Dimethylformamide → N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide

HRID 1795823Notes

Reaction equation

HRID 1795823 reaction equation
S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8]([OH:10])=O.CN(C)C=O.[F:21][C:22]([F:40])([F:39])[C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCCC1.O.C(N(CC)CC)C>[F:21][C:22]([F:39])([F:40])[C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][OH:31])[C:8](=[O:10])[C:7]1[C:11]([I:15])=[CH:12][CH:13]=[N:14][C:6]=1[Cl:5]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 116380193-(3,5-Bis(trifluoromethyl)benzylamino)propanolHCID 177501742-Chloro-4-iodonicotinic acid

Product 1

HCID 11786369N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamideYield 92%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
100 °C

Procedure

To thionyl chloride (20 mL), 2-chloro-4-iodonicotinic acid (8.40 g) were added along with N,N-dimethylformamide (3 droplets) and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was then distilled under reduced pressure to obtain a yellow residue. 3-(3,5-bis(trifluoromethyl)benzylamino)propanol (10.7 g) and triethylamine (20.6 mL) were dissolved in tetrahydrofuran (150 mL). While the mixture was chilled on an ice bath, a tetrahydrofuran solution of the yellow residue (50 mL) was added. After stirred for 1 hour, the mixture was further stirred for additional two hours at room temperature. Subsequently, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was then dried on anhydrous sodium sulfate. Following the removal of the solvent, the remaining residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=3:1) to obtain N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide (15.4 g, 92%).

Workup

  1. distillationThe reaction mixture was then distilled under reduced pressure
  2. customto obtain a yellow residue
  3. temperatureWhile the mixture was chilled on an ice bath
  4. stirringAfter stirred for 1 hour
  5. stirringthe mixture was further stirred for additional two hours at room temperature
  6. extractionthe mixture was extracted with ethyl acetate
  7. dry with materialThe extract was then dried on anhydrous sodium sulfate
  8. customthe removal of the solvent
  9. customthe remaining residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=3:1)

Sources & evidence

ORD record
ord-13abe883f4b346bf8536000001b197bc
Source dataset
uspto-grants-2006_04
Patent number
US07030107B2

Reaction notes

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