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

HRID 222677Notes

Reaction equation

HRID 222677 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-bec5eb090e694919833b8d2649a7a8b3
Source dataset
uspto-grants-2012_06
Patent number
US08207331B2

Reaction notes

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