Preparation method of iodixanol and its synthetic intermediate

A technology of iodixanol and intermediates, applied in the field of medicinal chemistry, can solve the problems of unreported synthesis reaction conditions and yields, etc.

Active Publication Date: 2015-08-05
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Priebe et al. once published an article (Acta Radiol.36 (1995), Suppi.399, 21-31) that tried to improve the yield of iodixanol chemical synthesis. The synthetic route described in this article can avoid the first synthetic route The dimerization reaction, but the corresponding synthesis reaction conditions and yields have not been reported

Method used

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  • Preparation method of iodixanol and its synthetic intermediate
  • Preparation method of iodixanol and its synthetic intermediate
  • Preparation method of iodixanol and its synthetic intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The synthesis of embodiment 1,5-acetylamino-2,4,6-triiodoisophthalic acid (formula 2)

[0050] Add 500g of 5-amino-2,4,6-triiodoisophthalic acid (1) and 500mL of acetic anhydride in sequence in the reaction flask, raise the temperature to 80°C, keep stirring for 18 hours, and evaporate under reduced pressure after the reaction is completed. solvent to obtain 505 g of off-white solid with a yield of 90%.

Embodiment 2、1

[0051] Example 2, 1,3-bis(acetylamino)-N,N'-bis(3,5-dicarboxy-2,4,6-triiodophenyl)-2-propanol (formula 3) synthesis

[0052] method one

[0053] 500 g of the intermediate (Formula 2) directly obtained in Example 1, and 3000 mL of 1-methoxy-2-propanol were sequentially added to the reaction flask, sodium hydroxide was added to adjust the pH of the solution to 12, and 1,3-dichloro - 64g of 2-propanol, reacted for 24h-48h, after the reaction, add concentrated hydrochloric acid to acidify to pH 0-1, precipitate off-white solid, filter, dry the filter cake to obtain off-white solid 310g, yield 59%.

[0054] Method Two

[0055] 500 g of the intermediate (Formula 2) directly obtained in Example 1, and 3000 mL of 1-methoxy-2-propanol were sequentially added to the reaction flask, potassium hydroxide was added to adjust the pH of the solution to 12, and 1,3-dichloro - 64g of 2-propanol, reacted for 24h-48h, after the reaction, add concentrated hydrochloric acid, precipitate of...

Embodiment 3

[0060] Example 3, 1,3-bis(acetylamino)-N,N'-bis(3,5-dicarboxy-2,4,6-triiodophenyl)-2-propanol acetate (formula 4) Synthesis of

[0061] 500 g of the intermediate (formula 3) directly obtained in Example 2, 1000 mL of acetic anhydride and 2 g of 4-dimethylaminopyridine were successively added to the reaction flask, the temperature was raised to 70 ° C, and the reaction was carried out for 12 hours. The solvent was evaporated under reduced pressure to obtain an off-white solid 510g.

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Abstract

The invention discloses iodixanol and a preparation method of a synthetic intermediate 1, 3-bi (acetamino)-N, N'-bi [3, 5-bi (chloroformyl)-2, 4, 6-triiodo-phenyl]-2-propanol acetate of iodixanol. A dimerization condensation reaction of 5-acetamino-N, N'-bi (2, 3-dihydroxy propyl)-2, 4, 6-triiodo-isophthalamide as a final step is avoided by the preparation method, so that the content of iodixanol in a product is effectively improved, the purity of the obtained iodixanol crude product is greater than 90%, and the highest content of single impurity is less than 2%, so that the difficulty of purifying the product is reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to iodixanol (formula II) and its intermediate 1,3-bis(acetylamino)-N,N'-bis[3,5-bis(chloroformyl)-2, A preparation method of 4,6-triiodophenyl]-2-propanol acetate (formula I). Background technique [0002] Iodixanol (Iodixanol, trade name Visipaque) is a kind of non-ionic, water-soluble X-ray contrast agent developed by Norway Nycomed company, listed in 1993, and in mass production; Its chemical name is 1,3 -Bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane . [0003] Iodixanol is a representative of dimer non-ionic iodine-containing contrast agents. Compared with traditional ionic contrast agents, it has low osmotic pressure, low viscosity, good hydrophilicity, and greatly reduces the chance of side effects. market prospects. The production of iodixanol includes the production of chemical raw materials (i.e. primary producti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/36C07C231/12C07C237/46
Inventor 彭岩刘飞张喜全仲兆柏
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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