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Preparation method and intermediates of iopromide

An iopromide and compound technology, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, etc., can solve the problem that acetyl groups are easily removed, acetyl protecting groups are easily removed, and are unfavorable for industrial production. And other issues

Active Publication Date: 2017-02-01
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0013] The above-mentioned route two can avoid the generation of the diacylated by-product shown in formula 18, but in the process of preparing the compound of formula 8 from the compound of formula 7, it is easy to generate the product of incomplete acetylation of four hydroxyl groups, and it is difficult to separate and purify, thereby reducing Purity of follow-up intermediates and final products; and during the iodination reaction process of the compound of formula 10 prepared from the compound of formula 9, the acetyl protecting group is easily removed, thereby reducing the yield and increasing the cost, which is not conducive to industrial production
[0014] The above route three can also avoid the generation of diacylated by-products shown in formula 18, but in the iodation reaction process, the acetyl group of the compound of formula 13 is also very easily removed

Method used

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  • Preparation method and intermediates of iopromide
  • Preparation method and intermediates of iopromide
  • Preparation method and intermediates of iopromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: Preparation of 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid (Formula III-1)

[0093]

[0094] Add 3-methoxycarbonyl-5-nitrobenzoic acid (Formula II, 45g, 0.2mol) into the reaction flask, add acetonitrile (180mL) to dissolve it, then add 3-amino-1,2-propanediol (54.6g, 0.6mol), the temperature of the reaction solution was raised to 75-80°C, and the reaction was carried out for 7 hours. After the reaction, the lower layer of the reaction solution was added to 500ml of 1N hydrochloric acid, crystallized overnight at 0-10°C, filtered, and the filter cake was washed once with an appropriate amount of water and ethyl acetate to obtain 3-((2,3-dihydroxy Propyl)carbamoyl)-5-nitrobenzoic acid (Formula III-1, 46.6g), yield 82%, purity ≥ 99%.

Embodiment 2

[0095] Example 2: Preparation of 3-nitro-5-(((2-oxo-1,3-dioxolan-4-yl)methyl)carbamoyl)benzoic acid (Formula IV-1)

[0096]

[0097] Dissolve 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid (Formula III-1, 28.4g, 0.1mol) in DMF (60mL), then add triethylamine (10.1g, 0.1mol), the temperature of the reaction solution was cooled to 0°C, and then CDI (24.3g, 0.15mol) was added in batches, the reaction solution was warmed to room temperature, and reacted for 1 hour. After the reaction, the reaction solution was added to 500ml of 1N hydrochloric acid for precipitation, filtered, and the filter cake was washed once with water to obtain 3-nitro-5-(((2-oxo-1,3-dioxolan-4-yl) Methyl)carbamoyl)benzoic acid (Formula IV-1, 19.2g), the yield is 62%, and the purity is ≥98%.

[0098] MS m / z[ESI]:311.0[M+1] + .

Embodiment 3

[0099] Embodiment three: N 1 -(2,3-Dihydroxypropyl)-N 1 -Methyl-5-nitro-N 3 Preparation of -((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide (formula Ⅴ-1)

[0100]

[0101] Add 3-nitro-5-(((2-oxo-1,3-dioxolan-4-yl)methyl)carbamoyl)benzoic acid (formula IV-1, 31g, 0.1mol ), added dichloromethane (100mL) to dissolve it, the reaction solution was cooled to 0°C, and oxalyl chloride (19.05g, 0.15mol) was added dropwise. The solution was concentrated, and the concentrate was redissolved with dichloromethane (100 mL). Dissolve 3-methylamino-1,2-propanediol (26.25g, 0.25mol) in ethanol (50mL), and add the above reconstituted acid chloride solution dropwise at -10°C. The whole dropping process is maintained for 2 hours, and the dropping is completed Stirring was then continued for 0.5 hours. After the reaction, the reaction solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain N 1 -(2,3-D...

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Abstract

The present invention relates to a preparation method and intermediates of iopromide. The method specifically comprises: adopting a compound represented by a formula II as a starting raw material, and sequentially carrying out an acylation reaction, a lactonization reaction, a further acylation reaction, a reduction reaction, an iodination reaction, a re-acylation reaction and a final hydrolysis reaction to obtain the iopromide represented by a formula I, wherein a compound represented by a formula VII and a compound represented by a formula V are introduced as the intermediates so as to avoid the generation of the bismer by-product, the lactone ring is not easily subjected to ring opening removing during the iodination reaction process, and the introduced intermediates are easy to separate and purify, such that the high-purity iopromide can be prepared in the high-yield manner.

Description

technical field [0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, specifically, the present invention relates to: N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxy The preparation method of acetyl) amino]-N-methyl-1,3-benzenedicarboxamide and its intermediate. 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-phthalamide, the structure of which is shown in formula I. Iopromide is widely used in the field of X-ray contrast agent. [0003] [0004] U.S. Patent No. 4,364,921 discloses three preparation methods of iopromide, and the reaction scheme is as follows: [0005] Route 1: [0006] [0007] Route two: [0008] [0009] Route three: [0010] [0011] In the above route one, in the process of preparing the compou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/46C07C231/12C07D317/36C07D327/10
Inventor 郭猛胡明通高大志王笃政
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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