Preparation method for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

A halogenated acetic acid and compound technology, applied in the field of medicinal chemistry, can solve the problems of unknown impurities, cumbersome process, low production capacity of intermediate DOTA, etc.

Inactive Publication Date: 2018-10-16
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The biggest drawback of this process is that the use of resin or nanofiltration to purify the intermediate DOTA has lo

Method used

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  • Preparation method for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • Preparation method for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • Preparation method for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059]

[0060] Add 11.8kg of chloroacetic acid and 12l of purified water into a 100L reactor, stir and dissolve, add 15l of water dissolved in 5kg of sodium hydroxide under an ice bath, suspend 3.2kg of rhodotendine in 6l of water and add it to the reaction, and heat up to 80~85℃, add dropwise 6L water dissolved with 5.2kg sodium hydroxide, control the pH of the reaction system at 10~11, react overnight, after cooling to room temperature, add 10.4l concentrated hydrochloric acid dropwise, adjust the pH to 2~2.5, stir and analyze crystal, the filter cake was collected by filtration, and dried to obtain 7.5 kg of DOTA crude product, the content of the compound of formula II was about 3.1%.

[0061] Add 7.5kg of crude DOTA and 18kg of purified water into a 50L reactor, heat and stir to dissolve, then cool and crystallize, filter, wash, and dry to obtain 6.21kg of DOTA with a yield of 82.7%, and the salt content is 2%, the compound of formula II The content is 0.05%.

Embodiment 2

[0062] Example 2: Exploration of DOTA Crude Refining Method

[0063] Take 20g DOTA crude product and put it into the reaction bottle, add the solvent to be screened respectively, after heating and dissolving, cool and stir to crystallize, filter to obtain DOTA samples, detect them respectively, and record the data as shown in Table 1 below:

[0064] Table 1

[0065]

[0066] Note:

[0067] a In the solvent screening, it can be detected by TLC (plate layer chromatography), and after obtaining a general evaluation, it can be further detected by HPLC and other detection means;

[0068] b After HPLC detection, the obtained DOTA was purified to 96.9%, with a salt content of 3.07%, and a compound of formula II of 0.02%;

[0069] c is detected by HPLC, and the obtained DOTA is purified to 95.7%, with a salt content of 10.27% (measured by titration method), and the compound amount of formula II is 0.05%;

[0070] d is detected by HPLC, and the obtained DOTA is purified to 95.1%,...

Embodiment 3

[0075]

[0076] In 50L of purified water, add 5.1kg of DOTA obtained in Example 1, heat and stir at 40-50°C to dissolve, add meglumine (2.5kg) and gadolinium oxide (2.33kg) respectively, the solution pH=7-9, and heat to react 3h, filtered, desalted with 001×7 and D311 resin in turn to obtain gadoterate meglumine solution that meets the requirements, concentrated to dryness or lyophilized to obtain 7.46kg of gadoterate meglumine, yield 78.5%, tested The formula II content is less than 0.01%, the free gadolinium content is less than 0.013%, and the salt content is zero.

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Abstract

The invention relates to a preparation method for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Specifically, the method uses a recrystallization method to obtain a high-purity compound represented by a formula I shown in the description, and further, meglumine and Gd2O3 are complexed with the compound represented by the formula I to obtain the gadoteric acid meglumine. The method disclosed by the invention is simple to operate, has low costs, and is green, environmentally friendly and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and a complex thereof. Background technique [0002] Gadoteric Acid Meglumine (Gadoteric Acid Meglumine), chemical name 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate gadoteric meglumine, was developed by Guerbet and marketed as an MRI contrast agent for cancer. [0003] Gadoterate meglumine is an ionic cyclic gadolinium preparation. Due to its structural characteristics, it is a low-risk drug. Among the nine gadolinium contrast agents that have been marketed, the risk of nephrogenic systemic fibrosis (NSF) is theoretically The above analysis is the lowest. Compared with other gadolinium contrast agents, this product has wider indications, except for the liver, this product can be used for central, systemic and angiography, [0004] [0005] At present, the existing literature reports have...

Claims

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Application Information

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IPC IPC(8): C07D257/02C07F5/00
Inventor 李明刘凯王俊琰梁冰
Owner JIANGSU HENGRUI MEDICINE CO LTD
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