Preparation method of macrocyclic chelating agent and intermediate thereof

A compound, the technology of cyclamenine, is applied in the field of preparation of gadoterol, gadobutrol and their intermediates, and can solve the problems of complicated purification, long reaction route, many by-products and the like

Active Publication Date: 2020-02-25
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The prior art discloses some preparation methods of gadoteridol or gadobutrol, such as CN1259939A, CN102399199A and CN102933562A, etc. The preparation of gadoteridol or gadobutrol usually has difficult control of reaction, long reaction route, many by-products, and high purity. Low, some difficulties such as complicated purification (such as needing ion exchange resin purification), so it is still urgent to obtain a method with short reaction route, short production cycle, mild reaction conditions, easy operation and easy preparation, high purity and high yield, and the solvent residue meets the quality requirements. Standard, the preparation method of gadoteridol and gadobutrol that can meet the needs of industrial production

Method used

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  • Preparation method of macrocyclic chelating agent and intermediate thereof
  • Preparation method of macrocyclic chelating agent and intermediate thereof
  • Preparation method of macrocyclic chelating agent and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] The preparation of embodiment 1t-Bu-DO3A

[0140]

[0141] Add 1.0Kg of cyclen to 7.5L of N,N-dimethylacetamide, add 1.57Kg of sodium acetate, and add N,N of tert-butyl bromoacetate at -5°C to 5°C -Dimethylacetamide solution (3.74Kg of tert-butyl bromoacetate dissolved in 2.5L of N,N-dimethylacetamide), after addition, react at room temperature for 24h, pour the reaction solution into 20L of purified water, drop Add 2.0 mol / L sodium hydroxide aqueous solution to adjust the pH to 8.5-9.5 to precipitate a solid, which is shaken and filtered to obtain a solid.

[0142] Dissolve the above solid in 16.0L of dichloromethane, wash the organic phase with 8.0L of purified water, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to saturation under reduced pressure at 20°C to 30°C (very small amount of solid Precipitate), stop concentrating, add 30L methyl tert-butyl ether, separate out a large amount of white solids, shake filter, dry ...

Embodiment 2

[0143] The preparation of embodiment 2DO3A

[0144]

[0145] Dissolve 2.7Kg of t-Bu-DO3A in 13.5L of anhydrous methanol, add aqueous sodium hydroxide solution (dissolve 1.45Kg of NaOH in about 2.7L of water), heat up to 65°C to 75°C after the addition, and stir to react 3h, concentrated under reduced pressure at 50℃~60℃ to nearly dryness to obtain DO3A.

Embodiment 3

[0146] The preparation of embodiment 3HP-DO3A

[0147]

[0148] The DO3A that embodiment 2 obtains is dissolved with the purified water of 13.5L, adjusts pH to 11.0-12.5 with the concentrated hydrochloric acid of 12.0mol / L, under the condition of controlled temperature 0 ℃~15 ℃, drip propylene oxide aqueous solution (526.6g epoxy Dissolve propane in about 5.3L of purified water), after addition, react at 20°C to 30°C for about 20h, adjust the pH of the reaction solution to 10.5-11.5 with 4mol / L aqueous sodium hydroxide solution, and filter the nanofilter at 65 Concentrate under reduced pressure and close to dryness at ℃~75℃, add 1L purified water to dissolve the solid, heat to 55℃~65℃, slowly add 20L isopropanol while keeping warm, cool down to 0℃~10℃, stir and crystallize, filter, The solid was dried to obtain 1.9 Kg of white solid HP-DO3A, the yield was 89.0%, and the purity by HPLC was 99.86% (area normalization method).

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Abstract

The invention relates to a preparation method of a macrocyclic chelating agent and an intermediate thereof, particularly to a preparation method of gadoteridol, gadobutrol and intermediates of gadoteridol and gadobutrol thereof. According to the method of the invention, high-purity t-Bu-DO3A can be simply and conveniently obtained from cyclen in one step, and gadoteridol or gadobutrol is obtainedthrough subsequent related reaction and purification; and the high purity of the final product is achieved by controlling the each link of the process so as to achieve the medicinal standard, the purification step of ion exchange chromatography is not needed, the operation is simple and convenient, the preparation is easy, the yield is high, and the method is particularly suitable for the requirements of industrial production.

Description

technical field [0001] The invention relates to a preparation method of a macrocyclic chelating agent and an intermediate thereof, in particular to a preparation method of gadoteridol, gadobutrol and the intermediate thereof. Background technique [0002] Magnetic resonance imaging (MRI for short) is a diagnostic technology that uses the nuclear magnetic resonance phenomenon of a certain nucleus in human tissue, and processes the radio frequency signal obtained by a computer to reconstruct an image of a certain level of the human body. It has been widely used at present. In clinical practice, it has become an indispensable tool for disease diagnosis. Gadoteridol and gadobutrol are extracellular distribution, non-tissue-specific, electrically neutral, non-ionic water-soluble gadolinium-containing MRI contrast agents with high relaxivity, good stability, good viscosity and permeability. Low-grade characteristics, mainly cleared by glomerular filtration, low toxicity, and its ...

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 周兴健赵瑞桑光明张爱明江竹莲吴刚夏春光张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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