WO2018228546A1

WO2018228546A1 - Highly efficient contrast agent synthesizing method, and application thereof

Info

Publication number: WO2018228546A1
Application number: PCT/CN2018/091558
Authority: WO
Inventors: 吴成龙; 黄金昆; 龚家福; 刘劲菲; 刘芍利; 孙健; 谢德建
Original assignee: 成都西岭源药业有限公司
Priority date: 2017-06-16
Filing date: 2018-06-15
Publication date: 2018-12-20
Also published as: CN109134289A; CN109134289B

Abstract

Disclosed is a highly efficient contrast agent synthesizing method, comprising the following steps: (I) preparing an intermediate mixture of a compound represented by formula (II) and a compound represented by formula (I) and/or formula (III); (II) performing separation to obtain the compound represented by formula (II) and the compound represented by formula (I) and/or formula (III); (III) taking the compound represented by formula (II) to prepare a contrast agent iopromid; and (IV) taking the compound represented by formula (III) to prepare a contrast agent iobitridol; and/or taking a compound represented by formula (I) to prepare a contrast agent iohexol, ioversol, iopentol, or iodixanol. According to the method, by synthesizing and separating intermediates of the compound represented by formula (II) as well as the compound represented by formula (I) and/or formula (III), and then separately preparing contrast agents using the intermediates as the raw materials, the problem of the need to remove a diacylated byproduct in an existing method is overcome, and all intermediates are effectively utilized, the efficiency is high, and the actual application prospect is good.

Description

一种高效率的造影剂合成方法及其应用High-efficiency contrast agent synthesis method and application thereof

技术领域Technical field

本发明属于造影剂领域，具体涉及一种高效率的造影剂合成方法及其应用。The invention belongs to the field of contrast agents, and in particular relates to a high-efficiency contrast agent synthesis method and application thereof.

背景技术Background technique

碘造影剂是一种常见的X射线造影剂，主要用于血管、尿路等体腔的造影，目前主要使用的是非离子型碘造影剂，主要有碘帕醇、碘海醇、碘佛醇、碘普罗胺、碘美普尔、碘喷托、碘比醇、碘曲仑、碘克沙醇等。Iodine contrast agent is a common X-ray contrast agent, mainly used for angiography of blood vessels, urinary tracts, etc. Currently, non-ionic iodine contrast agents are mainly used, mainly iopamidol, iohexol, iodophor, Iopromide, iomeprol, iodine, iodobutanol, iodine, iodixanol, and the like.

相对于其他非离子型碘造影剂，碘普罗胺具有最低的肾毒性，由德国先灵AG公司开发，商品名为Ultravist。由于其良好的安全性，在全球造影剂市场销售额稳居前列，据THOMSON

数据，其2012年全球碘普罗胺的需求量为775.2吨，据拜耳先灵公司2012年财务年报，全球Ultravist销售额为3.24亿欧元，比上一年增长了2.53％，可见其市场需求量巨大。 Iopromide has the lowest nephrotoxicity compared to other non-ionic iodine contrast agents, developed by Schering AG of Germany under the trade name Ultravist. Due to its good safety, sales in the global contrast agent market are at the forefront, according to THOMSON

According to the data, the global demand for iopromide in 2012 was 775.2 tons. According to Bayer Schering's 2012 financial year report, the global Ultratrast sales were 324 million euros, an increase of 2.53% over the previous year, showing that the market demand is huge. .

前述列举的造影剂，除碘普罗胺之外，苯环上的两个二羟基丙酰胺基均为对称结构，即两个酰氨基同时被氢或甲基取代，碘普罗胺的两个二羟基丙酰胺基则为不对称结构，其上的酰氨基一个被氢取代，另一个则被甲基取代。正是由于碘普罗胺的两个二羟基丙酰胺基的结构不对称，在合成过程中不可避免的会产生大量二酰化副产物(bismer)1和2，该杂质与碘普罗胺化学结构十分相近，分离纯化非常困难，中国专利CN102351735中明确指出二酰化副产物需要使用大量若干有机溶剂的许多结晶和过滤步骤才能除去，陆悠玲(陆悠玲，碘普罗胺的专利合成路线浅谈，广东化工，2015年第6期)也明确指出，终产品中的二酰化副产物极难分离，需要额外的诸如多步结晶、过树脂柱等纯化步骤，降低了产物收率，产品成本增加。In addition to iopromide, the two dihydroxypropionamido groups on the phenyl ring are symmetric structures, that is, two amido groups are simultaneously substituted by hydrogen or methyl groups, and two dihydroxy groups of iopromide. The propionamide group is an asymmetric structure in which one of the acylamino groups is substituted by hydrogen and the other is substituted by a methyl group. It is precisely because of the structural asymmetry of the two dihydroxypropionamide groups of iopromide that a large amount of diacylated by-products (bismer) 1 and 2 are inevitably produced during the synthesis, and the chemical structure of the impurity and iopromide is very high. Similar, separation and purification is very difficult, Chinese patent CN102351735 clearly pointed out that the two acylation by-products need to use a large number of organic solvents in many crystallization and filtration steps to remove, Lu Youling (Lu Youling, iopromide patent synthesis route, Guangdong Chemical, Also pointed out in the sixth issue of 2015) that the diacylated by-products in the final product are extremely difficult to separate, requiring additional purification steps such as multi-step crystallization and resin column reduction, which reduces product yield and increases product cost.

最初的碘普罗胺的制备方法是由美国专利US4364921公开的，有三条路线，其路线一如下：The original preparation method of iopromide is disclosed in U.S. Patent No. 4,346,921, which has three routes, the route of which is as follows:

路线一Route one

化合物2首先与甲氧基乙酰氯反应，得到化合物3，化合物3再与3-氨基-1,2-丙二醇反应得到化合物4，化合物4再与3-甲氨基-1,2-丙二醇反应得到碘普罗胺，该路线简洁，尽管专利中给出了每一步的收率分别为74％、74.5％、81％，但是文中并没有给出每一个中间体及碘普罗胺成品的HPLC纯度，也未给出构型比例，因此，不能判断其是否适于药物的工业化生产。 Compound 2 is first reacted with methoxyacetyl chloride to give compound 3, which is then reacted with 3-amino-1,2-propanediol to give compound 4, which is then reacted with 3-methylamino-1,2-propanediol to give iodine. Promethazine, the route is simple, although the yields of each step are 74%, 74.5%, 81%, respectively, but the HPLC purity of each intermediate and iopromide finished product is not given. The configuration ratio is given, and therefore, it cannot be judged whether it is suitable for industrial production of a drug.

并且，发明人根据该方法合成碘普罗胺时，同样遇到了二酰化副产物(bismer)难以除去的问题，正如前述文献所公开的情形。Further, when the inventors synthesized iopromide according to the method, the problem that the diacylated by-product (bismer) was difficult to remove was also encountered, as disclosed in the aforementioned document.

故而，本领域通常采取两种方式解决这个问题，一是通过避免二酰化副产物(bismer)的产生；二是通过除去或者降低二酰化副产物(bismer)来达到目的。Therefore, there are two ways to solve this problem in the art, one by avoiding the production of a diacylated by-product (bismer) and the other by removing or lowering the diacylated by-product (bismer).

现有技术中，以避免二酰化副产物的产生为策略的文献有：In the prior art, the literature to avoid the generation of diacylated by-products is:

US4364921公开了第二条及第三条合成路线；US4364921 discloses a second and third synthetic route;

路线二：Route 2:

化合物6首先与3-甲氨基1,2-丙二醇反应得到化合物7，化合物7经过乙酰化保护得到化合物8，化合物8经过还原及碘代得到化合物9，化合物9经过氯代反应得到酰氯10，酰氯10再与甲氧基乙酰氯反应得到化合物11，随后再与3-氨基-1,2-丙二醇反应得到化合物12，化合物12水解得到碘普罗胺。该路线避免了二酰化副产物(bismer)的生成，但是路线较长，中间体不易分离纯化，其中化合物8到化合物9的碘代反应由于反应条件剧烈，可能会产生羟基水解产物，从而使得化合物9到化合物10的氯代反应可能产生羟基氯代副产物，故此，该路线总收率仍然不高，不适合工业化生产。 Compound 6 is first reacted with 3-methylamino 1,2-propanediol to give compound 7, compound 7 is protected by acetylation to give compound 8, compound 8 is reduced and iodo substituted to give compound 9, and compound 9 is subjected to chlorination to give acid chloride 10, acid chloride. 10 is further reacted with methoxyacetyl chloride to give compound 11, which is then reacted with 3-amino-1,2-propanediol to give compound 12, which is hydrolyzed to give iopromide. This route avoids the formation of diacylated by-products (bismer), but the route is long, and the intermediates are not easily separated and purified. The iodide reaction of compound 8 to compound 9 may produce hydroxyl hydrolyzate due to the reaction conditions being severe, thereby The chlorination of compound 9 to compound 10 may produce hydroxychloro by-products. Therefore, the overall yield of the route is still not high and is not suitable for industrial production.

路线三：Route 3:

化合物7甲酯化得到化合物13，化合物13与3-氨基-1,2-丙二醇反应得到化合物14，随后将4个羟基全部乙酰化得到化合物15，随后再还原及碘代得到化合物50，化合物50再与甲氧基乙酰氯反应得到化合物51，化合物51脱保护得到碘普罗胺。该路线看起来也能够很好的“避免”二酰化副产物(bismer)的生成，但是，在对专利重复中，我们发现，在化合物13到化合物14的反应过程中，会发生酰胺的氨解，最后仍然会生成对称化合物18，且难以分离，从而将二酰化副产物(bismer)带入产品中，并且乙酰基在碘代反应中容易脱保护，造成产物杂乱，影响结晶。Methylation of compound 7 gives compound 13, compound 13 is reacted with 3-amino-1,2-propanediol to give compound 14, followed by acetylation of all four hydroxyl groups to give compound 15, followed by reduction and iodination to give compound 50, compound 50 Further, it is reacted with methoxyacetyl chloride to obtain compound 51, and compound 51 is deprotected to obtain iopromide. This route also appears to be very good at "avoiding" the formation of diacylated by-products (bismer), but in the patent repeats, we have found that during the reaction of compounds 13 to 14, amide ammonia occurs. Finally, a symmetric compound 18 is still formed and is difficult to separate, thereby bringing the diacylated by-product (bismer) into the product, and the acetyl group is easily deprotected in the iodo reaction, causing product clutter and affecting crystallization.

酰胺氨解反应方程式如下图所示：The amide aminolysis reaction equation is shown in the figure below:

所以，路线三不仅不能有效的避免二酰化副产物(bismer)的生成，路线也很长，中间体不易纯化，不适合工业化生产。Therefore, Route 3 can not only effectively avoid the formation of diacylated by-products (bismer), the route is also very long, the intermediates are not easy to be purified, and are not suitable for industrial production.

浙江司太立的王哲等在专利CN 102351735中公开了另外一种碘普罗胺的制备方法，他们利用化合物20作为起始原料，将化合物20与甲氧基乙酰氯反应，得到化合物21，随后将乙酰基水解，再氯代得到酰氯化合物4，随后将化合物4与3-甲氨基-1,2-丙二醇反应得到碘普罗胺。该路线避免了二酰化副产物的生成，但是加上起始原料20的合成，其路线冗长，并且，化合物22在氯代的时候容易生成羟基氯代副产物，仍然不是首选的工业化生产路线。Another method for the preparation of iopromide is disclosed in the patent CN 102351735, which uses compound 20 as a starting material to react compound 20 with methoxyacetyl chloride to obtain compound 21, followed by The acetyl group is hydrolyzed and chlorinated to give the acid chloride compound 4, followed by reacting the compound 4 with 3-methylamino-1,2-propanediol to give iopromide. This route avoids the formation of diacylated by-products, but with the addition of the starting material 20, the route is tedious, and the compound 22 tends to form hydroxychloro by-products during chlorination, which is still not the preferred industrial production route. .

以上“避免”产生二酰化副产物的路线有一个共同点均是将对称的间苯二甲酸官能团非对称化来实现，由于间苯二甲酸的两个羧基其化学环境完全等同，所以，要将其非对称化必然存在收率及纯化的问题，从而不可避免的使得合成路线冗长，总收率偏低。大部分“避免”二酰化副产物生成的路线实际上只是将另一种形式的“二酰化副产物”放在合成工艺路线的前端去除，使得后续路线不产生新的二酰化副产物。The above-mentioned routes of "avoiding" the production of diacylated by-products have one thing in common, which is achieved by asymmetry of symmetric isophthalic acid functional groups. Since the two carboxyl groups of isophthalic acid have completely identical chemical environments, Asymmetry has a problem of yield and purification, which inevitably makes the synthesis route lengthy and the total yield is low. Most of the routes to "avoid" the formation of diacylated by-products are actually to remove another form of "diacylated by-product" at the front end of the synthesis route so that subsequent routes do not produce new diacylated by-products. .

以除去或降低二酰化副产物的产生为策略的专利文献主要如下：The patent documents that remove or reduce the production of diacylated by-products are mainly as follows:

韩国专利WO2009134030公开了一种除去二酰化副产物的方法，通过引入中间体19，达到去除二酰化副产物的目的，在优化了3-氨基-1,2-丙二醇的用量及将中间体19精制之后，可以去除大量二酰化副产物，但是与专利US 4364921相比，其多了一个中间体，导致步骤增加，从而降低了其工业化应用价值，并且，其并未教导通过何种方式纯化中间体19，以及缺少中间体19的HPLC纯度数据。Korean Patent WO2009134030 discloses a method for removing a diacylated by-product by introducing an intermediate 19 to remove the diacylated by-product, optimizing the amount of 3-amino-1,2-propanediol and the intermediate. After refining 19, a large amount of diacylated by-products can be removed, but compared with the patent US 4364921, it has an additional intermediate, which leads to an increase in steps, thereby reducing its industrial application value, and it does not teach by any means. Intermediate 19 was purified, as well as HPLC purity data lacking Intermediate 19.

浙江大学陈炜梁在其硕士论文《非离子造影剂碘普罗胺的合成工艺优化》中公开了一条碘普罗胺的合成路线，合成路线如下：由化合物6作为起始原料，在氯化亚砜作用下得到酰氯56，随后利用酰氯与酯的反应活性差异，将化合物56与3-氨基-1,2-丙二醇反应，得到化合物57，然后再与3-甲氨基-1,2-丙二醇反应得到化合物14，随后在钯碳催化下还原硝基，所得产物不经纯化直接碘代得到式(Ⅱ)化合物，式(Ⅱ)化合物再利用醋酐将羟基乙酰化，得到乙酰化物50，化合物50再与甲氧基乙酰氯反应将氨基酰化，随后用氢氧化钠水解得到碘普罗胺。Chen Yuliang of Zhejiang University published a synthetic route for iopromide in his master's thesis "Optimization of the synthesis process of nonionic contrast agent iopromide". The synthetic route is as follows: Compound 6 is used as the starting material under the action of thionyl chloride. The acid chloride 56 is obtained, followed by the difference in reactivity of the acid chloride with the ester, and the compound 56 is reacted with 3-amino-1,2-propanediol to obtain the compound 57, which is then reacted with 3-methylamino-1,2-propanediol to obtain the compound 14. Subsequently, the nitro group is reduced under the catalysis of palladium carbon, and the obtained product is directly iodized without purification to obtain a compound of the formula (II). The compound of the formula (II) is acetylated with an acetic anhydride to obtain an acetylate 50, and the compound 50 is further reacted with A. The oxyacetyl chloride reaction acylates the amino group, followed by hydrolysis with sodium hydroxide to give iopromide.

