Refining method of iopamidol intermediate

A technology of iopamidol and asana, which is applied in the field of refining iopamidol intermediates, can solve the problems that iopamidol is difficult to reach the pharmaceutical grade, increase the difficulty of iopamidol synthesis route, and unfavorable reactions, so as to simplify production Process, easy operation, thorough reaction effect

Pending Publication Date: 2022-06-24
HAINAN PULIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The generation of this impurity has caused the yield of this step reaction to be low, and purity is low, and then is unfavorable for follow-up reaction to carry out, has increased the difficulty of iopamidol overall synthetic route
In addition, the formation of this impurity will also make it difficult for the final synthesized iopamidol to reach the pharmaceutical grade

Method used

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  • Refining method of iopamidol intermediate
  • Refining method of iopamidol intermediate
  • Refining method of iopamidol intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1, the preparation of compound of formula V

[0055] In 3L reaction kettle, add 450g formula II compound (this compound can be prepared according to the method in CN103086915A patent) and 2L purified water, be warming up to 70-80 ℃ of dissolving, transfer in 3L hydrogenation kettle, add 9g 5% palladium carbon , the temperature is controlled at 60-70°C, and the pressure is maintained at 0.6-1.4Mpa to carry out the hydrogenation reaction. After the reaction is completed for 5-10h, the filtrate is obtained by filtering.

Embodiment 2

[0056] Embodiment 2, the preparation of iopamidol intermediate formula III compound

[0057] In the reactor of 5L, add 500g water, sodium chloride 243g, iodine 374g, potassium iodate 158g, CF 3 CO 2 Ag14g, cooled to 5-20°C, and 456g of refined hydrochloric acid was added dropwise. After the addition, the temperature was controlled to 50-60°C and the filtrate obtained in Example 1 was slowly added dropwise, and the reaction was incubated for 17h. The temperature was controlled below 60°C, 50% sodium hydroxide solution was added dropwise, the pH was adjusted to 5-6, the temperature was slowly lowered to 10-25°C, the stirring was continued for 3 hours and then filtered, the filter cake was washed with 800g of water, and dried under reduced pressure to obtain 888g of intermediate formula III Compound, yield 99.9%, purity 96.7%, no diiodo-substituted impurity 1 compound was detected. The HPLC chromatogram of the diiodo-substituted impurity 1 compound is shown in the attached fi...

Embodiment 3

[0060] Embodiment 3, the preparation of iopamidol intermediate formula III compound

[0061] In the reactor of 5L, add 500g water, sodium chloride 243g, iodine 374g, potassium iodate 158g, CF 3 CO 2 Ag5.6g, cooled to 5-20°C, and 456g of refined hydrochloric acid was added dropwise. After the addition, the temperature was controlled at 50-60°C and the filtrate obtained in Example 1 was slowly added dropwise, and the reaction was incubated for 17h. The temperature is controlled below 60°C, 50% sodium hydroxide solution is added dropwise, the pH is adjusted to 5-6, the temperature is slowly lowered to 10-25°C, the stirring is continued for 3 hours and then filtered, the filter cake is washed with 800g of water, and dried under reduced pressure to obtain 826g of intermediate formula III Compound, yield 93%, purity 96.1%, no diiodine substituted impurity 1 compound was detected. The HPLC detection spectrum of the compound of formula III prepared in this example is as attached i...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly provides a refining method of an iopamidol intermediate, which is characterized in that a compound shown as a formula II is used for preparing a compound shown as a formula III of the iopamidol intermediate under the catalytic action of Lewis soft acid. According to the technical scheme, the high-purity and high-yield intermediate compound shown in the formula III can be obtained, the yield can reach 99.9%, the reaction is thorough, no raw material is left, the purity can reach 96% or above, and generation of a diiodo-substituted impurity 1 compound is thoroughly avoided. In addition, high-purity and high-yield iopamidol can be prepared by utilizing the intermediate compound as shown in the formula III, so that the technical scheme is more suitable for expanding industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and specifically, the invention provides a method for purifying an intermediate of iopamidol, which comprises using Lewis soft acid as a catalyst. Background technique [0002] In the process of medical diagnosis using X-ray fluoroscopy, a considerable part of the human tissue structure cannot be clearly displayed if only relying on their own density and thickness differences, so contrast agents must be introduced to achieve the purpose of clear imaging. Contrast agents can alter the contrast of an organ, injury, or any other surrounding structure, making this detail visible, which in turn can ensure an accurate diagnosis. [0003] Contrast agents were originally used in the field of radiology or MRI diagnosis. Depending on the field of application, these derivatives exhibit different structural features, for example, in the case of molecules used as contrast agents for X-ray analysis, th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/46C07C231/02C07C231/24G01N30/34G01N30/60
CPCC07C231/12C07C231/02C07C231/24G01N30/6039G01N30/34C07C237/46C07C237/32
Inventor 朱逸凡范敏华谢豪马岩查龙飞俞永浩蔡超慧赵巧男马瑞苑
Owner HAINAN PULIN PHARMA
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