Efficient contrast agent synthesizing method and application thereof

A synthesis method and contrast agent technology, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of reduced total reaction yield, long reaction route, utilization rate cannot reach 100%, etc.

Active Publication Date: 2019-01-04
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-produ

Method used

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  • Efficient contrast agent synthesizing method and application thereof
  • Efficient contrast agent synthesizing method and application thereof
  • Efficient contrast agent synthesizing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] The preparation of embodiment 1 intermediate mixture

[0196]

[0197] Method 1: Dissolve compound 2 in N,N-dimethylacetamide, under stirring, in order to make the reaction proceed more fully, you can add base to it to neutralize the hydrogen chloride generated in the reaction, and then add 3 -Amino-1,2-propanediol in N,N-dimethylacetamide solution, add and keep warm for 3 to 12 hours, then add dropwise 3-methylamino-1,2-propanediol in N,N-dimethylacetamide Base acetamide solution, after adding, keep warm for 3 to 12 hours, take a sample and measure the area percentage by HPLC. Material ratio and product ratio are shown in Table 1 (compound 2 equivalent is 1):

[0198] Table 1

[0199]

[0200]

[0201] As can be seen from the above table, when the reaction conditions are within the scope of the present invention, the content of one of the compounds of formula (I), formula (II) or formula (III) can be prepared to be greater than 50%, and, in the preferred Wi...

Embodiment 2

[0218] Example 2 intermediate preparation pilot test

[0219] Compound 2 (5.96kg, 10.0mol) was dissolved in N,N-dimethylacetamide, under stirring, in order to make the reaction more fully, tri-n-propylamine (2.87kg, 20.0mol) was added thereto to neutralize Hydrogen chloride generated in the reaction, then added dropwise 3-amino-1,2-propanediol (911g, 10.0mol) in N,N-dimethylacetamide solution, reacted at 25-30°C for 12 hours, and then Add 3-methylamino-1,2-propanediol (2.1kg, 20.0mol) in N,N-dimethylacetamide solution dropwise. After the addition, keep the temperature for reaction for 12 hours. After the reaction is complete, concentrate under reduced pressure. The intermediate mixture obtained is water After dissolving, macroporous adsorption resin column chromatography, HPLC monitors the elution effect, respectively collects formula (I), formula (II), formula (III) compound fractions, and concentrates to obtain formula (I) white solid 768g (see figure 2 , Figure 5 ), the...

Embodiment 3

[0225] Embodiment 3 is synthesized contrast agent by intermediate

[0226] (1) Synthesis of iopromide

[0227] Take the compound of formula (II) (143.8g, 200mmol) into a 1L three-neck flask, add 290mL of ethyl acetate, 45mL of N,N-dimethylacetamide, acetic anhydride (91.8g, 0.9mol) and 4-dimethylaminopyridine (2.44g, 20mmol), magnetic stirring, overnight reaction at room temperature, TLC monitors the reaction until the raw material point and the intermediate state disappear, to obtain 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),2.80~2.83(m,3H),2.03~2.05(m,12H)];

[0228] Then, methoxyacetyl chloride (43.4 g, 400 mmol) was added to the reaction solution of compound 50, and the temperature was raised to reflux for 2-8 hours. TLC monitored the reaction until the raw material point disappeared. After the reaction, cool down to room temperature, add 200mL of puri...

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Abstract

The invention discloses an efficient contrast agent synthesizing method. The method includes the following steps of firstly, preparing an intermediate mixture of a compound shown in the formula (II) and a compound shown in the formula (I) and/or (III); secondly, conducting separating to obtain the compound shown in the formula (II) and the compound shown in the formula (I) and/or (III); thirdly, taking the compound shown in the formula (II) to prepare a contrast agent (iopromide); fourthly, taking the compound shown in the formula (III) to prepare a contrast agent (iobitridol), and/or taking the compound shown in the formula (I) to prepare a contrast agent (iohexol, ioversol, iopentol or iodixanol). In the method, the iodic contrast agent is prepared by synthesizing and separating intermediates in the formula (II) and the formula (I) and/or the formula (III) and using the intermediates as the raw materials, the problem that diacylation byproducts need to be removed in an existing method is effectively solved, all the intermediates are effectively used, efficiency is high, and the actual application prospects are good. The formulas (I), (II) and (III) can be seen in the description.

Description

technical field [0001] The invention belongs to the field of contrast agents, and in particular relates to a high-efficiency contrast agent synthesis method and its application. Background technique [0002] Iodine contrast agent is a common X-ray contrast agent, which is mainly used for imaging of blood vessels, urinary tract and other body cavities. At present, non-ionic iodine contrast agents are mainly used, mainly including iopamidol, iohexol, ioversol, Iopromide, iomeprol, iopentol, iobitol, iotrolan, iodixanol, etc. [0003] [0004] Compared with other non-ionic iodine contrast agents, iopromide has the lowest nephrotoxicity. It was developed by Schering AG of Germany and its trade name is Ultravist. Due to its good safety, it ranks in the forefront of the global contrast agent market, according to THOMSON According to data, the global demand for iopromide in 2012 was 775.2 tons. According to the 2012 financial annual report of Bayer Schering AG, the global Ult...

Claims

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Application Information

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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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