前述方法是以化合物6为起始原料，先接3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇片段，通过精制将对称取代的二酰化副产物去除后，然后碘代，最后接甲氧基乙酰基的方式合成碘普罗胺，但是发明人重复实验发现，首先，化合物6在与氯化亚砜反应过程中，由于长时间加热反应，其中的甲酯官能团很可能被氯代形成酰氯，使非对称化合物变为对称化合物，从而在与3-氨基-1,2-丙二醇反应时生成化合物18，并在后续反应中产生二酰化副产物(bismer)；In the foregoing method, the compound 6 is used as a starting material, and the 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol fragments are firstly removed, and the symmetrically substituted diacylated by-products are removed by refining, and then Iodoprol is synthesized by iodo, and finally methoxyacetyl, but the inventors have repeatedly found that, firstly, in the reaction with compound sulfoxide, compound 6 has a long-term heating reaction, and the methyl ester functional group is very May form an acid chloride by chlorination, making the asymmetric compound a symmetrical compound, thereby forming compound 18 upon reaction with 3-amino-1,2-propanediol, and producing a diacylated by-product (bismer) in subsequent reactions;

其次化合物56与3-氨基-1,2-丙二醇反应时，尽管酰氯与酯的反应活性存在较大差异，但是酯也会与胺发生氨解反应，导致化合物18的生成，并在后续反应中产生二酰化副产物(bismer)，经过重复实验也发现，从化合物56到化合物57这一步骤的纯度低，非常难以纯化，为后续反应带来不便；Secondly, when compound 56 is reacted with 3-amino-1,2-propanediol, although the reactivity of the acid chloride with the ester is largely different, the ester undergoes an aminolysis reaction with the amine, resulting in the formation of compound 18, and in the subsequent reaction. The diacylated by-product (bismer) was produced, and it was found through repeated experiments that the purity of the step from compound 56 to compound 57 was low and it was very difficult to purify, which was inconvenient for subsequent reactions;

再次，该路线较长，步骤多，增加了大量的时间成本，不适合工业化生产；初始原料化合物6是通过将对称化合物去对称得到的，必然导致了化合物6的合成收率不高，并且化合物6不是一个容易获得的大宗工业化产品，成本高；Again, the route is longer, the steps are more, and the time cost is increased, which is not suitable for industrial production; the initial raw material compound 6 is obtained by desymmetry of the symmetric compound, which inevitably leads to the low synthesis yield of the compound 6, and the compound 6 is not an easy-to-obtain large-scale industrialized product with high cost;

前述造影剂的结构中，均含有式(Ⅰ)、式(Ⅱ)或式(Ⅲ)结构的母核，如果能够便利的获得高纯度的式(Ⅰ)、式(Ⅱ)或式(Ⅲ)，也为合成造影剂提供了一种路径。The structure of the aforementioned contrast agent contains a core of the formula (I), the formula (II) or the formula (III), and if it is convenient to obtain a high purity formula (I), formula (II) or formula (III) It also provides a path for the synthesis of contrast agents.

CN103086915公开了式(Ⅰ)的主要合成方法CN103086915 discloses a main synthesis method of formula (I)

由于支链位阻原因，该方法容易出现碘代不完全杂质，从公开的结果看来其二碘代杂质在0.7％～1.7％之间。Due to the steric hindrance of the branch, the method is prone to iodine incomplete impurities, and from the published results, the diiodide impurity is between 0.7% and 1.7%.

浙江大学陈炜梁在其硕士论文《非离子造影剂碘普罗胺的合成工艺优化》中公开了式(Ⅱ)的合成方法Chen Yuliang of Zhejiang University disclosed the synthesis method of formula (II) in his master's thesis "Optimization of the synthesis process of nonionic contrast agent iopromide"

与式(Ⅰ)方法类似，由于N-甲基的存在，侧链位阻比式(Ⅰ)更大，容易出现更大比例的碘代不完全杂质，由于具有特定(Z1+E1)：(Z2+E2)构型比例的碘普罗胺才能作为合格的原料药，我们认为从其论文中公开内容看，很难通过该路线得到合格构型的碘普罗胺成品。Similar to the method of formula (I), due to the presence of N-methyl group, the side chain steric hindrance is larger than formula (I), and a larger proportion of iodide incomplete impurities tends to occur due to the specific (Z1+E1): The Z2+E2) configuration ratio of iopromide can be used as a qualified drug substance. We believe that it is difficult to obtain a qualified configuration of iopromide by this route from the disclosure of the paper.

为了便于称呼，我们将碘普罗胺的苯环当做身体，而将3-氨基-1,2-丙二醇片段称为左手，3-甲氨基-1,2-丙二醇称为右手，甲氧基乙酰基片段称为尾巴。For ease of reference, we use the phenyl ring of iopromide as the body, and the 3-amino-1,2-propanediol fragment is called the left hand, 3-methylamino-1,2-propanediol is called the right hand, methoxyacetyl The fragment is called the tail.

已经公开的碘普罗胺合成路线按照碘代的先后顺序可以分为先上左右手再碘代及先碘代再上左右手两类。其主要原因是相对于碘造影剂来说，碘的价格昂贵，以碘普罗胺为例，碘普罗胺的分子量为791.12而三个碘原子的分子量就有380.71，占整个分子的48％，理论上来说，越在合成路线的后面引入碘，越能降低碘的损失，从而具有成本优势，但是后碘代存在如下几个缺点：The disclosed iopromide synthesis route can be divided into two types according to the order of iodide, iodide, iodine and iodine. The main reason is that iodine is expensive compared to iodine contrast agents. In the case of iopromide, the molecular weight of iopromide is 791.12 and the molecular weight of three iodine atoms is 380.71, accounting for 48% of the total molecule. In general, the more iodine is introduced behind the synthetic route, the more the iodine loss can be reduced, which has a cost advantage, but the post-iodine has the following disadvantages:

1)碘普罗胺具有Z1、Z2、E1、E2四个构型，只有这四个构型比例在一定范围内才能作为合格的原料药使用。上述工艺中采用后碘代的策略，由于酰胺氮原子上甲基的存在，导致位阻增加，阻碍了化学键的自由旋转，进而使得碘代不完全的风险非常大；另一方面，由于位阻的存在，要获得满足构型比例的合格原料药是不容易的。；1) Iopromide has four configurations of Z1, Z2, E1 and E2, and only these four configurations can be used as qualified drug substances within a certain range. The post-iodine strategy in the above process, due to the presence of a methyl group on the amide nitrogen atom, leads to an increase in steric hindrance, hinders the free rotation of the chemical bond, and thus the risk of incomplete iodine is very large; on the other hand, due to steric hindrance The existence of a qualified drug substance that satisfies the configuration ratio is not easy. ;

2)后碘代路线为了在碘代前消除二酰化副产物的影响，往往具有比较长的反应路线，从而造成反应总收率降低；2) Post-iodine route In order to eliminate the influence of diacylated by-products before iodo, it tends to have a relatively long reaction route, thereby causing a decrease in the overall reaction yield;

3)碘代步骤越靠近成品步骤，越容易使成品出现色泽不合格的风险。3) The closer the iodine step is to the finished product step, the easier it is to cause the finished product to be inaccurate in color.

先碘代存在以下几个缺点：First iodine has the following disadvantages:

1)由于碘比较早的引入了反应步骤，在后续反应中会造成碘的流失，从而使成本增加；1) Since the iodine is introduced earlier than the reaction step, the iodine is lost in the subsequent reaction, thereby increasing the cost;

2)在去除二酰化副产物过程中，必然会引起碘的流失，尽管许多文献提到了流失碘的回收再利用，但是其利用率不能达到100％，所以仍然会造成碘流失；2) In the process of removing the diacylated by-products, the loss of iodine is inevitably caused. Although many literatures mention the recovery and reuse of lost iodine, the utilization rate cannot reach 100%, so iodine loss is still caused;

总之，从碘普罗胺生产的现状来看，文献报道的各种工艺均不如人意。直至目前，由于碘普罗胺合成工艺过程中一直没有有效解决二酰化杂质的问题，导致合成成本居高不下，特别是在中国，进口碘普罗胺比自主生产更为合算，而德国先灵AG公司生产的碘普罗胺注射液是目前唯一通过中国CFDA审批的碘普罗胺产品。鉴于此，本发明人一直致力于开发一种新的、低成本、高产率地合成碘普罗胺的方法。In summary, from the current situation of iopromide production, the various processes reported in the literature are not satisfactory. Up to now, due to the problem of diacidification impurities have not been effectively solved in the iopromide synthesis process, the cost of synthesis has remained high, especially in China, the import of iopromide is more cost-effective than the independent production, and the German Schering AG The iopromide injection produced by the company is currently the only iopromide product approved by the Chinese CFDA. In view of this, the inventors have been working on a new, low-cost, high-yield method for synthesizing iopromide.

发明内容Summary of the invention

为解决上述问题，本发明设计了一条新的合成策略，将化合物2直接与3-氨基1,2-丙二醇及3-甲氨基1,2-丙二醇反应，同时得到下如所示式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物，如果能将这三个化合物实现分离，通过简单的步骤，可以将常见造影剂的合成路线集于一体，所采用路线除了可能产生的未知杂质以外不产生任何“废物”，达到了很好的原子经济性。In order to solve the above problems, the present invention devised a new synthesis strategy, which directly reacts compound 2 with 3-amino 1,2-propanediol and 3-methylamino 1,2-propanediol, and simultaneously obtains the formula (I) as shown below. The compound of formula (II) and formula (III), if the three compounds can be separated, the synthesis route of the common contrast agent can be integrated by a simple step, and the route adopted is not except for the unknown impurities which may be generated. Producing any "waste" has achieved good atomic economy.

由于N-甲基及苯环上碘的位阻原因，式(Ⅰ)可以得到固体，而式(Ⅱ)具有四个构型，式(Ⅲ)具有更多的构型，导致后两者在高温状态下为粘稠的油状物，在低温状态下为玻璃态固体，很难通过重结晶的方式加以纯化分离。Due to the steric hindrance of iodine on the N-methyl and phenyl rings, formula (I) can give a solid, while formula (II) has four configurations, and formula (III) has more configurations, resulting in the latter two. It is a viscous oil at high temperature and is a glassy solid at low temperature. It is difficult to purify and separate by recrystallization.

通常，对于多羟基化合物的分离方式可以使用树脂进行分离，常见的树脂分离洗脱体系以水作为基质，为了调节洗脱强度，可能会加入一定比例的水溶性有机溶剂，比如醇类、多羟基醇的醚类化合物或者丙酮等能够与水互溶的溶剂。通过查阅文献(Xinwei Zhang，Solubility of 5-Amino-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide in Ethanol+Water Mixtures，J.Chem.Eng.Data 2010,55,2355–2357)，式(Ⅰ)化合物在水中或者水醇混合溶剂中溶解度非常小，在80℃的纯水中，溶解度为0.18g/g，在40℃的纯水中，溶解度仅为0.013g/g，在80℃的30％(w/w)乙醇水中的溶解度为0.47g/g，在40℃的30％(w/w)乙醇水中的溶解度仅为0.02g/g。由于树脂为高分子聚合的有机物，通常在温度太高的情况下都不具有好的分离效果，根据以上溶解度数据，以本专业领域技术人员的视角，由于式(Ⅰ)的溶解度太小，也排除了树脂层析分离的可能。Generally, the separation method of the polyhydroxy compound can be carried out by using a resin. The common resin separation and elution system uses water as a matrix. In order to adjust the elution intensity, a certain proportion of water-soluble organic solvents such as alcohols and polyhydroxy groups may be added. An ether compound of an alcohol or a solvent which is miscible with water, such as acetone. By reference to the literature (Xinwei Zhang, Solubility of 5-Amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide in Ethanol+Water Mixtures, J.Chem. Eng.Data 2010, 55, 2355-2357), the solubility of the compound of formula (I) in water or a mixed solvent of hydroalcohol is very small, in a pure water of 80 ° C, the solubility is 0.18 g / g, pure water at 40 ° C The solubility is only 0.013g/g, the solubility in 30% (w/w) ethanol water at 80 ° C is 0.47g / g, and the solubility in 30% (w / w) ethanol water at 40 ° C is only 0.02g /g. Since the resin is a polymerized organic substance, it usually does not have a good separation effect when the temperature is too high. According to the above solubility data, the solubility of the formula (I) is too small, from the viewpoint of those skilled in the art. The possibility of resin chromatography separation is ruled out.

然而，我们惊喜的发现，化合物2与3-氨基1,2-丙二醇及3-甲氨基1,2-丙二醇在本发明特定配比下反应，可以得到溶于水的而未知杂质含量低的式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物这三种中间体的混合物，并且能够使用常规的分离纯化方式将式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物实现很好的分离，同时，三种中间体均为有用的中间体。发明人通过调节3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇的量，可以分别得到式(Ⅰ)或式(Ⅱ)或式(Ⅲ)之一为优势化合物的中间体混合物，可以根据生产需要，主要获得式(Ⅰ)或式(Ⅱ)或式(Ⅲ)，当它们分别为优势化合物时，以式(Ⅰ)、式(Ⅱ)、式(Ⅲ)分别为100％计，它们的收率均在80％以上(表5)；余下含有式(Ⅰ)和/或式(Ⅱ)和/或式(Ⅲ)的交叉组分可以合并在下一批物料中上样，循环分离。该方法不仅解决了二酰化副产物的问题，还避免了碘的流失。However, we have surprisingly found that compound 2 reacts with 3-amino 1,2-propanediol and 3-methylamino 1,2-propanediol in the specific ratio of the present invention to obtain a formula which is soluble in water and has a low content of unknown impurities. a mixture of three intermediates of (I), formula (II), and formula (III), and capable of achieving a good compound of formula (I), formula (II), and formula (III) by conventional separation and purification. Separation, at the same time, all three intermediates are useful intermediates. The inventors can obtain one of the compounds of formula (I) or formula (II) or formula (III) as the dominant compound by adjusting the amounts of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol, respectively. The intermediate mixture can be obtained according to the production requirements, and the formula (I) or the formula (II) or the formula (III) can be mainly obtained. When they are respectively the dominant compounds, the formula (I), the formula (II) and the formula (III) are respectively For 100%, their yields are all above 80% (Table 5); the remaining cross-components containing formula (I) and / or formula (II) and / or formula (III) can be combined in the next batch of materials Load, cycle separation. This method not only solves the problem of diacylated by-products, but also avoids the loss of iodine.

本发明提供了一种同时制备并分离式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物，并且利用这三个化合物合成碘造影剂的方法，步骤如下：The present invention provides a method for simultaneously preparing and isolating a compound of the formula (I), the formula (II), the formula (III), and synthesizing an iodine contrast agent using the three compounds, the steps are as follows:

(一)、制备包含中间体式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物的混合物；(a) preparing a mixture comprising a compound of the formula (II) and a compound of the formula (I) and / or formula (III);

(二)、分离得到式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物；(2) separating the compound represented by the formula (II) and the compound represented by the formula (I) and/or the formula (III);

(三)、取式(Ⅱ)所示化合物，制备造影剂碘普罗胺；(3) taking a compound represented by the formula (II) to prepare a contrast agent iopromide;

(四)、取式(Ⅲ)所示化合物，制备造影剂碘比醇；和/或，取式(Ⅰ)所示化合物，制备造影剂碘海醇、碘佛醇、碘喷托或者碘克沙醇。(4) taking a compound represented by the formula (III) to prepare a contrast agent iodine ratio alcohol; and/or, using the compound of the formula (I), preparing a contrast agent iohexol, iodophor, iodotropine or iodogram Sand alcohol.

前述步骤(一)到步骤(四)具体阐述如下：The foregoing steps (1) to (4) are specifically described as follows:

本发明提供了一种制备、分离式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物，并且利用这些化合物合成碘造影剂的方法。The present invention provides a process for preparing, isolating a compound of the formula (II) and a compound of the formula (I) and/or formula (III), and synthesizing an iodine contrast agent using these compounds.

