Toluene → ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylate

HRID 246959Notes

Reaction equation

HRID 246959 reaction equation
C1(C)C=CC=CC=1.[CH3:8][N:9]([CH3:12])[CH:10]=O.S(OC)(OC)(=O)=O.C[O-].[Na+].[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:45]([F:46])=[CH:44][C:35]([C:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:37])=[C:34]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])[N:33]=2)[CH2:28]1)(=[O:25])[CH3:24]>O.C(Cl)(Cl)Cl>[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:45]([F:46])=[CH:44][C:35]([C:36]([C:38](=[CH:8][N:9]([CH3:12])[CH3:10])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:37])=[C:34]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])[N:33]=2)[CH2:28]1)(=[O:25])[CH3:24]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10942334Sodium MethoxideHCID 11127270DMF dimethylsulfateHCID 13849322Ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate

Product 1

HCID 70391376ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylateYield 84.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6212ChloroformSolvent

Procedure

To 4 ml of toluene was added 245 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 66 mg of sodium methoxide was added thereto with ice-cooling after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate was added thereto, and the resulting mixture was subjected to reaction under reflux for 5 hours. To the reaction mixture were added 20 ml of chloroform and 20 ml of water, and the organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)] to obtain 190 mg (yield 84.9%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3 -(N,N-dimethylamino)acrylate having a melting point of 184°-186° C.

Workup

  1. additionwas added
  2. temperaturewith ice-cooling after which the resulting mixture
  3. customwas subjected to reaction at room temperature for 30 minutes
  4. customthe resulting mixture was subjected to reaction
  5. temperatureunder reflux for 5 hours
  6. customthe organic layer was separated
  7. washwashed with 20 ml of saturated aqueous sodium chloride solution
  8. dry with materialdried over anhydrous magnesium sulfate
  9. customThe solvent was removed by distillation under reduced pressure
  10. customthe residue thus obtained
  11. customwas purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform-ethanol (50:1 by volume)]

Sources & evidence

ORD record
ord-d5d3234db92b43dca8e17a67d2ebdbe6
Source dataset
uspto-grants-1987_11
Patent number
US04704459

Reaction notes

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