Pyridine → N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide

HRID 400987Notes

Reaction equation

HRID 400987 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]([F:36])([F:35])[F:34])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:22]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]([F:36])([F:34])[F:35])[CH:27]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:24][CH2:23]2

Participants

6

Reactant 3

HCID 1049PyridineHCID 156185574-Oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acidHCID 529133904-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline

Product 1

HCID 45273897N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
65 °C

Procedure

To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid (7) (9.1 g, 35.39 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11A) (9.2 g, 35.74 mmol) in 2-methyltetrahydrofuran (91.00 mL) was added propyl phosphonic acid cyclic anhydride (T3P (50% solution in ethyl acetate), 52.68 mL, 88.48 mmol) and pyridine (5.6 g, 5.73 mL, 70.78 mmol) at room temperature. The reaction flask was heated at 65° C. for 10 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was then diluted with ethyl acetate and quenched with saturated Na2CO3 solution (50 mL). The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to a tan solid. The crude solid was slurried in a 2:1 mixture of ethyl acetate and diethyl ether, collected by vacuum filtration, and washed twice more with ethyl acetate/diethyl ether mixture to provide the crude product as a light yellow crystalline powder. The powder was dissolved in warm ethyl acetate and absorbed onto Celite. Purification by silica gel chromatography (0-50% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Compound I) as a white crystalline solid in the solid form A. LC/MS m/z 496.0 [M+H]+, retention time 1.48 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1HNMR (400.0 MHz, DMSO-d6) δ 13.08 (s, 1H), 12.16 (s, 1H), 8.88 (s, 1H), 8.04 (dd, J=2.1, 7.4 Hz, 1H), 7.95-7.88 (m, 3H), 7.22 (dd, 2.5, 8.9 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 4.33 (s, 2H), 1.67 (d, J=6.9 Hz, 4H), 1.44 (d, J=6.9 Hz, 4H).

Workup

  1. temperatureAfter cooling to room temperature
  2. customquenched with saturated Na2CO3 solution (50 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted twice more with ethyl acetate
  5. washThe combined organic layers were washed with water
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to a tan solid
  9. additionThe crude solid was slurried in a 2:1 mixture of ethyl acetate and diethyl ether
  10. filtrationcollected by vacuum filtration
  11. washwashed twice more with ethyl acetate/diethyl ether mixture
  12. customto provide the crude product as a light yellow crystalline powder
  13. customabsorbed onto Celite
  14. customPurification by silica gel chromatography (0-50% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-e0d15e230e43430093adca6c2f76cfe3
Source dataset
uspto-grants-2014_06
Patent number
US08741922B2

Reaction notes

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