Process for the preparation of iodinated contrast agent

A technology of compounds and hydroxides, applied in chemical instruments and methods, preparation of carboxylic acid amides, preparation of organic compounds, etc., can solve problems such as impurity characteristics that damage yields

Active Publication Date: 2011-10-12
BRACCO IMAGINIG SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Further, the salts brought by the reaction of excess (S)-[2-(acetoxy)]propionic acid dichloride in the reaction system will likely be filtered together with the product, and thus they may Lead to impurity profiles that compromise overall yield and final product

Method used

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  • Process for the preparation of iodinated contrast agent
  • Process for the preparation of iodinated contrast agent
  • Process for the preparation of iodinated contrast agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Compounds of formula (III) are prepared starting from isolated compound (II) in the presence of calcium hydroxide.

[0081] Calcium hydroxide (12.8 g, 0.173 mol) was slowly added to a solution of compound (II) (120 g, 0.169 mol) in 305 g of DMA with stirring and keeping the temperature below 25°C.

[0082] Further, to the reaction mixture, a solution of 2-amino-1,3-propanediol in DMA (133 g, 28% w / w, 0.406 mol) was added dropwise over a period of about 45 minutes. The mixture was kept at about 30°C for 10 hours until the reaction was complete.

[0083] According to the procedure of Example 3 below, the crude reaction mass containing the derivative of formula (III) can be purified and hydrolyzed.

[0084] HPLC profile of the mixture after treating the sample with NaOH:

[0085] Iopamidol (IV): 97.9%;

[0086] F-Impurities: 0.2%.

Embodiment 2

[0088] Compounds of formula (III) are prepared starting from isolated compound (II) in the presence of sodium hydroxide.

[0089] Sodium hydroxide (13.9 g, 0.346 mol) was slowly added to a solution of compound (II) (120 g, 0.169 mol) in 305 g of DMA with stirring and keeping the temperature below 25°C.

[0090] Further, a solution of 2-amino-1,3-propanediol in DMA (133 g, 28% w / w, 0.406 mol) was added dropwise to the reaction mixture over about 45 minutes. The mixture was maintained at about 30°C for 10 hours until the reaction was complete.

[0091] According to the procedure of Example 3 below, the crude reaction mass containing the derivative of formula (III) can be purified and hydrolyzed.

[0092] HPLC profile of the mixture after treating the sample with NaOH:

[0093] Iopamidol (IV): 97.4%;

[0094] F-impurity: 0.3%.

Embodiment 3

[0096] Iopamidol (IV) is prepared starting from the isolated compound (II) in the presence of calcium hydroxide.

[0097] A solution of 2-amino-1,3-propanediol in DMA (610 g, 28% w / w, 1.87 mol) was added to compound (II) (600 g, 0.845 mol) in DMAC under stirring for about 45 minutes. (1510g) in solution.

[0098] Then, calcium hydroxide (70.0 g, 0.945 mol) was slowly added to the reaction mixture, keeping the temperature below 30°C. The mixture was further maintained at about 30° C. for 10 hours until the reaction was completed.

[0099] The crude reaction mixture was then distilled under vacuum (95 °C, 10 mbar, 7.5 mmHg) to remove most of the solvent until a viscous residue was obtained. The hot residue was then treated with deionized water (1455 g) and the pH was adjusted to 1.7 by adding hydrochloric acid (33 g, 34% w / w).

[0100] The resulting solution was passed through 1500 mL of Na + form of strong cation exchange resin (Dowex C350 from DOW TM ) to remove Ca 2+ io...

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Abstract

The present invention relies on a process for the preparation of non ionic iodinated contrast agents and, in more details, it relates to a process for the preparation of Iopamidol in high yields and with a high degree of purity. In more details, the invention discloses a process for the preparation of a compound of formula (III) comprising the 5 condensation reaction a compound of formula (II) with 2-amino-1,3-propandiol, being said reaction carried out in an aprotic dipolar solvent and in the presence of an alkaline or alkaline rare earth metal oxide or hydroxide.

Description

technical field [0001] The present invention relates generally to a process for the preparation of nonionic iodinated contrast agents, and more particularly it relates to a process for the preparation of iopamidol in high yield and high purity. Iopamidol, as well as other nonionic iodinated contrast agents, are used in the diagnostic field in X-ray imaging. Background technique [0002] N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-1-oxopropyl]-amino]-2,4,6 - Triiodo-1,3-benzenedicarboxamide (please refer to the following formula), commonly known as iopamidol (The Merck Index, XIII Ed., 2001, Nr.5073), which is widely used in diagnostic methods Chemical compounds: [0003] [0004] Various methods are known in the literature for the preparation of iopamidol, e.g. starting from 5-nitroisophtalic acid, contemplated using various reagents and solvent systems, optionally isolating synthetic intermediates and Purify the final product. The 5-nitroisophthalic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02
CPCC07C231/02C07C237/46
Inventor S·切拉焦利G·切尔西罗S·殷坎德拉P·米诺蒂
Owner BRACCO IMAGINIG SPA
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