Dimethylformamide → 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 629108Notes

Reaction equation

HRID 629108 reaction equation
CN(C=O)C.O=S(Cl)Cl.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:12]=1[I:20].CCN(C(C)C)C(C)C.[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C1COCC1.CC(OC)(C)C>[Cl:10][C:11]1[C:12]([I:20])=[CH:13][C:14]([C:17]([NH:37][C:36]2[CH:38]=[CH:39][C:33]([O:32][C:31]([F:30])([F:40])[F:41])=[CH:34][CH:35]=2)=[O:19])=[CH:15][N:16]=1

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 6008484-(Trifluoromethoxy)anilineHCID 222714776-Chloro-5-iodonicotinic acid

Product 1

HCID 867025996-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
80 °C

Procedure

DMF (1.927 mL, 24.89 mmol) and SOCl2 (18.17 mL, 249 mmol) were added to a suspension of 6-chloro-5-iodo-3-pyridinecarboxylic acid (24 g, 83 mmol) in toluene (165 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (165 mL). DIPEA (29.0 mL, 166 mmol) was added and the mixture was cooled down to −15° C., treated dropwise with a solution of 4-(trifluoromethoxy)aniline (15.43 g, 87 mmol) in THF (165 mL) and was stirred at RT for 1 h. The solvent was off under reduced pressure and the residue was dissolved in TBME (500 mL), washed with 1N HCl, a sat. aq. solution of NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the product was recrystallized from EtOAc/n-heptane to afford the title compound as a white solid. UPLC-MS (Condition 2) tR=1.23 min, m/z=440.8 [M−H]−.

Workup

  1. customThe solvent was evaporated off under reduced pressure
  2. dissolutionthe residue was dissolved in THF (165 mL)
  3. temperaturethe mixture was cooled down to −15° C.
  4. stirringwas stirred at RT for 1 h
  5. washwashed with 1N HCl
  6. dry with materiala sat. aq. solution of NaHCO3 and brine, dried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customthe product was recrystallized from EtOAc/n-heptane

Sources & evidence

ORD record
ord-6ad585d1021149d28bf83c30a7e382b5
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

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