反应详情

A suspension of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (18.1 gm, 93.7 mmole) in 85% aq. H3PO4 (250 mL) was heated at 110° C. for 3.5 h. After cooling to RT, ice water (500 mL) was added and the precipitate was collected, washed with water, and dried. This afforded 5.8 gm of the product as a brown solid. An additional 4.1 gm (total of 9.9 gm, 71%) of product was obtain by extraction of the filtrate with DCM (4×500 mL), drying (Na2SO4), and removal of the solvent. 1H NMR (CDCl3) δ 2.54 (s, 3H), 6.35 (d, 1H, J=3 Hz), 7.31 (d, 1H, J=3 Hz), 7.42 (s, 1H), 9.52 (br s, 1H); HPLC Ret Time: 1.17 min (YMC C18 S5, 4.6×50 mm column, 3 min gradient, 4 mL/min). Procedure II: A suspension of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (5.81 gm, 0.028 mol) in 85% aq. H3PO4 (60 mL) was heated at 110° C. for 6 h. After cooling to RT, ice (120 gm) was added and the precipitate was collected, washed with water and dried to afforded the product (3.47 gm, 83%). Procedure III: A solution of 3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (4.59 gm, 33 mmole) in dry DMF (100 mL) was added slowly to an ice cooled suspension of NaH (1.72 gm, 60% dispersion in oil, 1.3 equiv) in dry DMF (300 mL). After 30 min, O-(2,4-dinitro-phenyl)-hydroxylamine (1.53 gm, 1.1 equiv) was added in one portion and the reaction was left stirring in the ice bath for 1 hr. After 0.5 hr it was removed from the bath and diluted with brine. This was extracted with EtOAc (3 times) and the combined extracts were dried (Na2SO4) and the solvents were removed. The residue was chromatographed on a silica gel column (gradient elution with hexane containing 5 to 20% EtOAc) to give 1-amino-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (2.96 gm, 58%) as a yellow solid. 1H NMR (MeOH-D4) δ 2.25 (s, 3H), 3.81 (s, 3H), 5.83 (d, 1H, J=2 Hz), 6.82 (d, 1H, J=2 Hz); MS: 155 (M+H)+; HPLC Ret Time: 0.97 min (YMC Exterra ODS S7 3.0×50 mm, 2 min gradient, 5 mL/min). A mixture of this 1-amino-pyrrole (2.96 gm, 19.2 mmole) in formamide (30 mL) was heated at 165° C. for 10 hr. After cooling to RT, this was diluted with cold water and the precipitate was collected, washed with cold water followed by a mixture of Et2O and hexane (6:4). This gave 5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.83 gm, 64%) as a brown solid.

1. temperaturecooled
2. waitthe reaction was left
3. customAfter 0.5 hr it was removed from the bath
4. additiondiluted with brine
5. extractionThis was extracted with EtOAc (3 times)
6. dry with materialthe combined extracts were dried (Na2SO4)
7. customthe solvents were removed
8. customThe residue was chromatographed on a silica gel column (gradient elution with hexane containing 5 to 20% EtOAc)