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Preparation method and intermediates of iopromide

A technology of iopromide and dimethylacetamide, 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 increasing costs, reducing the purity of intermediates and final products, and acetyl protecting groups Easy to be taken off, etc.

Active Publication Date: 2017-02-01
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 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
[0012] 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

[0080] Embodiment 1: 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid methyl ester (formula VII-1)

[0081]

[0082]Add 3-methoxycarbonyl-5-nitrobenzoic acid (formula VIII) (50 g, 0.222 mol) into the reaction flask, add 400 mL of dichloromethane to dissolve it, add dropwise oxalyl chloride (28.5 mL, 0.335 mol) at room temperature, Continue to stir for 1-2 hours after the dropwise addition, then concentrate the reaction liquid, redissolve the concentrated liquid with dichloromethane (125 mL), cool the reaction liquid to below 0°C, add dropwise 3-amino-1,2-propanediol ( 48.5g, 0.53mol), the whole dropwise addition process was maintained for 4 hours, stirred for 0.5 hours after the dropwise addition was completed, the reaction solution was washed with water, the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 3-((2,3-di Hydroxypropyl)carbamoyl)-5-nitrobenzoic acid methyl ester (formula VII-1).

[0083] MS m / z[ESI]:298.1[M+1] ...

Embodiment 2

[0084] Embodiment two: N 1 ,N 3 -Bis-(2,3-dihydroxypropyl)-N 1 -Methyl-5-nitroisophthalamide (Formula VI)

[0085]

[0086] The 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid methyl ester (formula VII-1) (29.8g, 0.1mol) obtained in Example 1, 3-methylamino -1,2-Propanediol (15g, 0.14mol) was dissolved in DMF (30mL), reacted at 70-80°C for 5h, and the HPLC purity of the reaction solution was ≥95%.

Embodiment 3

[0087] Example 3: Methyl 3-((2,3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzoate (Formula VII-2)

[0088]

[0089] Add 3-methoxycarbonyl-5-nitrobenzoic acid (formula VIII) (50 g, 0.222 mol) into the reaction flask, add 400 mL of dichloromethane to dissolve it, add dropwise oxalyl chloride (28.5 mL, 0.335 mol) at room temperature, Continue to stir for 1-2 hours after the dropwise addition, then concentrate the reaction solution, redissolve the concentrate with dichloromethane (125mL), cool the reaction solution below 0°C, and add 3-methylamino-1,2-propanediol dropwise (55.7g, 0.53mol), the whole dropwise addition process was maintained for 4 hours, and after the dropwise addition, stirred for 0.5 hour and the reaction ended, the reaction solution was washed with water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 3-((2, Methyl 3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzoate (Formula VII-2).

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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 VIII as a starting raw material, and sequentially carrying out an acylation reaction, a further acylation reation, a bislactonization 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 III 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 bislactonization of the compound represented by the formula V is complete, the di-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, in particular, the present invention relates to N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxy Acetyl)amino]-N-methyl-1,3-benzenedicarboxamide 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-phthalamide, the structure of which is shown in formula I. Iopromide is widely used in the field of X-ray contrast agents. [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] In the above route one, in the process of preparing the compound of formula 3 from the compound of formula 2, the diacylat...

Claims

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Application Information

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IPC IPC(8): C07C237/46C07C231/12C07D317/36C07D327/10C07C233/69C07C231/02
Inventor 郭猛胡明通高大志王笃政
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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