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Intermediate of iodixanol and method for preparing iodixanol by using intermediate

A technology of iodixanol and intermediates, which is applied in the synthesis field of medicine and chemical industry, can solve the problems of long synthesis cycle, low purity of finished products, high equipment requirements, etc., and achieve the effect of stable product quality, low impurity content and high synthesis purity

Pending Publication Date: 2021-12-24
江苏宇田医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage is that the key intermediate "compound A" of the original research is not used, which does not constitute infringement compared with the original research patent; solids can be precipitated in each step to facilitate purification; the disadvantage is that the four-step chemical bonding reaction requires the use of thionyl chloride, which is complex and acidic. Strong, volatile, high equipment requirements, unfriendly to the environment, long synthesis cycle
The advantage is that thionyl chloride is not used, the environment is friendly, the requirements for equipment are not high, the post-treatment is convenient, the prepared sample is solid, and it is easy to purify; the disadvantage is that the synthesis cycle is long, the operation is complicated, and the purity of the finished product is low, especially the key impurity iodine Kexanol impurity G is too large

Method used

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  • Intermediate of iodixanol and method for preparing iodixanol by using intermediate
  • Intermediate of iodixanol and method for preparing iodixanol by using intermediate
  • Intermediate of iodixanol and method for preparing iodixanol by using intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Example 1: 1) Add dimethyl 5-nitroisophthalate (850g), aminoglycerin (680g), and anhydrous methanol (680g) into a 5L three-necked glass bottle, and stir for 15 minutes. The temperature of the reaction solution was controlled at 20° C. to 30° C., and sodium methoxide methanol solution (68 g) was added slowly. The temperature of the reaction solution is controlled at 30° C. to 40° C., and the reaction is stirred for 3 to 4 hours. After the reaction is finished, the temperature of the reaction solution is lowered to 15°C to 25°C, and the temperature of the reaction solution is controlled below 30°C and glacial acetic acid is added until the pH=5.0 to 5.5, and then the reaction is completed. The 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Formula II) reaction solution was obtained, which was used for the next step of production.

[0048] 2) Add the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (formula II) from the ...

Embodiment 2

[0054] Example 2: 1) Add dimethyl 5-nitroisophthalate (850g), aminoglycerin (680g), and anhydrous methanol (680g) into a 5L three-necked glass bottle, and stir for 15 minutes. The temperature of the reaction solution was controlled at 20° C. to 30° C., and sodium methoxide methanol solution (68 g) was added slowly. The temperature of the heating reaction solution is controlled at 30°C to 40°C, and the reaction is stirred for 3 to 4 hours. After the reaction is finished, the temperature of the reaction solution is lowered to 15°C to 25°C, and the temperature of the reaction solution is controlled below 30°C and glacial acetic acid is added until the pH=5.0 to 5.5, and then the reaction is completed. The 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Formula II) reaction solution was obtained, which was used for the next step of production.

[0055] 2) Add the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (formula II) from ...

Embodiment 3

[0061] Example 3: 1) Add dimethyl 5-nitroisophthalate (850g), aminoglycerin (680g), and anhydrous methanol (680g) into a 5L three-necked glass bottle, and stir for 15 minutes. The temperature of the reaction solution was controlled at 20° C. to 30° C., and sodium methoxide methanol solution (68 g) was added slowly. The temperature of the heating reaction solution is controlled at 30°C to 40°C, and the reaction is stirred for 3 to 4 hours. After the reaction is finished, the temperature of the reaction solution is lowered to 15°C to 25°C, and the temperature of the reaction solution is controlled below 30°C and glacial acetic acid is added until the pH=5.0 to 5.5, and then the reaction is completed. The 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Formula II) reaction solution was obtained, which was used for the next step of production.

[0062] 2) Add the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (formula II) from ...

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Abstract

The invention provides a method for preparing iodixanol from an intermediate of iodixanol. The intermediate of iodixanol is shown as a formula VI: 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide], and iodination is performed through the formula VI to obtain a finished product of iodixanol. The invention provides a brand new synthesis thought of forming a dimer first and then conducting iodinating, and in the prepared iodixanol finished product, the total impurity content is less than or equal to 1.0%, and the impurity G content is less than or equal to 0.5%. The method disclosed by the invention is mild in reaction condition, low in equipment damage, simple in process, green, environment-friendly, low in cost, capable of ensuring continuous production of high-quality products, relatively high in application value and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of synthesis of medicine and chemical industry, in particular to an intermediate of iodixanol and a method for preparing iodixanol. Background technique [0002] Iodixanol (Visipaque) is the third-generation isotonic non-ionic iodine contrast agent. According to the CHEMISTRY REVIEW (S) information released by the FDA, the dosage form of this product is injection, with two specifications of 270mg / ml and 320mg / ml. The principle is to combine iodine to absorb X-rays in blood vessels and tissues to produce image display. Has the following structural formula: [0003] [0004] Iodixanol was originally developed by Nycomed of Norway, and it was officially put on the market in 1993 and produced in large quantities. Its chemical name is: 5,5′-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N′-bis(2,3-dihydroxypropyl) -2,4,6-triiodo-1,3-benzenedicarboxamide]. [0005] Iodixanol is a representative of dimer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C231/02C07C237/46C07C237/42C07C237/32C07C327/40
CPCC07C231/12C07C231/02C07C237/46C07C237/32C07C237/40C07C237/42
Inventor 朱万里闫雪峰代国宏胡学建
Owner 江苏宇田医药有限公司
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