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Preparation methods of iopromide and intermediate of iopromide

A technology of iopromide and iodination, which is applied to the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, etc., can solve the problems of many by-products in the iodination reaction step, unfavorable industrial production, and difficult separation and purification. , to achieve the effects of easy separation and purification, reduction of by-product formation, and avoidance of diacylated by-products

Inactive Publication Date: 2018-03-09
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Although the above-mentioned route two and three can avoid the generation of the diacylated by-product shown in formula 18, there are many by-products in the iodination reaction step, the purity is low, and the separation and purification are difficult, which is not conducive to industrial production

Method used

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  • Preparation methods of iopromide and intermediate of iopromide
  • Preparation methods of iopromide and intermediate of iopromide
  • Preparation methods of iopromide and intermediate of iopromide

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Embodiment 1: the preparation of 2-methoxyacetyl chloride

[0056]

[0057] 2-Methoxyacetic acid (656.7mmol), dichloromethane (197mL) and DMF (21.9mmol) were added into a 500mL three-neck flask, the reaction solution was cooled to 10°C, and thionyl chloride (525.3mmol ), dropwise, react at room temperature for 12 hours, and concentrate the reaction solution at 25°C to obtain 2-methoxyacetyl chloride.

Embodiment 2

[0058] Embodiment 2: Preparation of 3-chloroformyl-5-nitrobenzoic acid methyl ester (compound of formula VIII)

[0059]

[0060] Add the compound of formula IX (66.62mmol) into a 250mL three-necked flask, add dichloromethane (45mL) and DMF (0.075mL), heat in a water bath at 25°C, disperse for 10 minutes, slowly add oxalyl chloride (99.9mmol) dropwise, and react After the liquid was clarified, continue to stir for half an hour, then concentrate, add dichloromethane (15mL×2) and continue to concentrate twice to obtain a white solid compound 3-chloroformyl-5-nitrobenzoic acid methyl ester, add di Chloromethane (37 mL) was dissolved for use.

Embodiment 3

[0061] Embodiment 3: Preparation of 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid methyl ester (compound of formula VII-1)

[0062]

[0063] Add aminoglycerol (159.9mmol) and absolute ethanol (22.5mL) into a three-neck flask, stir at room temperature to dissolve, then cool the reaction solution to -30°C-20°C, and slowly add the dichloromethane solution of the compound of formula VIII dropwise During the dropping process, the temperature of the feed liquid is controlled not to be higher than -13°C, and the stirring is continued for 0.5 hours after the dropping. After the reaction, add 1 mol / L dilute hydrochloric acid dropwise to adjust the pH to 1-2, stir for half an hour, warm up to room temperature, separate the liquids, wash the organic phase with 60 mL of water, combine the two water phases, add a mixture of dichloromethane / ethanol Extract twice with solvent (dichloromethane / ethanol=2:1) ​​(60mL×2), combine the organic phases, add anhydrous sodium sulfate to dry...

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Abstract

The application of the invention relates to preparation methods of iopromide and an intermediate of the iopromide. The method specifically comprises the following steps: conducting a reduction reaction, an iodination reaction and an acylation reaction on a compound shown in the formula VI to prepare a compound shown in the formula III, and further preparing to obtain the iopromide. The method notonly avoids the generation of double acylation byproducts, but also effectively reduces the generation of byproducts in the preparation process, the intermediate is easy to separate and purify, and ahigh-purity product is obtained at a relatively high yield.

Description

technical field [0001] This application belongs to the field of organic synthesis and medicinal chemistry, specifically related to N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino] -N-methyl-1,3-phthalamide and its intermediates. Background technique [0002] Iopromide (Iopromide) is a non-ionic iodine-containing contrast agent developed by Schering-Plough in Germany. Its chemical name is N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5 -[(methoxyacetyl)amino]-N-methyl-1,3-benzenedicarboxamide, its structure is shown in formula I, it can be used for angiography, renal arteriography, urography, CT contrast Enhanced examination, body cavity display (including arthrography, hysterosalpingography, fistulography). [0003] [0004] US patent US4364921, PCT patent WO2009134030, Chinese applications CN102351735, CN102964269, CN102015624 and the like disclose preparation methods of iopromide. [0005] U.S. Patent No. 4,364,921 discloses three preparation routes...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/46C07C237/42
CPCC07C231/12C07C231/14C07C237/42C07C237/32C07C237/46
Inventor 胡明通郭猛高大志邵磊王笃政
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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