阅读说明：本技术 一种碘克沙醇，碘海醇杂质的制备方法 (Preparation method of iodixanol and iohexol impurities ) 是由 段香江 陈曦 虞选旺 林照棋 曾永东 于 2019-09-25 设计创作，主要内容包括：本发明公开一种碘克沙醇,碘海醇杂质的制备方法,包括如下步骤：步骤一、制备2-羟基-3-氯丙基乙酸酯；步骤二、以5-乙酰氨基-2,4,6-三碘-N,N-双-(2,3-二羟丙基)-1,3-苯二甲酰胺和2-羟基-3-氯丙基乙酸酯为原料,在溶剂中反应,反应完成后经后处理得所述杂质5-[N-(2-羟丙基醋酸酯)乙酰氨基]-2,4,6-三碘-N,N’-双(2,3-二羟基丙基)-1,3-苯二甲酰胺。本发明杂质在碘克沙醇与碘海醇制备过程中极易产生,分离困难,对纯度有较大影响,目前现有技术中无该杂质相关制备方法,本发明将会填补该杂质在制备方法上的空白。(The invention discloses a preparation method of iodixanol and iohexol impurities, which comprises the following steps: step one, preparing 2-hydroxy-3-chloropropyl acetate; and step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide. The impurities are easy to generate in the preparation process of iodixanol and iohexol, are difficult to separate, have great influence on the purity, and the related preparation method of the impurities does not exist in the prior art.)

1. A preparation method of iodixanol and iohexol impurities is characterized by comprising the following steps:

step one, preparing 2-hydroxy-3-chloropropyl acetate;

and step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

2. The preparation method of iodixanol and iohexol impurity as claimed in claim 1, wherein the second step is mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with solvent, adjusting pH to 10-13, controlling temperature at 0-40 deg.C, dropwise adding 2-hydroxy-3-chloropropylacetate within 0.5-4h, keeping temperature for 5-24h, adjusting pH to 2-8 after reaction, filtering, concentrating, purifying XAD-18, XAD-1600N, LX-16 or LX-18 macroporous resin to obtain 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N as impurity, n' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

3. The preparation method of iodixanol and iohexol impurity as claimed in claim 1, wherein the second step is mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with solvent, adjusting pH to 11-13, controlling temperature at 15-30 deg.C, dropwise adding 2-hydroxy-3-chloropropylacetate within 1-3h, keeping temperature for reaction for 10-18h, adjusting pH to 4-7 after reaction, filtering, concentrating, purifying XAD-1600N or LX-16 macroporous resin to obtain 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

4. The preparation method of iodixanol and iohexol impurity as claimed in claim 1, wherein in the second step, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and solvent are mixed, pH is adjusted to 11.5-12, temperature is controlled at 20 ℃, 2h is dropwise added with 2-hydroxy-3-chloropropylacetate, reaction is kept for 16h, pH is adjusted to 6 after reaction is finished, filtration and concentration are carried out, XAD-1600N macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

5. The process for the preparation of iodixanol or iohexol as impurities in any one of claims 1 to 4 wherein the second solvent comprises water, N-methylpyrrolidone, ethylene glycol monomethyl ether, dimethylacetamide or methanol, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and solvent, the pH is adjusted by triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide after mixing, and the pH is adjusted by hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid after the reaction.

6. The process for the preparation of iodixanol or iohexol as impurities in any one of claims 1 to 4 wherein the second solvent comprises ethylene glycol monomethyl ether or dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, which are mixed and then adjusted in pH with sodium hydroxide or sodium methoxide, and after the reaction is completed, the pH is adjusted with phosphoric acid or acetic acid.

7. The process for the preparation of iodixanol or iohexol as impurities in any one of claims 1 to 4 wherein the second solvent comprises dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, wherein the pH is adjusted by sodium methoxide and acetic acid after the reaction.

8. The process of any one of claims 1 to 4, wherein epichlorohydrin and acetic acid are used as raw materials in the first step, and the reaction is carried out in the presence of anhydrous ferric chloride as a catalyst, and the reaction is followed by post-treatment to obtain 2-hydroxy-3-chloropropylacetate.

9. The process for the preparation of iodixanol, an iohexol impurity as claimed in claim 8 wherein step one is first reacted at low temperature; and then heating for reaction.

10. The process of claim 8, wherein the step one post-treatment comprises evaporation, dilution, filtration, washing, drying, concentration or comprises precipitation, evaporation, dilution, filtration, washing, drying, concentration.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of iodixanol and iohexol impurities.

Background

5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide is a key intermediate of iodixanol and iohexol as contrast agents. In the reaction process, the impurities are generated along with the continuous hydrolysis of the 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, the polarity of the impurities is very close to that of iodixanol, and the impurities are difficult to remove from the beginning of the reaction to the final product, so that the quality of the product is seriously influenced, and therefore, the research on the impurities is necessary, but no related preparation method of the impurities exists in the prior art at present.

