1-Bromo-2-Chloroethane → Ethyl 4-(2-chloroethyl)hexahydro-1-(phenylmethyl)-1H-azepine-4-carboxylate

HRID 383946Notes

Reaction equation

HRID 383946 reaction equation
C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:26][CH2:27][Cl:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 78491-Bromo-2-ChloroethaneHCID 11430Potassium CarbonateHCID 59291433HCID 59291433, compoundHCID 178418339Butyllithium

Product 1

HCID 59291310Ethyl 4-(2-chloroethyl)hexahydro-1-(phenylmethyl)-1H-azepine-4-carboxylateYield 66.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

To DIPA (3.22 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of 1-bromo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.

Workup

  1. stirringby stirring for 30 minutes
  2. stirringstirring for 2 hours
  3. extractionfollowed by extraction with EtOAc
  4. washThe organic layer was washed with water and brine in this order
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia)
  8. customDesired fractions were collected
  9. concentrationconcentrated under reduced pressure
  10. concentrationAfter concentration under reduced pressure
  11. additionwas added EtOAc
  12. customfollowed by purification by silica gel column chromatography (EtOAc)

Sources & evidence

ORD record
ord-2790e0d4702d412790042f8c52cf5e64
Source dataset
uspto-grants-2013_02
Patent number
US08367696B2

Reaction notes

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