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Preparation method for magnetic resonance imaging contrast medium gadobutrol

A technology of magnetic resonance imaging and gadobutrol, applied in organic chemistry and other directions, can solve the problems of harsh acyl hydrolysis conditions and high temperature of ring-opening reaction, and achieve the effects of low equipment requirements, high total yield, and mild reaction conditions.

Active Publication Date: 2014-03-05
安徽格太信控科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] Patent CN102933562A discloses the invention method of J. Platzek of Bayer Intellectual Property Co., Ltd. Although the method simplifies the synthesis method of EP0596586 in operation, it still fails to change the disadvantages of high ring-opening reaction temperature and harsh acyl hydrolysis conditions.

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  • Preparation method for magnetic resonance imaging contrast medium gadobutrol
  • Preparation method for magnetic resonance imaging contrast medium gadobutrol
  • Preparation method for magnetic resonance imaging contrast medium gadobutrol

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Embodiment 1

[0036] 180.2g (1.0mol) of the compound boron-protected 1,4,7,10-tetraazacyclododecane (I) was dissolved in 800mL of anhydrous tetrahydrofuran, and 45g of NaH (60%, 1.12 mol), warmed up to room temperature and stirred for 0.5h, added 151g (1.05mol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (Ⅱ) in batches, React for about 4h (TLC detects that the raw material (I) disappears, and the developing solvent CH 2 Cl 2 :MeOH=10:1), slowly add 300mL of water to the obtained reaction mixture intermediate (Ⅲ), stir for 30min until the intermediate (Ⅳ) is completely hydrolyzed, add 243g (6.0mol) of sodium hydroxide to the mixed system and 311g (3.31mmol) of chloroacetic acid was reacted at 60°C for 6h to obtain intermediate (Ⅴ), the reaction was lowered to room temperature and adjusted to pH 1-1.5 with concentrated hydrochloric acid, then heated and stirred at 50°C for 3h to reach the 4,4 of intermediate (Ⅴ) - The dimethyl ketal group is completely removed, slowly add 200 g (0.55 m...

Embodiment 2

[0040] 180.2 g (1.0 mol) of the boron-protected 1,4,7,10-tetraazacyclododecane (I) was dissolved in 1000 mL of anhydrous tetrahydrofuran, and 45 g of NaH (60%, 1.12 mol), warmed up to room temperature and stirred for 1.0h, then added 155g (1.1mol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (II) in batches, at room temperature React for about 4h (TLC detects that the raw material (I) disappears, and the developing solvent CH 2 Cl 2 :MeOH=10:1), slowly add 500mL of water to the obtained reaction mixture intermediate (Ⅲ), stir for 30min until the intermediate (Ⅳ) is completely hydrolyzed, add 243g (6.0mol) of sodium hydroxide to the mixed system and 311g (3.31mol) of chloroacetic acid was reacted at 70°C for 6h to obtain intermediate (Ⅴ), the reaction was lowered to room temperature and adjusted to pH 1-1.5 with concentrated hydrochloric acid, and then heated and stirred at 50°C for 3h to reach 4,4 of intermediate (Ⅴ). - The dimethyl ketal group is completely removed, slo...

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Abstract

A preparation method for magnetic resonance imaging contrast medium gadobutrol comprises the following steps: taking THF as a solvent, taking boron-protected 1, 4, 7, 10-tetraazacyclododecane (I) and 4, 4-dimehtyl-3, 5, 8-trioxabicyclo[5.1.0]octane (II) as raw materials, activating the raw materials by sodium hydride and performing ring-opening condensation to obtain an intermediate (III), performing mild hydrolysis to obtain an intermediate (IV), then successively reacting the intermediate (IV) with chloroacetic acid or bromoacetic acid and gadolinium oxide to prepare gadobutrol, performing desalting on the crude product, recrystallizing to obtain gadobutrol pure product. The preparation method comprises the beneficial effects of being mild in reaction condition, high in selectivity, relatively low in apparatus requirement, simple in technological operation, high in total yield, high in product purity, simple in purification, low in environment protection pressure, and relatively suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of gadobutrol, a magnetic resonance imaging contrast agent. Background technique [0002] Rare earths are lanthanide elements in the periodic table of chemical elements, which contain 17 elements in total. Since the 1960s, rare earth compounds have been found to have a series of special medical effects. Great progress has been made in researches on the role of So far, the most widely used clinically is that one of the rare earth elements is the metal gadolinium. The gadolinium-centered complex targeted magnetic resonance technology has become the core of the new magnetic resonance imaging technology produced in recent years. By the beginning of 2013, the FDA Seven gadolinium-containing contrast agents have been approved, including Magnevist, Prohance, Omniscan, Optimark, Multihance, Gadavist, and gadoterate meglumine. [0003] Gadolinium-containing contrast agents have become the most clinically used MRI...

Claims

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Application Information

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IPC IPC(8): C07D257/02
CPCC07D257/02
Inventor 秦华利熊峰张智
Owner 安徽格太信控科技有限公司
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