具体的，同时制备式(Ⅱ)与式(Ⅰ)和/或式(Ⅲ)化合物的方法如下所示；Specifically, the method for simultaneously preparing the compound of the formula (II) and the compound of the formula (I) and/or the formula (III) is as follows;

将化合物2与3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇反应，得到中间体混合物49，反应液树脂柱分离，收集各单一组分的洗脱液，分别浓缩，得到式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的纯品，干燥后获得固体，可以分别进行后续的合成反应；干燥的方式可以是喷雾干燥、真空干燥、常压干燥或冷冻干燥；含有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物交叉组分的洗脱液可以合并浓缩并套用至下一批样品上样分离。 Compound 2 is reacted with 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol to obtain intermediate mixture 49. The reaction liquid is separated by a resin column, and the eluents of each single component are collected and concentrated separately. The pure product of the formula (I), the formula (II) and the formula (III) is obtained, and after drying, a solid is obtained, and the subsequent synthesis reaction can be separately carried out; the drying method can be spray drying, vacuum drying, atmospheric drying or freezing. Drying; the eluate containing the cross-components of the compound of formula (I), formula (II), and formula (III) can be combined and concentrated and applied to the next batch of sample for separation.

其中R ₁及R ₂分别为甲基或者氢，其中，R ₁等于或不等于R ₂。 Wherein R ₁ and R ₂ are each a methyl group or a hydrogen, wherein R ₁ is equal to or not equal to R ₂ .

其中化合物2可以是游离碱，也可以是其氨基的盐，例如盐酸盐、硫酸盐、磷酸盐、氢溴酸盐等。The compound 2 may be a free base or a salt of an amino group thereof such as a hydrochloride, a sulfate, a phosphate, a hydrobromide or the like.

3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇的加料顺序没有限制。The order of addition of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol is not limited.

加料方式①：先将化合物2与3-氨基-1,2-丙二醇反应以后再与3-甲氨基-1,2-丙二醇反应；Feeding method 1: first reacting compound 2 with 3-amino-1,2-propanediol and then reacting with 3-methylamino-1,2-propanediol;

加料方式②：先将化合物2与3-甲氨基-1,2-丙二醇反应以后再与3-氨基-1,2-丙二醇反应；Feeding method 2: first reacting compound 2 with 3-methylamino-1,2-propanediol and then reacting with 3-amino-1,2-propanediol;

加料方式③：将3-氨基-1,2-丙二醇与3-甲氨基-1,2-丙二醇一起加入反应体系同时与化合物2反应。Feeding Mode 3: 3-Amino-1,2-propanediol was added to the reaction system together with 3-methylamino-1,2-propanediol while reacting with Compound 2.

优选的，反应过程中还可以加入有机碱或无机碱；所述加入碱的量与化合物2的摩尔比大于等于2.0。Preferably, an organic base or an inorganic base may be added during the reaction; the molar ratio of the added base to the compound 2 is 2.0 or more.

所述加入的碱是：三乙胺、三正丙胺、三正丁胺、二异丙基乙胺、1,8‐二氮杂二环十一碳‐7‐烯、二异丙基环己胺、碳酸钠、碳酸钾、氢氧化锂中的一种或两种以上的组合，优选三乙胺、三正丙胺、三正丁胺、二异丙基乙胺中的一种或两种以上的组合。The base added is: triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, 1,8-diazabicycloundecyl-7-ene, diisopropylcyclohexane One or a combination of two or more of an amine, sodium carbonate, potassium carbonate, and lithium hydroxide, preferably one or more of triethylamine, tri-n-propylamine, tri-n-butylamine, and diisopropylethylamine. The combination.

其中，加料方式①，3-氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3-甲氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0。Wherein, the molar ratio of the 1,3-amino-1,2-propanediol to the compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; 3-methylamino-1,2-propanediol and the compound 2 The molar ratio is from 0.2 to 3.5, preferably from 0.3 to 2.5, more preferably from 0.5 to 2.0.

加料方式②，3-甲氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3-氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0。The molar ratio of 2-methylamino-1,2-propanediol to compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; and the molar ratio of 3-amino-1,2-propanediol to compound 2 The ratio is from 0.2 to 3.5, preferably from 0.3 to 2.5, more preferably from 0.5 to 2.0.

加料方式③，3-氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3-甲氨基-1,2-丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0。The molar ratio of the 3,3-amino-1,2-propanediol to the compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; the molar ratio of 3-methylamino-1,2-propanediol to the compound 2 The ratio is from 0.2 to 3.5, preferably from 0.3 to 2.5, more preferably from 0.5 to 2.0.

进一步的，所述加料方式①、②、③中，3‐氨基‐1,2‐丙二醇与3‐甲氨基‐1,2‐ 丙二醇的量之和与化合物2的摩尔比大于等于2.0。Further, in the charging

methods

1, 2, and 3, the molar ratio of the sum of the amount of the 3-amino-1,2-propanediol to the 3-methylamino-1,2-propanediol to the compound 2 is 2.0 or more.

其中，反应溶剂可选的有N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4-二氧六环、异丙醇、乙醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合。Among them, the reaction solvent may optionally be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran. , a mixture of 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone or a mixture of two or more solvents, preferably N,N-dimethylformamide, N , one or two of N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone Mixing of the above solvents.

反应温度可选范围为-20℃～200℃，优选-10℃～150℃。The reaction temperature can be selected from the range of -20 ° C to 200 ° C, preferably from -10 ° C to 150 ° C.

反应的时间为3～24小时，优选6～24小时。The reaction time is 3 to 24 hours, preferably 6 to 24 hours.

本发明方法合成的中间体混合物由式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物组成，其中，式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％；优选的中间体混合物中，式(Ⅰ)、式(Ⅱ)和式(Ⅲ)的总含量大于等于90％。The intermediate mixture synthesized by the method of the present invention is composed of a compound represented by the formula (I), the formula (II) and the formula (III), wherein the content of one of the formula (I), the formula (II) or the formula (III) is greater than or equal to 50%; In a preferred intermediate mixture, the total content of the formula (I), the formula (II) and the formula (III) is 90% or more.

本发明的另一方面，还提供一种中间体混合物，它由式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物组成，其中，式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％；优选的，式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％，且中间体混合物中式(Ⅰ)、式(Ⅱ)和式(Ⅲ)的总含量同时大于等于90％。In another aspect of the invention, there is also provided an intermediate mixture consisting of a compound of formula (I), formula (II) and formula (III), wherein formula (I), formula (II) or formula ( The content of one of III) is 50% or more; preferably, the content of one of formula (I), formula (II) or formula (III) is 50% or more, and formula (I), formula (II) in the intermediate mixture The total content of the formula (III) is 90% or more at the same time.

本发明所述的中间体混合物中，当式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％时，即为中间体混合物的优势化合物。In the intermediate mixture of the present invention, when the content of one of the formula (I), the formula (II) or the formula (III) is 50% or more, it is a dominant compound of the intermediate mixture.

所述的中间体混合物优势化合物的含量及式(Ⅰ)、式(Ⅱ)和式(Ⅲ)的总含量指高效液相HPLC面积归一化法纯度。The content of the intermediate compound of the intermediate mixture and the total content of the formula (I), the formula (II) and the formula (III) refer to the high-performance liquid phase HPLC normalized purity.

本发明还提供一种前述由式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物组成的中间体混合物的分离方法，即：树脂柱分离，洗脱，收集各组分的洗脱液，浓缩，干燥，即得式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物成品。The invention also provides a method for separating the intermediate mixture composed of the compounds represented by the formula (I), the formula (II) and the formula (III), that is, the resin column is separated, eluted, and the elution of each component is collected. The liquid is concentrated, dried, and the finished compound of the formula (I), the formula (II) and the formula (III) is obtained.

其中树脂分离可选的树脂有离子交换树脂、大孔吸附树脂、葡聚糖凝胶。离子交换树脂具体的有阴离子交换树脂、阳离子交换树脂，阴离子交换树脂包括强碱性阴离子交换树脂、弱碱性阴离子交换树脂，阳离子交换树脂包括强酸性阳离子交换树脂，弱酸性阳离子交换树脂，大孔吸附树脂包括苯乙烯型大孔吸附树脂、丙烯酸型大孔吸附树脂，以上离子交换树脂、大孔吸附树脂及葡聚糖凝胶可以单独使用，也可以混合使用。Among the resins which can be separated by resin, there are ion exchange resins, macroporous adsorption resins, and dextran gels. The ion exchange resin specifically has an anion exchange resin, a cation exchange resin, an anion exchange resin including a strong basic anion exchange resin, a weakly basic anion exchange resin, a cation exchange resin including a strongly acidic cation exchange resin, a weakly acidic cation exchange resin, and a large pore. The adsorption resin includes a styrene type macroporous adsorption resin and an acrylic type macroporous adsorption resin, and the above ion exchange resin, macroporous adsorption resin, and dextran gel may be used singly or in combination.

方式一：由于式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的酰胺键分别含有2个、1个、0个氢，导致其分子的酸性存在差异，从而使用强碱性阴离子交换树脂过柱时，由于酸性差异造成式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物在离子交换柱上的保留时间不一致从而达到分离。Method 1: Since the amide bond of the compound of the formula (I), the formula (II) and the formula (III) respectively contains two, one, and zero hydrogens, the acidity of the molecule is different, thereby using a strong basic anion exchange resin. When the column is passed, the retention time of the compounds of the formula (I), the formula (II) and the formula (III) on the ion exchange column is inconsistent due to the difference in acidity, thereby achieving separation.

方式二：由于式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物含有氨基，具有一定碱性，式(Ⅰ)化合物不具有甲酰氨基结构，其酰胺键可以自由旋转，从而不存在阻转异构体，式(Ⅱ)化合物具有一个甲酰氨基结构，其酰胺键的旋转收到阻碍，存在阻转异构体，式(Ⅲ)化合物具有两个甲酰氨基结构，其两个酰胺键的旋转均受到阻碍，由于丙二醇的2‐位具有手性，导致其具有更多的阻转异构体。利用式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的构型差异及氨基的碱性，使用强酸性阳离子交换树脂能够对这三个化合物进行分离。Mode 2: Since the compound of formula (I), formula (II) and formula (III) contains an amino group and has a certain basicity, the compound of formula (I) does not have a formylamino structure, and the amide bond can be freely rotated, so that there is no resistance. a trans-isomer, the compound of formula (II) has a formylamino structure, the rotation of which is hindered by the rotation of the amide bond, and the atropisomer is present. The compound of formula (III) has two formylamino structures and two amides thereof. The rotation of the bond is hindered, and since the 2-position of propylene glycol is chiral, it has more atropisomers. The three compounds can be separated using a strongly acidic cation exchange resin using the configuration differences of the compounds of the formula (I), the formula (II), and the formula (III) and the basicity of the amino group.

方式三：由于式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的构型差异，其在大孔吸附树脂中的保留行为也存在差异，所以利用大孔吸附树脂也能够对这三个化合物进行分离。Mode 3: Due to the difference in the configuration of the compounds of the formula (I), the formula (II) and the formula (III), the retention behavior in the macroporous adsorption resin also differs, so the macroporous adsorption resin can also be used for these three The compound is isolated.

方式四：同样，由于式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的构型差异，其在排阻色谱葡聚糖凝胶中的保留行为也存在差异，可以利用葡聚糖凝胶排阻色谱对这三个化合物进行分离。Mode 4: Similarly, due to the difference in the configuration of the compounds of formula (I), formula (II) and formula (III), their retention behavior in the exclusion chromatography chromate gel is also different, and dextran condensation can be utilized. These three compounds were separated by size exclusion chromatography.

以上任一两种或三种或四种方式配合使用能够达到三个化合物的完全分离，也可以达到其中两个化合物的完全分离，如果只是用其中一种方式，可能会得到一部分交叉产物，但是所得交叉产物在经过简单的浓缩以后完全可以回收套用在下一批物料里面再进行分离，从而达到了式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物的全部利用。The combination of any two or three or four of the above methods can achieve complete separation of the three compounds, and can also achieve complete separation of the two compounds. If only one of them is used, a part of the cross product may be obtained, but After the simple concentration, the obtained cross product can be completely recovered and used in the next batch of materials for separation, thereby achieving the full utilization of the compound represented by formula (II) and the compound represented by formula (I) and/or formula (III). .

当树脂柱填料是阴离子交换树脂或者阳离子交换树脂的时候洗脱剂可以是水、水溶性极性溶剂或者它们的混合物，所述水溶性极性溶剂可以选自甲醇、乙醇、异丙醇、正丙醇、1-丁醇、2-丁醇、叔丁醇、乙二醇、丙三醇、1,2-丙二醇、1,3-丙二醇、丙二醇单甲醚、乙二醇单甲醚、丙酮等，优选甲醇、乙醇、异丙醇、乙二醇、丙酮。所述洗脱剂中，水溶性极性溶剂的体积占比为0～100％，优选为0～50％。When the resin column packing is an anion exchange resin or a cation exchange resin, the eluent may be water, a water-soluble polar solvent or a mixture thereof, and the water-soluble polar solvent may be selected from the group consisting of methanol, ethanol, isopropanol, and positive Propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, glycerol, 1,2-propanediol, 1,3-propanediol, propylene glycol monomethyl ether, ethylene glycol monomethyl ether, acetone Etc., preferably methanol, ethanol, isopropanol, ethylene glycol, acetone. In the eluent, the volume ratio of the water-soluble polar solvent is from 0 to 100%, preferably from 0 to 50%.

当树脂柱填料是强碱性离子交换树脂的时候洗脱剂可以添加弱碱以增加洗脱剂的洗脱能力，减小物料在树脂柱上的保留，可选的弱碱性物质有碳酸钠、碳酸氢钠、磷酸氢二钠、碳酸氢钾、醋酸钠、甲酸钠、氨水、甲氨、二甲胺、二乙胺、三乙胺、N,N-二异丙基乙胺、N,N-二异丙基环己胺、环己胺、0.1N氢氧化钠水溶液、0.1N氢氧化钾水溶液，优选碳酸钠、碳酸氢钠、磷酸氢二钠、碳酸氢钾、醋酸钠、甲酸钠、氨水、三乙胺、0.1N氢氧化钠水溶液、0.1N氢氧化钾水溶液。When the resin column packing is a strong basic ion exchange resin, the eluent may add a weak base to increase the elution ability of the eluent and reduce the retention of the material on the resin column. The optional weakly alkaline substance is sodium carbonate. , sodium bicarbonate, disodium hydrogen phosphate, potassium hydrogencarbonate, sodium acetate, sodium formate, ammonia, methylamine, dimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine, N,N - Diisopropylcyclohexylamine, cyclohexylamine, 0.1 N aqueous sodium hydroxide solution, 0.1 N potassium hydroxide aqueous solution, preferably sodium carbonate, sodium hydrogencarbonate, disodium hydrogen phosphate, potassium hydrogencarbonate, sodium acetate, sodium formate, ammonia , triethylamine, 0.1 N aqueous sodium hydroxide solution, 0.1 N potassium hydroxide aqueous solution.

当树脂柱填料是强酸性离子交换树脂的时候洗脱剂可以添加弱酸以增加洗脱剂的洗脱能力，减小物料在树脂柱上的保留，可选的弱酸性物质有甲酸、醋酸、磷酸二氢钠、0.1N盐酸水溶液、0.1N硫酸水溶液、0.1N磷酸水溶液、0.1N氢溴酸水溶液，优选甲酸、醋酸、0.1N盐酸水溶液、0.1N硫酸水溶液、0.1N磷酸水溶液。When the resin column packing is a strongly acidic ion exchange resin, the eluent may add a weak acid to increase the elution ability of the eluent and reduce the retention of the material on the resin column. The optional weakly acidic substances are formic acid, acetic acid, and phosphoric acid. Sodium dihydrogenate, 0.1 N aqueous hydrochloric acid solution, 0.1 N aqueous sulfuric acid solution, 0.1 N aqueous phosphoric acid solution, and 0.1 N aqueous hydrobromic acid solution are preferably formic acid, acetic acid, 0.1 N aqueous hydrochloric acid solution, 0.1 N sulfuric acid aqueous solution, and 0.1 N aqueous phosphoric acid solution.

