Hydrochloric Acid → (S)-N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide

HRID 2370831Notes

Reaction equation

HRID 2370831 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=O)=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:47][C:48]1[CH:49]=[C:50]([C@@H:59]([C:61]2[C:66]([F:67])=[CH:65][CH:64]=[CH:63][N:62]=2)[NH2:60])[CH:51]=[CH:52][C:53]=1[O:54][C:55]([F:58])([F:57])[F:56]>CN(C=O)C.CCCCCC.O.CCOC(C)=O>[F:47][C:48]1[CH:49]=[C:50]([C@@H:59]([C:61]2[C:66]([F:67])=[CH:65][CH:64]=[CH:63][N:62]=2)[NH:60][C:12](=[O:14])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([N+:9]([O-:11])=[O:10])[N:7]=2)[CH:51]=[CH:52][C:53]=1[O:54][C:55]([F:58])([F:57])[F:56]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 225980405-Methoxy-6-nitropicolinic acidHCID 86687985(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride2×

Product 1

HCID 71144173(S)-N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 5-methoxy-6-nitropicolinic acid (200 mg, 0.001 mol) in DMF was added EDCI. HCl (231.6 mg, 0.0012 mol, Molekula, India) followed by HOBt (164.7 mg, 0.0012 mol, Spectrochem, India), DIPEA (521.87 mg, 0.0040 mol, Spectrochem, India) and (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (349.83 mg, 0.0010 mmol, Intermediate 6) at 0° C. The reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), water (20 mL) was added to the reaction mixture, and the aqueous solution was extracted with EtOAc (20 mL×2). The combined organic layers were washed with water (100 mL×2). The organic layer was dried and concentrated providing a residue which was purified by silica gel (60-120 mesh) column chromatography eluting with 40-50% EtOAc in petroleum ether to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.83 (t, J=9.6 Hz, 1H), 7.58-7.55 (m, 3H), 7.35 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.04 (s, 3H). MS (ESI, positive ion) m/z: 485 (M+H).

Workup

  1. additionwas added to the reaction mixture
  2. extractionthe aqueous solution was extracted with EtOAc (20 mL×2)
  3. washThe combined organic layers were washed with water (100 mL×2)
  4. customThe organic layer was dried
  5. concentrationconcentrated
  6. customproviding a residue which
  7. customwas purified by silica gel (60-120 mesh) column chromatography
  8. washeluting with 40-50% EtOAc in petroleum ether

Sources & evidence

ORD record
ord-cd144443e12a496d861d9012a34e634c
Source dataset
uspto-grants-2014_04
Patent number
US08710043B2

Reaction notes

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