p-Toluenesulfonic acid → (S)-N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide

HRID 509392Notes

Reaction equation

HRID 509392 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li+].[Cl-].CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 8857Ethyl AcetateHCID 433294Lithium ChlorideHCID 71144173(S)-N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide

Product 1

HCID 71144193(S)-N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
180 °C

Procedure

To a stirred solution of (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl) (3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide (700 mg, 0.0011 mol) in NMP (7.0 mL) was added LiCl (183.79 mg, 0.0043 mol, Sigma Aldrich, India) followed by pTSA (746.63 mg, 0.0043 mol, Sigma Aldrich, India) at room temperature. The reaction mixture was stirred at 180° C. for 2 h. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was cooled to room temperature and water (50 mL) was added and the aqueous solution was extracted with EtOAc (25 mL×2). The organic extracts were washed with water (25 mL×2) and brine (25 mL) and dried over anhydrous sodium sulfate and concentrated. The resulting material was purified by silica gel (60-120 mesh) column chromatography eluting with 60-70% EtOAc in petroleum ether to give the title compound as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.77 (br. s., 1H), 9.43 (d, J=7.2 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.59-7.54 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 471 (M+H).

Workup

  1. temperaturethe reaction mixture was cooled to room temperature
  2. extractionthe aqueous solution was extracted with EtOAc (25 mL×2)
  3. washThe organic extracts were washed with water (25 mL×2) and brine (25 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated
  6. customThe resulting material was purified by silica gel (60-120 mesh) column chromatography
  7. washeluting with 60-70% EtOAc in petroleum ether

Sources & evidence

ORD record
ord-85a33b76b57f43ceb2177d4d7177f812
Source dataset
uspto-grants-2015_08
Patent number
US09096527B2

Reaction notes

Loading…