Hydrochloric Acid → 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525647

Reaction equation

HRID 525647 reaction equation
O=S(Cl)Cl.[Br:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.Cl>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Br:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=1)=[O:13]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 2854335-Bromo-6-chloropyridine-3-carboxylic acidHCID 6008484-(Trifluoromethoxy)aniline

Product 1

HCID 867025955-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

SOCl2 (1.089 mL, 14.92 mmol) and DMF (0.01 mL) were added dropwise to a suspension of 5-bromo-6-chloronicotinic acid (1.176 g, 4.97 mmol) in toluene (10 mL) and the RM was stirred at 85° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was diluted with THF (10 mL). DIPEA (1.74 mL, 9.95 mmol) was added and the mixture was cooled to −15° C. under argon atmosphere, treated with a solution of 4-trifluoromethoxyaniline (0.701 mL, 5.22 mmol) in THF (10 mL) and stirred at RT for 1 h. The solvent was off under reduced pressure and the residue was treated with aq. 1M HCl (50 mL), and extracted with TBME/EtOAc (4:1). The combined extracts were washed with aq. 1 M HCl, sat. aq. Na2CO3 and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product was purified by flash chromatography (Biotage Silica gel column, 50 g, cyclohexane/EtOAc from 5% to 25% EtOAc) to afford the title compound as an off-white solid. UPLC-MS (Condition 1) tR=3.09 min, m/z=394.9/396.8 [M+H]+, m/z=393.0/394.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.86 (d, J=9.0 Hz, 2H) 8.73 (d, J=2.2 Hz, 1H) 8.92 (d, J=2.0 Hz, 1H) 10.69 (s, 1H).

Workup

  1. customThe solvent was evaporated off under reduced pressure
  2. additionthe residue was diluted with THF (10 mL)
  3. temperaturethe mixture was cooled to −15° C. under argon atmosphere
  4. stirringstirred at RT for 1 h
  5. extractionextracted with TBME/EtOAc (4:1)
  6. washThe combined extracts were washed with aq. 1 M HCl, sat. aq. Na2CO3 and brine
  7. dry with materialdried over MgSO4
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give the crude product
  10. customwas purified by flash chromatography (Biotage Silica gel column, 50 g, cyclohexane/EtOAc from 5% to 25% EtOAc)

Sources & evidence

ORD record
ord-db4b2da4c2914ad5b8068eaab23b492a
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Linked notes

Loading…