Preparation method of iohexol hydrolysate

A technology of iohexol hydrolyzate and iodide, which is applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problems of high preparation cost, high equipment requirements, and many iodides, and achieve the goal of reaction Fewer by-products, low reaction temperature, and high reaction yield

Pending Publication Date: 2022-07-12
安庆朗坤药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are two main ways to prepare iohexol hydrolyzate: one is to use 5-amino-2,4,6-triiodoisophthaloyl chloride (37441-29-5) as raw material for acetylation reaction with acetyl chloride, and then Under the action of an acid-binding agent, react with aminoglycerin to prepare iohexol hydrolyzate, but this route uses 2,4,6-triiodoisophthaloyl chloride as a raw material, the preparation cost is high, and the reaction route has produced by-products such as sulfur dioxide, It has high requirements on equipment, and the preparation process needs to use acid-binding agents such as triethylamine, which is not friendly to the environment; another method is to use iodide (76801-93-9) as a raw material, react with acetic anhydride, and hydrolyze after the reaction is completed. Iohexol hydrolyzate, but due to the weak activity of acetic anhydride, the reaction requires a large amount of acetic anhydride as a solvent, the reaction time is longer, the unreacted iodide is more, and the yield of post-treatment products is low, which is also unfavorable for large-scale industrial application

Method used

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  • Preparation method of iohexol hydrolysate
  • Preparation method of iohexol hydrolysate
  • Preparation method of iohexol hydrolysate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 46g DMAC (N,N-dimethylacetamide, the same below) into a 500ml reaction flask, stir, add 35.3g (0.05mol) iodide, cool down to 5°C, slowly add 35.3g (0.45mol) acetyl chloride dropwise, The dropwise addition was completed in 30 minutes, and the temperature during the dropwise addition did not exceed 20 °C. After the addition was completed, the mixture was stirred for 30 minutes, heated to 50 °C, and kept stirring for 4 hours. HPLC detection showed that the residual raw material was less than 2%; then 100 ml of methanol and 100 ml of water were added. Incubate the reaction at 70°C for 12h, then concentrate under reduced pressure to remove methanol, cool to 5°C, keep stirring for 8h, suction filter, wash the filter cake with water, and blow dry at 60°C for more than 12h to obtain off-white solid iohexol hydrolyzate (II) 15.1 g, the yield is 40.3%, and the purity is 97.66%.

[0031] The purity detection method is the same as the central control method: liquid chromatograp...

Embodiment 2

[0034] Add 46g of DMAC to a 500ml reaction flask, stir, add 35.3g (0.05mol) of iodide, cool down to 5°C, slowly add 35.3g (0.45mol) of acetyl chloride dropwise, complete the dropwise addition in 30 minutes, and the temperature during the dropwise addition does not exceed 20 ℃, the addition was completed, stirred for 30 minutes, heated to 50 ℃, kept stirring for 6 hours, detected by HPLC, the reaction of the raw materials was complete, then added 100 ml methanol, kept the reaction at 70 ℃ for 12 hours, cooled to 5 ℃, kept stirring for 8 hours, suction filtration, filter cake After washing with a little water, air drying at 60°C for more than 12 hours to obtain 31.5 g of off-white solid iohexol hydrolyzate (II) with a yield of 84.2% and a purity of 99.41%. The chromatogram of the iohexol hydrolyzate obtained in this example turu figure 2 shown.

Embodiment 3

[0036] 1) Add 46g of organic solvent (DMAC) to a 500ml reaction flask, stir, add 35.3g (0.05mol) of iodide, cool down to 5°C, slowly add 35.3g (0.45mol) of acetyl chloride dropwise, complete the dropwise addition in 30 minutes, dropwise During the addition, the temperature did not exceed 20 °C. After the addition was completed, the mixture was stirred for 30 minutes, heated to 55 °C, kept stirring for 6 h, and detected by HPLC. There was almost no raw material remaining; in the specific implementation, the molar ratio of acetyl chloride and iodide (I) was controlled. Within the range of 5.5-10:1, the purpose of the invention can be achieved.

[0037] 2) Cool down to 5°C, then dropwise add 235g of 16% (0.94mol) sodium hydroxide solution, after adding, pH13.4, 45°C for 2 hours;

[0038] 3) Cool down to 5°C, adjust the pH of the solution to 5.8 with 37% acid (hydrochloric acid is used in this example, and in the specific implementation, at least one of hydrochloric acid, sulfuric...

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Abstract

The invention provides a preparation method of iohexol hydrate, which comprises the following steps: by taking iodide and acetyl chloride as raw materials, after acetylation reaction is completed, hydrolyzing under an alkaline condition, and then adjusting acid to obtain iohexol hydrolysate; the method is convenient to operate, mild in reaction condition, free of separation in the middle process, high in yield, high in purity and suitable for large-scale industrial production, and preparation is completed through a one-pot method.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a pharmaceutical intermediate iohexol hydrolyzate. Background technique [0002] Iohexol, the chemical name is 5-[acetyl [0003] (2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, It is a widely used non-ionic contrast agent raw material. Iohexol is usually passed through the pharmaceutical intermediate iohexol hydrolyzate 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3- Therefore, the preparation of high-purity iohexol hydrolyzate is of great significance to obtain iohexol. [0004] At present, iohexol hydrolyzate is mainly prepared in two ways: one is to use 5-amino-2,4,6-triiodoisophthaloyl chloride (37441-29-5) as raw material for acetylation reaction with acetyl chloride, and then in Under the action of acid binding agent, react with aminoglycerol to prepare iohexol hydr...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C231/12C07C237/46
CPCC07C231/02C07C231/12C07C237/46
Inventor 岳永力沈艳阳饶经纬顾建军鲁飞林立朱敏
Owner 安庆朗坤药业有限公司
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