阅读说明：本技术 碘海醇杂质i的制备方法 (Process for the preparation of iohexol impurity I ) 是由 刘成荡 刘颖平 吴涛 于 2020-06-18 设计创作，主要内容包括：本发明公开了一种碘海醇杂质I的制备方法,包括如下步骤：(1)以碘海醇I-1’为原料,在碱性条件下发生分子内偶联反应,以形成化合物I’,合成路线为<Image he="228" wi="700" file="DDA0002545028530000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,所述R<Sub>1</Sub>和R<Sub>2</Sub>各自独立为羟基保护基,所述羟基保护基为自烷基、环烷基、酰基、硅烷基、芳基和杂芳基中的一种；或者,R<Sub>1</Sub>和R<Sub>2</Sub>一起形成杂环基团；(2)脱除R<Sub>1</Sub>和R<Sub>2</Sub>羟基保护基,以形成碘海醇杂质I,合成路线为<Image he="266" wi="700" file="DDA0002545028530000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of iohexol impurity I, which comprises the following steps: (1) using iohexol I-1 'as raw material, and making intramolecular coupling reaction under the alkaline condition to form compound I', and its synthesis route is Wherein, R is 1 And R 2 Each independently is a hydroxyl protecting group which is one of alkyl, cycloalkyl, acyl, silyl, aryl and heteroaryl; or, R 1 And R 2 Together form a heterocyclic group; (2) removal of R 1 And R 2 A hydroxyl protecting group to form iohexol impurity I, the synthetic route being)

1. The preparation method of iohexol impurity I is characterized by comprising the following steps:

(1) using iohexol I-1 'as raw material, and making intramolecular coupling reaction under the alkaline condition to form compound I', and its synthesis route is

Wherein, R is₁And R₂Each independently is a hydroxyl protecting group which is one of alkyl, cycloalkyl, acyl, silyl, aryl and heteroaryl; or, R₁And R₂Together form a heterocyclic group;

(2) removal of R₁And R₂A hydroxyl protecting group to form iohexol impurity I, the synthetic route being

2. The process for producing iohexol impurity I according to claim 1, wherein the base under basic conditions is at least one of an alkali metal alkoxide, an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate and an alkaline earth metal hydroxide.

3. The process for the preparation of iohexol impurity I according to claim 1 or 2, wherein the solvent used for the intramolecular coupling reaction is one of methanol, ethanol, isopropanol, n-butanol, acetonitrile and water, preferably one of methanol and water.

4. The process for the preparation of iohexol impurity I according to claim 1 or 2, wherein the temperature of the intramolecular coupling reaction is between 0 and 100 ℃.

5. The process for producing iohexol impurity I according to claim 1 or 2, wherein the concentration of the reaction solution is from 10% to 60%.

6. The process for the preparation of iohexol impurity I according to claim 1 or 2, wherein the deprotection group conditions are acidic conditions wherein the acid is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid.

Technical Field

The invention relates to a preparation method of iohexol impurity I.

Background

Iohexol (Iohexol)5- (N-2, 3-dihydroxypropyl acetamido) -2, 4, 6-triiodo-N, N-bis (2, 3-dihydroxypropyl) isophthalamide is a non-ionic X-CT contrast agent introduced by norwegian necoming ltd in the eighties, and can be widely applied to cardiovascular radiography, urography, arterial radiography, venography, endoscopic pancreatography and the like. Iohexol, by virtue of its many advantages, such as good safety, high contrast, low osmotic pressure and low toxicity to humans, has become the best-selling photographic agent in the international market at a glance and has become the "gold standard" on which the medical community evaluates various X-ray photographic agents.

However, serious adverse reactions still occur frequently, and the adverse reactions are not only related to the pharmacological activity of iohexol itself, but also related to impurities existing in iohexol. The research on the preparation process of iohexol is required to be carried out normatively, so that the iohexol is in a state of safety, environmental protection, simple operation and controllable equipment. Not only the quality standard of the product obtained in each step of the process for preparing iohexol needs to be established, but also the related substances generated in each step need to be studied in detail and controlled strictly, thereby improving the quality standard of iohexol and having important guiding significance for the safe medication of the masses.

For pharmaceutical researchers, the main work is not only how to obtain high-quality raw material medicines (APIs), develop efficient synthesis processes, but also more importantly, how to research the types and sources of impurities in the raw material medicines and how to control the generation of process impurities. Generally, researchers firstly orient impurities generated in a synthesis process, and secondly develop an efficient impurity synthesis route so as to obtain a large number of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content determination, impurity structure confirmation and the like) of each batch of raw material medicines.

At present, the iohexol impurity I is obtained by preparing a liquid phase from a crude product obtained by synthesizing iohexol from a hydrolysate and purifying the liquid phase, and because the amount of impurities generated in the synthesis is small, a large amount of liquid phase preparation and purification are required, so that the cost is very high.

Disclosure of Invention

The object of the present invention is to solve the above mentioned disadvantages of the current process for the preparation of iohexol impurity I.

