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New preparation method of gadobenate dimeglumine

A technology of gadobenate meglumine and its synthesis method, which is applied in the field of synthesis research of nuclear magnetic resonance contrast agents, can solve problems affecting the purity of the final product, a large amount of hydrochloric acid, and low product purity, and is beneficial to the control of product quality and reaction conditions Simple, quality control and stable results

Inactive Publication Date: 2012-04-11
TIANJIN HAIWEN PUNING TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is: the product purity of intermediate raw material 2-chloro-3-benzyloxy propionic acid is lower, affects the purity of end product; Ion exchange resin technique needs to use a large amount of hydrochloric acid, and easily produces the 6 Lactam by-products, the product quality does not meet the technical requirements for drug declaration
[0006] (1), the preparation of 2-chloro-3-benzyloxypropionic acid needs to be operated under conditions such as pressurization and chlorine gas flow. This high-pressure, toxic gas reaction will easily cause serious environmental pollution in future industrial production and is not suitable for large-scale preparation;
[0007] (2) For the preparation of compounds, in order to avoid lactam by-products, the pH value and water volume must be strictly controlled. At the same time, special nanofiltration equipment is required for concentration and desalination. The control of reaction conditions, equipment requirements, and energy consumption are relatively strict and complicated. Therefore, the operation of this step reaction is not convenient for large-scale production in the future
The new preparation process of gadobenate meglumine described in the present invention has not yet seen relevant reports at home and abroad so far

Method used

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  • New preparation method of gadobenate dimeglumine
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  • New preparation method of gadobenate dimeglumine

Examples

Experimental program
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Effect test

Embodiment 1

[0041] "Example 1" Preparation of 2-chloro-3-benzyloxypropionic acid potassium salt (III)

[0042] In a 1L three-necked reaction flask, at room temperature, add 389g of benzyl alcohol and 0.83g of sodium metal, stir for 10 minutes, then add 105g of 2-chloroacrylonitrile dropwise in an ice bath. Continue to react in the bath for 1 hour, then stir and react at room temperature for 2 hours, add 300ml of ethyl acetate, and dropwise add 200ml of dilute hydrochloric acid with a content of 10%. 10% NaHCO 3 The solution was washed, washed with water, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the filtrate was concentrated to obtain a dark red oil.

[0043]Add the oil to 20% sodium hydroxide (360ml) solution, stir at 50°C for 30min, add 500ml of water, extract with ethyl acetate (500ml×2), adjust the pH of the aqueous layer to 2 with concentrated hydrochloric acid, extract with ethyl acetate (500ml×3), combined, dried with anhydrous sulfuric acid, f...

Embodiment 2

[0044] "Example 2": Preparation of tert-butyl 2-chloro-3-benzyloxypropionate (IV)

[0045] In a 1L reaction flask, 42.8g of 2-chloro-3-benzyloxypropionic acid was dissolved in 200ml of acetonitrile, under ice cooling, the temperature was controlled at 0-5°C, 29.6g of tert-butanol and 2.44g of DMAP were added, Add 45.3 g of DCC in batches. After the addition, keep the reaction in ice bath for 30 minutes, and react at room temperature for 8 hours, filter, concentrate the filtrate until a yellow oily substance is obtained, separate by column, use petroleum ether as eluent, separate and purify, concentrate and wash The liquid was removed to obtain 43 g of a colorless oily substance, namely tert-butyl 2-chloro-3-benzyloxypropionate, with a yield of 86% (calculated according to 2-chloro-3-benzyloxypropionic acid). "Example 3" Preparation of 2-(diethylenetriamino)-3-benzyloxy propionate tert-butyl fumarate (V)

Embodiment 3

[0045] In a 1L reaction flask, 42.8g of 2-chloro-3-benzyloxypropionic acid was dissolved in 200ml of acetonitrile, under ice cooling, the temperature was controlled at 0-5°C, 29.6g of tert-butanol and 2.44g of DMAP were added, Add 45.3 g of DCC in batches. After the addition, keep the reaction in ice bath for 30 minutes, and react at room temperature for 8 hours, filter, concentrate the filtrate until a yellow oily substance is obtained, separate by column, use petroleum ether as eluent, separate and purify, concentrate and wash The liquid was removed to obtain 43 g of a colorless oily substance, namely tert-butyl 2-chloro-3-benzyloxypropionate, with a yield of 86% (calculated according to 2-chloro-3-benzyloxypropionic acid). "Example 3" Preparation of 2-(diethylenetriamino)-3-benzyloxy propionate tert-butyl fumarate (V)

[0046] In a 500ml reaction flask, dissolve 76g of diethylenetriamine in 80ml of DMF, and slowly add 40g of tert-butyl 2-chloro-3-benzyloxypropionate and 40m...

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Abstract

The invention provides a preparation method of a magnetic resonance contrast agent gadobenate dimeglumine and relates to a synthetic process of a new intermediate. In order to overcome the defects of the prior arts, the process is optimized and improved, the chlorine addition reaction is omitted and the reaction and operation of high-pressure and toxic gas are avoided; and the synthesized intermediate of each step can be purified through recrystallization, the quality control of the product is stable and the operation process is more suitable for industrialized large-scale preparation.

Description

Technical field: [0001] The invention relates to the field of synthesis research of nuclear magnetic resonance contrast agents, in particular to a preparation method of gadobenate meglumine and an intermediate thereof. Background technique: [0002] Magnetic resonance imaging (MRI) is a commonly used imaging diagnostic method based on traditional imaging technology and uses special molecules as imaging objects. It is currently developing very rapidly in clinical use. It is non-destructive to the measured object and can perform three-dimensional High-resolution imaging and other advantages. In 1984, Carr used gadolinium pentetic acid meglumine (Gd-DTPA) for the first time to study the enhanced imaging of human brain tumors. In 1987, Gd-DTPA was officially approved by the US Food and Drug Administration (FDA) as an MRI contrast agent. In recent years, with the rapid development of various clinical technologies, such as high superconducting magnetic field, high radio frequency...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/76C07C227/18C07C229/16C07C69/708
Inventor 赵光普李剑
Owner TIANJIN HAIWEN PUNING TECH DEV
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