Triethylamine → 3-[1,4']Bipiperidinyl-1'-ylmethyl-2-phenyl-quinoline-4-carboxylic Acid ((S)-1-cyclohexyl-ethyl)-amide Dihydrochloride

HRID 1837383Notes

Reaction equation

HRID 1837383 reaction equation
[ClH:1].Cl.[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=O)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:66]1([CH:72]([NH2:74])[CH3:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1.C1([C@@H](N)C)CCCCC1>C(Cl)Cl.CC#N.C(Cl)Cl>[ClH:1].[ClH:1].[CH:66]1([C@@H:72]([NH:74][C:26]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]=2[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH2:14][CH2:13]2)=[O:28])[CH3:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 1107331-CyclohexylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 5325951(S)-(+)-1-CyclohexylethylamineHCID 695475013-[1,4']Bipiperidinyl-1'-ylmethyl-2-phenyl-quinoline-4-carboxylic acid dihydrochloride

Product 1

HCID 98303603-[1,4']Bipiperidinyl-1'-ylmethyl-2-phenyl-quinoline-4-carboxylic Acid ((S)-1-cyclohexyl-ethyl)-amide Dihydrochloride

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21877088Acetonitrile methylene chlorideSolvent

Conditions

Temperature
0 °C

Procedure

4.0 g (8.0 mmol) of crude 3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 2) were dissolved in 300 ml of a 1:1 mixture of CH2Cl2/CH3CN; 3.4 ml (24.6 mmol) of triethylamine (TEA) and 4.0 g (10.7 mmol) of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) were added and the reaction mixture was cooled at 0° C. 1.22 ml (8.2 mmol) of (S) 1-cyclohexylethylamine, dissolved in 10 ml of dry CH2Cl2, were added dropwise and the reaction mixture was stirred at room temperature for 24 h. Additional 2.0 g (5.3 mmol) of HBTU and 2.0 ml (13.4 mmol) of (S)-1-cyclohexyl-ethylamine were added and the reaction mixture was heated to 40° C. for 8 h. The solvent was evaporated in vacuo to dryness and the residue was taken up with EtOAc and washed with H2O, 1 N NaOH and brine, dried over Na2SO4 and evaporated to dryness to yield a crude material which was purified by flash column cromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 containing 0.5% NH4OH (28%). The residue was dissolved in acetone and acidified with HCl/Et2O; the precipitate so formed was recovered by suction filtration to yield 3.2 g of title compound as a pale yellow solid.

Workup

  1. additionwere added dropwise
  2. temperaturethe reaction mixture was heated to 40° C. for 8 h
  3. customThe solvent was evaporated in vacuo to dryness
  4. washwashed with H2O, 1 N NaOH and brine
  5. dry with materialdried over Na2SO4
  6. customevaporated to dryness
  7. customto yield a crude material which
  8. customwas purified by flash column cromatography on 230-400 mesh silica gel, utilising
  9. additiona mixture of EtOAc/MeOH 95:5 containing 0.5% NH4OH (28%)
  10. dissolutionThe residue was dissolved in acetone
  11. customthe precipitate so formed
  12. filtrationwas recovered by suction filtration

Sources & evidence

ORD record
ord-c5f75396b7da477383c0cccdf27d5765
Source dataset
uspto-grants-2004_08
Patent number
US06780875B2

Reaction notes

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