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Synthesis of iodixanol in water

A technology of iodine and triiodophenyl is applied in the field of synthesizing iodixanol in water, and can solve the problems of low concentration and high impurity content

Active Publication Date: 2015-09-02
GE HEALTHCARE AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the concentration of Compound A in water is low and the amount of impurities in the final product is high

Method used

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  • Synthesis of iodixanol in water
  • Synthesis of iodixanol in water
  • Synthesis of iodixanol in water

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[0021] The most important impurities in reactions with regard to work-up importance are the so-called backpeaks. The term refers to retention times in reverse phase HPLC where the latter peak has a slightly longer retention time than iodixanol itself. Most of the back peaks are trimers or O-alkylated dimers. Two examples are as follows:

[0022]

[0023] primary (primary) O-alkyl iodixanol

[0024]

[0025] Iodixanol Primary O-Alkyl Trimer

[0026] Other important by-products are eg iohexol and N-acetylcyclized iodixanol, the structures of which are shown below. Iohexol is relatively easy to remove during the subsequent crystallization of iodixanol, even when it is present at a few weight percent.

[0027]

[0028] N-acetyl cyclized iodixanol

[0029]

[0030] iohexol

[0031] Typical selectivities required to enable economically viable work-up and obtain the desired product quality are 50-60% conversion of Compound A to iodixanol with no more than 2% of the ...

Embodiment 1

[0049]Dissolve sodium hydroxide pellets (1.19eq.) in water (250ml), add 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo - Isophthalamide (compound A) (50 g). The pH was adjusted from 12.7 to 12.2 with 2M hydrochloric acid, the mixture was cooled to 20°C, and epichlorohydrin (0.27eq) was added in 3 portions over 70 minutes. HPLC analysis after 48 hours showed the following composition: 43.5% iodixanol, 0.8% back peak and 5.1% iohexol.

Embodiment 2

[0051] Dissolve sodium hydroxide pellets (1.19eq.) in water (150ml), add 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo - Isophthalamide (compound A) (50 g). The pH was adjusted from 12.7 to 12.2 with 2M hydrochloric acid, the mixture was cooled to 20°C, and epichlorohydrin (0.27eq) was added in 3 portions over 70 minutes. HPLC analysis after 24 hours showed the following composition: 45.6% iodixanol, 1.4% back peak and 4.6% iohexol.

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Abstract

This invention relates to the synthesis of iodixanol (1,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), more specifically to the dimerisation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide with water as solvent.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to US Provisional Application No. 61 / 227,094, filed July 21, 2009, the entire disclosure of which is incorporated herein by reference. technical field [0003] The present invention relates to iodixanol (1,3-bis(acetylamino)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-tri The synthesis of iodophenyl]-2-hydroxypropane) relates more specifically to the reaction of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- Triiodo-isophthalamide dimerization. Background of the invention [0004] Iodixanol is available as Visipaque TM A nonproprietary name for a non-ionic X-ray contrast agent chemical that is marketed under a trade name. Visipaque TM It is one of the drugs most commonly used in diagnostic X-ray procedures and is produced in large quantities. [0005] The production of such non-ionic X-ray contrast agents involves the preparation of chemical d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/46C07C231/12
CPCC07C231/12C07C237/46
Inventor G·布雷克O·罗格尼T·克恩利T·斯文德森
Owner GE HEALTHCARE AS
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