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Iodination method for preparing 3,5-disubstituted-2,4,6-triiodo aromatic amine compound

A compound and mixture technology, applied in the field of chlorine-free iodination reagent system, can solve the problem of less mention of iodine recovery and utilization

Inactive Publication Date: 2013-05-08
上海亿脉利医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

From the perspective of industrial production, iodine is a relatively expensive component in the reactant, but the technology disclosed in the cited patent documents seldom mentions the recovery and utilization of iodine, but mostly directly adds sodium sulfite after the reaction is over. Reducing agents such as to eliminate residual iodine

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  • Iodination method for preparing 3,5-disubstituted-2,4,6-triiodo aromatic amine compound
  • Iodination method for preparing 3,5-disubstituted-2,4,6-triiodo aromatic amine compound
  • Iodination method for preparing 3,5-disubstituted-2,4,6-triiodo aromatic amine compound

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preparation example Construction

[0086] An example of the preparation method of the novel iodination reagent system among the present invention is, to the water or recovery reaction mother liquor that is 2.5 / 1 relative to the substrate mass ratio of formula (I), drop into relative to the substrate molar ratio is 1.28 / 1 1 elemental iodine, potassium iodate relative to the substrate molar ratio of 0.59 / 1 and sodium sulfate relative to the substrate molar ratio of 0.12 / 1, and finally the 98% concentration relative to the substrate molar ratio of 0.6 / 1 Add sulfuric acid slowly, stir for 1-1.5h, and the system temperature should always be lower than 50°C, preferably 38-42°C.

[0087] An example of the method for adding the substrate solution or suspension of formula (I) in the present invention to the iodinating reagent system is to continue adding within 4 hours, gradually slowing down the adding speed while maintaining good stirring. The preferred method is to add 3 / 4 of the substrate in the first 2h, and add 1 / ...

Embodiment 1

[0109] Preparation of 5-amino-N, N'-bis[2-hydroxyl-1-hydroxymethyl-ethyl]-2,4,6-triiodo-isophthalamide

[0110] In a 1000mL three-necked flask, add water (100mL), add iodine (45.1g, 0.178mol), potassium iodate (15.6g, 0.073mol), anhydrous sodium sulfate (2.1g, 0.015mol) under mechanical stirring, dropwise 15% sulfuric acid (50 g, 0.076 mol). After stirring at 40°C for 2h, an aqueous solution of 5-amino-N,N'-bis[2-hydroxy-1-hydroxymethyl-ethyl]-isophthalamide (380mL, 0.124mol ), the dropwise addition was completed within 4 hours. After reacting at 80°C for 12 hours, potassium iodate (2.2 g, 0.010 mol) was added, and the reaction was continued for 20 hours while keeping warm. After the reaction is finished, the temperature rises to sublimate the remaining elemental iodine in the reaction system and trap it in the iodine trap.

[0111] Cool down to 20°C and filter with suction. The filter cake was suspended in water (250 mL) and stirred at 80 °C for 1 h. Cool down to 10°C, a...

Embodiment 2

[0115] Preparation of 5-amino-N, N'-bis[2-hydroxyl-1-hydroxymethyl-ethyl]-2,4,6-triiodo-isophthalamide

[0116] In a 1000mL three-necked flask, add water (120mL), add iodine (59.5g, 0.234mol) under mechanical stirring, potassium iodate (25.1g, 0.117mol), anhydrous sodium sulfate (3g, 0.021mol), drop 15 % sulfuric acid (66 g, 0.101 mol). After stirring at 40°C for 2h, an aqueous solution of 5-amino-N,N'-bis[2-hydroxy-1-hydroxymethyl-ethyl]-isophthalamide (473mL, 0.168mol ), the dropwise addition was completed within 4 hours. After reacting at 80° C. for 12 h, potassium iodate (3 g, 0.014 mol) was added, and the reaction was continued for 24 h while keeping warm. After the reaction is finished, the temperature rises to sublimate the remaining elemental iodine in the reaction system and trap it in the iodine trap.

[0117] Cool down to 20°C and filter with suction. The filter cake was suspended in water (600 mL), stirred at 80°C for 2h, cooled to 10°C, stirred for 2h, and fil...

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Abstract

The invention discloses an improved method for preparing 3,5-disubstituted-2,4,6-triiodo aromatic amine represented by a formula (II), wherein R1 and R2 are defined in the instruction, and the compound represented by the formula (II) is a key intermediate for synthesizing iopamidol, iohexol, iodixanol and a series of non-ionic contrast agents. The method comprises: adopting a chlorine-free iodination reagent and a 3,5-disubstituted aromatic amine compound to carry out an iodination reaction to obtain the 3,5-disubstituted-2,4,6-triiodo aromatic amine represented by the formula (II), wherein a mole yield of the iodination reaction can be 89%.

Description

technical field [0001] The invention relates to a large-scale industrial-scale preparation process of polyiodide aromatic compounds. Specifically, the present invention relates to a process suitable for large-scale industrial preparation of 3,5-disubstituted-2,4,6-triiodoaromatic amine compounds. The key point of its innovation lies in the successful development of a novel chlorine-free iodide Reagent system. Since the triiodo aromatic amine compound is a key intermediate for preparing a series of iodo nonionic contrast agents, the present invention belongs to the technical field of chemical pharmaceutical technology, specifically the technical field of industrial production of nonionic contrast agents. Background technique [0002] In the process of using X-ray fluoroscopy for medical diagnosis, a considerable part of the human tissue structure cannot be displayed only by their own density and thickness differences. Therefore, substances that change the X-ray absorption r...

Claims

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Application Information

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IPC IPC(8): C07C237/48C07C231/12
Inventor 胡志奇邢宏灯李磊
Owner 上海亿脉利医药科技有限公司
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