The specific information of the impurities is as follows:

name: 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide

The molecular formula is as follows: c₂₁H₂₈I₃N₃O₁₀

Molecular weight: 863.18

Structural formula (xvi):

disclosure of Invention

The invention aims to provide a preparation method of iodixanol and iohexol impurities, which aims to overcome the defects of the prior art.

The invention adopts the following technical scheme:

a method for preparing iodixanol and iohexol impurities comprises the following steps:

step one, preparing 2-hydroxy-3-chloropropyl acetate;

and step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

Further, in the second step, 5-acetamido-2, 4, 6-triiodo-N, N '-bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent are mixed, the pH is adjusted to 10-13, the temperature is controlled to be 0-40 ℃, 2-hydroxy-3-chloropropylacetate is dropwise added within 0.5-4h, the reaction is kept for 5-24h, the pH is adjusted to 2-8 after the reaction is finished, the mixture is filtered and concentrated, XAD-18, XAD-1600N, LX-16 or LX-18 macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

Further, in the second step, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent are mixed, the pH value is adjusted to 11-13, the temperature is controlled to be 15-30 ℃, 2-hydroxy-3-chloropropylacetate is dropwise added within 1-3h, the heat preservation reaction is carried out for 10-18h, the pH value is adjusted to 4-7 after the reaction is finished, the mixture is filtered and concentrated, and XAD-1600N or LX-16 macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

Further, in the second step, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent are mixed, the pH value is adjusted to 11.5-12, the temperature is controlled to be 20 ℃, 2-hydroxy-3-chloropropylacetate is dropwise added within 2h, the heat preservation reaction is carried out for 16h, the pH value is adjusted to 6 after the reaction is finished, the filtration, the concentration and the XAD-1600N macroporous resin purification are carried out to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

Further, the second solvent in the step (II) comprises water, N-methyl pyrrolidone, ethylene glycol monomethyl ether, dimethyl acetamide or methanol, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide after the mixture is mixed, and the pH is adjusted by hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid after the reaction is finished.

Further, the second solvent in the step comprises ethylene glycol monomethyl ether or dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by sodium hydroxide or sodium methoxide after the mixture is mixed, and the pH is adjusted by phosphoric acid or acetic acid after the reaction is finished.

Further, the second solvent of the step comprises dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by sodium methoxide after the mixture is mixed, and the pH is adjusted by acetic acid after the reaction is finished.

And further, reacting epichlorohydrin and acetic acid serving as raw materials under the action of a catalyst anhydrous ferric chloride, and performing post-treatment after the reaction is finished to obtain the 2-hydroxy-3-chloropropyl acetate.

Further, the first step is firstly reaction at low temperature; and then heating for reaction.

Further, the step one post-treatment comprises evaporation, dilution, filtration, washing, drying, concentration or comprises precipitation, evaporation, dilution, filtration, washing, drying, concentration.

The invention has the beneficial effects that:

1. the impurities are easy to generate in the preparation process of iodixanol and iohexol, are difficult to separate, have great influence on the purity, and the related preparation method of the impurities does not exist in the prior art.

2. The invention achieves the effect of reducing the generation of byproducts by controlling various process conditions, and prepares high-purity finished product impurities by macroporous resin purification, and the conversion rate is higher.

Detailed Description

The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.

A method for preparing iodixanol and iohexol impurities comprises the following steps:

taking epoxy chloropropane and acetic acid as raw materials, firstly reacting at low temperature under the action of a catalyst anhydrous ferric chloride, and then heating for reaction; after the reaction is finished, evaporating, diluting, filtering, washing, drying and concentrating or precipitating, evaporating, diluting, filtering, washing, drying and concentrating to obtain 2-hydroxy-3-chloropropylacetic acid ester;

step two, mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with a solvent, wherein the solvent comprises water, N-methylpyrrolidone (NMP), ethylene glycol monomethyl ether, Dimethylacetamide (DMA) or methanol, preferably ethylene glycol monomethyl ether or DMA, and more preferably DMA; adjusting the pH to 10-13, preferably 11-13, more preferably 11.5-12 (the pH is adjusted to be more critical, the pH is lower, the compound III cannot be dissolved in the solvent, the pH is higher, the destruction of the compound IV can be promoted, and the reaction conversion rate is influenced) by using triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide, preferably sodium hydroxide or sodium methoxide, more preferably sodium methoxide; controlling the temperature at 0-40 deg.C, preferably 15-30 deg.C, more preferably 20 deg.C, within 0.5-4h, preferably 1-3h, more preferably 2h, and dropwise adding 2-hydroxy-3-chloropropyl acetate; keeping the temperature for reaction for 5-24h, preferably 10-18h, more preferably 16 h; adjusting the pH to 2-8, preferably 4-7, more preferably 6 (the pH is critical for terminating the reaction, and the reaction system is viscous, gelatinous, and unstable due to the use of tai acid, and the resin adsorption is reduced due to the subsequent column chromatography), filtering, concentrating, adding XAD-18, XAD-1600N, LX-16 or LX-18 macroporous resin, preferably XAD-1600N or LX-16 macroporous resin, more preferably XAD-1600N macroporous resin, purifying to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.

The synthesis process is as follows: