Pyridine → (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl)-1-phenyl-ethanol

HRID 1350527Notes

Reaction equation

HRID 1350527 reaction equation
FC(F)(F)S(OC)(=O)=O.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14](=S)[C:13]=2[CH:12]=1.[C:26]1([C@@H:32]([OH:40])[CH2:33][CH:34]2[CH2:39][NH:38][CH2:37][CH2:36][NH:35]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>ClCCl.CO.ClCCl>[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:38]3[CH2:37][CH2:36][NH:35][C@H:34]([CH2:33][C@@H:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:40])[CH2:39]3)[C:13]=2[CH:12]=1.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][C@@H:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:40])[CH2:39]3)[C:13]=2[CH:12]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 9526Methyl triflateHCID 210935012-Methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepine-4-thioneHCID 69489678(S)-1-Phenyl-2-piperazin-2-yl-ethanol

Product 2

HCID 135900337(S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl)-1-phenyl-ethanolHCID 136360204(S,R)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
0 °C

Procedure

Add methyl trifluoromethanesulfonate (174 μL, 1.53 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (315 mg, 1.28 mmol) in dichloromethane (4 mL). Stir 1 h at 0° C. then warm to ambient temperature and stir 18 h. Concentrate the reaction to an orange powder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol (264 mg, 1.28 mmol) and pyridine (5 mL). Heat to 110° C. for 5.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-dichloromethane (10%). Concentrate and purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2.5%–3%) as the eluent to give 39 mg of (S,R)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol and 130 mg of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol.

Workup

  1. temperaturethen warm to ambient temperature
  2. stirringstir 18 h
  3. concentrationConcentrate
  4. customthe reaction to an orange powder
  5. temperatureHeat to 110° C. for 5.5 h
  6. stirringstir at ambient temperature for 18 h
  7. concentrationConcentrate
  8. customthe reaction
  9. washWash the column with methanol-dichloromethane
  10. customto remove impurities
  11. washthen elute the product with 2N ammonia in methanol-dichloromethane (10%)
  12. concentrationConcentrate
  13. custompurify by radial silica gel chromatography

Sources & evidence

ORD record
ord-e915d6d77c5446f8bc8d985e1ddab518
Source dataset
uspto-grants-2007_05
Patent number
US07214673B2

Reaction notes

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