Water → 2-[2-(2-(2-Methoxy-ethyl)-4-(2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene-10-yl)-piperazin-1-yl)-ethoxy]-ethanol

HRID 131510Notes

Reaction equation

HRID 131510 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.[C:29](=[O:32])([O-])[O-].[K+].[K+].[I-].[Na+].O.[C:38]([O:41][CH2:42]C)(=O)[CH3:39]>C(O)C>[NH3:7].[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:6][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:8][CH2:9][N:10]1[CH2:39][CH2:38][O:41][CH2:42][CH2:29][OH:32]

Participants

8

Reactant 5

HCID 962WaterHCID 5238Sodium Iodide2×HCID 8857Ethyl AcetateHCID 11430Potassium Carbonate2×HCID 135457486(S)-10-[3-(2-Methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Product 2

HCID 222AmmoniaHCID 1363841542-[2-(2-(2-Methoxy-ethyl)-4-(2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene-10-yl)-piperazin-1-yl)-ethoxy]-ethanolYield 23%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Add (S)2-(2-chloro-ethoxy)-ethanol (0.267 mL, 2.53 mmol) to a slurry of (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.52 g, 1.26 mmol), powdered potassium carbonate (0.87 g, 6.32 mmol), and sodium iodide (0.95 g, 6.32 mmol) in absolute ethanol (5.2 mL), and heat to reflux. After 22 hours, cool and add powdered potassium carbonate (0.09 g, 0.65 mmol), sodium iodide (0.09 g, 0.60 mmol), and (S)-(2-2-chloro-ethoxy)-ethanol (0.100 mL, 0.938 mmol); rinse in solids with absolute ethanol, and reflux. After 4 hours, add (S)-2-(2-chloro-ethoxy)-ethanol (0.307 mL, 2.88 mmol) and reflux. After 17.5 hours, cool and add deionized water and ethyl acetate. After separation of layers, extract aqueous layer with ethyl acetate (2×), and combine, dry (sodium sulfate), filter, and concentrate organics under reduced pressure to a solid (1.54 g). Purify the solid by flash chromatography, eluting with a gradient of solutions of 2M ammonia in methanol: ethyl acetate (1%-5% 2M ammonia in methanol in ethyl acetate over 61 minutes), and then with a 5% solution of 2M ammonia in methanol, in ethyl acetate for 30 minutes to give the title compound (0.146 g, 23%): mass spectrum (APCI, m/e): 500 (M+1); NMR (1H, 300 MHz, DMSO-d6) δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.71 (m, 1H), 4.60 (t, 1H, J=5.1 Hz), 3.56-3.10 (m, 15H), 2.76 (m, 2H), 2.61-2.41 (m, 3H), 1.68 (m, 2H).

Workup

  1. temperatureheat to reflux
  2. temperaturecool
  3. washrinse in solids with absolute ethanol
  4. temperaturereflux
  5. waitAfter 4 hours
  6. temperaturereflux
  7. waitAfter 17.5 hours
  8. temperaturecool
  9. customAfter separation of layers
  10. extractionextract aqueous layer with ethyl acetate (2×)
  11. dry with materialdry (sodium sulfate)
  12. filtrationfilter
  13. concentrationconcentrate organics under reduced pressure to a solid (1.54 g)
  14. customPurify the solid by flash chromatography
  15. washeluting with a gradient of solutions of 2M ammonia in methanol

Sources & evidence

ORD record
ord-e7b23c007eb94807bcb0355dae53d17b
Source dataset
uspto-grants-2008_06
Patent number
US07384934B2

Reaction notes

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