当树脂柱填料是大孔吸附树脂及葡聚糖凝胶的时候，洗脱剂可以是水和水溶性极性溶剂的组合，常见的水溶性极性溶剂可以选自甲醇、乙醇、异丙醇、正丙醇、1-丁醇、2-丁醇、叔丁醇、乙二醇、丙三醇、1,2-丙二醇、1,3-丙二醇、丙二醇单甲醚、乙二醇单甲醚、丙酮，优选甲醇、乙醇、异丙醇、乙二醇、丙酮。所述洗脱剂中，水溶性极性溶剂的体积占比为0～100％，优选为0～50％。When the resin column packing is a macroporous adsorption resin and a dextran gel, the eluent may be a combination of water and a water-soluble polar solvent, and the common water-soluble polar solvent may be selected from the group consisting of methanol, ethanol, and isopropanol. , n-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, glycerol, 1,2-propanediol, 1,3-propanediol, propylene glycol monomethyl ether, ethylene glycol monomethyl ether Acetone, preferably methanol, ethanol, isopropanol, ethylene glycol, acetone. In the eluent, the volume ratio of the water-soluble polar solvent is from 0 to 100%, preferably from 0 to 50%.

树脂柱过柱过程物料重量比柱体积百分比范围可选1％～25％，优选5％～15％。其中，物料是指溶液中的溶质。The resin column through the column process material weight ratio column volume percentage range may be 1% to 25%, preferably 5% to 15%. Among them, the material refers to the solute in the solution.

树脂柱洗脱的速度可选范围为0.5～8柱体积每小时，优选洗脱的速度为1～5柱体积每小时，进一步优选1～3柱体积每小时。The rate of elution of the resin column can be selected from 0.5 to 8 column volumes per hour, preferably from 1 to 5 column volumes per hour, and more preferably from 1 to 3 column volumes per hour.

式(Ⅰ)化合物可参考WO 9808805方法合成碘海醇。Compounds of formula (I) can be synthesized by reference to the method of WO 9808805.

式(Ⅰ)化合物可参考WO 2008104853方法合成碘佛醇。Compounds of formula (I) can be synthesized by reference to the method of WO 2008104853.

式(Ⅰ)化合物可参考WO 9808805方法合成碘喷托。Compounds of formula (I) can be synthesized by reference to the method of WO 9808805.

式(Ⅰ)化合物可参考WO 2015082719方法合成碘克沙醇。Compounds of formula (I) can be synthesized with reference to the method of WO 2015082719 for the synthesis of iodixanol.

式(Ⅱ)化合物可以用两种方法合成碘普罗胺：Compounds of formula (II) can be synthesized in two ways: iopromide:

方法一：method one:

式(Ⅱ)化合物首先乙酰化生成化合物50，随后化合物50再与甲氧基乙酰氯反应得到化合物51，化合物51脱保护得到碘普罗胺(式(IV))。The compound of formula (II) is first acetylated to form compound 50, followed by reaction of compound 50 with methoxyacetyl chloride to give compound 51, which is deprotected to give iopromide (formula (IV)).

其中乙酰化试剂可选的有乙酸酐，乙酰氯，优选乙酸酐。Among them, an acetylating agent may optionally be acetic anhydride, acetyl chloride, preferably acetic anhydride.

反应溶剂可选的有N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4-二氧六环、异丙醇、乙醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合。The reaction solvent may optionally be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2 - a mixture of one or more of methyl tetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone, preferably N,N-dimethylformamide, N,N - one or more solvents of dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone the mix of.

中间体50可以选择分离以后再进行下一步反应，也可以不经分离直接进行下一步反应。The intermediate 50 can be selected for further reaction after separation, or can be directly subjected to the next reaction without isolation.

甲氧基乙酰化反应温度可选范围为-20℃～200℃，优选-10℃～150℃。The methoxyacetylation reaction temperature can be selected from the range of -20 ° C to 200 ° C, preferably from -10 ° C to 150 ° C.

甲氧基乙酰化反应溶剂可选的有N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4-二氧六环、异丙醇、乙醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合。The methoxyacetylation reaction solvent may optionally be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane. a mixture of one or more of a ring, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone, preferably N,N-dimethyl A One of amide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone Or a mixture of two or more solvents.

脱保护可选的方法有水解及氨解及醇解，优选水解；Alternative methods of deprotection include hydrolysis and aminolysis and alcoholysis, preferably hydrolysis;

水解可选的碱有碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、磷酸氢二钾、磷酸钾、氢氧化锂、氢氧化钠、氢氧化钾、碳酸铯。The bases which can be hydrolyzed are sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium carbonate.

氨解可选的有氨水、甲氨、二甲胺、乙胺、二乙胺、丙胺、二丙胺、丁胺、二丁胺。Ammonia solution may be selected from the group consisting of ammonia, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, butylamine and dibutylamine.

醇解方法为用醇作为溶剂，添加碱性物质作为试剂进行；The alcoholysis method is carried out by using an alcohol as a solvent and adding a basic substance as a reagent;

醇解的溶剂选自甲醇、乙醇、异丙醇、丙二醇甲醚；The solvent for alcoholysis is selected from the group consisting of methanol, ethanol, isopropanol, and propylene glycol methyl ether;

碱性物质选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾。The alkaline substance is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, and uncle. Sodium butoxide, potassium t-butoxide.

中间体51可以选择分离以后再进行下一步反应，也可以不经分离直接进行下一步反应。The intermediate 51 can be selected for further reaction after separation, or can be directly subjected to the next reaction without isolation.

方法二：Method Two:

式(Ⅱ)化合物直接与甲氧基乙酰氯发生甲氧基乙酰化反应，得到化合物52，随后化合物52羟基脱保护得到碘普罗胺。The compound of formula (II) is directly methoxyacetylated with methoxyacetyl chloride to give compound 52, followed by deprotection of compound 52 to give iopromide.

中间体52可以选择分离以后再进行下一步反应，也可以不经分离直接进行下一步反应。The intermediate 52 can be selected for further reaction after separation, or can be directly subjected to the next reaction without isolation.

式(Ⅲ)化合物可用两种方法合成碘比醇。The compound of formula (III) can be synthesized in two ways.

方法一：method one:

式(Ⅲ)化合物首先乙酰化生成化合物53，随后化合物53再与2-异丙基-1,3-二氧六环-5-甲酰氯反应得到化合物54，化合物54脱保护得到碘比醇(式(V))。The compound of formula (III) is first acetylated to give compound 53, which is then reacted with 2-isopropyl-1,3-dioxane-5-formyl chloride to give compound 54 which is deprotected to give the iodine ratio alcohol ( Formula (V)).

中间体53可以选择分离以后再进行下一步反应，也可以不经分离直接进行下一步反应。The intermediate 53 can be selected for further reaction after separation, or can be directly subjected to the next reaction without isolation.

化合物53与2-异丙基-1,3-二氧六环-5-甲酰氯反应步骤可以是用2-异丙基-5-羧基-1,3-二氧六环原位生成的2-异丙基-1,3-二氧六环-5-甲酰氯，也可以是制备并分离好2-异丙基-1,3-二氧六环-5-甲酰氯后再与化合物53反应。The reaction step of compound 53 with 2-isopropyl-1,3-dioxane-5-formyl chloride may be carried out in situ using 2-isopropyl-5-carboxy-1,3-dioxane. -Isopropyl-1,3-dioxane-5-formyl chloride, may also be prepared and isolated 2-isopropyl-1,3-dioxane-5-formyl chloride followed by compound 53 reaction.

化合物53与2-异丙基-1,3-二氧六环-5-甲酰氯反应温度可选范围为-20℃～200℃，优选-10℃～150℃。The reaction temperature of the compound 53 with 2-isopropyl-1,3-dioxane-5-formyl chloride can be selected from the range of -20 ° C to 200 ° C, preferably from -10 ° C to 150 ° C.

化合物53与2-异丙基-1,3-二氧六环-5-甲酰氯反应溶剂可选的有N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4-二氧六环、异丙醇、乙醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合。The reaction solvent of compound 53 with 2-isopropyl-1,3-dioxane-5-formyl chloride may be optionally N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, One of acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone Or a mixture of two or more solvents, preferably N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, One or a mixture of two or more solvents of ethanol, dimethyl sulfoxide, and N-methylpyrrolidone.

脱保护可分为连续的中间体不分离的两步，也可以分为不连续的中间体分离的两步，分别为脱乙酰基和脱1,3二氧六环保护，可以先脱乙酰基保护再脱1,3二氧六环保护，也可以先脱1,3二氧六环保护再脱乙酰基保护；Deprotection can be divided into two steps: continuous intermediates are not separated, and can also be divided into two steps of separation of discontinuous intermediates, which are deacetylated and deprotected by 1,3 dioxane, which can be deacetylated first. Protection and protection of 1,3 dioxane ring protection, can also be removed first 1,3 dioxane protection and then deacetylation protection;

脱乙酰基保护可以水解及氨解及醇解；Deacetylation protection can be hydrolyzed and aminolysis and alcoholysis;

脱1,3二氧六环保护参考华东理工大学出版社出版的《有机合成中的保护基》中的脱保护方法，优选醋酸水体系、盐酸水体系；Deprotection method for the protection of 1,3 dioxane ring reference "protective group in organic synthesis" published by East China University of Science and Technology Press, preferably acetic acid water system, hydrochloric acid water system;

脱1,3二氧六环保护温度可选范围为-20℃～200℃，优选10℃～150℃。The deprotection temperature of 1,3 dioxane can be selected from -20 ° C to 200 ° C, preferably from 10 ° C to 150 ° C.

方法二：Method Two:

式(Ⅲ)化合物直接与2-异丙基-1,3-二氧六环-5-甲酰氯发生酰化反应，得到化合物55，随后化合物55脱保护得到碘比醇。The compound of formula (III) is directly acylated with 2-isopropyl-1,3-dioxane-5-formyl chloride to give compound 55, followed by deprotection of compound 55 to give the iodine ratio alcohol.

酰化反应温度可选范围为-20℃～200℃，优选-10℃～150℃。The acylation reaction temperature can be selected from the range of -20 ° C to 200 ° C, preferably from -10 ° C to 150 ° C.

酰化反应溶剂可选的有N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4-二氧六环、异丙醇、乙醇、二甲基亚砜、N-甲基吡咯烷酮中的一种或两种以上溶剂的混合。The acylation solvent may optionally be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran. , a mixture of 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone or a mixture of two or more solvents, preferably N,N-dimethylformamide, N , one or two of N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone Mixing of the above solvents.

脱保护可分为连续的中间体不分离的两步，也可以分为不连续的中间体分离的两步，分别为脱丙二醇酯基和脱1,3二氧六环保护，可以先脱丙二醇酯基保护再脱1,3二氧六环保护，也可以先脱1,3二氧六环保护再脱丙二醇酯基保护；Deprotection can be divided into two steps: continuous intermediates are not separated, and can also be divided into two steps of separation of discontinuous intermediates, respectively, depropylene glycol ester group and deprotected 1,3 dioxane ring, which can be depropylene glycol first. The ester group protects and removes the 1,3 dioxane ring protection, and can also be protected by the 1,3 dioxane ring and then the propylene glycol ester group;

脱丙二醇酯基保护可以水解及氨解及醇解；Depropylene glycol ester group protection can be hydrolyzed and aminolysis and alcoholysis;

碱性物质选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾。The basic substance is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, and uncle Sodium butoxide, potassium t-butoxide.

中间体55可以选择分离以后再进行下一步反应，也可以不经分离直接进行下一步反应。The intermediate 55 can be selected for further reaction after separation, or can be directly subjected to the next reaction without isolation.

采用本发明的特定方法，通过先上左右手的方式，先合成中间体式(Ⅱ)与式(Ⅰ)和/或式(Ⅲ)，每个中间体都是可利用的，分离时根本不需要担心终产物损失，分离后再以这些中间体为原料分别制备得到碘造影剂，有效解决了现有制备碘普罗胺的方法中生成大量二酰化副产物、路线长、碘流失、成本高和收率低等问题。By using the specific method of the present invention, the intermediate formula (II) and the formula (I) and/or formula (III) are first synthesized by first-hand right and left hands, and each intermediate is available, and there is no need to worry when separating. The loss of the final product, after separation, the iodine contrast agent is prepared by using these intermediates as raw materials, which effectively solves the problem of generating a large amount of diacylated by-products, long route, iodine loss, high cost and recovery in the preparation method of iopromide. Low rate and other issues.

新工艺具有以下几个优点：The new process has several advantages:

1)能够将已公开的其它工艺的二酰化副产物变废为宝，综合利用，符合原子经济学理念；1) The diacylated by-products of other processes that have been disclosed can be turned into waste, comprehensive utilization, in line with the concept of atomic economics;

2)反应过程中无需严格控制3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇与化合物2的比例，且对3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇的加料顺序没有特别要求。2) There is no need to strictly control the ratio of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol to compound 2 during the reaction, and to 3-amino-1,2-propanediol and 3-methylamino The order of addition of -1,2-propanediol is not specifically required.

3)过柱过程中的交叉产物能够通过简单的浓缩回收套用至下一批使用；3) The cross product in the process of passing through the column can be applied to the next batch by simple concentration recovery;

4)树脂柱过柱过程物料重量比柱体积百分比最大可达25％，并且洗脱速度最高可达8个柱体积每小时，分离纯化效率非常高。4) Resin column through column process material weight ratio column volume percentage up to 25%, and elution speed up to 8 column volume per hour, separation and purification efficiency is very high.

5)路线简洁，操作简单，可大工业生产。5) The route is simple, the operation is simple, and it can be produced in large industries.

6)所用起始物料化合物2为易得的大宗工业化商品，并且由于化合物2位阻小，其存在一碘代或二碘代副产物的风险可忽略不计。6) The starting material compound 2 used is a readily available bulk industrial product, and the risk of the presence of monoiodo or diiodo by-products is negligible due to the small resistance of the compound 2 position.

7)通过控制反应条件，能够方便的控制碘普罗胺四个异构体的比例，使其符合原料药质量标准要求。7) By controlling the reaction conditions, the ratio of the four isomers of iopromide can be conveniently controlled to meet the requirements of the quality standards of the drug substance.

显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

附图说明DRAWINGS

图1碘普罗胺HPLC图谱(从24min开始分别是E1、E2、Z1、Z2)Figure 1 HPLC map of iopromide (E1, E2, Z1, Z2 from 24min)

图2式(Ⅰ)化合物HPLC图谱Figure 2 HPLC diagram of the compound of formula (I)

图3式(Ⅱ)化合物HPLC图谱Figure 3 HPLC diagram of the compound of formula (II)

图4式(Ⅲ)化合物HPLC图谱Figure 4 HPLC chromatogram of the compound of formula (III)

图5式(Ⅰ)化合物质谱图Figure 5 is a mass spectrum of the compound of formula (I)

图6式(Ⅱ)化合物质谱图Figure 6 Compound (II) mass spectrum

图7式(Ⅲ)化合物质谱图Figure 7 Compound (III) mass spectrum

具体实施方式detailed description

化合物结构通过核磁共振(NMR)和质谱(MS)来确定的，NMR位移(δ)以ppm的单位给出，NMR的测定是用Bruker AvanceIII 400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、重水(D ₂O)，内标为四甲基硅烷(TMS)。 The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was given in ppm. The NMR was measured using a Bruker Avance III 400 nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide. (DMSO-d6), heavy water (D ₂ O), internal standard is tetramethylsilane (TMS).

LC-MS的测定使用安捷伦液质联用仪(Agilent G6210(ESI))。The LC-MS was measured using an Agilent LC/MS (Agilent G6210 (ESI)).

HPLC的测定使用安捷伦高效液相色谱仪(Agilent 1260、Agilent 1200、Agilent 1100)。The HPLC was measured using an Agilent high performance liquid chromatograph (Agilent 1260, Agilent 1200, Agilent 1100).

薄层层析硅胶板用青岛海洋或青岛海浪GF254硅胶板。The thin layer chromatography silica gel plate was made of Qingdao Ocean or Qingdao Ocean Wave GF254 silica gel plate.

