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Preparation method of gadobutrol and intermediate thereof

An ethanol, reaction time technology, applied in organic chemistry, bulk chemical production, etc., can solve problems such as non-compliance with regulatory requirements, elimination, risks, etc., to avoid drug safety and/or environmental pollution, less by-products, The effect of mild process conditions

Pending Publication Date: 2022-06-03
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no matter which method it is, it faces the same problem: the selectivity of the cyclen reaction site (the reactivity of the four NH groups is the same); that is, in the preparation of gadobutrol or its intermediate In the process, the biggest technical problem that needs to be solved is: how to reduce the occurrence of side reactions, so as to reduce the residue of by-products in the target product
[0009] It can be seen that although the above-mentioned prior art method can reduce the residue of by-products in the target product to a certain extent under its process conditions, no matter in the reaction stage or in the subsequent separation and purification stage, it is inevitable Dichloromethane, a toxic and harmful solvent, is used (in October 2017, the International Agency for Research on Cancer of the World Health Organization included methylene chloride in the list of 2A carcinogens; in January 2019, methylene chloride was included in the list of toxic and harmful air pollution Inventory (2018); in July 2019, dichloromethane was included in the list of toxic and harmful water pollutants (the first batch)), which has relatively large risks and hidden dangers in terms of safety and environmental protection, and does not meet the requirements of my country's Regulatory requirements for drug safety and the scientific development concept of "lucid waters and lush mountains are golden mountains and silver mountains", so it is very likely to face the embarrassing situation of being eliminated

Method used

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  • Preparation method of gadobutrol and intermediate thereof
  • Preparation method of gadobutrol and intermediate thereof
  • Preparation method of gadobutrol and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078]1. Prepare DO3A-T-BU-ESTER

[0079]

[0080] These include the following steps:

[0081] (1), the 10g (about 58mmol) cyclen (Name: 1,4,7,10-tetraazacyclododecane) and 15.71g (about 191.6mmol) sodium anhydrous acetate were added to 90mL DMF (N, N-dimethylformamide), and then added 40.76g (about 209mmol) tert-butyl bromoacetate and 30mL DMF mixed solution, reacted at 20 ~ 30 °C for 6h, to give the reaction solution;

[0082] (2), add 330mL of purified water to the resulting reaction solution, and then adjust the pH value to 8.8~9.0 with an aqueous sodium carbonate solution (mass percentage concentration of 8.0%), pump filtration, and the filter cake is rinsed twice with purified water (20mL×2) to obtain wet products; The wet product (about 30g) was added to 90mL ethanol, heated to 40 ~ 45 ° C, dissolved, and then added 270mL of purified water, stirred at room temperature for 2h, filtered, filter cake with purified water twice (20mL×2), 50 ~ 60 ° C blast dried, to give the pr...

Embodiment 2～4

[0115]The same content as Example 1 is no longer repeated, the difference is that in the step (1) of the DO3A-T-BU-ESTER preparation method, the anhydrous sodium acetate is changed to potassium carbonate, lithium hydroxide, sodium bicarbonate (the dosage is 191.6mmol, i.e., 3.3 equivalents), the reaction liquid is obtained, and then subsequent separation and purification are carried out according to the same method to obtain the product DO3A-T-BU-ESTER.

[0116] According to the same method as In Example 1, the above reaction liquid and the product DO3A-T-BU-ESTER were performed with high performance liquid chromatography (HPLC), the results are shown in Table 2.

[0117] Table 2, HPLC test results of Example 2 to 4

[0118]

[0119]

[0120]

[0121] The above results show that under the same other process conditions, the main product when using potassium carbonate is impurity 4 (tetraesteride product content is 73.10%), and there are more impurities 4 (tetraesteride produc...

Embodiment 5～7

[0123] The same content as Example 1 is no longer repeated, the difference is that in the step (1) of the DO3A-T-BU-ESTER preparation method, the solvent DMF is changed to ethanol, N, N- dimethylacetamide, acetonitrile (the amount of solvent is unchanged), the reaction liquid is obtained, and then subsequent separation and purification is carried out according to the same method to obtain the product DO3A-T-BU-ESTER.

[0124] According to the same method as In Example 1, the above reaction liquid and the product DO3A-T-BU-ESTER were tested by high performance liquid chromatography (HPLC), and the results are seen separately Figures 3 to 9 and Tables 3 to 9.

[0125] Table 3, EXAMPLE 5 of the resulting reaction solution of hplc ( Figure 3 ) data

[0126]

[0127]Table 4, Example 5 of the product DO3A-T-BU-ESTER HPLC ( Figure 4 ) data

[0128]

[0129] Table 5, Example 6 of the resulting reaction solution of the HPLC ( Figure 5 ) data

[0130]

[0131] Table 6, Example 6 of th...

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Abstract

The invention discloses a preparation method of gadobutrol and an intermediate thereof. The invention provides a preparation method of a compound B or a salt thereof, which comprises the following step: in the presence of acetate and N, N-dimethylformamide, carrying out substitution reaction on cycleanine and a compound A to generate the compound B or the salt thereof. According to the method, side reactions such as primary esterification and secondary esterification can be well controlled and reduced, so that the content of impurities such as a monoester product, a diester product and a tetraester product in a reaction solution is low, and the impurities generated by the side reactions can be removed from a target product by using safe and nontoxic ethanol and water; the problems of drug safety and / or environmental pollution and the like possibly caused by using toxic solvents such as dichloromethane are effectively avoided, and the method is safe, environmentally friendly and more suitable for being applied to large-scale production.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical or interbody synthesis thereof, specifically relates to a method for preparing gadolinium butanol and an intermediate thereof. Background [0002] Gadolinium butanol, CAS number: 138071-82-6, Chemical Name: 10-(2,3-Dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate(III). Due to its good tolerance and low incidence of adverse reactions, gadolinium butanol is widely used as a contrast agent in magnetic resonance imaging technology to detect tumors, inflammation, demyelinating and other diseases of the central nervous system, and has been successfully marketed in many countries or regions. [0003] At present, the preparation method of gadolinium butanol is mainly divided into the following two types: [0004] [0005] (1) first introduce 2,3-dihydroxy-1-hydroxymethylpropyl on one NH group of the starting cyclen, and then simultaneously introduce an acetate group on th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02
CPCC07D257/02Y02P20/55
Inventor 魏彦君阳赶宋庭黄长全张伟安浩云
Owner SHANGHAI VIWIT PHARMA CO LTD
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