Sodium hydride → HCID 18465101, compound

HRID 2230559Notes

Reaction equation

HRID 2230559 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].[H-].[Na+].Cl[CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31].[Cl-].[NH4+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].CO.ClCCl.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[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

10

Reactant 4

HCID 24758Sodium hydride2×HCID 25517Ammonium ChlorideHCID 799932-Pentanone, 5-chloro-2×HCID 184646551-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane

Product 1

HCID 18465101HCID 18465101, compound

Reagents, catalysts & solvents 5

HCID 74236Tetrabutylammonium BromideCatalystHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.10 g, 3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in oil, 5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene ketal (0.79 mL, 5.22 mmol) and tetra-n-butylammonium bromide (112 mg, 0.35 mmol) and warm to ambient temperature. Heat to reflux. After 18 hours, cool, add sodium hydride (0.1 g) and 5-chloropentan-2-one, ethylene ketal (0.50 mL) and again heat to reflux. After 24 hours, cool in a dry-ice/acetone bath and add a saturated aqueous solution of ammonium chloride. Warm to ambient temperature and dilute the reaction mixture with a saturated aqueous solution of sodium bicarbonate. Concentrate in vacuo to remove most to the tetrahydrofuran and extract three times with ethyl acetate. Extract the combined organic layers with water and then brine, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution to give 1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane, ethylene ketal: Rf=0.47 (silica gel, 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution).

Workup

  1. temperatureCool in an ice bath
  2. temperatureHeat to reflux
  3. waitAfter 18 hours
  4. temperaturecool
  5. temperatureagain heat to reflux
  6. waitAfter 24 hours
  7. temperaturecool in a dry-ice/acetone bath
  8. temperatureWarm to ambient temperature
  9. concentrationConcentrate in vacuo
  10. customto remove most to the tetrahydrofuran
  11. extractionextract three times with ethyl acetate
  12. extractionExtract the combined organic layers with water
  13. dry with materialbrine, dry the organic layer over Na2SO4
  14. filtrationfilter
  15. customevaporate in vacuo
  16. customto give a residue

Sources & evidence

ORD record
ord-c01dd4060c9d42a1b0bba050bd0fd85c
Source dataset
uspto-grants-2002_07
Patent number
US06423704B1

Reaction notes

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