Energy-saving environment-friendly continuous preparation method of iohexol

An energy-saving and environment-friendly iohexol technology, applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid amides, etc., can solve the problems of high energy consumption and environmental pollution

Inactive Publication Date: 2018-06-22
天津河清化学工业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above method, a large amount of waste water is produced in the second step hydrolysis reaction, and the third step alkylation reaction requires anhydrous as far as possible, so the compound of formula [4] must be washed, filtered, and dried many times, and a large amount of waste water will be generated. waste water, which pollutes the environment a lot, and the process of filtering and drying consumes a lot of energy

Method used

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  • Energy-saving environment-friendly continuous preparation method of iohexol
  • Energy-saving environment-friendly continuous preparation method of iohexol
  • Energy-saving environment-friendly continuous preparation method of iohexol

Examples

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preparation example Construction

[0015] A kind of iohexol [5-[N-(2,3-dihydroxypropyl) acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo -1,3-phthalamide] an energy-saving and environment-friendly continuous preparation method, the steps are as follows:

[0016] ⑴Acylation reaction: Formula [2] compound 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-1,3-phthalamide and ester The anhydride is reacted under the environment of hydrochloric acid to obtain the compound of formula [3] 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3-diacetoxypropyl)-1,3 - phthalamide;

[0017] (2) transesterification reaction: the compound of formula [3] reacts with liquid alcohol under appropriate conditions to obtain the compound of formula [4] 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3 -dihydroxypropyl)-1,3-benzenedicarboxamide.

[0018] (3) Alkylation reaction: the compound of formula [4] reacts with 3-chloro-1,2-propanediol under the conditions of a mixture of methanol and sodium methylate to obtain the compound of formula [...

Embodiment 1

[0030] A continuous preparation method for energy saving and environmental protection of iohexol, the specific steps are as follows:

[0031] ⑴Acylation reaction: Formula [2] compound 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-1,3-phthalamide and ester For anhydride reaction, raise the temperature to 65°C-70°C and keep it warm for 2-6 hours. TLC monitors the completion of the reaction of the raw materials. Concentrate under reduced pressure and dry to obtain the sticky substance formula [3] compound 5-acetylamino-2,4,6-triiodo- N,N'-bis(2,3-diacetoxypropyl)-1,3-benzenedicarboxamide;

[0032] (2) Transesterification reaction: In the formula [3] compound 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3-diacetoxypropyl)-1,3-benzenedi Add methanol to formamide, use concentrated hydrochloric acid as a catalyst, and rectify for 3 hours. Light components such as methyl acetate are extracted from the gas phase, and the by-product methyl acetate is obtained by separation and purifica...

Embodiment 2

[0036] A continuous preparation method for energy saving and environmental protection of iohexol, the specific steps are as follows:

[0037] 2. (1) Starting with the compound 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide of formula [2] As a raw material, take 30g of the compound and add it to a 250ml reaction flask, add 120ml of acetic anhydride and dropwise add 0.1g of concentrated hydrochloric acid. The temperature is raised to 65°C-70°C and the temperature is kept for 26h. The conversion rate of the raw material is not less than 97% as monitored by TLC. Concentrate under reduced pressure to remove part of acetic anhydride and acetic acid to obtain a mixture of the compound of formula [3], acetic anhydride and acetic acid. No need for purification, directly proceed to the next step reaction;

[0038] (2) Lower the temperature of the sticky substance formula [3] mixture obtained in the previous step to 70°C, slowly add anhydrous methanol under...

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Abstract

The invention relates to an energy-saving environment-friendly continuous preparation method of iohexol. The preparation method comprises the following steps: (1) acylation reaction: carrying out a reaction on a compound of a formula [2] with acetic anhydride in an environment of hydrochloric acid to obtain a compound of a formula [3]; (2) transesterification: carrying out a reaction on the compound of the formula [3] with a small-molecule liquid alcohol under an appropriate conditions to obtain a compound of a formula [4]; (3) alkylation reaction: carrying out a reaction on the compound of the formula [4] with and 3-chloro-1,2-propanediol under a condition of a mixed solution of methanol and sodium methoxide to obtain an iohexol crude product; and (4) purification: purifying the iohexol crude product to obtain an iohexol pure product. According to method, the transesterification reaction is carried out on the liquid alcohol with 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3-diacetoxypropyl)-1,3-phthalamide, then the alkylation reaction is carrred out with the alkylation reagent 3-chloro-1,2-propanediol in a methanol solution of the sodium methoxide, and the obtained iohexol crude product is purified to obtain the pure iohexol product.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to an energy-saving and environment-friendly continuous preparation method of iohexol. Background technique [0002] Iohexol (Iohexol) belongs to the second generation of non-ionic monomeric contrast agent, and its trade name is "Omnipaque". It was developed and listed by the Norwegian company Nycomed in the early 1980s. In 1982, Omnipaque was first launched in Norway and Sweden. In 1985, it was approved by the US FDA to be launched in the United States. With the rapid development of imaging diagnostic equipment in the world, X-CT contrast agents based on iodine contrast agents have achieved unprecedented development. Iohexol has many advantages such as high safety, high contrast, low osmotic pressure and low human toxicity. It has become the best-selling contrast agent in the international market, and has become the "gold standard" on which the medical community ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/08C07C237/46
CPCC07C231/02C07C231/08C07C231/12C07C237/46
Inventor 刘国平李毅
Owner 天津河清化学工业有限公司
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