Synthesis Of Dipyridamole And Process Optimization

Dipyridamole alias for double pyrimidine amine alcohol, dipyridamole. In Japan, the development of technology was introduced by Tanabe Pharma. It has effect on expanding the coronary blood vessels, promoting the formation of collateral circulation and antiviral mild anticoagulant. This drug is used for acute and chronic coronary blood supply shortage, treatment after myocardial infarction, angina, heart failure. The world market has large demand for dipyridamole. In China, the annual consumption is about 3500 tons, but its production capacity is only 2000 tons per year. This is mainly because of the current dipyridamole complex production process conditions, and there are a lot of safety and environmental issues, which limit the promotion of production scale. Therefore, improving the production process dipyridamole, reducing its production costs, safety and environmental issues to resolve, expanding production scale, have great important social and economic benefits.In this paper, orotic acid as a starting material, obtained nitro orotic acid after the nitration reaction, then obtained an amino orotic acid by reducing the nitro group, then amino orotic acid was reacted with urea to give 1,5-dihydro-pyrimido [5,4-d] pyrimidine2,4,6,8-four ketones, after chlorination, and a series of nucleophilic substitution reaction, we got dipyridamole. And for the key step, it had been optimized the yield of the nitration reaction、cyclization reaction and the N-alkylation reaction, getting the following conclusions:Its first step, nitrification can yield up to 94.0% in sulfuric acid and nitric acid nitration reaction molar ratio of 3:1, the mole ratio of nitric acid and 2.5:1, reaction time 5 h, the reaction temperature is 90℃,while in the current production process, the first step is a nitro oxidation reaction by using fuming nitric acid and concentrated sulfuric acid, it has a very serious security problem, the reaction yield is only 61.7%, compared to it, the sesis had improved the yield and reduced the synthesis process safety issues. The third step cyclization reaction yield can reach 83.3% under diethylene glycol solvent, reaction temperature 210℃, feed ratio of 8.3:1, while the current process, the reaction yield is only about 70%, compared that it had improved the yield. The final step in the reaction of 1-methyl-2-pyrrolidone as solvent,6 equivalents of diethanolamine as reactants, the reaction at 190℃ reacted 24 h, the yield can reach 70.7%, so the total revenues through process optimization rate is up to 42.9%, the present production process yield is also 70%, but it reduces the amount of diethanolamine and the production costs. Finally, through process optimization total yield is 42.9%, the total yield of the production process is currently 25.2%, compared to that, it improves the yield and the synthetic route has been shortened. Accordingly, in contrast with 6-methyl-lH-pyrimidine-2,4-dione,6-methyl-lH-pyrimidine-2,4-dione is by nitration and oxidation directly, orotic acid as raw materials is more reasonable safer, in the same time, we can not only reduce equipment requirements, but also decrease environmental polution problems, the most important thing is to reduce the production of security issues, it has more value of industrial production.