Hydrochloric Acid → 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester

HRID 2372402Notes

Reaction equation

HRID 2372402 reaction equation
[CH2:1]([O:3][C:4](=[O:9])[C:5]([NH:7][CH3:8])=O)[CH3:2].C(Cl)(Cl)=O.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][C:23]([NH:25][NH2:26])=O.Cl>ClC(Cl)Cl.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:7]([CH3:8])[C:23]([CH2:22][C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])=[N:25][N:26]=1)=[O:9])[CH3:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 6371PhosgeneHCID 3413434Ethyl 2-(methylamino)-2-oxoacetateHCID 199075982-(2,6-Difluorophenyl)acetohydrazide

Product 1

HCID 543382725-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 1140TolueneSolventHCID 6212ChloroformSolvent

Procedure

18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127-128° is obtained.

Workup

  1. stirringis subsequently stirred for 40 minutes at room temperature
  2. additionpoured onto ice-water
  3. extractionextracted three times with ether
  4. extractionextracted
  5. stirringby shaking three times with dichloromethane
  6. washThe combined dichloromethane phases are washed twice with water
  7. dry with materialdried over magnesium sulphate
  8. concentrationconcentrated by evaporation
  9. stirringstirred
  10. temperatureunder reflux for 9 hours
  11. concentrationThe reaction mixture is then concentrated
  12. customchromatographed over silica gel
  13. concentrationThe eluate is concentrated by evaporation
  14. customthe crystalline residue is recrystallised from ethyl acetate/ether

Sources & evidence

ORD record
ord-42185a891df44c6ca805bb7fb8eb3234
Source dataset
uspto-grants-1992_03
Patent number
US05098922

Reaction notes

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