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Process for iohexol manufacture

A technology of iohexol and reaction, applied in the field of non-ionic X-CT contrast agent, can solve problems such as difficult to remove, large product loss, etc., achieve prevention of O-alkylation by-products, low production cost, and easy operation safe effect

Active Publication Date: 2007-02-07
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Therefore, it is also necessary to purify the crude iohexol containing O-alkylated by-products and residual reaction solvents, that is, to carry out crystallization or recrystallization again, to obtain higher purity iohexol, due to impurities and crude iohexol The structure is similar, it is difficult to remove by ordinary refining methods, and the product loss is relatively large

Method used

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  • Process for iohexol manufacture
  • Process for iohexol manufacture
  • Process for iohexol manufacture

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Reaction 1: Preparation of 5-acetylamino-2,4,6-triiodo-1,3-benzoyl chloride

[0035] 120 g of 5-amino-2,4,6-triiodo-1,3 benzoyl chloride and 360 ml of dioxane were heated to 40°C-50°C to dissolve completely, and then a small amount of catalyst was added. 17.4 g of acetyl chloride was added dropwise while keeping warm. After the drop was completed, the stirring was continued for 30 minutes, and the temperature was raised to reflux for 4 hours. Part of the solvent was evaporated under reduced pressure, and 800 ml of dichloromethane was added. A solid precipitated overnight, filtered, and dried. 116.8 g of the product was obtained, yield 91%, melting point: 91°C

[0036] Reaction 2: Preparation of 5-acetylamino-2,4,6-triiodo-1,3-aminopropylketal pyridene benzamide

[0037] 128g of 5-acetylamino-2,4,6-triiodo-1,3-benzoyl chloride, 320ml of DMAC, stirred and dissolved, then 60ml of triethylamine was added, and 58g of aminopropyl ketal fork was added dropwise at a temperat...

Embodiment 2

[0043] Put 5-amino-2,4,6-triiodo-1,3 benzoyl chloride (120g) and dioxane (360ml) into a three-neck flask, heat up to 40-50°C and dissolve completely, then add a little catalyst. Acetyl chloride (17.4 g) was added dropwise while keeping warm. After the drop was complete, stirring was continued for 30 minutes, and the temperature was raised to reflux for 4 hours. Part of the solvent was evaporated under reduced pressure, and dichloromethane (800ml) was added. A solid precipitated overnight, filtered, and dried. The product (116.8g) was obtained, yield 91%, melting point: 91°C

[0044] Stir 5-acetylamino-2,4,6-triiodo-1,3-benzoyl chloride, DMA, and triethylamine evenly, cool to 0-5°C, add 3-aminopropaneketal dropwise, and control the dropwise The acceleration is 15-20d / min, the dropping temperature is 0-5°C, the stirring reaction is continued for 1h after the dropping, and the solvent is recovered by distillation under reduced pressure. Purified water was added, and after stir...

Embodiment 3

[0045] Embodiment three: this embodiment reaction 1, reaction 2 are the same as example two, the difference is that in reaction 3, 3-chloro-1,2-propanediol (9.9g) is replaced by 3-chloro-1,2-propanediol Ketoylidene (13.5g) was hydrolyzed after complete reaction to obtain iohexol, and then was removed with isopropanol, frozen and crystallized, overnight, and suction filtered. The product (72.4 g) was obtained in 85% yield.

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Abstract

The invention provides a preparation method for an iohexol of 5-[N-(2, 3-dihydroxypropyl)acetyl]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-3-triiodo-1,3-benzamide, belonging to a non-ionic X-CT contrast agent (organic compound) technology field. The invention improves the existing technology by protecting side-chain hydroxyl with amino-acetonide before N-alkylation so as to avoid O-alkylation at the time of N-alkylation. Positive resin / methanol-water system is used as protection system. The invention greatly reduce main impurity oxygen alkyl compound in iohexol and improve the yield.

Description

technical field [0001] The present invention relates to a kind of iohexol, namely 5-[N-(2,3-dihydroxypropyl) acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4, The production method of 6-triiodo-1,3-benzamide belongs to the technical field of non-ionic X-CT contrast agent (organic compound). Background technique [0002] Iohexol is a non-ionic X-CT contrast agent named OMNIPAQUE that has achieved significant market success. It can be widely used in urography, arteriography, venography, and endoscopic contrast. The preparation of this non-ionic contrast agent includes the preparation of chemicals (primary production) and the formulation of pharmaceutical products (secondary production). Primary production usually includes chemical synthesis (crude iohexol preparation) and a purification stage (crude iohexol purification) and therefore, for the formulation of pharmaceutical products (secondary production), efficient and economical primary production stages are ...

Claims

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Application Information

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IPC IPC(8): C07C237/46C07C231/02
Inventor 叶树祥陈建堂徐成苗
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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