Triethylamine → N-trifluoroethyl benzazepine

HRID 1630692Notes

Reaction equation

HRID 1630692 reaction equation
[N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C.CS(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>CC(C)=O>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 81531DiisopropylethylamineHCID 5565652,2,2-Trifluoroethyl MethanesulfonateHCID 866101862H-benzazepine

Product 1

HCID 66965237N-trifluoroethyl benzazepineYield 119.5%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

To a solution of the 2H-benzazepine (80 mg, 0.26 mmol) from step J above in acetone (5 mL) were added triethylamine (0.06 mL, 0.43 mmol), N,N-diisopropylethylamine (0.025 mL, 0.26 mmol) and 2,2,2-trifluoroethyl methanesulfonate (60 mg, 0.26 mmol). The reaction solution was heated under reflux for 1 hour and then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by flash column chromatography (90:10 to 80:20 hexanes/ethyl acetate) to give the N-trifluoroethyl benzazepine (70 mg, 69%) as a white foam: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.72 (s, 1H), 6.67-6.50 (br, 2H), 4.29 (d, J=8.0 Hz, 1H), 4.19-4.07 (br, 1H), 3.90 (d, J=15.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.32-3.26 (br, 2H), 3.16-3.12 (m, 4H), 3.03-2.89 (m, 2H), 2.26-2.19 (m, 1H), 2.09-2.00 (m, 1H). To a solution of the N-trifluoroethyl benzazepine (65 mg, 0.17 mmol) in methanol (2 mL) were added maleic acid (19 mg, 0.17 mmol) and water (10 mL). The resultant solution was lyophilized overnight to give 4-(5-phenyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]-azepin-8-yl)morpholine, maleate salt (84 mg, >99.0% AUC HPLC) as a light pink solid: 1H NMR (CD3OD, 500 MHz) δ 7.32 (t, J=7.5 Hz, 2H), 7.23 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.84 (d, J=2.5 Hz, 1H), 6.75 (d, J=6.5 Hz, 1H), 6.71-6.54 (br, 1H), 6.30 (s, 2H), 4.35 (d, J=7.5 Hz, 1H), 4.21-4.04 (br, 1H), 3.92 (d, J=15.0 Hz, 1H), 3.84 (t, J=5.0 Hz, 4H), 3.29-3.25 (m, 2H), 3.22-3.07 (m, 6H), 2.34-2.27 (m, 1H), 2.06 (d, J=13.5 Hz, 1H); ESI MS m/z 391 [M+H]+.

Workup

  1. temperatureThe reaction solution was heated
  2. temperatureunder reflux for 1 hour
  3. concentrationconcentrated in vacuo
  4. customThe residue obtained
  5. customwas purified by flash column chromatography (90:10 to 80:20 hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-98a1d69bb63640c89491bd5a877acde5
Source dataset
uspto-grants-2014_07
Patent number
US08791101B2

Reaction notes

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