本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于成都贝斯特试剂有限公司、成都科龙化工试剂厂、韶远化学科技、成都润泽本土化工有限公司等公司。The raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products. Known starting materials can be synthesized by or according to methods known in the art, or can be purchased from Chengdu Best Chemical Co., Ltd., Chengdu Kelon Chemical Reagent Factory, Suiyuan Chemical Technology Co., Ltd., Chengdu Runze Local Chemical Co., Ltd., etc. .

N是当量浓度，w/v表示质量体积浓度，v/v表示体积体积浓度，eq表示当量。N is an equivalent concentration, w/v represents a mass volume concentration, v/v represents a volume volume concentration, and eq represents an equivalent.

实施例中的中间体混合物三种化合物总含量及中间体混合物中的优势化合物的含量指HPLC面积归一化法纯度。The total content of the three compounds in the intermediate mixture in the examples and the content of the dominant compound in the intermediate mixture refer to the HPLC area normalized purity.

实施例中的总收率％指中间体混合物三种化合物的总HPLC面积归一化法纯度。The total yield % in the examples refers to the total HPLC area normalized purity of the three compounds of the intermediate mixture.

实施例1中间体混合物的制备Preparation of the intermediate mixture of Example 1

方法1：将化合物2用N,N-二甲基乙酰胺溶解，搅拌下，为了使反应更充分的进行，可以向其中加入碱，以中和反应中生成的氯化氢，随后向其中滴加入3-氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕保温反应3～12小时，然后再滴加入3-甲氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕保温反应3～12小时，取样HPLC测定面积百分比。物料比例与产物比例见表1(化合物2当量为1)：Method 1: Dissolving Compound 2 with N,N-dimethylacetamide, and stirring, in order to allow the reaction to proceed more fully, a base may be added thereto to neutralize hydrogen chloride formed in the reaction, followed by dropwise addition thereto 3 -N,N-dimethylacetamide solution of amino-1,2-propanediol, added to the incubation reaction for 3 to 12 hours, and then added dropwise N,N-dimethyl 3-methylamino-1,2-propanediol The acetamide solution was added to the incubation reaction for 3 to 12 hours, and the area percentage was determined by sampling HPLC. The ratio of material to product is shown in Table 1 (Compound 2 is 1):

表1Table 1

从上表可以看出，当反应条件在本发明的范围内取值时，可以制备得到式(Ⅰ)、式(Ⅱ)或式(Ⅲ)化合物之一含量大于50％，并且，在优选的范围内，可以制备得到式(Ⅰ)、式(Ⅱ)或式(Ⅲ)化合物之一含量大于50％，并且，前述三种化合物总收率达到90％以上的中间体混合物。As can be seen from the above table, when the reaction conditions are within the scope of the present invention, one of the compounds of the formula (I), the formula (II) or the formula (III) can be prepared in an amount of more than 50%, and, preferably, In the range, it is possible to prepare an intermediate mixture in which the content of one of the compounds of the formula (I), the formula (II) or the formula (III) is more than 50%, and the total yield of the above three compounds is 90% or more.

方法2：将化合物2用N,N-二甲基乙酰胺溶解，搅拌下，为了使反应更充分的进行，可以向其中加入碱(二异丙基乙胺，2.5eq)，以中和反应中生成的氯化氢，随后向其中滴加入3-甲氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕保温反应3～12小时，然后再滴加入3-氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕保温反应3～12小时，取样HPLC测定面积百分比。物料比例与产物比例见表2(化合物2当量为1)：Method 2: Compound 2 is dissolved with N,N-dimethylacetamide, and under stirring, in order to allow the reaction to proceed more fully, a base (diisopropylethylamine, 2.5 eq) may be added thereto to neutralize the reaction. Hydrogen chloride formed in the middle, followed by dropwise addition of 3-methylamino-1,2-propanediol in N,N-dimethylacetamide solution, adding the incubation reaction for 3 to 12 hours, and then adding 3-amino-1 dropwise The solution of 2-propanediol in N,N-dimethylacetamide was added to the incubation reaction for 3 to 12 hours, and the area percentage was determined by sampling HPLC. The ratio of material to product is shown in Table 2 (Compound 2 is 1):

表2Table 2

从上表可以看出，当反应条件在本发明的范围内取值时，可以制备得到式(Ⅰ)、式(Ⅱ)或式(Ⅲ)化合物之一含量大于50％，三种化合物总收率在90％以上的中间体混合物。As can be seen from the above table, when the reaction conditions are within the scope of the present invention, the content of one of the compounds of the formula (I), the formula (II) or the formula (III) can be prepared to be more than 50%, and the total of the three compounds is collected. An intermediate mixture with a rate of over 90%.

方法3：将化合物2用N,N-二甲基乙酰胺溶解，搅拌下，为了使反应更充分的进行，可以向其中加入碱(二异丙基乙胺，2.5eq)，以中和反应中生成的氯化氢，随后向其中滴加入3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕保温反应3～12小时，取样HPLC测定面积百分比。物料比例与产物比例见表3(化合物2当量为1)：Method 3: Dissolving Compound 2 with N,N-dimethylacetamide, and stirring, in order to allow the reaction to proceed more fully, a base (diisopropylethylamine, 2.5 eq) may be added thereto to neutralize the reaction. Hydrogen chloride formed in the middle, followed by dropwise addition of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol in N,N-dimethylacetamide solution, adding the incubation reaction for 3 to 12 hours The area percentage was determined by sampling HPLC. The ratio of material to product is shown in Table 3 (compound 2 of compound 2 is 1):

表3table 3

方法4：将化合物2用溶剂溶解，搅拌下，为了使反应更充分的进行，可以向其中加入碱(二异丙基乙胺，2.5eq)，以中和反应中生成的氯化氢，随后向其中滴加入3-氨基-1,2-丙二醇及3-甲氨基-1,2-丙二醇的N,N-二甲基乙酰胺溶液，加毕20～30℃反应3～12小时，取样HPLC测定面积百分比。物料比例与产物比例见表4(化合物2当量为1)：Method 4: Compound 2 is dissolved in a solvent, and under stirring, in order to allow the reaction to proceed more fully, a base (diisopropylethylamine, 2.5 eq) may be added thereto to neutralize hydrogen chloride formed in the reaction, followed by A solution of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol in N,N-dimethylacetamide was added dropwise, and the reaction was carried out at 20 to 30 ° C for 3 to 12 hours, and the area was determined by HPLC. percentage. The ratio of material to product is shown in Table 4 (Compound 2 is 1):

表4Table 4

我们选取了优势化合物含量不同的式(Ⅰ)、式(Ⅱ)、式(Ⅲ)中间体混合物进行分离洗脱，结果如表5所示，其中收率均是以式(Ⅰ)、式(Ⅱ)、式(Ⅲ)为100％计。We selected the intermediate mixtures of formula (I), formula (II) and formula (III) with different dominant compound contents for separation and elution. The results are shown in Table 5, wherein the yields are all based on formula (I) and formula (I). II), formula (III) is 100%.

表5table 5

从上表可以看出，当中间体混合物中优势化合物含量达到50.58％，上样量就可以达到5％，说明中间体混合物的分离效果良好；并且随着优势化合物含量的增加，上样量从5％增加到了25％；本发明中间体混合物经一次洗脱，分离效果显著，经过浓缩，可方便地得到式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物的纯品(其HPLC面积归一化法纯度大于等于99.5％)，便于后续合成高纯度的非离子型碘造影剂。It can be seen from the above table that when the content of the dominant compound in the intermediate mixture reaches 50.58%, the loading amount can reach 5%, indicating that the separation effect of the intermediate mixture is good; and as the content of the dominant compound increases, the loading amount is from The 5% is increased to 25%; the intermediate mixture of the invention is eluted once, and the separation effect is remarkable. After concentration, the pure product of the compound of the formula (I), the formula (II) and the formula (III) can be conveniently obtained (the HPLC area thereof) The normalization method has a purity of 99.5% or more, which facilitates the subsequent synthesis of a high-purity nonionic iodine contrast agent.

实施例2中间体制备中试Example 2 Intermediate Preparation Pilot

将化合物2(5.96kg，10.0mol)用N,N-二甲基乙酰胺溶解，搅拌下，为了使反应更充分的进行，向其中加入三正丙胺(2.87kg，20.0mol)，以中和反应中生成的氯化氢，随后向其中滴加入3-氨基-1,2-丙二醇(911g，10.0mol)的N,N-二甲基乙酰胺溶液，加毕25～30℃反应12小时，然后再滴加入3-甲氨基-1,2-丙二醇(2.1kg，20.0mol)的N,N-二甲基乙酰胺溶液，加毕保温反应12小时，反应毕，减压浓缩，所得中间体混合物用水溶解后大孔吸附树脂柱层析，HPLC监测洗脱效果，分别收集式(Ⅰ)、式(Ⅱ)、式(Ⅲ)化合物流分，浓缩得式(Ⅰ)白色固体768g(见图2、图5)，质谱和氢谱数据如下：Compound 2 (5.96 kg, 10.0 mol) was dissolved with N,N-dimethylacetamide, and while stirring, in order to proceed more fully, tri-n-propylamine (2.87 kg, 20.0 mol) was added thereto to neutralize Hydrogen chloride formed in the reaction, followed by dropwise addition of 3-amino-1,2-propanediol (911 g, 10.0 mol) of N,N-dimethylacetamide solution, and addition reaction at 25-30 ° C for 12 hours, and then Add 3-methylamino-1,2-propanediol (2.1 kg, 20.0 mol) to N,N-dimethylacetamide solution, add the incubation reaction for 12 hours, complete the reaction, concentrate under reduced pressure, and obtain the intermediate mixture with water. After dissolution, the macroporous adsorption resin column chromatography was carried out, and the elution effect was monitored by HPLC. The fractions of the compound of formula (I), formula (II) and formula (III) were separately collected and concentrated to obtain 768 g of white solid of formula (I) (see Fig. 2). Figure 5), mass spectrometry and hydrogen spectrum data are as follows:

MS(ESI+):705.8[M+1] ⁺, ¹H NMR(400MH _Z,DMSO-d6):δ7.97～7.99,8.35～8.38(m,2H),5.44～5.48(m,2H),4.67～4.77(m,2H),4.46～4.55(m,2H),3.65～3.71(m,2H),3.45～3.52(m,2H),3.24～3.40(m,4H),3.08～3.16(m,2H). MS (ESI+): 705.8 [M+1] ⁺ , ¹ H NMR (400 MH _Z , DMSO-d6): δ 7.97 - 7.99, 8.35 - 8.38 (m, 2H), 5.44 - 5.48 (m, 2H), 4.67 ~4.77 (m, 2H), 4.46 to 4.55 (m, 2H), 3.65 to 3.71 (m, 2H), 3.45 to 3.52 (m, 2H), 3.24 to 3.40 (m, 4H), 3.08 to 3.16 (m, 2H).

以反应液式(Ⅰ)100％计收率75％，得式(Ⅱ)类白色玻璃态固体4.8kg(见图3、图6)，质谱和氢谱数据如下：The yield was 7% by weight of 100% of the reaction liquid of formula (I), and 4.8 kg of white glassy solid of formula (II) was obtained (see Fig. 3 and Fig. 6). The mass spectrometry and hydrogen spectrum data are as follows:

MS(ESI+):719.8[M+1] ⁺, ¹H NMR(400MH _Z,DMSO-d6):δ8.35～8.42(m,1H),5.50(s,2H),4.68～4.78(m,2H),4.58～4.62(m,1H),4.47～4.54(m,1H),3.89(brs,1H),3.61～3.70(m,2H),3.03～3.51(m,7H),2.82～2.86(m,3H). MS (ESI+): 719.8 [M+1] ⁺ , ¹ H NMR (400 MH _Z , DMSO-d6): δ 8.35 - 8.42 (m, 1H), 5.50 (s, 2H), 4.68 - 4.78 (m, 2H) ), 4.58 to 4.62 (m, 1H), 4.47 to 4.54 (m, 1H), 3.89 (brs, 1H), 3.61 to 3.70 (m, 2H), 3.03 to 3.51 (m, 7H), 2.82 to 2.86 (m) , 3H).

以反应液式(Ⅱ)100％计收率89％，得式(Ⅲ)淡黄色玻璃态固体485g(见图4、图7)，以反应液式(Ⅲ)100％计收率95％，质谱和氢谱数据如下：The yield of the reaction liquid of the formula (II) is 89%, and 485 g of the pale yellow glassy solid of the formula (III) is obtained (see FIG. 4 and FIG. 7), and the yield is 95% based on 100% of the reaction liquid (III). The mass spectrum and hydrogen spectrum data are as follows:

MS(ESI+):733.8[M+1] ⁺, ¹H NMR(400MH _Z,DMSO-d6):δ5.33～5.55(m,2H),4.87～4.97(m,2H),4.62～4.71(m,2H),3.73～3.79(m,2H),3.59～3.70(m,2H),3.40～3.49(m,6H),3.12～3.33(m,3H),2.80～2.83(m,3H). MS (ESI+): 733.8 [M+1] ⁺ , ¹ H NMR (400 MH _Z , DMSO-d6): δ 5.33 - 5.55 (m, 2H), 4.87 - 4.97 (m, 2H), 4.62 - 4.71 (m) , 2H), 3.73 to 3.79 (m, 2H), 3.59 to 3.70 (m, 2H), 3.40 to 3.49 (m, 6H), 3.12 to 3.33 (m, 3H), 2.80 to 2.83 (m, 3H).

实施例3由中间体合成造影剂Example 3 Synthesis of a contrast agent from an intermediate

(1)碘普罗胺的合成(1) Synthesis of iopromide

取式(Ⅱ)化合物(143.8g，200mmol)加入1L三口瓶中，加入290mL乙酸乙酯，45mLN,N-二甲基乙酰胺，乙酸酐(91.8g，0.9mol)和4-二甲氨基吡啶(2.44g，20mmol)，磁力搅拌，室温反应过夜，TLC监控反应至原料点及中间态消失，得到化合物50,【 ¹H NMR(400MH _Z,DMSO-d6):δ8.61～8.75(m,1H),5.56(s,2H),5.29(brs,1H),5.08(brs,1H),4.31～4.40(m,2H),4.16～4.22(m,2H),3.69～3.77(m,1H),3.31～3.61(m,3H),2.80～2.83(m,3H),2.03～2.05(m,12H)】； The compound of formula (II) (143.8 g, 200 mmol) was added to a 1 L three-necked flask, 290 mL of ethyl acetate, 45 mL of N,N-dimethylacetamide, acetic anhydride (91.8 g, 0.9 mol) and 4-dimethylaminopyridine were added. (2.44g, 20mmol), magnetically stirred at rt overnight, TLC monitored the reaction to the raw material and the intermediate point state disappeared, to give compound 50, ^{_{[1 H NMR (400MH Z, DMSO}} -d6): δ8.61 ~ 8.75 (m, 1H), 5.56 (s, 2H), 5.29 (brs, 1H), 5.08 (brs, 1H), 4.31 to 4.40 (m, 2H), 4.16 to 4.22 (m, 2H), 3.69 to 3.77 (m, 1H) , 3.31 to 3.61 (m, 3H), 2.80 to 2.83 (m, 3H), 2.03 to 2.05 (m, 12H)];

