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Preparation method of iopromide intermediate and application thereof

A technology of iopromide and compounds, applied in the field of drug synthesis, can solve the problems of many by-products in the iodination reaction step, unfavorable industrial production, and difficult separation and purification, so as to avoid the generation of diacylated by-products and facilitate separation and purification , Good industrial applicability

Pending Publication Date: 2020-07-14
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 method of iopromide intermediate and application thereof
  • Preparation method of iopromide intermediate and application thereof
  • Preparation method of iopromide intermediate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: the preparation of 2-methoxyacetyl chloride

[0057]

[0058] 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

[0059] Embodiment 2: Preparation of 3-chloroformyl-5-nitrobenzoic acid methyl ester (compound of formula VIII)

[0060]

[0061] 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

[0062] Embodiment 3: Preparation of 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid methyl ester (compound of formula VII-1)

[0063]

[0064] 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, slowly add the formula VIII prepared in Example 2 dropwise For the dichloromethane solution of the compound, the temperature of the feed liquid is controlled not to be higher than -13° C. during the dropwise addition, and the stirring is continued for 0.5 hours after the dropwise addition. After the reaction was finished, 1mol / L dilute hydrochloric acid was added dropwise to adjust the pH to 1-2, stirred for half an hour, warmed up to room temperature, separated, the organic phase was washed with 60mL of water, the aqueous phase was combined, and a mixed solvent of dichloromethane / ethanol was added ( Dichloromethane / ethanol=2:1) ​​(60mL×2) extracted twice, com...

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Abstract

The invention relates to a preparation method of an iopromide intermediate and an application of the iopromide intermediate in preparation of iopromide. The method comprises the step that a compound shown in the formula VI is subjected to a reduction reaction under the action of raney nickel / hydrazine hydrate to obtain a compound shown in the formula V. The reaction is carried out under normal pressure, the operation is simple and safe, the generated intermediate has few impurities, and the method is more suitable for industrial production. When the method is used for preparing iopromide, thegeneration of diacylation byproducts can be avoided, the generation of byproducts can be effectively reduced in the preparation process, the intermediate is easy to separate and purify, and high-purity iopromide can be obtained at high yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for preparing an iopromide intermediate, more specifically to 5-amino-N 1 , N 3 -Bis(2,3-dihydroxypropyl)-N 1 - Process for the preparation of methylisophthalamide and its use for the preparation of iopromide. 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. [...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/40C07C237/46
CPCC07C231/12C07C231/02C07C201/12C07C51/60C07C237/40C07C233/69C07C205/57C07C59/135C07C237/46
Inventor 谭永华郭猛王勇王德发余孔强张喜全江竹莲马嫣琼金宪丹
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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