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Preparation method of iopromide

A technology of iopromide and amidomethyl ester, which is applied in the field of preparation of iopromide, can solve problems such as difficult acquisition of raw materials, difficulty in purchasing, and difficulty in purification, so as to avoid the introduction of ionic compounds or salts, avoid large water consumption, and avoid Effect of desalination operation

Active Publication Date: 2017-05-24
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] This route uses allyl ammonia that is not easily available as a raw material, which is difficult to purchase and has a high price; and in the subsequent steps, an oxidizing agent needs to be used for oxidation operation, which is complicated and cumbersome, which is not conducive to large-scale production, and the factory cost is relatively high
[0022] In summary, the above-mentioned several schemes inevitably have disadvantages such as difficult availability of raw materials, high price, long reaction steps, difficult purification, low yield, and long production cycle. Therefore, it is necessary to develop a more effective, less reaction steps, and raw material Cheap and easy to get, high yield, high purity process for preparing iopromide is of great significance

Method used

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  • Preparation method of iopromide

Examples

Experimental program
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Effect test

Embodiment 1

[0044] (S1) Sulfuric acid catalyzed preparation of 5-amino-2,4,6-triiodoisophthalic acid methyl ester (formula 4)

[0045] Add 22.5kg of 5-amino-2,4,6-triiodoisophthalic acid and 120kg of methanol into a 200L reactor, slowly add 200g of sulfuric acid, turn on steam and heat to reflux, stir, and react for 4 hours. The liquid phase monitors the complete conversion of raw materials. Concentrate under reduced pressure to recover methanol. Methanol was recovered, cooled to 30°C, poured into 160kg of ice water, continued to cool down to 10°C, kept warm and crystallized for 2 hours, centrifuged to obtain off-white solid, dried to obtain 22.3kg, yield 95%, HPLC: 99.2%.

[0046] (S2) Preparation of 5-methoxyacetamido-2,4,6-triiodoisophthalamide (formula 3)

[0047] Add 17.6kg of formula 4 and 2.5kg of methoxyacetyl chloride into the reactor containing 80kg of dioxane, raise the temperature to reflux, stir, and react for 4 hours. High-efficiency liquid phase monitors that the convers...

Embodiment 2

[0053] (S1) Methanesulfonic acid catalyzed preparation of 5-amino-2,4,6-triiodoisophthalic acid methyl ester (formula 4)

[0054] Add 22.5kg of 5-amino-2,4,6-triiodoisophthalic acid and 120kg of methanol into a 200L reactor, slowly add 196g of methanesulfonic acid, turn on steam and heat to reflux, stir, and react for 4 hours. The liquid phase monitors the complete conversion of raw materials. Concentrate under reduced pressure to recover methanol. Methanol was recovered, cooled to 30°C, poured into 160kg of ice water, continued to cool down to 10°C, kept warm and crystallized for 2 hours, centrifuged to obtain off-white solid, dried to obtain 22.5kg, yield 95.9%, HPLC: 99.5%.

[0055] (S2) Preparation of 5-methoxyacetamido-2,4,6-triiodoisophthalamide (formula 3)

[0056] Add 17.6kg of formula 4 and 2.5kg of methoxyacetyl chloride into the reactor containing 80kg of dioxane, raise the temperature to reflux, stir, and react for 4 hours. High-efficiency liquid phase monitors ...

Embodiment 3

[0062] (S1) catalyzed preparation of 5-amino-2,4,6-triiodoisophthalic acid methyl ester by p-toluenesulfonic acid (Formula 4)

[0063] Add 22.5kg of 5-amino-2,4,6-triiodoisophthalic acid and 120kg of methanol into a 200L reactor, slowly add 305g of p-toluenesulfonic acid, turn on the steam, heat to reflux, stir, and react for 4 hours. The liquid phase monitors the complete conversion of raw materials. Concentrate under reduced pressure to recover methanol. Methanol was recovered, cooled to 30°C, poured into 160kg of ice water, continued to cool down to 10°C, kept warm and crystallized for 2 hours, centrifuged to obtain off-white solid, dried to obtain 22.2kg, yield 94.6%, HPLC: 99.5%.

[0064] (S2) Preparation of 5-methoxyacetamido-2,4,6-triiodoisophthalamide (formula 3)

[0065] Add 17.6kg of formula 4 and 2.5kg of methoxyacetyl chloride into the reactor containing 80kg of dioxane, raise the temperature to reflux, stir, and react for 4 hours. High-efficiency liquid phase m...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of iopromide. The method comprises the steps that 5-amino-2,4,6-triiodo isophthalic acid is adopted as a raw material to obtain diester to react with methoxyacetyl chloride, and the product is subjected to an ester ammonolysis reaction with side-chain 3-amino propylene glycol and 3-methylamino propylene glycol respectively to obtain iopromide. The preparation method of the iopromide, a catalyst and a by-product methyl alcohol can be removed only through solvent crystallization, green production can be achieved, no industrial wastewater or waste gases or residues exist, and the preparation method is particularly suitable for preparing iopromide in industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of iopromide. Background technique [0002] The chemical name of iopromide is N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(2-methoxyacetyl)amino]-N'- Methylphenyl-1,3-carboxamide, the chemical formula is: [0003] Iopromide is a widely used X-ray contrast agent. It is widely used clinically for angiography, renal arteriography, urography, CT contrast-enhanced examination, and body cavity display (arthrography, hysterosalpingography, fistula tract radiography). Its preparation method was publicly published by German Schilling with the US patent US4364921, and then many countries published various improved processes and new methods, all of which inevitably have defects, which have great resistance to industrialization, large investment, and large environmental pollution. [0004] Patent US4364921 discloses three preparation method...

Claims

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Application Information

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IPC IPC(8): C07C231/14C07C237/46
CPCC07C227/18C07C231/02C07C231/14C07C237/46C07C229/62C07C235/16
Inventor 胡俊峰王庭见王文新李春杰李跃东
Owner 山东诚汇双达药业有限公司
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