Phosgene → 4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1h-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylic acid diethylamide

HRID 645811Notes

Reaction equation

HRID 645811 reaction equation
[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(Cl)=[O:24].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:27]([N:29]([CH2:30][CH3:31])[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)[CH2:18][CH2:19]1)=[O:24])[CH3:28]

Participants

7

Reactant 4

HCID 6371PhosgeneHCID 8021DiethylamineHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 685061053-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 104535604-(3-Cyclobutyl-2,3,4,5-tetrahydro-1h-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylic acid diethylamide

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 6344DichloromethaneSolvent

Procedure

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (1.5 g, 5 mmol) dissolved in toluene (40 ml) was added slowly to a 20% phosgene in toluene solution (12.5 ml, 25 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo to afford a crude residue (1.91 g). The crude product (300 mg, 0.75 mmol) was then added to a stirred slurry of diethylamine (207 μL, 2 mmol) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.41 g, 4.5 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E61). MS (ES+) m/e 400 [M+H]+.

Workup

  1. concentrationconcentrated in vacuo
  2. customto afford a crude residue (1.91 g)
  3. stirringThe reaction mixture was stirred at room temperature for 16 hours
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude residue was purified by column chromatography
  7. washeluting with dichloromethane
  8. additiona mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90)

Sources & evidence

ORD record
ord-d0158d05d1f24e1aa626d7d73e6e9850
Source dataset
uspto-grants-2010_04
Patent number
US07704994B2

Reaction notes

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