再往化合物50的反应液中加入甲氧基乙酰氯(43.4g，400mmol)，升温回流反应2-8h，TLC监控至反应至原料点消失。反应结束后，降温至室温，加入200mL纯化水，分液，水相用乙酸乙酯(100mL*2)萃取，合并有机相，饱和食盐水100mL洗一次，无水硫酸钠干燥，过滤，减压浓缩，得179.4g类白色固体化合物51，收率为93.5％，HPLC纯度为98.1％,【 ¹H NMR(400MH _Z,DMSO-d6):δ9.93～10.14(m,1H),8.68～8.95(m,1H),5.29(brs,1H),5.09(brs,1H),4.28～4.39(m,2H),3.92～4.22(m,7H),3.23～3.77(m,4H),2.81～2.84(m,3H),2.03～2.05(m,12H)】； Further, methoxyacetyl chloride (43.4 g, 400 mmol) was added to the reaction mixture of the compound 50, and the mixture was refluxed and reacted for 2 to 8 hours, and the reaction was monitored by TLC until the starting material disappeared. After the reaction was completed, the temperature was lowered to room temperature, 200 mL of purified water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phase was combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. concentrated to give white solid compound 51 179.4g, a yield of 93.5%, HPLC purity 98.1%, ^{_{[1 H NMR (400MH Z, DMSO}} -d6): δ9.93 ~ 10.14 (m, 1H), 8.68 ~ 8.95 (m, 1H), 5.29 (brs, 1H), 5.09 (brs, 1H), 4.28 to 4.39 (m, 2H), 3.92 to 4.22 (m, 7H), 3.23 to 3.77 (m, 4H), 2.81 to 2.84 (m, 3H), 2.03 to 2.05 (m, 12H)];

取化合物51(143.9g，150mmol)加入到500mL反应瓶中，加入300mL浓氨水，固体悬浮在液面上，于50℃反应，反应至得到澄清溶液。反应结束后，降温至室温，加盐酸调pH至7，离子交换树脂除盐，活性炭脱色，乙醇重结晶，得99.2g白色碘普罗胺固体，收率为83.6％，HPLC纯度为99.1％,【MS(ESI+):791.3[M+1] ⁺, ¹H NMR(400MH _Z,DMSO-d6):δ9.22～10.08(m,1H),8.53～8.67(m,1H),4.68～4.76(m,2H),4.60～4.62(m,1H),4.46～4.55(m,1H),4.01(s,2H),3.88～3.90(m,1H),3.62～3.71(m,2H),3.35～3.50(m,7H),3.02～3.15(m,3H),2.83～2.85(m,3H), ¹³C NMR(100MH _Z,D ₂O):δ172.36～171.98(m,3C),149.59,148.46～148.38(m,1C),142.54～142.39(m,1C),97.90～97.59(m,2C),89.28～89.04(m,1C),71.26,69.75,69.37,63.98,63.67,60.08～60.05(m,1C),50.36,42.25,37.71】。 Compound 51 (143.9 g, 150 mmol) was added to a 500 mL reaction flask, 300 mL of concentrated aqueous ammonia was added, and the solid was suspended on the liquid surface, and reacted at 50 ° C to obtain a clear solution. After the reaction is completed, the temperature is lowered to room temperature, hydrochloric acid is added to adjust the pH to 7, the ion exchange resin is desalted, the activated carbon is decolorized, and the ethanol is recrystallized to obtain 99.2 g of white iodoprozide solid, the yield is 83.6%, and the HPLC purity is 99.1%. MS (ESI+): 791.3 [M+1] ⁺ , ¹ H NMR (400 MH _Z , DMSO-d6): δ 9.22 - 10.08 (m, 1H), 8.53 - 8.67 (m, 1H), 4.68 - 4.76 (m) , 2H), 4.60 to 4.62 (m, 1H), 4.46 to 4.55 (m, 1H), 4.01 (s, 2H), 3.88 to 3.90 (m, 1H), 3.62 to 3.71 (m, 2H), 3.35 to 3.50 (m, 7H), 3.02 to 3.15 (m, 3H), 2.83 to 2.85 (m, 3H), ¹³ C NMR (100 MH _Z , D ₂ O): δ 172.36 to 171.98 (m, 3C), 149.59, 148.46 ～148.38(m,1C), 142.44～142.39(m,1C),97.90～97.59(m,2C),89.28～89.04(m,1C),71.26,69.75,69.37,63.98,63.67,60.08～60.05(m , 1C), 50.36, 42.25, 37.71].

从碳谱数据可以看出，由于已知碘普罗胺拥有E1、Z1、E2、Z2四个构型，所以某些碳峰存在多重峰的情况。。It can be seen from the carbon spectrum data that since iopromide is known to have four configurations of E1, Z1, E2, and Z2, there are multiple peaks in some carbon peaks. .

(2)碘普罗胺的合成(2) Synthesis of iopromide

取式(Ⅱ)化合物(3.6kg，5mol)加入20L玻璃反应釜中，加入7.3L乙酸乙酯，1.1LN,N-二甲基乙酰胺，乙酸酐(2.3kg，22.5mol)和4-二甲氨基吡啶(12.2g，100mmol)，搅拌，室温反应过夜，TLC监控反应至原料点及中间态消失，反应毕，向其中加入5L纯化水洗涤，然后再加入5L 10％碳酸钠洗涤，收集有机层，浓缩得到化合物50油状物；The compound of formula (II) (3.6 kg, 5 mol) was added to a 20 L glass reactor, and 7.3 L of ethyl acetate, 1.1 L of N, dimethylacetamide, acetic anhydride (2.3 kg, 22.5 mol) and 4-di were added. Methylaminopyridine (12.2 g, 100 mmol), stirred, and reacted at room temperature overnight. The reaction was stopped by TLC until the starting point and the intermediate state disappeared. After the reaction was completed, 5 L of purified water was added thereto, and then 5 L of 10% sodium carbonate was added for washing to collect organic matter. Layer, concentrated to give compound 50 oil;

将化合物50用10L乙酸乙酯溶解，随后向其中加入甲氧基乙酰氯(705g， 6.5mol)，升温回流反应6h，TLC监控至反应至原料点消失。反应结束后，降温至室温，加入5L纯化水，分液，水相用乙酸乙酯(2L*2)萃取，合并有机相，饱和食盐水5L洗一次，无水硫酸钠干燥，过滤，减压浓缩，得类白色泡沫状固体4.18kg，两步收率为87.1％，HPLC纯度为97.9％； Compound 50 was dissolved in 10 L of ethyl acetate, and then methoxyacetyl chloride (705 g, 6.5 mol) was added thereto, and the mixture was refluxed and reacted for 6 hours, and the reaction was monitored by TLC until the starting material disappeared. After the reaction was completed, the temperature was lowered to room temperature, 5 L of purified water was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (2L*2). The organic phase was combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate Concentrated to give a white foamy solid 4.18 kg, a two-step yield of 87.1%, HPLC purity of 97.9%;

取化合物51(4.18kg，4.36mol)向其中加入5L乙醇及5L水溶解，随后冰浴下向其中分批加入氢氧化钠(1.4kg，34.9mol)，加毕室温反应8小时，反应毕，离子交换树脂除盐，活性炭脱色，乙醇重结晶，得2.83kg白色碘普罗胺固体(见图1)，收率为82.1％，HPLC纯度为99.15％，E1+Z1＝43.96％，E2+Z2＝56.04％，符合EP8.0药用标准。经计算，原研药(美国专利US4364921)的终产物收率为44.65％，本发明方法得到的碘普罗胺的收率为47.7％～55.25％，略优于原研药，但合成途径完全不同。Compound 51 (4.18 kg, 4.36 mol) was added thereto to dissolve 5 L of ethanol and 5 L of water, and then sodium hydroxide (1.4 kg, 34.9 mol) was added thereto in an ice bath, and the reaction was carried out for 8 hours at room temperature. Deionization of ion exchange resin, decolorization of activated carbon and recrystallization of ethanol gave 2.83 kg of white iodoprozamide solid (see Figure 1). The yield was 82.1%, HPLC purity was 99.15%, E1+Z1=43.96%, E2+Z2= 56.04%, in line with the EP8.0 medicinal standard. The final product yield of the original drug (US Patent No. 4,346,921) was calculated to be 44.65%, and the yield of iopromide obtained by the method of the present invention was 47.7% to 55.25%, which was slightly better than the original drug, but the synthesis route was completely different.

(3)碘比醇的合成(3) Synthesis of iodine ratio alcohol

取式(Ⅲ)化合物(146.6g，200mmol)加入1L三口瓶中，加入290mL乙酸乙酯，45mLN,N-二甲基乙酰胺，乙酸酐(91.8g，0.9mol)和4-二甲氨基吡啶(2.44g，20mmol)，磁力搅拌，室温反应过夜，TLC监控反应至原料点及中间态消失，得到化合物53，将所得反应液直接进行下步反应；The compound of formula (III) (146.6 g, 200 mmol) was added to a 1 L three-necked flask, 290 mL of ethyl acetate, 45 mL of N,N-dimethylacetamide, acetic anhydride (91.8 g, 0.9 mol) and 4-dimethylaminopyridine were added. (2.44g, 20mmol), magnetically stirred, reacted at room temperature overnight, the reaction was monitored by TLC until the starting point and the intermediate state disappeared to obtain compound 53, and the obtained reaction liquid was directly subjected to the next reaction;

向反应瓶中加入2-异丙基-5-羧基-1,3-二氧六环(69.7g，400mmol)，200mL乙酸乙酯，冰浴下向其中逐滴加入氯化亚砜(95.2g，800mmol)，加毕回流反应7h，随后减压蒸馏除去乙酸乙酯及氯化亚砜，残余物用100mL乙酸乙酯溶解，冰浴下逐滴加入化合物53的反应液中，加入毕，60～70℃搅拌反应2-8h，TLC监控至反应至原料点消失。反应结束后，降温至室温，加入200mL纯化水，分液，水相用乙酸乙酯(100mL*2)萃取，合并有机相，饱和食盐水100mL洗一次，无水硫酸钠干燥，过滤，减压浓缩，得193.1g类白色固体化合物54，收率为91.3％，HPLC纯度为97.3％。2-isopropyl-5-carboxy-1,3-dioxane (69.7 g, 400 mmol) was added to the reaction flask, and ethyl acetate (200 mL) was added dropwise to the mixture. , 800 mmol), adding reflux reaction for 7 h, then distilling off ethyl acetate and thionyl chloride under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, and the reaction mixture of compound 53 was added dropwise under ice bath, and added, 60 The reaction was stirred at -70 ° C for 2-8 h, and the reaction was monitored by TLC until the starting material disappeared. After the reaction was completed, the temperature was lowered to room temperature, 200 mL of purified water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phase was combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Concentration gave 193.1 g of an off-white solid compound 54 in a yield of 91.3%.

取化合物54(105.7g，100mmol)加入到反应瓶中，加入200mL甲醇。取氢氧化钠(18.0g，450mmol)溶于200mL水中，冷却至室温后，将氢氧化钠溶液加入化合物54的甲醇溶液中，室温搅拌反应3-4h，TLC监控至原料及中间态消失，随后冰浴下向其中滴加入浓盐酸(75mL，900mmol)，加毕室温反应6-8h，TLC监控至原料消失，冰浴下用10％氢氧化钠调节pH至7-8，离子交换树脂除盐后将水浓缩至干，所得残余物用异丙醇重结晶得68.1g白色碘比醇固体，收率81.5％，HPLC纯度98.2％。Compound 54 (105.7 g, 100 mmol) was added to a reaction flask and 200 mL of methanol was added. Sodium hydroxide (18.0 g, 450 mmol) was dissolved in 200 mL of water, and after cooling to room temperature, the sodium hydroxide solution was added to the methanol solution of the compound 54 and stirred at room temperature for 3-4 h, and the TLC was monitored until the starting material and the intermediate state disappeared. Concentrated hydrochloric acid (75 mL, 900 mmol) was added dropwise to the mixture under ice-cooling, and the mixture was reacted at room temperature for 6-8 h. The mixture was monitored by TLC until the starting material disappeared. The pH was adjusted to 7-8 with 10% sodium hydroxide in an ice bath, and the ion exchange resin was desalted. After that, the water was concentrated to dryness, and the obtained residue was crystallized from isopropyl alcohol to give 68.1 g of white iodine as an alcohol solid, yield 81.5%, HPLC purity 98.2%.

(4)碘海醇的合成(4) Synthesis of iohexol

取式(Ⅰ)化合物(200g，0.28mol)加入1L三口瓶中，向其中加入乙酸酐(432g，4.23mol)和对甲苯磺酸一水合物(1g，5.42mmol)，搅拌加热回流3.0小时，随后减压浓缩至刚好能够搅动，向反应液中分批加入甲醇(25g)，搅拌1.0小时后再向其中加入甲醇(140g)，加毕搅拌反应1.0小时，减压浓缩至刚好能够搅动，随后向其中加入纯化水(20g)，加毕60℃搅拌过夜。A compound of the formula (I) (200 g, 0.28 mol) was added to a 1 L three-necked flask, and acetic anhydride (432 g, 4.23 mol) and p-toluenesulfonic acid monohydrate (1 g, 5.42 mmol) were added thereto, and the mixture was heated under reflux for 3.0 hours. Then, it was concentrated under reduced pressure until it was just stirred, and methanol (25 g) was added portionwise to the reaction mixture. After stirring for 1.0 hour, methanol (140 g) was added thereto, and the reaction was stirred for 1.0 hour, and concentrated under reduced pressure until it was just stirred. Purified water (20 g) was added thereto, and stirred at 60 ° C overnight.

将反应液降温至30℃以下，取反应液200mL，搅拌下用50％w/v氢氧化钠水溶液将反应液pH调节至12，向反应液中加入1-氯-2,3-丙二醇(20g，0.18mol)，反应过程中通过补加50％w/v氢氧化钠水溶液的方式保持反应液的pH在11～12之间，反应12.0小时后向其中补加1-氯-2,3-丙二醇(3g，29.29mmol)，加毕继续反应48.0小时，反应液取样HPLC检测，碘海醇纯度为89.9％。The reaction solution was cooled to 30 ° C or lower, 200 mL of the reaction liquid was taken, and the pH of the reaction liquid was adjusted to 12 with a 50% w/v sodium hydroxide aqueous solution under stirring, and 1-chloro-2,3-propanediol (20 g) was added to the reaction liquid. , 0.18 mol), the pH of the reaction solution was maintained between 11 and 12 by adding 50% w/v sodium hydroxide aqueous solution during the reaction, and 1-chloro-2,3- was added thereto after 12.0 hours of reaction. Propylene glycol (3 g, 29.29 mmol) was further reacted for 48.0 hours, and the reaction liquid was sampled by HPLC. The purity of iohexol was 89.9%.

(5)碘佛醇的合成(5) Synthesis of iodophor

取式(Ⅰ)化合物(200g，0.28mol)加入1L三口瓶中，向其中加入N-甲基吡咯烷酮(200mL)，搅拌下向其中加入氯乙酰氯(200mL)，加毕50-53℃反应3.0小时，反应毕，降温至20℃，将反应液缓慢加入甲醇(2000mL)中。加毕，回流9.0小时，反应毕，降温至25℃，抽滤，滤饼用甲醇洗涤，烘干，得白色固体177g，收率79.8％，HPLC纯度98.3％。A compound of the formula (I) (200 g, 0.28 mol) was added to a 1 L three-necked flask, and N-methylpyrrolidone (200 mL) was added thereto, and chloroacetyl chloride (200 mL) was added thereto with stirring, and the reaction was carried out at 50-53 ° C. After the reaction was completed, the temperature was lowered to 20 ° C, and the reaction mixture was slowly added to methanol (2000 mL). After the addition, refluxing for 9.0 hours, the reaction was completed, the temperature was lowered to 25 ° C, suction filtration, and the filter cake was washed with methanol and dried to obtain 177 g of a white solid, yield 79.8%, HPLC purity 98.3%.

取上一步所得固体(150g，0.19mol)加入1L三口瓶中，向其中加入纯化水300mL，醋酸钠三水合物(183g，1.34mol)加毕回流反应，反应过程中通过补加50％w/v氢氧化钠水溶液的方式保持反应液的pH在5-6之间，反应毕，向反应液中加入浓盐酸，调节pH3-4，搅拌3.0小时后过滤，滤饼用纯化水洗涤至中性，烘干，得白色固体127g，收率86.7％，HPLC98.4％。The solid obtained in the previous step (150 g, 0.19 mol) was added to a 1 L three-necked flask, and 300 mL of purified water was added thereto, and sodium acetate trihydrate (183 g, 1.34 mol) was added to the reflux reaction, and 50% w/ was added during the reaction. v The aqueous sodium hydroxide solution maintains the pH of the reaction solution between 5 and 6. After the reaction is completed, concentrated hydrochloric acid is added to the reaction solution to adjust the pH 3-4, stirred for 3.0 hours, and then filtered, and the filter cake is washed with purified water until neutral. , dried, gave a white solid 127g, yield 86.7%, HPLC 98.4%.

