Pyridine → N-[4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)phenyl]-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxamide

HRID 1908227Notes

Reaction equation

HRID 1908227 reaction equation
[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.CCOC(C)=O>[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2

Participants

7

Reactant 4

HCID 1049PyridineHCID 111923Propylphosphonic anhydrideHCID 156185574-Oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acidHCID 575168474-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)aniline

Product 1

HCID 46194561N-[4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)phenyl]-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxamideYield 22.5%

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid 17 (19 mg, 0.07 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline 27 (20 mg, 0.07 mmol) in 2-methyltetrahydrofuran (190.9 μL) was added T3P (118 mg, 0.19 mmol) and pyridine (12 mg, 12 μL, 0.15 mmol). The reaction was heated at 100° C. for 30 min under microwave irradiation. The reaction was diluted with EtOAc and quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organics were washed once with water, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC (0-99% CH3CN/0.05% TFA) to give N-[4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)phenyl]-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxamide (8 mg, 17% yield). LC/MS m/z 509.7 [M+H]+, retention time 1.06 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 13.23 (d, J=6.8 Hz, 1H), 12.40 (s, 1H), 10.31 (s, 1H), 8.96 (d, J=6.6 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.08-8.06 (m, H), 8.07 (dd, J=1.5 Hz, 8.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.15-7.09 (m, 2H), 4.49 (s, 2H), 4.29 (s, 2H), 2.94 (s, 6H), 1.67 (d, J=7.2 Hz, 4H), 1.44 (d, J=7.0 Hz, 4H).

Workup

  1. customquenched with saturated aqueous NaHCO3 (50 mL)
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted twice with EtOAc
  4. washThe combined organics were washed once with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by reverse phase HPLC (0-99% CH3CN/0.05% TFA)

Sources & evidence

ORD record
ord-649b2f0baf86443cb062d0114cf87768
Source dataset
uspto-grants-2013_12
Patent number
US08598205B2

Reaction notes

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