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Synthetic method of iohexol impurity F and application thereof in synthesis of iohexol impurity G, impurity H and impurity M

A synthesis method and technology of iohexol are applied in the field of medicine to achieve the effect of improving quality standards

Inactive Publication Date: 2019-06-21
BROTHER ENTERPRISES HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, serious adverse reactions still occur from time to time, and the occurrence of adverse reactions is not only related to the pharmacological activity of iohexol itself, but also has a lot to do with the impurities in iohexol

Method used

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  • Synthetic method of iohexol impurity F and application thereof in synthesis of iohexol impurity G, impurity H and impurity M
  • Synthetic method of iohexol impurity F and application thereof in synthesis of iohexol impurity G, impurity H and impurity M
  • Synthetic method of iohexol impurity F and application thereof in synthesis of iohexol impurity G, impurity H and impurity M

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Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1: the synthesis of iohexol impurity F (compound of formula 1)

[0035] 1. Synthesis of 5-nitro-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (compound of formula 3)

[0036] Prepare raw materials according to the molar ratio of dimethyl 5-nitro-1,3-phthalate to 2,3-dihydroxypropylamine at 1:1.2. Put 50g of dimethyl 5-nitro-1,3-phthalate into a 500ml reaction bottle, add 80mL of methanol, stir evenly, then add 22.8g of 2,3-dihydroxypropylamine dropwise, and add 5g of Sodium methoxide, keep the temperature at 20-50°C and react for 20-40 hours. HPLC detects that the raw material is ≤0.1% and the reaction is complete. Cool down to room temperature and adjust the pH to 6 with hydrochloric acid. Add 250mL of water and mix to obtain about 450mL of transesterification reaction solution for the following One-step hydrogenation reduction reaction.

[0037] 2. Synthesis of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbox...

Embodiment 2

[0041] Embodiment 2: the synthesis of iohexol impurity G (compound of formula 6)

[0042] According to formula 1 compound and acetic anhydride molar ratio 1:4, add 34.3g acetic anhydride, concentrated sulfuric acid (mass concentration 70% H 2 SO 4 Aqueous solution) 130mL, 50g compound of formula 1, stir evenly and heat up to 50-100°C, react for 10-20 hours, HPLC detects that the reaction is complete, evaporate unreacted acetic anhydride, add 100mL of water, at room temperature, add an appropriate amount of hydroxide Sodium, adjust the pH to 9-11, HPLC detects the completion of the reaction, adjust the pH to 5-7 with hydrochloric acid, cool down to 0-15°C and crystallize to obtain 5-acetylamino-N,N'-bis(2,3-di Hydroxypropyl)-2,4,6-triiodo-1,3-phthalamide solid (compound of formula 6), purity 97.2%.

Embodiment 3

[0043] Embodiment 3: the synthesis of iohexol impurity H (compound of formula 7)

[0044]According to formula 6 compound and 3-chloro-1,2-propanediol, the molar ratio of sodium hydroxide is 1:1:1, add 20g compound formula 6, ethylene glycol monomethyl ether 60mL, sodium hydroxide 1.25g, 3-Chloro-1,2-propanediol 3.45g, heat to 30-100°C for 10-20 hours, distill out ethylene glycol monomethyl ether, add 30mL of water, adjust the pH to 5-7 with hydrochloric acid, add isopropanol 60mL, cooled to 5-10°C, precipitated crystals, dried to obtain 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N′-bis(2,3-dihydroxypropyl)-2 , 4,6-triiodo-1,3-benzenedicarboxamide solid (compound of formula 7), purity 96.4%.

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Abstract

The invention relates to a synthetic method of iohexol impurities, in particular to a synthetic method of an iohexol impurity F and an application thereof in synthesis of an iohexol impurity G, an impurity H and an impurity M and belongs to the technical field of medicines. The method comprises the steps as follows: a compound in formula 3 is prepared from raw materials including 5-nitro-1,3-dimethyl phthalate (a compound in formula 2) and 2,3-dihydroxyl propylamine, the compound in formula 3 and hydrogen are subjected to a reduction reaction to prepare a compound in formula 4, and the compound in formula 4 reacts with iodine chloride to obtain the iohexol impurity F. 5-amino-N,N'-bis(2,3-dihydroxypropyl)-diiodo-1,3-benzenedicarboxamide (a compound in formula 1) is synthesized from 5-nitro-1,3-dimethyl phthalate (the compound in formula 2) as the initial material, the impurity G, the impurity H and the impurity M are synthesized from the compound in formula 1 as the initial material, and qualified impurity reference substances are provided for quality control of iohexol.

Description

technical field [0001] The invention relates to a synthesis method of iohexol impurity, in particular to a synthesis method of iohexol impurity F and its application in the synthesis of iohexol impurity G, impurity H and impurity M, belonging to the technical field of medicine. Background technique [0002] Iohexol is currently one of the most widely used non-ionic X-ray contrast agents. Its iohexol impurity F, impurity G, impurity H and impurity M are strictly controlled in the European Pharmacopoeia, and its self-structure is as follows: [0003] [0004] The synthesis of iohexol impurity F, impurity G, impurity H and impurity M has not been done domestically. However, serious adverse reactions still occur from time to time, and the occurrence of adverse reactions is not only related to the pharmacological activity of iohexol itself, but also has a lot to do with the impurities in iohexol. Carry out the research of impurity so standardly, and it is controlled in a safe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/32
Inventor 詹国武熊安伟周中平钱志达
Owner BROTHER ENTERPRISES HLDG CO LTD
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