Novel technology with introduced catalyst to optimize synthesis of dipyridamole

Abstract

The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2/HOAc/AIBN/O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI/PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.

Description

technical field [0001] The invention relates to a new process for optimizing the synthesis of dipyridamole by introducing a catalyst, which belongs to the technical field of pharmaceutical intermediates. Background technique [0002] Dipyridamole has been extensively studied and applied as a cardiovascular disease drug. Studies have shown that dipyridamole dilates blood vessels, inhibits platelet aggregation and adhesion, and has antithrombotic effects. In addition, it can be used to prevent thrombosis after artificial heart valve or artificial blood vessel transplantation, secondary prevention after myocardial infarction, ischemic cerebrovascular disease and other diseases, and the market demand is very large. The traditional process includes a series of processes such as nitrification, reduction, condensation, chlorination, connection with piperidine, synthesis of final product, salt formation, desalination, decolorization and pressure filtration. [0003] But there are ...

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Problems solved by technology

[0003] But there are some problems in this method, the yield of oxidation and nitration steps is low, the process of reducing nitro to amino requires the use of sodium hydrosulfite, which has strong reducibility, but pollutants such as sodium sulfite and sodium sulfate will be produced in the reaction, and insurance The powder is easily hydrolyzed in water to produce hydrogen gas, and it is easy to oxidize and decompose when it encounters moisture and acid, which has the potential danger of burning and explosion; phosphorus oxychloride and phosphorus pentachloride are used in the chlorination process, these two substances are extremely corrosive, and the environment Severe pollution and difficult post-processing; preparation of 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine from perchloropyrimido[5,4-d]pyrimidine In the process, the selectivity of the reaction is poor, the yield is low, and the post-processing is very difficult.

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