Background and overview of the preparation method of 6-methoxy-2,3-diaminopyridine dihydrochloride
6-Methoxy-2,3-diaminopyridine dihydrochloride is a chemical intermediate.
Preparation method of 6-methoxy-2,3-diaminopyridine dihydrochloride
Step 1
Synthesis of 2,6-dichloro-3-nitropyridine
Slowly add 25.0g (0.168mol) 2,6-dichloropyridine to concentrated sulfuric acid at 20℃-25℃ under constant stirring. To this solution, slowly add 75.0 g of concentrated nitric acid (98.0%), keeping the reaction temperature below 50 °C. After addition, the resulting mixture was heated to 100°C-105°C for 5.0 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to 50°C and poured into ice water. The resulting precipitate was filtered through boric acid and washed with water. The wet cake thus obtained was dried to obtain 24.5 g of 2,6-dichloro-3-nitropyridine. The yield of 2,6-dichloro-3-nitropyridine was 75.38%, and the GC purity was 99.5%.
Step 2
Synthesis of 2-amino-6-chloro-3-nitropyridine
Dissolve 25.0g (0.129mol) 2,6-dichloro-3-nitropyridine in methanol (50.0ml) at room temperature. To the solution thus obtained, 12.2 ml (0.179 mol) of a 25.0% ammonia aqueous solution was added at room temperature. The resulting mixture was heated to 35°C-40°C for 2.0 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to 20°C. The solid obtained was washed, filtered with methanol and dried to obtain 12.50 g of 2-amino-6-methoxy-3-nitropyridine (56.45%). HPLC purity was 99.3%: melting point 192°C-195°C; 1 HNMR: (DMSO-D6) δ6.75-6.77ppm (d, 1H), δ8.38-8.40 (d, 1H).
Step 3
Synthesis of 2-amino-6-methoxy-3-nitropyridine
Mix 7.78g sodium methoxide (0.144mol) and 50.0ml methanol and cool to 15°C. To this solution were added 25.0 g of 2-aminomethanol and -6-chloro-3-nitropyridine (0.144 mol) while maintaining the temperature at 15 °C by external cooling. The resulting mixture was heated to 25°C-30°C and maintained at this temperature for 4-5 hours with constant stirring. The reaction was monitored for completion by TLC. After the reaction is completed, the reaction mixture is poured into water. The resulting precipitate was filtered and washed with water. After drying, 21.0 g of 2-amino-3-nitro-6-methoxypyridine was obtained (yield 86.5%) with HPLC purity of 99.0%. Melting point 167°C-169°C; 1HNMR (CDCl3) δ3.89ppm (s, -3H, OCH3), 66.14- 6.16ppm (d, 1H), 68.24-8.27ppm (d, 1H), 68.16ppm (s, -2H, -NH2).
Step 4
Synthesis of 2,3-diamino-6-methoxypyridine dihydrochloride
Add 25.0g 2-amino-6-methoxy-3-nitropyridine (0.147mol) to concentrated hydrochloric acid (250ml) at room temperature. The resulting solution was cooled to 15°C and 66.7 g of stannous chloride dihydrate (0.294 mol) were slowly added. The reaction mass was heated to 35°C-40°C and the dimethoxypyridine was mixed with constant stirring for 5-6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to 20°C and stirred for 1 hour. The resulting mixture was filtered and dried to give 27.0 g of 2,3-diamino-6-methoxypyridine dihydrochloride (yield = 86.4%); melting point 211 to 213 °C. HPLC purity was 99.0%.
