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A kind of synthetic method and application of contrast agent intermediate

A technology for intermediates and contrast agents, applied in the field of synthesis of contrast agent intermediates, can solve the problems of unqualified color of finished products, long reaction routes, recovery and reuse of lost iodine, etc., and achieve simple routes, high separation and purification efficiency, and simple operation Effect

Active Publication Date: 2021-06-11
XILING LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0048] 2) The post-iodination route often has a relatively long reaction route in order to eliminate the influence of diacylation by-products before iodation, thereby causing the overall reaction yield to decrease;
[0049] 3) The closer the iodine step is to the finished product step, the easier it is to cause the risk of unqualified color of the finished product
[0051] 1) Since iodine is introduced into the reaction step earlier, the loss of iodine will be caused in the follow-up reaction, thereby increasing the cost;
[0052] 2) in the process of removing diacylated by-products, the loss of iodine will inevitably be caused. Although many documents have mentioned the recovery and reuse of lost iodine, its utilization rate can not reach 100%, so it will still cause iodine loss;
Up to now, the problem of diacylated impurities has not been effectively solved in the synthesis process of iopromide, resulting in high synthesis cost, especially in China, importing iopromide is more cost-effective than self-production, and German Schering AG The iopromide injection produced by the company is currently the only iopromide product approved by China CFDA

Method used

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  • A kind of synthetic method and application of contrast agent intermediate
  • A kind of synthetic method and application of contrast agent intermediate
  • A kind of synthetic method and application of contrast agent intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Example 1 Preparation of Intermediate Mixture

[0196]

[0197] Method 1: The compound 2 is dissolved with N, N-dimethylacetamide, stirred, in order to make the reaction more fully proceed, the base can be added thereto, the hydrogen chloride formed in the neutralization reaction, then add 3 thereof. - N, N-dimethylacetamide solution of amino-1,2-propanediol, 2 ~ 12 hours of additional insulation reaction, then add 3-methyl amino-1,2-propanediol N, N-dimethyl The base of the aceralamide solution, the additional insulation reaction for 3 to 12 hours, and the amount of the Sampling HPLC was measured. The material ratio and product ratio are shown in Table 1 (2 equivalents of Compound 2):

[0198] Table 1

[0199]

[0200]

[0201] As can be seen from the above, when the reaction conditions are in the range of the present invention, one of the compounds of formula (I), the formula (II) or the formula (III), and in the preferred In the range, one of the compounds of formu...

Embodiment 2

[0218] Example 2 Intermediate system preparation

[0219] Compound 2 (5.96 kg, 10.0 mol) was dissolved with N, N-dimethylacetamide, stirring, in order to make the reaction performed more sufficiently, add triamine (2.87 kg, 20.0 mol), neutralized Hydrogen chloride produced in the reaction, then adding 3-amino-1,2-propylene glycol (911 g, 10.0 mol) of N, N-dimethylacetamide solution, adding 25 to 30 ° C for 12 hours, then then 3-methylene-1,2-propylene glycol (2.1 kg, 20.0 mol) of N, N-dimethylacetamide solution was added dropwise, and it was added for 12 hours, and the reaction was concentrated, and the resulting intermediate mixture was concentrated. After dissolving, the macroporous adsorption resin column chromatography, HPLC monitors elution effect, collected in formula (I), formula (II), formula (III), concentrated formula (I) white solid 768g (see figure 2 , Figure 5 The mass spectrometry and hydrogen spectrum data are as follows:

[0220] MS (ESI +): 705.8 [M + 1] + , 1 H N...

Embodiment 3

[0225] Example 3 Synthesis of Contrast

[0226] (1) Synthesis of iodobromide

[0227] The compound (II) compound (143.8 g, 200 mmol) was added to 1 L of three bottles, and 290 ml of ethyl acetate, 45 mln, N-dimethylacetamide, acetic anhydride (91.8 g, 0.9 mol) and 4-dimethylaminopyridine were added. (2.44 g, 20 mmol), magnetic stirring, room temperature reactions overnight, TLC monitoring reaction to the raw material point and the intermediate state disappeared, obtained compound 50, [ 1 H NMR (400MH Z DMSO-D6): Δ8.61 ~ 8.75 (m, 1H), 5.56 (S, 2H), 5.29 (BRS, 1H), 5.08 (BRS, 1H), 4.31 ~ 4.40 (m, 2H), 4.16 ~ 4.22 (M, 2H), 3.69 ~ 3.77 (m, 1H), 3.31 ~ 3.61 (m, 3H), 2.80 ~ 2.05 (m, 3H), 2.03 ~ 2.05 (m, 12H)];

[0228] The reaction solution to the compound 50 was added to methoxyacetyl chloride (43.4 g, 400 mmol), and the heated reflux reaction was 2-8h, and TLC was monitored to the reactive to the material point disappeared. After completion of the reaction, it was lowered to room temp...

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Abstract

The invention discloses a high-efficiency synthesis method of a contrast agent, the steps are as follows: (1), preparing an intermediate mixture of a compound represented by formula (II) and a compound represented by formula (I) and / or formula (III); (2) ), separating and obtaining the compound shown in the formula (II) and the compound shown in the formula (I) and / or formula (III); (3), taking the compound shown in the formula (II) to prepare the contrast agent iopromide; (4) 1. Taking the compound represented by formula (III) to prepare the contrast agent iohexol, ioversol, iopentol or iodixanol; The method of the present invention synthesizes and separates the intermediate formula (II) and formula (I) and / or formula (III), and then prepares the iodine contrast agent with the intermediate as a raw material, which effectively overcomes the need to remove diacyl The problem of chemical by-products is eliminated, all intermediates are effectively utilized, the efficiency is high, and the practical application prospect is good.

Description

Technical field [0001] The present invention belongs to the field of contrast agents, and more particularly to the synthesis method of contrast agent intermediate and its application thereof. Background technique [0002] Iodine production agent is a common X-ray contrast agent, mainly used in angiography of blood vessels, urinary tract, etc., which is mainly used to use nonionic iodine iodine artifacts, mainly iodopane, iodate, iodine, Iodopodamine, iodineme, iodine spray, iodine, iodine, iodis, and the like. [0003] [0004] Compared to other nonionic iodine production agents, iodine propamine has the lowest nephrotoxicity, developed by Germany, and trade names Ultravist. Due to its good safety, sales in the global contrast agent market is rampage, according to THOMSON Data, its demand for global iodine propurlamine in 2012 is 775.2 tons. According to Bayer's 2012 Financial Annual, the global Ultravist sales is 324 million euros, an increase of 2.53% over the previous year,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/02C07C231/24C07C231/12C07C237/46
CPCC07C231/02C07C231/12C07C231/24C07C237/46
Inventor 吴成龙黄金昆龚家福刘劲菲刘芍利孙健谢德建
Owner XILING LAB CO LTD
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