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Preparation method of ioversol

A technology of ioversol and acid-binding agent, which is applied in the field of preparation of ioversol, to achieve the effects of reducing the number of refining times, avoiding rearrangement of impurities, and reducing the content of impurities

Pending Publication Date: 2019-07-19
大道隆达(北京)医药科技发展有限公司
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The currently disclosed ioversol preparation methods cannot effectively avoid the generation of impurity II, and the prepared finished product needs to be refined many times to meet the medicinal requirements.

Method used

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  • Preparation method of ioversol

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1 (preparation of formula (IV))

[0039]Add formula (V) 5-hydroxyacetamido-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedimethanol in a 5L reaction flask Stir and dissolve amide 1kg and 2L dimethyl sulfoxide, add 1.5kg of anhydrous potassium carbonate and cool down to 20°C, add 1.1kg of tert-butyldimethylsilyl chloride dropwise, after the addition is complete, control the temperature at 30-35°C and stir for 10 hours . used directly in the next reaction.

Embodiment 2

[0040] Embodiment 2 (preparation of formula (IV))

[0041] 440 g of 2-bromoethyl acetate was added to the reaction solution obtained in Example 1, and the temperature was controlled at 30-35° C. and stirred for 16 hours. The insoluble matter was removed by filtration, and the filtrate was directly used in the next reaction.

Embodiment 3

[0042] Embodiment 3 (Ioversol crude product preparation)

[0043] Add the filtrate obtained in Example 2 to 1% sulfuric acid aqueous solution to adjust the pH value to 1-3, raise the temperature to 40-50° C. and stir for reaction, keep the pH value at 1-3 during the reaction process, and stir for 5 hours. After the reaction is complete, neutralize with 1% sodium hydroxide solution to pH 6-7. Concentrate under reduced pressure at 50-60°C until no obvious solvent is evaporated, add dichloromethane to the concentrated residue, stir and crystallize, filter, add methanol to the solid and stir well The insoluble matter was filtered off, and the filtrate was concentrated to dryness to obtain 861 g of crude ioversol, with a yield of 81.4%. (HPLC detection: purity 97.8%, impurity II content 0.39%)

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Abstract

The present invention provides a novel preparation method of ioversol. The method comprises the following steps: adding a protection group to 5-hydroxyacetylamino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, conducting an alkylation reaction under an alkaline condition, and carrying out deprotection, so as to prepare ioversol. According to the preparation method disclosedby the invention, hydroxyl is protected before alkylation, so that the generation of ioversol rearrangement impurities (impurity II) in the alkylation preparation process is effectively controlled, the refining difficulty of a finished product is reduced, the refining yield is increased, and the preparation method is more suitable for industrialization.

Description

technical field [0001] The invention belongs to the technical field of medicine and specifically describes a new method for preparing ioversol. Ioversol is a non-ionic X-ray contrast agent, which is suitable for angiography of the adult cardiovascular system, CT examination of the head and body, and urinary road imaging etc. Background technique [0002] Ivoersol (Ivoersol) is a new type of non-ionic contrast agent developed by Mallinckrodt Medical Inc. in the United States. It was approved by the FDA in 1988 and is currently available in Japan, the United Kingdom, France and China. Listed in other regions. After ioversol is injected, due to its high iodine content, X-rays are attenuated, and the passing blood vessels can be visualized clearly. [0003] The chemical name of ioversol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamino]-2,4,6-triiodo- 1,3-phthalamide, chemical structural formula (I): [0004] [0005] There are many reports on the preparat...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/32
CPCC07C231/12C07C237/32Y02P20/55
Inventor 石创业孟令桥周英朱小雷王国苍陈雪飞李萍
Owner 大道隆达(北京)医药科技发展有限公司
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