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A kind of method for preparing ioversol

A technology of ioversol and iodoethanol, which is applied in the field of preparation of ioversol, can solve the problems of increased production cost, large amount of alkali used, difficult recovery and mechanical application, etc., and achieves the effects of less impurities, mild reaction conditions and simple operation

Active Publication Date: 2022-05-27
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This process route was invented by Liu Yunlong of Hubei Tianshu Pharmaceutical Co., Ltd. in 2018. Its patent application number is CN201811238639.8. The advantage is that the alkali is very single, and the alkalinity is milder than sodium hydroxide and potassium hydroxide, so the yield is high. Certainly improved, but not very much
The disadvantage is that the amount of alkali used is large, and the formed barium chloride and barium hydroxide are mixed and difficult to recycle.
Therefore, the production cost has also increased a lot, and it has also caused a waste of resources.

Method used

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  • A kind of method for preparing ioversol
  • A kind of method for preparing ioversol
  • A kind of method for preparing ioversol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of ioversol

[0029] In a 1000 mL reaction kettle, add 200 mL of methanol, 10.6 g (0.075 mol) of disodium hydrogen phosphate, and 76.3 g (0.1 mol) of compound I, start stirring, heat up to 30 °C, and after stirring evenly, slowly add chloroethanol dropwise Methanol solution (8.85g (0.11mol) of chloroethanol and 100ml of methanol), and 16.5g (0.035mol) of 30wt% disodium hydrogen phosphate solution was added dropwise at the same time, the pH of the reaction system was controlled at 12-13, and the dropwise addition was completed in 6h. Incubate the reaction for 24h. After cooling to room temperature, neutralize with dilute hydrochloric acid, filter, pass the filtrate through anion and cation exchange resin (special resin factory of Xi'an Lanxiao Technology Co., Ltd., cation exchange resin D101, anion exchange resin D201) for desalting, and the filtrate is concentrated and recrystallized with methanol 3 76.7 g of ioversol was obtained, HPLC≥99.5%, an...

Embodiment 2

[0031] Example 2: Preparation of ioversol

[0032] In a 1000 mL reaction kettle, add 200 mL of methanol, 13.1 g (0.075 mol) of dipotassium hydrogen phosphate, 76.3 g (0.1 mol) of compound I, turn on stirring, heat up to 35°C, and after stirring evenly, slowly add chloroethanol dropwise Methanol solution (8.85g (0.11mol) of chloroethanol and 100ml of methanol) was added dropwise with 20.9g (0.036mol) of 30wt% dipotassium hydrogen phosphate solution, the pH of the reaction system was controlled at 12-13, and the dropwise addition was completed in 6h. Incubate the reaction for 28h. After being cooled to room temperature, neutralized with dilute hydrochloric acid, filtered, the filtrate was desalted through anion and cation exchange resin (same as in Example 1), the filtrate was concentrated and recrystallized with methanol 3 times to obtain ioversol 78.6g, HPLC≥99.5%, yield 97.4%.

Embodiment 3

[0033] Example 3: Preparation of ioversol

[0034] In a 1000mL reaction kettle, add 200mL of water, 11.8g (0.068mol) of dipotassium hydrogen phosphate, 76.3g (0.1mol) of compound I, start stirring, heat up to 25°C, and after stirring evenly, slowly add chloroethanol dropwise Aqueous solution (9.66g (0.12mol) of chloroethanol and 100ml of water), 34.2g (0.059mol) of 30wt% dipotassium hydrogen phosphate solution was added dropwise at the same time, the pH of the reaction system was controlled at 12-13, and the dropwise addition was completed in 6h. Incubate the reaction for 30h. After being cooled to room temperature, neutralized with dilute hydrochloric acid, filtered, the filtrate was desalted through anion and cation exchange resin (same as Example 1), the filtrate was concentrated and recrystallized with water 3 times to obtain ioversol 79g, HPLC≥99.5%, yield 98% .

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Abstract

The invention discloses a method for preparing ioversol. Compound I: [5-hydroxyacetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo ‑1,3‑phthalamide, chloroethanol or its analogues are used as raw materials, and disodium hydrogen phosphate or dipotassium hydrogen phosphate is used as an acid application agent, reacted in a solvent, and after the reaction is completed, ioversol is obtained through post-treatment. By buffering alkali disodium hydrogen phosphate or dipotassium hydrogen phosphate as an acid-binding agent, the reaction conditions are relatively mild, which overcomes the shortcoming of unstable pH in the reaction process, so the present invention prepares ioversol with few and small impurities, especially alkoxy Basic impurities can be controlled below 0.5%, the yield is high, up to 90-98%, green and environmentally friendly, and the operation is simple.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing ioversol. Background technique [0002] Ioversol is a new hypotonic nonionic contrast agent containing triiodine. The trade name of this contrast agent is iovesol. This product is mainly used for various vascular radiography examinations, including: cerebral angiography, peripheral arteriography, visceral artery, renal artery and aorta angiography, cardiovascular angiography including coronary angiography, arterial and venous digital subtraction angiography Wait. This product can also be used for intravenous urography and CT enhanced examination (including head and body CT). [0003] There are currently two main preparation methods for ioversol. The first is the use of [5-hydroxyacetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide and chlorine Ethanol (or similar). The reaction equation is as follows: [0004] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C231/24C07C237/46
CPCC07C231/12C07C231/24C07C237/46
Inventor 王俊华怀哲明袁继雷佘鹰刘乙平蒋冬华冉波
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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