Preparation method of high-purity iopromide

A technology of iopromide and diamide, which is applied in the field of preparation of high-purity iopromide, can solve the problems of low reaction yield, long reaction route, difficult industrialized production and the like, and achieves the effect of high yield

Active Publication Date: 2015-04-01
内蒙古白医制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] These methods require many steps to improve the functional groups to be reacted and steps such as filtration and drying; purification of almost every step of the reaction intermediates, therefore, similar to the preparation method of reaction scheme 1, they have lower reaction yields and longer reaction routes, The post-processing is cumbersome and it is difficult to carry out industrial production
[0026] The United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP) have all formulated strict quality control standards and methods for iopromide, and related impurities have been controlled, such as USP 35 and EP7.5 editions, respectively for the impurities of iopromide raw materials A, impurity B, impurity C, impurity D, impurity E, impurity F, and unknown impurities have been controlled, but according to the above-mentioned technology, the raw material standards such as USP and EP have not been met at present, therefore, it involves the synthesis of iopromide The above-mentioned difficult problem of method needs to effectively remove the by-product of iopromide by improving synthetic method and route, and obtains the high-purity iopromide of high yield

Method used

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preparation example Construction

[0036] The preparation method of iopromide of formula (1) according to the present invention is shown in Reaction Scheme 5 below.

[0037] [Reaction Scheme 5]

[0038]

[0039] step 1

[0040] Wherein, in N, N dimethylformamide solvent, the compound of formula (2) is reacted with methoxyacetyl chloride to synthesize the compound of formula (3), and then in the presence of triethylamine, N, N Dimethylformamide is used as a solvent, and the compound of formula (3) is reacted with 2,3-dihydroxypropylamine to synthesize the compound of formula (4), as shown in Scheme 6.

[0041] [Reaction Scheme 6]

[0042]

[0043] In reaction scheme 6, the 2,3-dihydroxypropylamine used is preferably 0.7-1,0 equivalent, more preferably 0.8 equivalent, then can obtain the compound crude product of formula (1) in reasonable yield, make formula (1) The crude compound produces less by-products.

[0044] step 2

[0045] In the presence of the catalyst pyridine, using dichloromethane as a so...

Embodiment 1

[0052] Embodiment 1: the synthesis of 5-methoxyacetylamino-2,4,6-triiodophthaloyl chloride (formula 3)

[0053] Dissolve 5-amino-2,4,6-triiodo-1,3-phthaloyl chloride (200g, 0.34mol) in N,N-dimethylformamide (400mL), stir to dissolve, at room temperature , to which methoxyacetyl chloride (73.6g, 0.68mol) was added dropwise for 30min, then stirred at room temperature for 6 hours, detected by thin-layer chromatography, developer: methylene chloride: methanol = 5: 1 (V: V), raw material The main spots basically disappeared, and the reaction ended. The reaction solution was poured into ice water (2L), and a large amount of white solid was precipitated, then dichloromethane (1L) was added to dissolve, the water layer was separated, the organic phase was dried overnight with anhydrous magnesium sulfate, and the solvent was spin-off under reduced pressure to obtain a light yellow oil (203.6g, yield 92.8%).

Embodiment 2

[0054] Example 2: N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(2-methoxyacetyl)amino]-N'-methyl Synthesis of crude product of phenyl-1,3-carboxamide (formula 1)

[0055]With the US4364921 method, 5-methoxyacetamido-2,4,6-triiodo-1,3-phthaloyl chloride (203.6g, 0.31mol) was dissolved in N,N-dimethylformamide (250mL) , stirred to dissolve, the mixture was cooled to 0°C, and 3-amino-1,2-propanediol (22.9g, 0.25mol) in N,N-dimethylformamide (50mL) was slowly added dropwise thereto, and the addition was completed gradually After reaching room temperature, it was detected by thin-layer chromatography that the reaction of the raw materials was complete, and the developer: dichloromethane:methanol=5:1 (V:V), and the reaction was terminated. The reaction solution was added to a solution (3 L) of dichloromethane:petroleum ether=1:4 (V / V), and an oily substance gradually precipitated out. The supernatant was poured out and used directly in the next step. The oil was dissolved with ...

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Abstract

The invention relates to a preparation method of a high-purity contrast medium raw material iopromide, wherein byproducts generated in the preparation process can be removed by introducing a compound shown in a formula (19): 5-methoxyl acetamido-2, 4, 6-triiodo isophthalic acid [(2, 3-diacetoxyl-N-methyl propyl)-(2, 3-diacetoxyl propyl)] diamide serving as an intermediate. The invention provides the preparation method of iopromide with high purity.

Description

technical field [0001] The present invention relates to the preparation method of high-purity iopromide, more specifically, relate to by introducing the 5-methoxyacetamido-2 of formula (19), 4,6-triiodoisophthalic acid [(2,3 - a method for the preparation of iopromide with diacetoxy-N-methylpropyl)-(2,3-diacetoxypropyl)] diamide as an intermediate. [0002] [Formula 19] [0003] [0004] According to the present invention, a series of by-products produced during the preparation of iopromide can be easily removed by simply crystallizing the intermediate of formula (19), without requiring a large amount of recrystallization, and high yields can be obtained and high-purity iopromide. Background technique [0005] Iopromide (Iopromide) is a non-ionic iodine-containing contrast agent first developed by Schering, Germany. Its chemical name is: N, N'-bis(2,3-dihydroxypropyl)-2,4,6- Triiodo-5-[(2-methoxyacetyl)amino]-N'-methylphenyl-1,3-carboxamide, the structural formula is: ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/46C07C231/12
Inventor 李科研曹志华胡军刘烽张勇
Owner 内蒙古白医制药股份有限公司
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