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Preparation method of magnetic resonance imaging contrast agent

A technology of magnetic resonance imaging and contrast agent, applied in the direction of nuclear magnetic resonance/magnetic resonance imaging contrast agent, organic chemistry, etc., can solve the problems of unsuitability for industrial production, high cost of industrial production, low total yield, etc. The effect of low equipment requirements and a wide range of sources

Active Publication Date: 2012-04-04
广州康臣药业有限公司
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AI Technical Summary

Problems solved by technology

But at present all main synthetic methods (DE4009119; Inorg.Chem.1997,36,6086-6093; DE19724186.7; DE10064467.8; MI97A001371) are basically based on 1,4,7,10-tetraazacyclodeca Dioxane (cyclen) is the raw material, which is very expensive and the industrial production cost is extremely high
Inorg.Chem. (1997, 36, 6086-6093) used trans 5-amino-6-hydroxyl-2,2-dimethyl-1,3-dioxepane as the starting material to synthesize gadocloth Alcohol, although this raw material is cheaper than 1,4,7,10-tetraazacyclododecane, it is still quite expensive, and the total yield of synthesis is not high (<10%), so it is not suitable for industrial production

Method used

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  • Preparation method of magnetic resonance imaging contrast agent
  • Preparation method of magnetic resonance imaging contrast agent
  • Preparation method of magnetic resonance imaging contrast agent

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Experimental program
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Embodiment 1

[0025] Embodiment 1: Preparation of gadobutrol

[0026]

[0027] A) Preparation of N, N', N"-tris(2-ethoxy-2-carbonylethyl)diethylenetriamine

[0028] Disperse 1.03kg (10mol) of diethylenetriamine and 100g of anhydrous potassium carbonate in 3L of acetonitrile, slowly add 3.43kg (28mol) of ethyl chloroacetate dropwise while stirring, and control the dropping time for not less than 3 hours. After the addition was complete, the reaction was stirred for 3 hours, and the acetonitrile was recovered under reduced pressure to obtain the desired compound.

[0029] B) Preparation of N, N', N"-tris(2-ethoxy-2-carbonylethyl) diethylenetriamine disodium salt (IV)

[0030] Dissolve and disperse the product in A) in 1.5L of ethanol, add 1.36kg (20mol) of sodium ethoxide, heat and stir under reflux for 5 hours, and filter to obtain N,N',N"-tris(2-ethoxy- 2-Carbonylethyl) diethylenetriamine disodium salt 2.93 kg (8.2 mol, yield 82%) of white solid, the purity was detected by HPLC, and th...

Embodiment 2

[0039] Embodiment 2: Synthetic gadolinium

[0040]

[0041] A)-D) steps are consistent with the synthesis method of gadobutrol in Example 1.

[0042]E) Dissolve the target product obtained in D) in water, adjust the pH to 12.3 with hydrochloric acid, add 363 g (6.26 mol) of propylene oxide, react at 40 ° C for 4 hours and react at 80 ° C for 8 hours, and then cool the solution to 50°C, add 6.2mol gadolinium trichloride in 5.5kg aqueous solution. After 1 hour the mixture was cooled to 17°C and acidified to pH 1.7 with concentrated hydrochloric acid and kept stirring for 2 hours. Then the temperature was raised to 50° C., the pH was adjusted to 7 with sodium hydroxide, and the reaction was stirred for 1 hour.

[0043] The desalination and purification of gadolidol were the same as in Example 1F), and finally 2.49kg of white powder was obtained with a total yield of 55%. IR, MS and NMR were consistent with the specified structure, and its purity was 99.1% by HPLC analysis.

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Abstract

The invention relates to a preparation method of a magnetic resonance imaging contrast agent, especially a preparation method of gadobutrol and gadoteridol. The invention takes cheap diethylenetriamine and aminodiethanol as starting raw materials, which then undergo simple substitution, cyclization, and alkylation and other reactions as well as the processes of desalination, centrifugation, purification and the like, so that gadobutrol or gadoteridol can be prepared. Specifically, when R1=R2=-CH2OH (ethylene oxide 2, 3-dimethanol), the method can be used for preparing gadobutrol; and when R1=H, R2=-CH3 (propylene oxide), the method can be used for preparing gadoteridol. Compared with prior art, the method in the invention has the advantages of widely available and cheap raw materials, low requirement for equipment, simple technical operation, high total yield of synthesis, and environment friendliness, thus being suitable for large scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of a magnetic resonance imaging contrast agent, in particular to a preparation method of gadobutrol and gadoteridol. Background technique [0002] Magnetic resonance imaging (MRI for short) is a diagnostic technique 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. For more than 30 years since Lauterbur first realized magnetic resonance imaging in 1973, MRI has achieved rapid development and wide application in the fields of medicine, biology, and material science. In the field of diagnosis, MRI is the latest imaging diagnostic technology following CT scanning. It has the advantages of high resolution, good contrast, arbitrary imaging, large amount of information, and no radiation damage. It provides a new type of medical imaging technology for...

Claims

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Application Information

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IPC IPC(8): C07D257/02A61K49/06
Inventor 朱荃石兴华郑兆广欧小敏汤丹王汝上顾斐何宝段婷婷程慧荃黄晓玲黄云斌黄艳霞陈瑜玲
Owner 广州康臣药业有限公司
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