Process for synthesizing diatrizoic acid by using solid-phase load method

A technology of solid-phase loading and diatrizoic acid, which is applied in the preparation of organic compounds, carboxylic acid amides, chemical instruments and methods, etc., can solve the problems of difficult removal of impurities, cumbersome purification steps, and complicated production process of diatrizoic acid. Achieve the effects of short production cycle, high product purity, and avoiding hidden dangers in clinical use

Active Publication Date: 2014-09-10
HUNAN XIANGYIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the disadvantages of complex production process of diatrizoic acid, cumbersome subsequent purification steps, and difficult removal of impurities, and provide a synthetic process for injection-grade products with simple separation and low impurity content

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Put 5 g of 3,5-diaminobenzoic acid, 3.5 g of NaOH, and 10 g of methylol resin (100-200 mesh, loading capacity of 3.0-5.0) into a 100 ml three-necked flask, add 25 ml of toluene, and heat up in an oil bath To 100°C-105°C, react for 4-6 hours, during the reaction process, the water generated by the reaction is separated by a water separator. The reaction was monitored by thin-layer chromatography. After the reaction of 3,5-diaminobenzoic acid was complete, it was cooled to room temperature, filtered, washed with water, washed with 0.1mol / L citric acid, and dried to obtain 14.0 g of the bonded product. The yield was 90%.

[0035] Put 14.0 g of the bonded product, 0.3 g of potassium iodide, and 13.5 g of triethylamine into a 250 ml three-necked flask, add 70 ml of DMF, control the temperature in an ice bath to 0°C to 10°C, and add 15.5g of iodine chloride dropwise into a constant pressure funnel, The dropwise addition was completed within 30 minutes. After reacting for 1-2...

Embodiment 2

[0040] Put 15.2 g of 3,5-diaminobenzoic acid, 10 g of NaOH, and 25 g of methylol resin (100-200 mesh, loading capacity of 3.0-5.0) into a 250 ml three-necked flask, add 75 ml of toluene, and heat up in an oil bath To 100°C-105°C, react for 4-6 hours, during the reaction process, the water generated by the reaction is separated by a water separator. The reaction was monitored by thin-layer chromatography. After the reaction of 3,5-diaminobenzoic acid was complete, it was cooled to room temperature, filtered, washed with water, washed with 0.1mol / L citric acid, and dried to obtain 35.3 g of the bonded product. The yield was 92%.

[0041]Put 35.3g of the bonded product, 0.8g of potassium iodide, and 42g of triethylamine into a 500ml three-neck flask, add 175ml of DMF, control the temperature in an ice bath to 0°C to 10°C, and add 45.6g of iodine chloride dropwise into a constant pressure funnel, 30 The dropwise addition was completed within 1 minute. After reacting for 1-2 hours...

Embodiment 3

[0046] Put 152 g of 3,5-diaminobenzoic acid, 100 g of NaOH, and 250 g of methylol resin (100-200 mesh, loading capacity of 3.0-5.0) into a 3000 ml three-necked flask, add 750 ml of toluene, and heat up in an oil bath To 100°C-105°C, react for 4-6 hours, during the reaction process, the water generated by the reaction is separated by a water separator. The reaction was monitored by thin-layer chromatography. After the reaction of 3,5-diaminobenzoic acid was complete, it was cooled to room temperature, filtered, washed with water, washed with 0.1mol / L citric acid, and dried to obtain 349.2 g of the bonded product. The yield was 91%.

[0047] Put 349.2 g of bonded product, 8.2 g of potassium iodide, and 450 g of triethylamine into a 5000 ml three-necked flask, add 1750 ml of DMF, control the temperature in an ice bath to 0°C to 10°C, and add 460 g of iodine chloride dropwise into a constant pressure funnel, The dropwise addition was completed within 30 minutes. After reacting fo...

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PUM

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Abstract

The invention discloses a process for synthesizing diatrizoic acid by a solid phase method, which belongs to the technical field of medicine synthesis. It solves the problems of complex purification process and difficult removal of impurity residues in the traditional synthesis process. The synthesis steps include: under the action of a base, 3,5-diaminobenzoic acid is bonded to a methylol resin; iodine chloride reacts with the bonded substrate to obtain triiodide through iodination; and then reacts with acetic anhydride The diatrizoic acid bonded resin is obtained through acylation reaction; finally, the diatrizoic acid is obtained after removal by the action of trifluoroacetic acid, and the methylol resin is recovered and reused.

Description

technical field [0001] The invention relates to a process method for synthesizing diatrizoic acid by a solid-phase loading method, which belongs to the technical field of medicine synthesis. Background technique [0002] Diatrizoic acid, whose chemical name is 3,5-diacetamido-2,4,6-triiodobenzoic acid, is a positive contrast agent for X-ray diagnosis and is now included in the "Chinese Pharmacopoeia". It is generally formulated as diatrizoate meglumine, diatrizoate sodium or compound diatrizoate meglumine injection before application. It is suitable for cardiovascular, aortic, various venous, excretory or retrograde urography, etc. It is also used for enhanced scanning of brain or whole body computerized tomography (CT). As a commonly used diagnostic injection API, the impurity content of the product directly affects whether the product can be used. [0003] The traditional synthesis method of diatrizoic acid is included in the "National Compendium of Raw Materials Process...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/54C07C231/12A61K49/00
Inventor 帅放文王向峰章家伟
Owner HUNAN XIANGYIKANG PHARMA
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