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

HRID 1829910Notes

Reaction equation

HRID 1829910 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][NH:10][C:9]2=O)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C.OP([O-])([O-])=O.[K+].[K+]>O.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

7

Reactant 4

HCID 24450Potassium Phosphate, DibasicHCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 135438448Ethyl 5-methyl-4-oxo-1,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Product 1

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

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
111 °C

Procedure

A 2L 3-neck flask was charged with 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (50 g, 226 mmol) and dry toluene (750 ml). POCl3 (41.6 g, 271.5 mmol) was added in one portion, followed by slow addition of DIEA (32.2 g, 248.9 mmol) at a rate, which maintained the temperature below 30° C. The resulting suspension was heated to 111° C. for 24 h becoming homogeneous at 80° C. The reaction was monitored by HPLC after quenching with 2 M MeNH2/THF (10 μl reaction mixture, 20 μl MeNH2/THF in 200 μl acetonitrile). Upon completion, reaction was cooled to −8° C. and a solution of K2HPO4 in H2O (170 g/775 ml) was added maintaining temperature below 1° C. The mixture was stirred for 20 min at −8° C. then warmed to ambient temperature for 1 h. The resulting light suspension was filtered through a pad of celite and the layers were separated. The organic layer was washed with K2HPO4 in H2O (27 g/130 ml), followed by water (250 ml) and dried (Na2SO4). The solution was filtered and concentrated to a yellow foam 4A (54.0 g, 100%). MS: 235 (MeNH2 adduct) (M+H)+; HPLC Ret Time (MeNH2 adduct): 2.240 min (YMC S5 ODS 4.6×50 mm column, 4 min gradient, 3 mL/min).

Workup

  1. temperaturemaintained the temperature below 30° C
  2. custombecoming homogeneous at 80° C
  3. customafter quenching with 2 M MeNH2/THF (10 μl reaction mixture, 20 μl MeNH2/THF in 200 μl acetonitrile)
  4. customUpon completion, reaction
  5. temperaturewas cooled to −8° C.
  6. temperaturemaintaining temperature below 1° C
  7. temperaturethen warmed to ambient temperature for 1 h
  8. filtrationThe resulting light suspension was filtered through a pad of celite
  9. customthe layers were separated
  10. washThe organic layer was washed with K2HPO4 in H2O (27 g/130 ml)
  11. dry with materialdried (Na2SO4)
  12. filtrationThe solution was filtered
  13. concentrationconcentrated to a yellow foam 4A (54.0 g, 100%)
  14. custom2.240 min (YMC S5 ODS 4.6×50 mm column, 4 min gradient, 3 mL/min)

Sources & evidence

ORD record
ord-6c04d01c4d8a4732bf58c20bc9222c56
Source dataset
uspto-grants-2006_06
Patent number
US07064203B2

Reaction notes

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