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Gadobutrol intermediate, preparation method thereof and application of gadobutrol intermediate in preparation of gadobutrol

A technology of gadobutrol and intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of low product purity, poor economy, and high cost, and achieve the effects of high product purity, high total yield, and reasonable route design

Active Publication Date: 2022-01-04
SUZHOU BAILINGWEI HYPERFINE MATERIAL
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Problems solved by technology

[0011] In view of the above-mentioned problems in the prior art, the present invention provides a gadobutrol intermediate and its preparation method and its application in the preparation of gadobutrol, which are used to solve the problems existing in the synthesis process of gadobutrol in the prior art. Problems such as poor economy, high cost, low product purity and low yield

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  • Gadobutrol intermediate, preparation method thereof and application of gadobutrol intermediate in preparation of gadobutrol
  • Gadobutrol intermediate, preparation method thereof and application of gadobutrol intermediate in preparation of gadobutrol

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Experimental program
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Effect test

Embodiment 1

[0035]

[0036] Step (1): Preparation of formula 2 compound 1,2-bis(4,5-dihydro-1H-imidazol-1-yl)ethane

[0037] Maintaining a slight positive pressure of nitrogen, add 600mL of 2-methyltetrahydrofuran, 146.24g (1.0mol) of triethylenetetramine and 222.85g (2.1mol) of trimethyl orthoformate to the 2L reaction flask in sequence. After the addition, Stir well; the temperature of the reaction solution is raised to 80°C for reaction, and the reaction solution appears to reflux at this time. The reaction solution was kept at 80° C. to continue the reaction for 5 hours, and the reaction was completed.

[0038] The reaction solution was cooled and crystallized to obtain 158.25 g (0.952 mol) of a white solid product.

[0039] Yield 95.2%, HPLC purity 99.2%, 1 H NMR (400 MHz, CDCl3): δ6.72 (s, 2H), 3.74 (7, 4H), 3.11-3.24 (m, 8H).

[0040]Step (2): Formula 3 compound 1,2,2a1,3,4,6,7,8-octahydro-5H-2a,4a,6a,8a-tetraazol[fg]acenaphthylen-6a-ium Preparation of bromide salt

[0041]...

Embodiment 2

[0063]

[0064] Step (1): Preparation of formula 2 compound 1,2-bis(4,5-dihydro-1H-imidazol-1-yl)ethane

[0065] Maintaining a slight positive pressure of nitrogen, add 300mL of ethylene glycol dimethyl ether, 146.24g (1.0mol) of the compound of formula 1 triethylenetetramine and 370.5g (2.5mol) of triethyl orthoformate to the 1L reaction flask in sequence. , stir well; the temperature of the reaction solution was raised to 85°C for reaction, at which time the reaction solution appeared to reflux. The reaction solution was kept at 85° C. to continue the reaction for 7 hours, and the reaction was completed.

[0066] The reaction solution was cooled and crystallized to obtain 150.44 g (0.905 mol) of a white solid product.

[0067] Yield 90.5%, HPLC purity 99.4%, 1 H NMR (400MHz, CDCl3): δ 6.72 (s, 2H), 3.73 (7, 4H), 3.11-3.24 (m, 8H).

[0068] Step (2): Formula 3 compound 1,2,2a1,3,4,6,7,8-octahydro-5H-2a,4a,6a,8a-tetraazol[fg]acenaphthylen-6a-ium Preparation of bromide s...

Embodiment 3

[0090]

[0091] Step (1): Preparation of formula 2 compound 1,2-bis(4,5-dihydro-1H-imidazol-1-yl)ethane

[0092] Maintaining a slight positive pressure of nitrogen, add 500mL tetrahydrofuran, 146.24g (1.0mol) triethylenetetramine and 180.15g (3.0mol) methyl formate to the 2L reaction flask in sequence. After the addition, stir well; the temperature of the reaction solution is raised Reaction was carried out at 66°C, and the reaction solution was refluxed at this time. The reaction solution was kept at 66° C. to continue the reaction for 5 hours, and the reaction was completed.

[0093] The reaction solution was cooled and crystallized to obtain 152.60 g (0.918 mol) of a white solid product.

[0094] Yield 91.80%, HPLC purity 99.4%, 1 H NMR (400MHz, CDCl3): δ6.71 (s, 2H), 3.73 (7, 4H), 3.11-3.24 (m, 8H).

[0095] Step (2): Formula 3 compound 1,2,2a1,3,4,6,7,8-octahydro-5H-2a,4a,6a,8a-tetraazol[fg]acenaphthylen-6a-ium Preparation of Chloride

[0096] Add 600mL of acetoni...

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Abstract

The invention discloses a gadobutrol intermediate, a preparation method thereof and application of the gadobutrol intermediate in preparation of gadobutrol. The gadobutrol intermediate is represented by a chemical formula 4 in the specification. The invention also discloses a method for preparing gadobutrol by using the gadobutrol intermediate. The method is reasonable in route design, low in raw material price, high in total yield, high in product purity, low in purification cost and good in economical efficiency, and can fully meet the requirements of industrial production of products.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a gadobutrol intermediate, its preparation method and its application in the preparation of gadobutrol. Background technique [0002] Gadobutrol is an extracellular distribution, non-tissue-specific, electrically neutral, non-ionic, water-soluble gadolinium-based contrast agent (GBCA), which can enhance tissue magnetic resonance imaging (Magnetic resonance imaging). Resonance Imaging (MRI for short) contrast effect, commonly used in MRI examination of brain, spinal cord, liver and other body parts. Gadobutrol has the advantages of high relaxivity, good stability, low viscosity and permeability, etc. It is mainly cleared by glomerular filtration and has low toxicity. Its high-concentration preparation has unique advantages in MRI imaging. [0003] The molecular formula of gadobutrol is C18H31GdN4O 9 , which is composed of gadolinium (Ⅲ) ion and m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22C07D257/02
CPCC07D487/22C07D257/02
Inventor 龙韬张军陈丕证邹增龙
Owner SUZHOU BAILINGWEI HYPERFINE MATERIAL
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