Phosphorus oxychloride → HCID 22379833, compound

Participants

Reaction Conditions

Reaction Steps

A 1 L round bottomed flask was charged with methyl 5-ethyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (25.0 g, 113 mmol), toluene (375 mL) and diisopropylethylamine (11.8 g, 91.6 mmol). Phosphorous oxychloride (20.7 g, 135 mmol) was then added drop-wise at room temperature (exothermic). Once the addition was complete the reaction mixture was heated to 100° C. for 20 hrs. Analysis of an aliquot by HPLC indicated that the starting material had been completely consumed (Rt starting material=10.6 min, Rt product=15.2 min). The reaction was then cooled and slowly poured into a mixture of saturated sodium hydrogen carbonate solution (500 mL), toluene (500 mL) and ice water (350 mL). After stirring for 30 minutes the organic layer was separated and washed with saturated sodium hydrogen carbonate solution (500 mL). Drying over sodium sulfate, filtration and concentration afforded 30.5 g (>100%) of crude methyl 4-chloro-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate. This material was dissolved in acetonitrile (800 mL) and the solution charged to a 2 L round bottomed flask. Sodium hydrogen carbonate (15.1 g, 180 mmol) and 5-amino-1-benzylindazole (27.8 g, 124 mmol) were then added followed by additional acetonitrile (400 mL). The resulting suspension was then stirred at room temperature for 16 h. HPLC analysis after this time indicated that approximately 17% of the starting indazole remained. The mixture was then heated to reflux for 1 hr after which time only 5% of the starting indazole remained. After cooling, the mixture was concentrated and the residue partitioned between methylene chloride (800 mL) and water (300 mL). The lower organic layer was separated and washed further with water (300 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded 51.3 g (100%) of methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate, which was used without further purification.

Provenance & Evidence