Sodium hydride → 3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041112Notes

Reaction equation

HRID 2041112 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([OH:22])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 680214-Fluorobenzyl bromideHCID 574477413-tert-Butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 667064083-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
65 °C

Procedure

Prepare a slurry of sodium hydride (60% in mineral oil; 99 mg, 2.5 mmol) in DMF (4 mL) and heat to 65° C. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.84 mmol) in DMF (5 mL) dropwise and stir for 1 h. Add a solution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF (1 mL), stir at 65° C. for 1.5 h and cool to ambient temperature. Add water (1 mL) and concentrate the mixture to an oily residue. Partition the residue between EtOAc/hexane (1:1) and water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, wash with 2N aqueous NaOH, dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and 7:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.

Workup

  1. stirringstir at 65° C. for 1.5 h
  2. temperaturecool to ambient temperature
  3. concentrationAdd water (1 mL) and concentrate the mixture to an oily residue
  4. customPartition the residue between EtOAc/hexane (1:1) and water
  5. dry with materialDry the organic layer over Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate in vacuo
  8. dissolutionDissolve the residue in DCM
  9. washwash with 2N aqueous NaOH
  10. dry with materialdry the organic layer over Na2SO4
  11. filtrationfilter
  12. concentrationconcentrate in vacuo
  13. customPurify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and 7:1)

Sources & evidence

ORD record
ord-46aeecdb79b34fbaadda539afbc2d1d2
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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