 67994898benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamateHCID 86599969Ethyl glyoxylate toluene

Produkt 1

HCID 67994938ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylateAusbeute 38,3 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 23938PalladiumKatalysatorHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

To a homogeneous, colorless solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate (1.3975 g, 2.87 mmol) in dioxane (Volume: 143 ml) under nitrogen were added 50% ethyl 2-oxoacetate/toluene (1.136 ml, 5.73 mmol) and 4 N hydrochloric acid/1,4-dioxane (1.433 ml, 5.73 mmol). After stirring overnight, the reaction was concentrated in vacuo, dissolved in EtOAc (75 mL) and saturated aqueous NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×75 mL). the organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give crude cyclized product as a burgundy oil which was used in the next step. p-Xylene (Volume: 82 ml) and 10% palladium on carbon (0.916 g, 0.861 mmol) were added, and the reaction was heated at 120° C. After 3 h, the reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, dissolved in EtOAc (125 mL) and washed with water (25 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 80 g column eluting with 20-75% EtOAc/hexane. Appropriate fractions were collected and concentrated in vacuo to give ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (0.6232 g, 1.098 mmol, 38.3% yield) as a tan solid, LC/MS (M+H)=568.24.

Aufarbeitung

  1. concentrationthe reaction was concentrated in vacuo
  2. dissolutiondissolved in EtOAc (75 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×75 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give crude cyclized product as a burgundy oil which
  9. waitAfter 3 h
  10. temperaturethe reaction was cooled to room temperature
  11. filtrationfiltered through a wad of CELITE®
  12. concentrationThe filtrate was concentrated in vacuo
  13. dissolutiondissolved in EtOAc (125 mL)
  14. washwashed with water (25 mL)
  15. customThe layers were separated
  16. dry with materialthe organic layer was dried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo
  19. customThe residue was purified by flash chromatography
  20. washeluting with 20-75% EtOAc/hexane
  21. customAppropriate fractions were collected
  22. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-28518019d6314036ab84d2bad0cdb183
Quelldatensatz
uspto-grants-2014_04
Patentnummer
US08685969B2

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