Potassium Phosphate, Dibasic → Ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

HRID 1163044Notes

Reaction equation

HRID 1163044 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C.OP([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]

Participants

6

Reactant 4

HCID 24450Potassium Phosphate, DibasicHCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 178469453HCID 178469453, compound

Product 1

HCID 17998719Ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A 10 L reactor was charged with 4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (155.1 g, 0.70 mol) and toluene (2.7 L). Phosphorous oxychloride (128.8 g, 78 mL, 0.84 mol) was then added followed by the addition of diisopropylethylamine (94.2 g, 127 mL, 0.70 mol). The reaction mixture was stirred for 5 min at room temperature and then heated at reflux for 20 h. HPLC analysis indicated complete disappearance of starting material. The reaction mixture was then cooled to 0° C. and cold K2HPO4 solution (527 g in 2.4 L of water) was added at a rate to maintain the internal temperature of the reaction mixture below 5° C. The final pH of the mixture was 8. The mixture was then stirred at between 0° C. to 5° C. for 20 min and then at room temperature for 1 h. The organic phase was separated and washed with K2HPO4 solution (85 g in 405 mL of water) and water (345 mL) and then filtered and concentrated in vacuo until yellow solids began to precipitate. Dimethyl formamide (1 L) was added and the remaining toluene was removed in vacuo (bath temperature=38° C., pressure=9 Torr). After concentration, approximately 4% toluene was observable by HPLC.

Workup

  1. temperatureheated
  2. temperatureat reflux for 20 h
  3. temperatureThe reaction mixture was then cooled to 0° C.
  4. temperatureto maintain the internal temperature of the reaction mixture below 5° C
  5. stirringThe mixture was then stirred at between 0° C. to 5° C. for 20 min
  6. waitat room temperature for 1 h
  7. customThe organic phase was separated
  8. washwashed with K2HPO4 solution (85 g in 405 mL of water) and water (345 mL)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo until yellow solids
  11. customto precipitate
  12. additionDimethyl formamide (1 L) was added
  13. customthe remaining toluene was removed in vacuo (bath temperature=38° C., pressure=9 Torr)
  14. concentrationAfter concentration, approximately 4% toluene

Sources & evidence

ORD record
ord-34df620edfa443caabae750a21ce8b98
Source dataset
uspto-grants-2010_10
Patent number
US07820814B2

Reaction notes

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