Ioversol and synthesis method thereof

Abstract

The invention belongs to the technical field of organic compound preparation, and discloses ioversol and a synthesis method thereof. The chemical name of ioversol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-hydroxyacetamido]-2,4,6-triiodo-1,3-benzenedicarboxamide. 5-hydroxyacetylamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide and an alkylation agent carry outalkylation reactions under an alkaline condition to generate ioversol. Bromoethanol and sodium hydroxide are taken as reagents; glycol and anhydrous ethanol are taken as a mixed solvent, in the absence of water, a substrate can be well dissolved; the hydrolysis of the alkylation agent is avoided, the raw material loss is largely reduced, the utilization rate is increased, the reaction yield is increased, and the cost is reduced. At the same time, dangerous and toxic reagents such as chloroethanol, ethylene oxide, and the like are not used, the safety hazard is reduced, the damage to human body is reduced, and the stability of industrial production is guaranteed.

Description

technical field [0001] The invention belongs to the technical field of organic compound preparation, and in particular relates to ioversol and a synthesis method thereof. Background technique [0002] The chemical name of ioversol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamide]-2,4,6-triiodo -1,3-Phenylenedicarboxamide has the advantages of large water solubility, low viscosity, low osmotic pressure and low incidence of adverse reactions. This compound is a non-ionic X-ray contrast agent and is mainly used for various angiography examinations Including: cerebral angiography, peripheral arteriography, visceral artery, renal artery and aorta angiography, cardiovascular angiography including coronary angiography, arterial and venous digital subtraction angiography, etc. Intravenous urography and enhanced CT examination (including head and body CT), etc. [0003] The prior art has disclosed multiple synthetic routes, as follows: [0004] 1. US4396598A repo...

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Problems solved by technology

[0008] All use chloroethanol as alkylation reagent in four documents, carry out alkylation reaction and prepare ioversol in sodium hydroxide aqueous solution, shortcoming has 1. chloroethanol is easily hydrolyzed in sodium hydroxide aqueous solution, substrate and alkyl The molar ratio of chemical reagents is usually 1:3-4, which reduces the utilization rate of raw materials and increases the cost; ②The hydrolysis of chloroethanol in water leads to increased side reactions, increased impurities, and increased difficulty in purification; ③The danger of chloroethanol is high. Open flames and high heat can cause combustion and explosion, and highly toxic phosgene can be decomposed under high heat. Relevant studies have shown that chloroethanol also has mutation toxicity, which is highly toxic to the human body in large-scale production, and at the same time has a greater safety hazard

[0010] Compared with the methods reported in above-mentioned US4396598A etc., although there is no chloroethanol in this document as alkylating agent, the problem of hydrolysis of alkylating agent has been avoided, but in the article, ethylene oxide is selected as alkylating agent, and shortcoming is ① The toxicity of ethylene oxide is the same as that of chlorohydrin. It is mainly carcinogenic and reproductive toxic, and it is more harmful to the human body; ② Ethylene oxide exists in a gaseous state. Difficult to control; ③ Ethylene oxide is flammable and explosive, difficult to store, which leads to increased investment in production equipment

[0012] ①Using water as a solvent, under alkaline conditions, causes the hydrolysis of the alkylating reagent, consumes a large amount of alkylating reagent and alkali, low raw material utilization rate, and increases the cost; ②After the alkylating reagent is hydrolyzed, side reactions occur, resulting in Impurities in the reaction solution increase, making purification more difficult; ③Alkylation reagents have relatively high toxicity, such as the mutagenic toxicity of chlorohydrin, carcinogenicity and reproductive toxicity of ethylene oxide; ④Alkylation reagents are easy to decompose, and the decomposition releases Highly toxic gas, difficult to industrial production and management

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