取上步所得固体(100g，0.13mol)，加入1L三口瓶中，向其中加入纯化水300mL，氯化钠(46.5g，0.796mol)，加毕，升温至50℃，向其中加入10N氢氧化钠水溶液(39.3mL)及2-氯乙醇(63.5g，0.79mol)，加毕保温48-52℃反应5.0小时，反应毕，向其中加入浓盐酸调节pH6.5，反应液HPLC检测，碘海醇纯度89.7％。The solid obtained in the above step (100 g, 0.13 mol) was added to a 1 L three-necked flask, and 300 mL of purified water, sodium chloride (46.5 g, 0.796 mol) was added thereto, and the mixture was heated to 50 ° C, and 10 N hydroxide was added thereto. Aqueous sodium solution (39.3 mL) and 2-chloroethanol (63.5 g, 0.79 mol) were added to the reaction at 48-52 ° C for 5.0 hours. After the reaction was completed, concentrated hydrochloric acid was added thereto to adjust pH 6.5, and the reaction liquid was detected by HPLC. The alcohol purity was 89.7%.

(6)碘喷托的合成(6) Synthesis of iodine spray

取式(Ⅰ)化合物(200g，0.28mol)加入1L三口瓶中，向其中加入乙酸酐(432g，4.23mol)和对甲苯磺酸一水合物(1g，5.42mmol)，搅拌加热回流3.0小时，随后减压浓缩至刚好能够搅动，向反应液中分批加入甲醇(25g)，搅拌 1.0小时后再向其中加入甲醇(140g)，加毕搅拌反应1.0小时，减压浓缩至刚好能够搅动，随后向其中加入纯化水(20g)，加毕60℃搅拌过夜。A compound of the formula (I) (200 g, 0.28 mol) was added to a 1 L three-necked flask, and acetic anhydride (432 g, 4.23 mol) and p-toluenesulfonic acid monohydrate (1 g, 5.42 mmol) were added thereto, and the mixture was heated under reflux for 3.0 hours. Then, it was concentrated under reduced pressure until it was just stirred, and methanol (25 g) was added portionwise to the reaction mixture. After stirring for 1.0 hour, methanol (140 g) was added thereto, and the reaction was stirred for 1.0 hour, and concentrated under reduced pressure until it was just stirred. Purified water (20 g) was added thereto, and stirred at 60 ° C overnight.

将反应液降温至30℃以下，取反应液200mL，搅拌下用50％w/v氢氧化钠水溶液将反应液pH调节至12，向反应液中加入1-氯-3-甲氧基-2-丙醇(22.5g，0.18mol)，反应过程中通过补加50％w/v氢氧化钠水溶液的方式保持反应液的pH在11～12之间，反应12.0小时后向其中补加1-氯-2,3-丙二醇(3.4g，29.29mmol)，加毕继续反应48.0小时，反应液取样HPLC检测，碘喷托纯度为91.3％。The reaction solution was cooled to 30 ° C or lower, 200 mL of the reaction liquid was taken, and the pH of the reaction liquid was adjusted to 12 with a 50% w/v sodium hydroxide aqueous solution under stirring, and 1-chloro-3-methoxy-2 was added to the reaction liquid. -propanol (22.5g, 0.18mol), the pH of the reaction solution was maintained between 11 and 12 by adding 50% w/v aqueous sodium hydroxide solution during the reaction. After the reaction was carried out for 12.0 hours, 1-1 was added thereto. Chloro-2,3-propanediol (3.4 g, 29.29 mmol) was further reacted for 48.0 hours after the addition, and the reaction liquid was sampled by HPLC, and the purity of the iodine spray was 91.3%.

(7)碘克沙醇的合成(7) Synthesis of iodixanol

取式(Ⅰ)化合物(200g，0.28mol)加入1L三口瓶中，向其中加入乙酸酐(207g，2.03mol)，乙酸(103.3mL)，对甲苯磺酸一水合物(1g，5.42mmol)，加毕将反应液加热至60℃开始反应，当反应液温度到达120-125℃后保温30分钟，降温，浓缩至刚好能搅拌后向其中加入50％v/v(600mL)，向其中缓慢滴加入50％w/v氢氧化钠水溶液，反应过程中通过补加50％w/v氢氧化钠水溶液的方式保持反应液的pH在11～12之间，反应温度保持在40-45℃，反应毕，向反应液中加入浓盐酸调节pH3-4，搅拌3.0小时后抽滤，滤饼用水洗涤至中性，烘干，得白色固体187g，收率88.2％，HPLC98.14％。A compound of the formula (I) (200 g, 0.28 mol) was added to a 1 L three-necked flask, and acetic anhydride (207 g, 2.03 mol), acetic acid (103.3 mL), p-toluenesulfonic acid monohydrate (1 g, 5.42 mmol) was added thereto. After the addition, the reaction solution was heated to 60 ° C to start the reaction. When the temperature of the reaction solution reached 120-125 ° C, the temperature was kept for 30 minutes, the temperature was lowered, and the mixture was concentrated until it was just stirred, and then 50% v/v (600 mL) was added thereto, and slowly dripped thereinto. Add 50% w/v sodium hydroxide aqueous solution, and maintain the pH of the reaction solution between 11 and 12 by adding 50% w/v sodium hydroxide aqueous solution during the reaction, and keep the reaction temperature at 40-45 ° C. After completion, concentrated hydrochloric acid was added to the reaction solution to adjust pH 3-4, stirred for 3.0 hours, and then suction filtered, and the filter cake was washed with water until neutral, and dried to give 187 g of white solid, yield 88.2%, HPLC 98.14%.

去上步所得固体(150g，0.2mol)加入三口瓶中，向其中加入氢氧化钠(14.4g，0.36mol)，纯化水(300mL)，环氧氯丙烷(27.9g，0.30mol)，加毕30-35℃反应72.0小时，反应毕，用浓盐酸调节pH3-4，碘克沙醇HPLC纯度72.5％，碘海醇HPLC11.3％。The solid obtained in the above step (150 g, 0.2 mol) was added to a three-necked flask, and sodium hydroxide (14.4 g, 0.36 mol), purified water (300 mL), and epichlorohydrin (27.9 g, 0.30 mol) were added thereto. The reaction was carried out at 30-35 ° C for 72.0 hours. After completion of the reaction, pH 3-4 was adjusted with concentrated hydrochloric acid, the HPLC purity of iodixanol was 72.5%, and the iohexol HPLC was 11.3%.

综上，本发明的方法操作简单，得到的式(Ⅰ)、式(Ⅱ)或式(Ⅲ)三个中间体都能作为合成碘造影剂的原料，没有真正意义上的副产物；更重要的是，可以方便的合成碘普罗胺，不会有二酰化副产物产生，与原研药的生产工艺相比，工艺路线完全不同，收率高，成本低，为工业化生产碘普罗胺提供了一种非常有效的、全新的途径，应用前景广阔。In summary, the method of the present invention is simple to operate, and the obtained three intermediates of formula (I), formula (II) or formula (III) can be used as raw materials for synthesizing iodine contrast agent, and there is no real by-product; more important It is convenient to synthesize iopromide, and there is no diacylation by-product. Compared with the original production process, the process route is completely different, the yield is high, and the cost is low, which provides industrial production of iopromide. A very effective and completely new approach with broad application prospects.

Claims

一种造影剂中间体的合成方法，其特征在于：步骤如下：取化合物2或者其氨基盐，加入3‐氨基‐1,2‐丙二醇和3‐甲氨基‐1,2‐丙二醇，反应，得到式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物的中间体混合物；A method for synthesizing a contrast agent intermediate, characterized in that the steps are as follows: taking compound 2 or an amino salt thereof, adding 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol, and reacting An intermediate mixture of a compound of formula (II) with a compound of formula (I) and/or formula (III);

所述化合物2的结构式如下：The structural formula of the compound 2 is as follows:

式(Ⅰ)、式(Ⅱ)和式(Ⅲ)如下：Formula (I), Formula (II) and Formula (III) are as follows:
根据权利要求1所述的方法，其特征在于：所述氨基盐是盐酸盐、硫酸盐、磷酸盐、氢溴酸盐。The method of claim 1 wherein said amino salt is a hydrochloride, a sulfate, a phosphate or a hydrobromide.
根据权利要求1所述的方法，其特征在于：3‐氨基‐1,2‐丙二醇及3‐甲氨基‐1,2‐丙二醇的加料方式为：The method of claim 1 wherein the 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol are fed in the following manner:

①：先将化合物2与3‐氨基‐1,2‐丙二醇反应以后，再与3‐甲氨基‐1,2‐丙二醇反应；1: reacting compound 2 with 3-amino-1,2-propanediol, and then reacting with 3-methylamino-1,2-propanediol;

或，②：先将化合物2与3‐甲氨基‐1,2‐丙二醇反应以后，再与3‐氨基‐1,2‐丙二醇反应；Or, 2: reacting compound 2 with 3-methylamino-1,2-propanediol, and then reacting with 3-amino-1,2-propanediol;

或，③：将3‐氨基‐1,2‐丙二醇与3‐甲氨基‐1,2‐丙二醇一起加入反应体系，同时与化合物2反应。Or, 3: 3-Amino-1,2-propanediol is added to the reaction system together with 3-methylamino-1,2-propanediol while reacting with Compound 2.
根据权利要求3所述的方法，其特征在于：反应过程中加入有机碱或无机碱。The method according to claim 3, characterized in that an organic base or an inorganic base is added during the reaction.
根据权利要求4所述的方法，其特征在于：所述加入碱的量与化合物2的摩尔比大于等于2.0。The method according to claim 4, wherein the molar ratio of the amount of the added base to the compound 2 is 2.0 or more.
根据权利要求5所述的方法，其特征是：所述碱为：三乙胺、三正丙胺、三正丁胺、二异丙基乙胺、1,8‐二氮杂二环十一碳‐7‐烯、二异丙基环己胺、碳酸钠、碳酸钾、氢氧化锂中的一种或两种以上的组合，优选三乙胺、三正丙胺、三正丁胺、二异丙基乙胺中的一种或两种以上的组合。The method according to claim 5, wherein the base is: triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, 1,8-diazabicycloundecene One or a combination of two or more of -7-ene, diisopropylcyclohexylamine, sodium carbonate, potassium carbonate, and lithium hydroxide, preferably triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropyl One or a combination of two or more of the ethylamines.
根据权利要求1所述的方法，其特征在于：The method of claim 1 wherein:

所述加料方式①中，3‐氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3‐甲氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；In the feeding method 1, the molar ratio of 3-amino-1,2-propanediol to compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; 3 to methylamino-1,2-propanediol and compound 2 molar ratio is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0;

所述加料方式②中，3‐甲氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3‐氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；In the charging mode 2, the molar ratio of 3-methylamino-1,2-propanediol to the compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; 3 -amino-1,2-propanediol and a compound 2 molar ratio is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0;

所述加料方式③中，3‐氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0；3‐甲氨基‐1,2‐丙二醇与化合物2的摩尔比为0.2～3.5，优选0.3～2.5，再优选0.5～2.0。In the charging mode 3, the molar ratio of 3-amino-1,2-propanediol to the compound 2 is 0.2 to 3.5, preferably 0.3 to 2.5, more preferably 0.5 to 2.0; 3 to methylamino-1,2-propanediol and the compound The molar ratio of 2 is from 0.2 to 3.5, preferably from 0.3 to 2.5, more preferably from 0.5 to 2.0.
根据权利要求7所述的方法，其特征是：所述加料方式①、②、③中，3‐氨基‐1,2‐丙二醇与3‐甲氨基‐1,2‐丙二醇的量之和与化合物2的摩尔比大于等于2.0。The method according to claim 7, wherein the sum of the amounts of 3-amino-1,2-propanediol and 3-methylamino-1,2-propanediol in the feeding modes 1, 2, and 3 The molar ratio of 2 is greater than or equal to 2.0.
根据权利要求1所述的方法，其特征在于：所述反应的溶剂选自N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4‐二氧六环、四氢呋喃、2‐甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合；The method according to claim 1, wherein the solvent for the reaction is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, and dichlorobenzene. a mixture of one or more of methane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone;

