This project belongs to the field of medicine and chemical industry. Diatrizoic acid is a widely used contrast agent in medicine. Its annual demand in the international market reaches about 2,000 tons. However, my country's annual output is only about 100 tons. Its share in the international market is very small. The main reason is that the quality of domestic products and international standards are far from each other. In addition, due to the high impurity content of diatrizoate acid produced in China, many patients are prone to allergic and other adverse reactions when using it, which limits the use of this drug to a certain extent. Therefore, the improvement of product quality and the reduction of impurities are of great significance to my country's economic construction and social development. At present, there is a mature production process for diatrizoic acid in China, but the products produced have long had the problem of exceeding the standard of free aromatic amines and failing to meet international standards. In addition, there are safety hazards such as difficult control of the reaction process and easy flushing of materials during production.
Since 2003, with the support of major scientific and technological research projects of the Shanghai City Science and Technology Commission, this project has optimized the production process of diatritic acid using multi-functional automatic control pilot synthesis technology. The main innovations are as follows:
(1) In response to the need to adjust a large number of reaction parameters in real time during the development of new process routes, this project has developed a multi-functional automatic control pilot synthesis device. The device uses a computer control system to control multiple parameters including temperature, pressure, weight, flow, time, pH, and rotational speed. Each set of reaction devices can be controlled in parallel, and each set of reaction devices can be connected in series, parallel, etc. different combinations according to needs. This multifunctional automatic control pilot synthesis device can monitor reaction parameters in real time, quickly screen reaction conditions, optimize reaction routes, and improve process development efficiency.
(2) In view of the problem that the reduction reaction step in the original production process is prone to incomplete reactions, and the intermediate product monoamino compounds (3-nitro-5-aminobenzoic acid hydrochloride) cannot be completely acylated in the subsequent acylation reaction, resulting in the product's free aromatic amine content exceeding the standard, this project uses multi-functional automatic control pilot synthesis technology to quickly optimize the reduction conditions and reduce or eliminate the formation of monoamino compounds and azo compounds.
(3) In view of the problem that residual iodides, monoamino compounds and monoacylate (3-amino-5-acetamido-2,4,6-triiodobenzoic acid hydrochloride) are prone to exist in the acetylation reaction step in the original production process. The free aromatic amine content of the product exceeds the standard, this project uses multi-functional automatic control pilot synthesis technology to quickly optimize the acylation conditions, and adopts solvent application measures to effectively solve the hundreds of tons of solvent wasted every year in the original process, which is conducive to environmental protection. The multiple parallel reactors used in this project also solve the problems of easy flushing of materials and difficult control of the reaction process in the original process, ensuring production safety.
(4) In view of the problems of easy hydrolysis and low yield of acylate in the decoloring and refining steps in the original production process, this project uses multi-functional automatic control pilot synthesis technology to quickly optimize decoloring and refining conditions, effectively reducing the content of free aromatic amines and improving the yield.
The related technology of this project has obtained 5 national utility model patents and has been used in the industrial production of diatritic acid. At present, it has an annual production capacity of 100 tons of diatritic acid, and the cumulative direct economic benefits have reached more than 30 million yuan. The technology of this project effectively reduces the free aromatic amine from the original 500 - 1000ppm to 100 - 150ppm. The product quality has the same quality standard as imported diatriate acid, which reduces adverse drug reactions, enhances drug safety, and improves patient satisfaction. The price is only one-tenth of the price of imported diatrizoic acid, which greatly reduces the medical cost of patients and has huge social and economic benefits.
The overall technical level and main technical indicators of this project have reached the advanced level of similar international technologies, filling the domestic gap. This technology is of great significance to ending disorderly competition in China's API market, improving the market competitiveness of China API, and promoting environmental protection and optimization and upgrading of industrial structure.