Industrial preparation method of iodixanol

A technology of iodixanol and compounds, which is applied in the field of industrial preparation of iodixanol, can solve the problems of low yield of iodixanol, achieve the effects of improving reaction conversion efficiency, improving reaction efficiency, and reducing the generation of impurities

Pending Publication Date: 2022-07-08
ANHUI POLY PHARM CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

US2012184773A1 discloses that the compound of formula II uses dimethylacetamide (DMAc) and water as a mixed solvent, and under the condition of adding potassium iodide, while dimerizing epichlorohydrin into iodixanol, it also generates iohexol, impurities G, and the iodixanol yield is also low, only 52%; and the reaction substrate formula II compound is still unreacted after 45 hours, and the residual amount reaches more than 38%

Method used

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  • Industrial preparation method of iodixanol
  • Industrial preparation method of iodixanol
  • Industrial preparation method of iodixanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of iodixanol

[0036] In a 3000L reactor, epichlorohydrin (49.54kg, 535.43mol) was dissolved in 1000kg dimethylformamide, and the compound of formula II (800kg, 1070.86mol) and zinc chloride (7.3kg, 53.543mol) were added under stirring. Dissolve in, react at room temperature for 5 hours, add 900kg potassium hydroxide solution (25% w / v) to adjust the pH to 6-7, keep stirring for 20 minutes, the HPLC purity of the reaction solution is 71.46%. HPLC spectrum such as figure 1 , the integral data are as follows:

[0037]

[0038] Those skilled in the art know that the retention time 25.957-29.872 is the peak position of iodixanol. Therefore, to calculate the integral content of iodixanol in the reaction solution, the values ​​in the range of 25.957-29.872 should be added, that is, in figure 1 Among them, the concentration of iodixanol is 27.67%+43.79%=71.46%.

Embodiment 2

[0039] Example 2: Preparation of iodixanol

[0040] In a 2000ml reaction flask, epichlorohydrin (33g, 0.36mol) was dissolved in 500g dimethylformamide, and the compound of formula II (533g, 0.71mol) and aluminum chloride (4.74g, 0.0355mol) were added under stirring, The reaction was carried out at room temperature for 3 hours, 600 g of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6 to 7, and the mixture was kept stirring for 10 minutes. The HPLC purity of the reaction solution was 68.59%.

Embodiment 3

[0041] Example 3: Preparation of iodixanol

[0042] In a 2000ml reaction flask, epichlorohydrin (33g, 0.36mol) was dissolved in 500g dimethylformamide, and the compound of formula II (533g, 0.71mol) and ferric chloride (5.76g, 0.0355mol) were added under stirring, The reaction was carried out at room temperature for 3 hours, 600 g of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6-7, and the mixture was stirred for 10 minutes. The HPLC purity of the reaction solution was 69.34%.

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Abstract

The invention relates to the technical field of pharmaceutical chemicals, in particular to an industrial preparation method of iodixanol. The method comprises the following steps: carrying out dimerization reaction on N, N '-bis (2, 3-dihydroxypropyl)-2, 4, 6-triiodo-isophthalamide (a compound shown as a formula II) under the action of a catalyst to synthesize a crude iodixanol product, and recrystallizing by using ethanol to obtain a finished iodixanol product. The method is simple in process route, impurities can be effectively reduced, the reaction conversion efficiency can be greatly improved, reaction substrates can be completely converted, compared with the prior art, the yield is greatly improved, the HPLC purity of reaction liquid reaches 70% or above, and the method is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and particularly relates to an industrialized preparation method of iodixanol. Background technique [0002] Iodixonal is a non-ionic X-ray contrast agent developed by Norway's Nycomed Company, the chemical name is 5,5'-((2-hydroxy-1,3-propane)bis(acetylidene) Ammonia)) bis(N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, its molecular structure is shown in formula I: [0003] [0004] Some studies have shown that iodixanol is more effective than other contrast agents in reducing complications and is safer and more effective to use. Iodixanol is administered directly by injection, and the dosage used is relatively high, so this has higher requirements on the quality of iodixanol APIs, so it is necessary to focus on the production and purification process of iodixanol . [0005] The existing iodixanol production is mainly through 5-acetamido-N,N'-b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/08C07C237/46
CPCC07C231/08C07C237/46Y02P20/584
Inventor 朱逸凡范敏华海杰黄霂张丽俞永浩田淑雅
Owner ANHUI POLY PHARM CO LTD
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