优选地，溶剂选自N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4‐二氧六环、异丙醇、乙醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合。Preferably, the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, and Mixing one or more of methyl sulfoxide and N-methylpyrrolidone.
根据权利要求1所述的方法，其特征在于：所述反应的温度为‐20℃～200℃，优选‐10℃～150℃。The method according to claim 1, characterized in that the temperature of the reaction is from -20 ° C to 200 ° C, preferably from 1-10 ° C to 150 ° C.
根据权利要求1所述的方法，其特征是：所述反应的时间为3～24小时，优选6～24小时。The method according to claim 1, wherein the reaction is carried out for a period of from 3 to 24 hours, preferably from 6 to 24 hours.
根据权利要求1所述的方法，其特征是：所述的中间体混合物由式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物组成，其中，式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％。The method of claim 1 wherein said intermediate mixture consists of a compound of formula (I), formula (II) and formula (III), wherein formula (I), formula (II) Or the content of one of the formula (III) is 50% or more.
根据权利要求12所述的方法，其特征是：中间体混合物中，式(Ⅰ)、式(Ⅱ)和式(Ⅲ)的总含量大于等于90％。The method according to claim 12, wherein the total amount of the formula (I), the formula (II) and the formula (III) in the intermediate mixture is 90% or more.
一种中间体混合物，其特征在于：由式(Ⅰ)、式(Ⅱ)和式(Ⅲ)所示化合物组成，其中，式(Ⅰ)、式(Ⅱ)或式(Ⅲ)之一的含量大于等于50％。An intermediate mixture comprising: a compound represented by formula (I), formula (II) and formula (III), wherein the content of one of formula (I), formula (II) or formula (III) Greater than or equal to 50%.
根据权利要求14所述的中间体混合物，其特征是：式(Ⅰ)、式(Ⅱ)和式(Ⅲ)的总含量大于等于90％。The intermediate mixture according to claim 14, wherein the total content of the formula (I), the formula (II) and the formula (III) is 90% or more.
一种分离式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物的方法，其特征在于：取权利要求1～13任意一项所述方法制备得到的中间体混合物或权利要求14所述的中间体混合物，树脂柱分离，洗脱，收集各组分的洗脱液，浓缩，干燥。A method for separating a compound of the formula (II) and a compound of the formula (I) and/or formula (III), characterized in that the intermediate mixture prepared by the method according to any one of claims 1 to 13 Or the intermediate mixture of claim 14, the resin column is separated, eluted, and the eluate of each component is collected, concentrated, and dried.
根据权利要求16所述的方法，其特征在于：所述树脂选自离子交换树脂、大孔吸附树脂、葡聚糖凝胶中的一种或者多种。The method according to claim 16, wherein the resin is one or more selected from the group consisting of an ion exchange resin, a macroporous adsorption resin, and a dextran gel.
根据权利要求17所述的方法，其特征在于：所述离子交换树脂可以是阴离子交换树脂或者阳离子交换树脂，阴离子交换树脂包括强碱性阴离子交换树脂、弱碱性阴离子交换树脂，阳离子交换树脂包括强酸性阳离子交换树脂，弱酸性阳离子交换树脂，大孔吸附树脂包括苯乙烯型大孔吸附树脂、丙烯酸型大孔吸附树脂。The method according to claim 17, wherein said ion exchange resin may be an anion exchange resin or a cation exchange resin, and the anion exchange resin comprises a strongly basic anion exchange resin, a weakly basic anion exchange resin, and a cation exchange resin. Strong acid cation exchange resin, weakly acidic cation exchange resin, macroporous adsorption resin including styrene type macroporous adsorption resin, acrylic type macroporous adsorption resin.
根据权利要求16所述的方法，其特征在于：洗脱采用的洗脱剂是水、水溶性极性溶剂或者它们的混合物，所述水溶性极性溶剂可以选自甲醇、乙醇、异丙醇、正丙醇、1‐丁醇、2‐丁醇、叔丁醇、乙二醇、丙三醇、1,2‐丙二醇、1,3‐丙二醇、丙二醇单甲醚、乙二醇单甲醚、丙酮等，优选甲醇、乙醇、异丙醇、乙二醇、丙酮。The method according to claim 16, wherein the eluent used for elution is water, a water-soluble polar solvent or a mixture thereof, and the water-soluble polar solvent may be selected from the group consisting of methanol, ethanol, and isopropanol. , n-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, glycerol, 1,2-propanediol, 1,3-propanediol, propylene glycol monomethyl ether, ethylene glycol monomethyl ether Acetone or the like is preferably methanol, ethanol, isopropanol, ethylene glycol or acetone.
根据权利要求19所述的方法，其特征在于：当树脂柱填料是强碱性离子交换树脂时，洗脱剂可以添加弱碱；当树脂柱填料是强酸性离子交换树脂时，洗脱剂可以添加弱酸；所述弱碱可以是碳酸钠、碳酸氢钠、磷酸氢二钠、碳酸氢钾、醋酸钠、甲酸钠、氨水、甲氨、二甲胺、二乙胺、三乙胺、N,N‐二异丙基乙胺、N,N‐二异丙基环己胺、环己胺、0.1N氢氧化钠水溶液、0.1N氢氧化钾水溶液，优选碳酸钠、碳酸氢钠、磷酸氢二钠、碳酸氢钾、醋酸钠、甲酸钠、氨水、三乙胺、0.1N氢氧化钠水溶液、0.1N氢氧化钾水溶液；所述弱酸可以是甲酸、醋酸、磷酸二氢钠、0.1N盐酸水溶液、0.1N硫酸水溶液、0.1N磷酸水溶液、0.1N氢溴酸水溶液，优选甲酸、醋酸、0.1N盐酸水溶液、0.1N硫酸水溶液、0.1N磷酸水溶液。The method according to claim 19, wherein when the resin column packing is a strong basic ion exchange resin, the eluent may be added with a weak base; when the resin column packing is a strongly acidic ion exchange resin, the eluent may be Adding a weak acid; the weak base may be sodium carbonate, sodium hydrogencarbonate, disodium hydrogen phosphate, potassium hydrogencarbonate, sodium acetate, sodium formate, ammonia, methylamine, dimethylamine, diethylamine, triethylamine, N,N -Diisopropylethylamine, N,N-diisopropylcyclohexylamine, cyclohexylamine, 0.1 N aqueous sodium hydroxide solution, 0.1 N aqueous potassium hydroxide solution, preferably sodium carbonate, sodium hydrogencarbonate, disodium hydrogen phosphate , potassium hydrogencarbonate, sodium acetate, sodium formate, ammonia, triethylamine, 0.1 N aqueous sodium hydroxide solution, 0.1 N potassium hydroxide aqueous solution; the weak acid may be formic acid, acetic acid, sodium dihydrogen phosphate, 0.1 N hydrochloric acid aqueous solution, 0.1 An aqueous solution of N sulfuric acid, a 0.1 N aqueous phosphoric acid solution, and a 0.1 N aqueous solution of hydrobromic acid are preferably formic acid, acetic acid, 0.1 N aqueous hydrochloric acid solution, 0.1 N sulfuric acid aqueous solution, and 0.1 N aqueous phosphoric acid solution.
根据权利要求19或20所述的方法，其特征在于：所述洗脱剂中，水溶性极性溶剂的体积占比为0～100％，优选为0～50％。The method according to claim 19 or 20, wherein the volume of the water-soluble polar solvent in the eluent is from 0 to 100%, preferably from 0 to 50%.
根据权利要求16所述的方法，其特征在于：树脂柱分离时，物料重量与柱体积的百分比范围可选1％～25％，优选5％～20％。The method according to claim 16, wherein the percentage of the weight of the material and the volume of the column is from 1% to 25%, preferably from 5% to 20%, when the resin column is separated.
根据权利要求16所述的方法，其特征在于：洗脱的速度可选范围为0.5～8柱体积每小时，优选洗脱的速度为1～5柱体积每小时，进一步优选1～3柱体积每小时。The method according to claim 16, wherein the elution rate is optionally in the range of 0.5 to 8 column volumes per hour, preferably at a rate of from 1 to 5 column volumes per hour, further preferably from 1 to 3 column volumes. per hour.
根据权利要求16所述的方法，其特征在于：所述浓缩采用常压蒸馏浓缩、减压蒸馏浓缩、薄膜蒸发浓缩、超滤膜浓缩或纳滤膜浓缩；或，所述干燥为喷雾干燥、真空干燥、常压干燥或冷冻干燥。The method according to claim 16, wherein the concentration is concentrated by atmospheric distillation, concentrated by vacuum distillation, concentrated by thin film evaporation, concentrated by ultrafiltration membrane or concentrated by a nanofiltration membrane; or, the drying is spray drying, Vacuum drying, atmospheric drying or freeze drying.
式(Ⅱ)所示化合物合成碘普罗胺的方法，其特征在于：步骤如下：A method for synthesizing iopromide of a compound of the formula (II), characterized in that the steps are as follows:

a、合成权利要求14或15所述的中间体混合物，分离得式(Ⅱ)所示化合物；a synthesis of the intermediate mixture of claim 14 or 15 to isolate the compound of formula (II);

b、取式(Ⅱ)所示化合物，与甲氧基乙酰氯反应；b, taking the compound of formula (II), and reacting with methoxyacetyl chloride;

c、脱保护得到碘普罗胺。c. Deprotection gives iopromide.
根据权利要求25所述的方法，其特征在于：步骤b中，式(Ⅱ)所述化合物，先乙酰化生成化合物50，再与甲氧基乙酰氯反应得到化合物51；The method according to claim 25, wherein in step b, the compound of formula (II) is first acetylated to form compound 50, and then reacted with methoxyacetyl chloride to obtain compound 51;

化合物50为
Compound 50 is

所述化合物51为
The compound 51 is
根据权利要求26所述的方法，其特征在于：The method of claim 26 wherein:

所述乙酰化试剂选自乙酸酐，乙酰氯，优选乙酸酐；The acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, preferably acetic anhydride;

反应温度可选范围为‐20℃～200℃，优选‐10℃～150℃；The reaction temperature can be selected from the range of -20 ° C to 200 ° C, preferably 1-10 ° C to 150 ° C;

反应溶剂可选的有N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4‐二氧六环、四氢呋喃、2‐甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4‐二氧六环、异丙醇、乙醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合。The reaction solvent may optionally be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2 a mixture of one or two or more solvents of -methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone, preferably N,N-dimethylformamide, N,N One or two or more solvents selected from the group consisting of dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, and N-methylpyrrolidone the mix of.
根据权利要求25所述的方法，其特征在于：式(Ⅱ)所示化合物直接与甲氧基乙酰氯发生甲氧基乙酰化反应，得到化合物52，所述化合物52为The method according to claim 25, wherein the compound of the formula (II) is directly subjected to a methoxyacetylation reaction with methoxyacetyl chloride to obtain a compound 52, wherein the compound 52 is
根据权利要求25～28任意一项所述的方法，其特征在于：步骤b中，The method according to any one of claims 25 to 28, wherein in step b,

甲氧基乙酰化反应的温度可选范围为‐20℃～200℃，优选‐10℃～150℃；The temperature of the methoxyacetylation reaction can be selected from the range of -20 ° C to 200 ° C, preferably 1-10 ° C to 150 ° C;

甲氧基乙酰化反应的溶剂选自N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4‐二氧六环、四氢呋喃、2‐甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4‐二氧六环、异丙醇、乙醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合。The solvent for the methoxyacetylation reaction is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane , a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone or a mixture of two or more solvents, preferably N,N-dimethylformamide , one of N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone or Mixing of two or more solvents.
根据权利要求25所述的方法，其特征在于：步骤c中，The method of claim 25, wherein in step c,

脱保护的方法可以是水解或者氨解或者醇解，优选水解；The method of deprotection may be hydrolysis or aminolysis or alcoholysis, preferably hydrolysis;

所述水解所需要的碱选自碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、磷酸氢二钾、磷酸钾、氢氧化锂、氢氧化钠、氢氧化钾、碳酸铯；The base required for the hydrolysis is selected from the group consisting of sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate;

所述氨解选自氨水、甲氨、二甲胺、乙胺、二乙胺、丙胺、二丙胺、丁胺、二丁胺；The ammoniation is selected from the group consisting of ammonia water, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, butylamine, and dibutylamine;

所述醇解方法为用醇作为溶剂，添加碱性物质作为试剂进行；优选地，所述醇解的溶剂选自甲醇、乙醇、丙醇、异丙醇、丙二醇甲醚；优选地，所述碱性物质选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾。The alcoholysis method is carried out by using an alcohol as a solvent and adding a basic substance as a reagent; preferably, the solvent for alcoholysis is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and propylene glycol methyl ether; preferably, the The alkaline substance is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, and uncle. Sodium butoxide, potassium t-butoxide.
式(Ⅲ)所述化合物合成碘比醇的方法，其特征在于：步骤如下：A method for synthesizing iodine specific alcohol of the compound of formula (III), characterized in that the steps are as follows:

(1)取式(Ⅲ)所示化合物，与2‐异丙基‐1,3‐二氧六环‐5‐甲酰氯反应；(1) reacting a compound of the formula (III) with 2 - isopropyl-1,3-dioxane-5-formyl chloride;

(2)脱保护得到碘比醇。(2) Deprotection gives an iodine ratio alcohol.
根据权利要求31所示的方法，其特征在于：步骤(1)中，式(Ⅲ)所述化合物，先乙酰化生成化合物53，再与2‐异丙基‐1,3‐二氧六环‐5‐甲酰氯反应得到化合物54；The method according to claim 31, wherein in the step (1), the compound of the formula (III) is first acetylated to form the compound 53 and then with 2 - isopropyl-1,3-dioxane. ‐5-formyl chloride reaction to give compound 54;

化合物53为
Compound 53 is

所述化合物54为
The compound 54 is
根据权利要求32所述的方法，其特征在于：The method of claim 32 wherein:

乙酰化试剂选自乙酸酐，乙酰氯，优选乙酸酐；The acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, preferably acetic anhydride;

反应温度范围为‐20℃～200℃，优选‐10℃～150℃；The reaction temperature ranges from -20 ° C to 200 ° C, preferably from 1-10 ° C to 150 ° C;

反应溶剂选自N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4‐二氧六环、四氢呋喃、2‐甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4‐二氧六环、异丙醇、乙醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合。The reaction solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyl a mixture of one or more of tetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone, preferably N,N-dimethylformamide, N,N-II Mixture of one or more solvents of methyl acetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone .
根据权利要求31所述的方法，其特征在于：步骤(1)中，式(Ⅲ)所示化合物直接与2‐异丙基‐1,3‐二氧六环‐5‐甲酰氯反应，得到化合物55，所述化合物55为
The method according to claim 31, wherein in the step (1), the compound of the formula (III) is directly reacted with 2 - isopropyl-1,3-dioxane-5-formyl chloride to obtain Compound 55, the compound 55 is
根据权利要求31所示的方法，其特征在于：步骤(1)中，与2‐异丙基‐1,3‐二氧六环‐5‐甲酰氯反应的温度可选范围为‐20℃～200℃，优选‐10℃～150℃；The method according to claim 31, wherein in the step (1), the temperature for reacting with 2 - isopropyl-1,3-dioxane-5-formyl chloride is in the range of -20 ° C. 200 ° C, preferably ‐10 ° C ~ 150 ° C;

反应的溶剂可以是N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、二氯甲烷、1,4‐二氧六环、四氢呋喃、2‐甲基四氢呋喃、异丙醇、乙醇、甲醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合，优选N,N‐二甲基甲酰胺、N,N‐二甲基乙酰胺、乙腈、丙酮、乙酸乙酯、1,4‐二氧六环、异丙醇、乙醇、二甲基亚砜、N‐甲基吡咯烷酮中的一种或两种以上溶剂的混合。The solvent for the reaction may be N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2- Mixing one or more of methyltetrahydrofuran, isopropanol, ethanol, methanol, dimethyl sulfoxide, N-methylpyrrolidone, preferably N,N-dimethylformamide, N,N- One or more solvents of dimethylacetamide, acetonitrile, acetone, ethyl acetate, 1,4-dioxane, isopropanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone mixing.
根据权利要求31所示的方法，其特征在于：步骤(2)中，The method of claim 31, wherein in step (2),

脱保护可以按照如下两种方式进行；Deprotection can be carried out in the following two ways;

1)先脱乙酰基保护再脱1,3二氧六环保护；1) first deacetylation protection and then 1,3 dioxane protection;

2)先脱1,3二氧六环保护再脱乙酰基保护；2) first deprotected by 1,3 dioxane and then deacetylated;

进一步地，脱乙酰基保护可以水解、氨解或者醇解；Further, the deacetylation protection may be hydrolysis, aminolysis or alcoholysis;

所述水解所需要的碱选自碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、磷酸氢二钾、磷酸钾、氢氧化锂、氢氧化钠、氢氧化钾、碳酸铯；The base required for the hydrolysis is selected from the group consisting of sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate;

所述氨解选自氨水、甲氨、二甲胺、乙胺、二乙胺、丙胺、二丙胺、丁胺、二丁胺；The ammoniation is selected from the group consisting of ammonia water, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, butylamine, and dibutylamine;

所述醇解方法为用醇作为溶剂，添加碱性物质作为试剂进行；优选地，所述醇解的溶剂选自甲醇、乙醇、丙醇、异丙醇、丙二醇甲醚；优选地，所述碱性物质选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾。The alcoholysis method is carried out by using an alcohol as a solvent and adding a basic substance as a reagent; preferably, the solvent for alcoholysis is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and propylene glycol methyl ether; preferably, the The alkaline substance is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, and uncle. Sodium butoxide, potassium t-butoxide.

所述脱1,3二氧六环保护采用的体系为醋酸水体系或者盐酸水体系；The system used for the protection of the 1,3 dioxane ring is an acetic acid water system or a hydrochloric acid water system;

所述脱1,3二氧六环保护温度范围为‐20℃～200℃，优选10℃～150℃。The deprotected 1,3 dioxane protection temperature ranges from -20 ° C to 200 ° C, preferably from 10 ° C to 150 ° C.
一种造影剂的高效合成方法，其特征在于：步骤如下：An efficient method for synthesizing a contrast agent, characterized in that the steps are as follows:

(一)、按照权利要求1～13任意一项所述方法制备中间体的混合物；(a) a mixture of intermediates prepared according to the method of any one of claims 1 to 13;

(二)、按照权利要求16～23任意一项所述方法分离得到权利要求式(Ⅱ)所示化合物与式(Ⅰ)和/或式(Ⅲ)所示化合物；(2) The compound of the formula (II) and the compound of the formula (I) and/or the formula (III) are isolated according to the method of any one of claims 16 to 23;

(三)、取式(Ⅱ)所示化合物，按照权利要求25～30任意一项所述方法制备造影剂碘普罗胺；(3) taking a compound of the formula (II), and preparing a contrast agent iopromide according to the method of any one of claims 25 to 30;

(四)、取式(Ⅲ)所示化合物，按照权利要求31～36任意一项所述方法制备造影剂碘比醇；和/或，取式(Ⅰ)所示化合物，制备造影剂碘海醇、碘佛醇、碘喷托或者碘克沙醇。(4) taking a compound of the formula (III), preparing a contrast agent iodine ratio alcohol according to the method of any one of claims 31 to 36; and/or, using the compound of the formula (I), preparing a contrast agent iodine sea Alcohol, iodulol, iodotropine or iodixanol.