Diethyl disulfide → (4R,9aR)-6-Ethylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

HRID 11957

Reaktionsgleichung

Reaktionsgleichung von HRID 11957
C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20](COCCO)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:32]([S:34]SCC)[CH3:33].C([O-])(=O)C.[NH4+]>C1COCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([S:34][CH2:32][CH3:33])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]

Komponenten

8

Edukt 4

HCID 8077Diethyl disulfideHCID 517165Ammonium AcetateHCID 69557393(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester2×HCID 178418339Butyllithium

Produkt 1

HCID 69359585(4R,9aR)-6-Ethylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl esterAusbeute 53 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittel3×HCID 962WaterLösungsmittel2×HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

THF (5 mL) was cooled to −78° C. under an argon atmosphere. n-Butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added and the mixture was stirred at −78° C. for 5 min. A mixture of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (0.2 g, 0.54 mmol) in THF (5 mL) was added dropwise, maintaining the temperature below −70° C. The resultant dark red solution was stirred at −78° C. for 30 min and ethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was stirred at −78° C. for 2 h and left to warm to room temperature over 2 h. Water (1 mL) was added and the mixture was poured onto an isolute HM-N SPE cartridge and eluted with ethyl acetate (10 mL). The eluant was evaporated under reduced pressure and the crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.071 g, 53% yield) as a pale yellow oil: m/z 350.14 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 6.21 min. (4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

Aufarbeitung

  1. additionwas added dropwise
  2. temperaturemaintaining the temperature below −70° C
  3. stirringThe resultant dark red solution was stirred at −78° C. for 30 min
  4. stirringThe mixture was stirred at −78° C. for 2 h
  5. waitleft
  6. temperatureto warm to room temperature over 2 h
  7. additionthe mixture was poured onto an isolute HM-N SPE cartridge
  8. washeluted with ethyl acetate (10 mL)
  9. customThe eluant was evaporated under reduced pressure
  10. customthe crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR

Quellen und Nachweise

ORD-Eintrag
ord-b693e70e23a741d6b2c133e26b82a717
Quelldatensatz
uspto-grants-2006_08
Patentnummer
US07098337B2

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