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Synthesis method of diatrizoic acid

A synthesis method, the technology of diatrizoic acid, which is applied in chemical instruments and methods, preparation of carboxylic acid amides, preparation of organic compounds, etc., can solve the problems of low resin recovery rate, three wastes, energy consumption, and high production cost

Pending Publication Date: 2022-05-13
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In addition, there are reports in the literature that after using methylol resin to bond compound 1, the process of amidation through the traditional process, and then removing the methylol resin, but this process has high cost, and in the actual production process, the resin recovery rate is low, Disadvantages such as limited yield and output
[0010] Most of the relevant literature on the refining of diatrizoic acid uses alkali-dissolved acid analysis in water, and a large amount of activated carbon to adsorb impurities to achieve the effect of impurity removal and decolorization, which makes the actual production process cumbersome to operate, large material loss, low yield, and production The disadvantages of the three wastes
[0011] In view of the relatively strict impurity limit requirements of this product, the alkali-soluble acid crystallization process in the traditional process needs repeated operations to make the product meet the quality requirements, so that a large amount of three wastes and energy consumption will be generated during the refining process, resulting in While the production cost is too high, it is difficult to increase the production capacity of the product

Method used

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  • Synthesis method of diatrizoic acid
  • Synthesis method of diatrizoic acid
  • Synthesis method of diatrizoic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1: Preparation of 3,5-diacetylamino-2,4,6-triiodobenzoyl chloride

[0033] Add 30g of 3,5-diamino 2,4,6-triiodobenzoic acid (0.0566mol) into the reaction flask, add 30g of acetic acid (0.5mol) and heat up to 50°C to dissolve, then transfer to the dropping funnel for later use 300ml (4.13mol) thionyl chloride is added in the reaction flask, 0.5g of 4-dimethylaminopyridine is added as a catalyst, stirred at 50° C., the solution in the dropping funnel is added dropwise into the reaction flask, and the dropping speed Control the internal temperature not to exceed 60°C. After the dropwise addition, keep the reaction for 24 hours, and then reduce the pressure to 60°C to evaporate the solvent in the reaction bottle to obtain about 40 g of oil.

[0034] In embodiment 1, 4-dimethylaminopyridine can be replaced by dimethylformamide, N,N-dimethylaniline or pyridine; Thionyl chloride here also acts as a solvent, if other solvents are selected, such as chloroform, two Oxyhe...

Embodiment 2

[0035] Embodiment 2: the preparation of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester

[0036] Add 40g of the 3,5-diacetylamino-2,4,6-triiodobenzoyl chloride oil prepared above into the reaction bottle, add 300ml of methanol, heat up to reflux, reflux and stir for 12h, and control the acid chloride in HPLC Stop the reaction when the compound is less than 0.5%. At this time, a large amount of white solid precipitates out. Cool down to 20-25°C to crystallize for 6 hours, filter with suction, rinse the filter cake with 10ml of methanol three times, and dry the solid to obtain 3,5-diacetylamino -2,4,6-triiodobenzoic acid methyl ester 33g (0.0525mol), molar yield 92.76% (calculated based on compound 1: 3,5-diamino-2,4,6-triiodobenzoic acid), HPLC Content 99.1%.

[0037] Methyl alcohol in embodiment 2 can be replaced with ethanol, Virahol, n-propanol, n-butanol or tert-butanol, can obtain corresponding formate compound like this.

Embodiment 3

[0038] Embodiment 3: the preparation of 3,5-diacetamido-2,4,6-triiodobenzoic acid

[0039]Add the above 33g of 3,5-diacetylamino-2,4,6-triiodobenzoic acid methyl ester into the reaction flask, add 200ml of deionized water, stir for 30min, then add 20% sodium hydroxide aqueous solution dropwise, Add dropwise to the reaction bottle to completely dissolve, adjust the pH to 10-11, maintain the pH, keep the temperature at 50-55°C for 2 hours, control the content of methyl ester compounds in HPLC to not more than 0.5%, and use concentrated hydrochloric acid to adjust the pH to 3 -3.5, stir and heat up to 90-95°C, add 0.15g of activated carbon, continue to stir for 3h, filter while hot, after the filtrate cools to 60°C, add concentrated hydrochloric acid dropwise to adjust the pH to 1-1.5, keep stirring and crystallize for 3h, pump filter, the filter cake was rinsed 3 times with 10ml deionized water, and dried to obtain 30g (0.0489mol) of diatrizoic acid crude product, with a molar y...

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Abstract

According to the synthesis method of the diatrizoic acid, 3, 5-diamino-2, 4, 6-triiodobenzoic acid serves as a raw material, an acyl chloride compound is prepared through an acyl chloride and amidation one-pot method, then esterification and hydrolysis are conducted through lower alcohol, dissolution is conducted in an ammonia water-methanol solution, and acid precipitation is conducted to obtain a finished diatrizoic acid product. According to the method, one-time recrystallization is needed, three wastes generated in the recrystallization process are greatly reduced, the yield is greatly improved (the molar yield can reach 80% or above), and the reaction cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a method for synthesizing diatrizoic acid. Background technique [0002] Diatrizoic acid, chemical name: 3,5-diacetylamino-2,4,6-triiodobenzoic acid, structural formula: [0003] [0004] As an X-ray contrast agent, diatrizoic acid is a positive contrast agent for X-ray diagnosis, and it is used after preparing diatrizoate meglumine, diatrizoate sodium or compound diatrizoate meglumine injection. Diatrizoic acid is widely used in medical imaging. As a commonly used CT contrast agent, due to the existence of two amino active groups in it, and because in the ICH guidelines, aromatic amines as genotoxicity warning structures need to be strictly controlled, and the impurity limit is low, so the impurity content of this product As a technical barrier, there are fewer preparation companies for this product at home and abroad, and the available literature is not comprehensiv...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C231/12C07C231/24C07C233/54
CPCC07C231/02C07C231/12C07C231/24C07C233/54
Inventor 赵旭李朋伟谢豪杰
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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