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Preparation method of iopromide intermediate

A technology for iopromide and intermediates, applied in the field of preparation of iopromide intermediates, can solve the problems of large amount of organic solvent, low yield, long route, etc.

Active Publication Date: 2022-05-06
CHENGDU BRILLIANT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Compound 3 is obtained by crystallization, extraction, and concentration, and iopromide is obtained by hydrolysis of sodium hydroxide in the process from compound 8 to compound 1. The process is cumbersome, and the total yield of compound 2 to compound 7 is only about 50%.
[0019] It can be seen that the existing synthetic iopromide method has the problems of generating more by-products, cumbersome and complicated operation, low yield, large amount of organic solvent, long route, etc., resulting in the labor cost of the whole preparation process, The economic cost is high and needs to be improved

Method used

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  • Preparation method of iopromide intermediate
  • Preparation method of iopromide intermediate
  • Preparation method of iopromide intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0069] 100g (0.17mol) of the starting material was dissolved by adding 100ml DMA, and 27.3g (0.25mol) of methoxyacetyl chloride was added dropwise at 20°C for about 1 hour, and kept at 20-30°C for 5-8h. Cool down to 5°C, add 1g (0.06mol) of water, slowly add 58.7g (0.42mol) of potassium carbonate, continue to add 400ml of dichloromethane, slowly add 17.8g (0.2mol) of 3-amino-1,2-propanediol dropwise, drop After the addition was completed and the reaction was completed for about 8 hours, the reaction solution was quickly added to 400ml of cold water, crystallized at 0-5°C for 2 hours, filtered, washed with a small amount of water, and dried to obtain 118.1g of compound 4 with a yield of 97.4% and a main peak of 99.4%.

[0070] The obtained compound 4 is characterized by structure:

[0071]

[0072] 1 H NMR (400MHz, DMSO-d 6 )δ10.13 (d, J=58.7Hz, 1H, -NHAr), 8.71 (dd, J=35.9, 29.2Hz, 1H, -NHCO), 4.03 (d, J=2.8Hz, 2H, H-13) ,3.69(h,J=5.4Hz,1H,H-9),3.47(s,4H,H-14andH-8a),3.4...

Embodiment 2

[0075] 100g (0.17mol) of the starting material was dissolved by adding 100ml of DMF, and 27.3g (0.25mol) of methoxyacetyl chloride was added dropwise at 20-25°C for about 1 hour, and kept at 20-30°C for 5-8h. Cool down to 0°C, add 1g (0.06mol) of water, slowly add 58.7g (0.42mol) of potassium carbonate, continue to add 400ml of ethyl acetate, slowly add 17.8g (0.2mol) of 3-amino-1,2-propanediol, dropwise After the addition was completed and the reaction was completed for about 8 hours, the reaction solution was quickly added to 400ml of cold water, crystallized at -5 to 0°C for 2 hours, filtered, washed with a small amount of water, and dried to obtain 115.8g of compound 4, with a yield of 95.5% and a main peak of 99.3%.

Embodiment 3

[0077] 100g (0.17mol) of the starting material was dissolved by adding 100ml of DMA, and 27.3g (0.25mol) of methoxyacetyl chloride was added dropwise at 20°C for about 1 hour, and the reaction was carried out at 25°C for 5-8h. Cool down to 0°C, add 1g (0.06mol) of water, slowly add 58.7g (0.42mol) of potassium carbonate, continue to add 600ml of dichloromethane, slowly add 17.8g (0.2mol) of 3-amino-1,2-propanediol, dropwise After the addition was completed and the reaction was completed for about 8 hours, the reaction solution was quickly added to 600ml of cold water, crystallized at 0-5°C for 2 hours, filtered, washed with a small amount of water, and dried to obtain 116.1g of compound 4 with a yield of 95.7% and a main peak of 99.1%.

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Abstract

The invention discloses a preparation method of an iopromide intermediate, which comprises the following steps: (I) mixing a compound 2, a first solvent and methoxyacetyl chloride, the first solvent being selected from DMA and / or DMF; (II) continuously adding an acid-binding agent and 3-amino-1, 2-propylene glycol into the system after the reaction in the step (I), adding the reaction liquid into a third solvent for crystallization after the reaction is finished, and adding a second solvent into the reaction liquid before or simultaneously adding the reaction liquid into the third solvent. The method has the advantages of efficient and convenient synthesis process, high yield and high product purity, can greatly reduce the production cost, is more suitable for actual production and application, and is applied to preparation of iopromide.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of an iopromide intermediate. Background technique [0002] Contrast agents (also known as contrast agents) are chemicals that are injected (or taken) into human tissues or organs to enhance the effect of image observation. The density of these products is higher or lower than that of the surrounding tissue, and the contrast formed is displayed with certain devices, such as iodine preparations and barium sulfate, which are commonly used in X-ray observation. [0003] Iopromide is a new type of non-ionic low-osmolar contrast agent. Animal experiments have proved that it is suitable for angiography, brain and abdominal CT scan, and urethrography. [0004] It has been reported that multiple synthetic routes and methods can be used to prepare iopromide, as disclosed in U.S. Patent No. 4,364,921 following synthetic routes: [0005] [0006] According to the abov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/14C07C237/46C07C231/02C07C235/16
CPCC07C231/14C07C231/02C07C235/16C07C237/46Y02P20/55
Inventor 黄浩喜张善军商国宁陈祥胡飞马青伟黄金昆谢德建苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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