Iodine Ioxilan preparation method

A technology of triiodo-m-formamide and dihydroxypropyl, which is applied in the field of preparation of ioxilan, can solve the problems of low conversion rate, complex post-treatment, similar chemical structure of impurity oxyalkyl compounds, etc., and achieve the goal of reducing damage Possibility, shortening of reaction steps, effect of cost reduction

Active Publication Date: 2006-07-12
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the competition between these two alkylation reactions, the conversion rate of this reaction is not high. From the experimental results, it was found that the conversion rate of the reaction was 88%.
Moreover, the impurity oxyalkyl compounds produced are not easy to separate and remove because of their similar chemical structures.
The method provided in this patent is that the alkylation reaction is completed, the solvent is evaporated to dryness, and the residue is directly carried out to the next step reaction without separation, so the impurities produced in this reaction are always carried into the last step reaction, which is not conducive to the purification of the final product and affects the Purity of the final product
The second step reaction is to protect the hydroxyl group. The method provided in the patent is to distill off acetic anhydride and acetic acid at the end of the reaction, then azeotropically distill twice with toluene, and dissolve the residue in saturated aqueous sodium carbonate and ethyl acetate. , the separated water layer was extracted twice with ethyl acetate, and the precipitated solid in the water layer was acidified and extracted three times with ethyl acetate, and the organic layer was combined, washed, dried, and then removed from a series of operations such as solvent, so the The post-treatment of the first step reaction is too complicated, which is not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of 5-acetamido-N-(2-acetoxyethyl)-2,4,6-triiodo-m-carboxamide benzoic acid:

[0025]In a three-necked flask equipped with a stirrer and a reflux condenser, add 80g (0.133mol) of 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodo-m-formamide benzoic acid and 300mL (3.18mol) acetic anhydride, after stirring evenly, add 0.36mL (0.004mol) perchloric acid dropwise, then raise the temperature to the acylation reaction temperature of 50°C, stir for 25 hours to end the reaction, and use 0.33g (0.004mol) acetic acid Sodium to neutralize perchloric acid. After acetic anhydride and acetic acid are evaporated under reduced pressure, the residue can be directly used for the next step (Example 3 or 4) without purification.

Embodiment 2

[0027] The acylation reaction temperature was 90° C., and the reaction time was 10 hours. The rest of the operations were the same as in Example 1.

Embodiment 3

[0029] Synthesis of 5-acetamido-N-(2-acetoxyethyl)-2,4,6-triiodo-m-formamide benzoyl chloride:

[0030] Dissolve the 5-acetamido-N-(2-acetoxyethyl)-2,4,6-triiodo-m-formamide benzoic acid obtained in the previous step (Example 1) in 250 mL (2.53 mol) at room temperature In ethyl acetate, after stirring evenly, add 29 mL (0.4 mol) of thionyl chloride, then raise the temperature to the acid chloride reaction temperature of 50°C, and stir for 6 hours to complete the reaction. After ethyl acetate and thionyl chloride were evaporated under reduced pressure, 100 mL of ethyl acetate was added to the residue, and the solvent was evaporated again. The obtained residue could be directly used in the next step (Example 5 or 6) without purification.

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Abstract

The invention relates to a method for preparing for iodine yucca in the field of non-ionic X-ray contrast agent preparing technology. The chemical name of the iodine yucca is 5-5-[acetyl (2, 3-dihydroxy propyl)amido]-N-(2,3-dihydroxy propyl)-N'-(2-hydroxyl ethyl)-2,4,6-triiodide-1,3-benzene diformamide. The invention uses 5-amido -N-(2-hydroxyl ethyl)-2, 4, 6-triiodide formamide benzene carbonic acid as starting raw material to do acylating reaction, acylating chlorination reaction, amidation reaction and alkanisation reaction to obtain the iodine yucca product, which is a new type of non-ionic X-ray contrast agent.

Description

technical field [0001] The invention discloses a preparation method of ioxilan, which belongs to the preparation technology of non-ionic X-ray contrast agent. The chemical name of ioxiram is 5-[acetyl(2,3-dihydroxypropyl)amino]-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)- 2,4,6-Triiodo-1,3-benzenedicarboxamide, the compound is generally called Ioxilan, is a new generation non-ionic X-ray contrast agent showing excellent safety and contrast effect. Background technique [0002] Ioxilan chemical name: 5-[acetyl(2,3-dihydroxypropyl)amino]-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-2 , 4,6-triiodo-1,3-benzenedicarboxamide, this compound is commonly referred to as Ioxilan, and the trade name of its preparation is called Oxilan, structural formula (I): [0003] [0004] Ioxilan is a non-ionic X-ray contrast agent developed by Cooking Contrast Media Company of the United States and Chugai Pharmaceutical Co., Ltd. in Japan for preparation research and clinical development. It ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C237/46A61K49/04
Inventor 邹霈刘娅灵谢敏浩罗世能何拥军吴军王洪勇
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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