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

HRID 924104Notes

Reaction equation

HRID 924104 reaction equation
CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[C:21]([I:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=1.CCN(C(C)C)C(C)C.[F:32][C:33]([F:43])([F:42])[O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCCCCC>[Cl:12][C:13]1[C:21]([I:22])=[CH:20][C:16]([C:17]([NH:39][C:38]2[CH:40]=[CH:41][C:35]([O:34][C:33]([F:32])([F:42])[F:43])=[CH:36][CH:37]=2)=[O:19])=[CH:15][N:14]=1

Participants

9

Reactant 6

HCID 311Citric AcidHCID 6228DimethylformamideHCID 65578Oxalyl 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 2

HCID 6344DichloromethaneSolvent2×HCID 8058HexaneSolvent

Procedure

DMF (0.014 mL, 0.176 mmol) and oxalyl chloride (2.316 mL, 26.5 mmol) were added to a solution of 6-chloro-5-iodonicotinic acid (5 g, 17.64 mmol) in DCM (80 mL) and the RM was stirred for 2 h at RT under a nitrogen atmosphere. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (60 mL). DIPEA (9.24 mL, 52.9 mmol) was added and the mixture was cooled down to 5° C., treated dropwise with a solution of 4-(trifluoro methoxy)aniline (2.62 mL, 19.40 mmol) in DCM (20 mL) and stirred at 5° C. for 30 min and at RT for 1 h. The solvent was off under reduced pressure and the residue was treated with aq. 10% citric acid (70 mL) and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product was suspended in n-hexane, and filtered to afford the title compound as a beige solid. UPLC-MS (Condition 3) tR=1.22 min, 440.9/442.9 [M−H]−.

Workup

  1. customThe solvent was evaporated off under reduced pressure
  2. dissolutionthe residue was dissolved in THF (60 mL)
  3. temperaturethe mixture was cooled down to 5° C.
  4. stirringstirred at 5° C. for 30 min and at RT for 1 h
  5. extractionextracted with EtOAc
  6. washThe combined extracts were washed with sat. aq. Na2CO3 and brine
  7. dry with materialdried over Na2SO4
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give the crude product
  10. filtrationfiltered

Sources & evidence

ORD record
ord-e631dfe7452642fdaaf9a5c1abdb24ed
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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