p-Toluenesulfonic acid → (S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide

HRID 2370874Notes

Reaction equation

HRID 2370874 reaction equation
[NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][N:5]=[C:4]([C:10]([NH:12][C@@H:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[C:23]([F:32])[CH:22]=2)[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:11])[CH:3]=1.[Li+].[Cl-].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:10]([NH:12][C@@H:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[C:23]([F:32])[CH:22]=2)[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:11])[CH:3]=1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 433294Lithium ChlorideHCID 516892Sodium BicarbonateHCID 71144233(S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide

Product 1

HCID 71144326(S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
180 °C

Procedure

To a stirred solution of (S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl) (3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide (600 mg, 0.0013 mol) in NMP (10 mL) was added LiCl (168 mg, 0.0039 mol, Aldrich) followed by pTSA (754 mg, 0.0039 mol, Aldrich) at rt. The reaction mixture was stirred at 180° C. for 2 h. After completion of the reaction (monitored by TLC, 50% EtOAc in petroleum ether), the reaction mixture was cooled to room temperature and sat'd NaHCO3 (50 mL) was added and the aqueous solution was extracted with EtOAc (25 mL×2). The combined organic layers were washed with water (25 mL×2), saturated NaCl (25 mL) and dried over anhydrous sodium sulfate. The product thus obtained 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 ppm 9.90 (s, 1H), 9.51 (d, J=8 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.46 (d, J=1.6 Hz, 10.4 Hz, 1H), 7.30 (d, J=12.8, 2H), 6.48 (d, J=4.4 Hz, 1H), 5.78 (s, 2H). MS (ESI, positive ion) m/z: 441.3 (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 combined organic layers were washed with water (25 mL×2), saturated NaCl (25 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe product thus obtained
  6. customwas purified by silica gel (60-120 mesh) column chromatography
  7. washeluting with 60-70% EtOAc in petroleum ether

Sources & evidence

ORD record
ord-e222ed31f8a14b4b97bd790ba2ccae90
Source dataset
uspto-grants-2014_04
Patent number
US08710043B2

Reaction notes

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