Tetrahydrofuran → 1-t-butoxycarbonyl-4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane

HRID 2230731Notes

Reaction equation

HRID 2230731 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].I[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 27751891,1,1-Trifluoro-4-iodobutaneHCID 184646551-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane

Product 1

HCID 212236081-t-butoxycarbonyl-4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazol-2-yl)[1,4]diazepaneYield 95.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5 mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir at room temperatue for 30 minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to room temperature and stir overnight at room temperature. Cool to 5° C., quench by addition of ice and saturated ammonium chloride solution (5 mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve the residue in ethyl acetate (150 mL), wash the organic phase with water (3×40 mL), dry (Na2SO4), filter and concentrate to afford a yellow oil. Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60% ethyl acetate in hexane. Concentrate the appropriate fractions in vacuo and dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.40 (silica gel, ethyl acetate).

Workup

  1. temperatureAllow to warm slowly to room temperature
  2. stirringstir overnight at room temperature
  3. temperatureCool to 5° C.
  4. customquench by addition of ice and saturated ammonium chloride solution (5 mL)
  5. concentrationconcentrate in vacuo
  6. customto remove the tetrahydrofuran
  7. dissolutionDissolve the residue in ethyl acetate (150 mL)
  8. washwash the organic phase with water (3×40 mL)
  9. dry with materialdry (Na2SO4)
  10. filtrationfilter
  11. concentrationconcentrate
  12. customto afford a yellow oil
  13. customPurify by flash chromatography (silica gel, 7×40 cm)
  14. washeluting with 60% ethyl acetate in hexane
  15. concentrationConcentrate the appropriate fractions in vacuo
  16. customdry the residue (1.2 Torr, 50° C., 2 hours)

Sources & evidence

ORD record
ord-1a4d71496fae4eb9881554fb420eea34
Source dataset
uspto-grants-2002_07
Patent number
US06423704B1

Reaction notes

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