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Process for the manufacture of iohexol

A technology of iohexol and ethanol, which is applied in the field of preparation of iohexol, can solve problems such as increased cost, increased degradation risk of products, time and energy consumption, and achieves the effect of reducing industrial costs

Inactive Publication Date: 2008-12-31
霍维奥恩联合有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Industrially, removing high boiling point solvents is a time-consuming and energy-consuming operation
There is also an increased risk of degradation of the product if high temperatures are involved during this concentration step
Furthermore, from an environmental point of view, both aqueous and organic streams must be treated in the process, which adds significantly to the cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] 5-Acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (200 g, 0.27 mol) was added to 2-(2-methoxy Ethoxy) ethanol (300ml), heated to 44-46°C. At this temperature, a previously prepared solution of sodium hydroxide (15.0 g) and water (18.3 ml) was added and the mixture was heated to 50-52°C until dissolved. The solution was cooled to 29-31°C, and 1-chloro-2,3-propanediol (37.2 g) was added to the solution. The temperature was set at 29-31 °C and stirred until complete reaction (21 h). The reaction was terminated by adding concentrated hydrochloric acid until the pH was 4-5. Part of the solvent was distilled off under vacuum until the water content in the reaction mixture, determined by Karl-Fischer, was 0.04% by weight.

[0019] The solution was added slowly to acetone (1600ml) preheated to 55°C. The suspension was cooled to 0°C-5°C, filtered under nitrogen, the solid was suspended in acetone (800ml) at 0°C, filtered under nitrogen, washed with aceton...

Embodiment 2

[0021] 5-Acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (100 g) was added to 2-(2-methoxyethoxy ) in ethanol (125ml), heated to 44-46°C. At this temperature, a previously prepared solution of sodium hydroxide (7.48g) and water (9.12ml) was added and the mixture was heated to 50-52°C until dissolved. The equipment used to prepare the sodium hydroxide solution was washed with 25 ml of 2-(2-methoxyethoxy)ethanol and added to the reaction mixture. After about 1 hour at 52°C the reaction mixture was heated to 60°C and held at this temperature for 20 minutes after which time dissolution was observed. The solution was cooled to 29-31 °C, then 1-chloro-2,3-propanediol (18.8 g) was added to the reaction mixture. The temperature was set at 29-31 °C and stirred until the reaction was complete (21 h). The reaction was stopped by adding 1.72 ml of concentrated hydrochloric acid. Part of the solvent was distilled off under vacuum until the water content in the react...

Embodiment 3

[0024] Under the experimental conditions as described in Example 2, 100g of 5-acetylamino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is converted into iodide alcohol. After complete conversion the reaction was stopped by adding 0.8 ml of glacial acetic acid.

[0025]Half of the reaction mixture was heated to 60-70°C and 12 ml of solvent were distilled under vacuum. The water content after distillation was 0.16% by weight. The warmed solution of iohexol in 2-(2-methoxyethoxy)ethanol was slowly added to 400 ml of acetone preheated to 50-55° C. while stirring at this temperature for 30 minutes. The suspension was cooled to 0-5°C, filtered under nitrogen, the solid suspended in acetone (200ml) and stored overnight at room temperature. The suspension was cooled to 0-5°C and stirred at this temperature for 30 minutes. The solid was collected by filtration, washed with acetone (124ml) and dried at 60°C. 56.16 g of crude iohexol were obtained with a 2-(2-methoxyet...

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PUM

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Abstract

A process for the production of iohexol comprises alkylating 5-Acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodoisophthalamide using 2(2-methoxy-ethoxy)-ethanol as solvent in the presence of a base, and optionally isolating crude iohexol from the reaction mixture. Preferably, the alkylating agent is 1-chloro-2,3 propanediol and the base is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

Description

technical field [0001] The present invention relates to iohexol (5-[N-(2,3-dihydroxypropyl)-acetylamino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- The preparation method of triiodoisophthalamide). Background technique [0002] Iohexol is one of the most commonly used nonionic iodinated X-ray contrast agents. A multi-step synthesis is involved in the preparation of iohexol. [0003] Various methods for the synthesis of iohexol have been disclosed in the literature. It is known that doses of iohexol as high as, or even higher than, 100 g can be administered for short periods of time. Since it is expected that some residual solvent (even at low levels) will always be left in the final product, it is extremely important to use solvents of low toxicity in the final steps. From an industrial point of view, readily available and low-toxicity solvents are preferred when carrying out the final step of the process. Efficient and industrially feasible purification and crystallization s...

Claims

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Application Information

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IPC IPC(8): C07C233/69
CPCC07C231/08C07C237/46C07C231/02C07C233/69
Inventor J·加林德罗S·马托J·A·M·班达拉W·赫吉
Owner 霍维奥恩联合有限公司
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