Preparation of 2-Amino-5,7-dimethoxy[1,2,4]trizolo[1,5-a]pyrimidine Starting with 2-Chloro-4,6-dimethoxypyrimidine
Publication Date: 2004-May-10
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2-Amino-5,7-dimethoxy[1,2,4]triazolo-[1,5-a]pyrimidine is prepared in 4 steps from 2-chloro-4,6-dimethoxypyrimidine.
2-Amino-5,7-dimethoxy[1,2,4]triazolo[1,5-a]pyrimidine 1 can be used as an intermediate for the preparation of biologically active materials. A new route starting with 2-chloro-4,6-dimethoxypyrimidine 2 has been demonstrated for this intermediate as illustrated in Scheme A.
Reaction of chloropyrimidine 2 with sodium cyanamide gave cyanoaminopyrimidine 3. Treatment of 3 with hydroxylamine afforded N-hydroxyguanidine 4, which then was O-acylated by reaction with ethylchloroformate to give 5. Heating 5 in ethanol at reflux provided the desired heterocycle 1.
2-Cyanoamino-4,6-dimethoxypyrimidine (3). A 125 mL three neck vessel was purged with N2 and then fitted with a thermometer, a condenser/N2 inlet, a stopper and a stir bar. To the pot was added the chloropyrimidine 2 (10.0 g, 57.3 mmol) and NMP (50 mL). The resulting solution was treated with sodium cyanamide (8.3 g, 0.13 mol) and the mixture stirred at room temperature until the reaction was complete as determined by HPLC (several days). To the thin slurry was added water (100 mL) causing complete dissolution of all solids. Conc. HCl was added dropwise with stirring to a pH of 6. The resulting thick slurry was treated with ice (97 g) and the mixture stirred until all the ice had melted. The precipitate was collected by filtration and the solid was washed with one cake volume of water. The material was air dried overnight and then dried to a constant weight (55°C/5 mmHg) providing the product as a fluffy white solid (9.4 g, 91 %): mp 195°C; 1H NMR (DMSO-d6) 3.86 (s, 6H), 5.86 (s, 1H),11.46 (bs, 1H); MS (LC, ESI) 181 (M+, 100).
N-(4,6-Dimethoxy-2-pyrimidinyl)-N'-hydroxyguanidine (4). A 100 mL three-neck vessel was flushed with N2 and then fitted with a thermometer, reflux condenser/N2 inlet, a stopper and a stir bar. The cyanoaminopyrimidine 3 (4.9 g, 27.2 mmol), CH3OH (30 mL) and hydroxylamine hydrochloride (2.0 g, 29 mmol) were charged into the vessel. Triethylamine (4.2 mL, 30 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction was warmed to 45°C and stirred overnight. After stirring for an additional 3 h at 45°C, HPLC analysis indicated no change. Hydroxylamine hydrochloride (0.5 g) and ...