In order to achieve the above object, the present invention provides a method for preparing iohexol impurity I, comprising the steps of: (1) using iohexol I-1 'as raw material, and making intramolecular coupling reaction under the alkaline condition to form compound I', and its synthesis route is

Wherein, R is₁And R₂Each independently is a hydroxyl protecting group which is one of alkyl, cycloalkyl, acyl, silyl, aryl and heteroaryl; or, R₁And R₂Together form a heterocyclic group;

(2) removal of R₁And R₂A hydroxyl protecting group to form iohexol impurity I, the synthetic route being

Further, the base of the basic condition is at least one of an alkali metal alkoxide, an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, and an alkaline earth metal hydroxide, preferably at least one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide, and more preferably at least one of sodium methoxide, sodium tert-butoxide, sodium hydroxide, and potassium hydroxide.

Further, the solvent used in the intramolecular coupling reaction is one of methanol, ethanol, isopropanol, n-butanol, acetonitrile and water, preferably one of methanol and water.

Further, the temperature of the intramolecular coupling reaction is 0 to 100 ℃, preferably 10 to 100 ℃, and more preferably 20 to 100 ℃.

Further, the concentration of the reaction solution is 10% to 60%, preferably 20% to 50%.

Further, the deprotection condition is an acidic condition, wherein the acid is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid.

Compared with the prior art, the invention has the beneficial effects that:

the method has the advantages of easily obtained raw materials, controllable reaction conditions, high product conversion rate, simple post-treatment, no need of preparing a large amount of liquid phase and low cost.

Drawings

FIG. 1 is a 1H NMR chart of iohexol impurity I prepared by one example of the present invention.

FIG. 2 is a mass spectrum of iohexol impurity I prepared by one embodiment of the present invention.

Detailed Description

The present invention will now be described in detail with reference to the accompanying drawings.

In the present invention, all parts and percentages are by weight, unless otherwise specified, and the equipment and materials used are commercially available or commonly used in the art. The methods in the following examples are conventional in the art unless otherwise specified.

The invention provides a preparation method of iohexol impurity I, which comprises the following steps: (1) using iohexol I-1 'as raw material, and making intramolecular coupling reaction under the alkaline condition to form compound I', and its synthesis route is

Wherein, R is₁And R₂Each independently is a hydroxyl protecting group which is one of alkyl, cycloalkyl, acyl, silyl, aryl and heteroaryl; or, R₁And R₂Together form a heterocyclic group;

(2) removal of R₁And R₂A hydroxyl protecting group to form iohexol impurity I, the synthetic route being

Preferably, the base of the basic condition is at least one of an alkali metal alkoxide, an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, and an alkaline earth metal hydroxide, preferably at least one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide, more preferably at least one of sodium methoxide, sodium tert-butoxide, sodium hydroxide, and potassium hydroxide. The alkali metal compound is used in an amount of 1.2 to 6.0 mol% (relative to the molar amount of the starting material compound of formula I-1'), preferably 1.5 to 5.0 mol%, more preferably 2.0 to 4.0 mol%.

Preferably, the solvent used for the intramolecular coupling reaction is one of methanol, ethanol, isopropanol, n-butanol, acetonitrile and water, preferably one of methanol and water.

Preferably, the temperature of the intramolecular coupling reaction is between 0 ℃ and 100 ℃, preferably between 10 ℃ and 100 ℃, more preferably between 20 ℃ and 100 ℃. The reaction temperature can be realized by a conventional oil bath or water bath heating mode, and in a specific embodiment, the oil bath or water bath has better influence on the reaction yield, the conversion rate or the product quality, so that the product with higher quality and yield can be obtained. The heating conditions of the oil bath or the water bath are as follows: the reaction time is 0 to 48 hours, preferably 10 to 48 hours, more preferably 15 to 30 hours.

Preferably, the concentration of the reaction solution is 10% -60%, preferably 20% -50%.

Further, the deprotection condition is an acidic condition, wherein the acid is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid.

The "hydroxyl-protecting Groups" according to the invention are suitable Groups known in the art for hydroxyl protection, see the literature ("Protective Groups in Organic Synthesis", 5)^Th.Ed.T.W.Greene&P.g.m.wuts) or 1, 2-diol, preferably the monohydroxy protection may be alkyl, cycloalkyl, acyl, silyl, aryl or heteroaryl, the acyl may be mono-but not limited to acetyl, benzoyl or pivaloyl, the silyl may be but not limited to tert-butyldimethylsilane, tert-butyldiphenylsilyl, triisopropylsilyloxymethyl or triisopropylsilyl; the 1, 2-diol protection can be achieved using cyclic acetals and ketals (e.g., acetonides, cyclopentylidene ketals, cyclohexylidene ketals, cycloheptylidene ketals, and benzylidene acetals)And (6) protecting.

The length of the alkyl group or the number of atoms in the alkyl group, aryl group is not particularly limited and should be known to or can be determined by one of ordinary skill in the art. In particular embodiments, the alkyl group is a C_1-6An alkyl group. In another embodiment, the aryl group is a C_6-14And (4) an aryl group.

"alkyl" refers to a saturated aliphatic hydrocarbon group selected from alkyl groups containing 1 to 6 carbon atoms (which may be described as C)_1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-butyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl.

"heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group containing one or more heteroatoms, including 4 to 12 ring atoms, preferably containing 5 to 8 ring atoms, most preferably 5 to 6 ring atoms, wherein the heteroatom is oxygen, sulfur or nitrogen. Non-limiting examples include heterocyclopentyl, heterocyclopentenyl, heterocyclohexyl, heterocyclohexenyl, heterocyclohexene, and the like. The heterocyclic group may be optionally substituted, and preferred substituents include alkyl, alkoxy, halogen, hydroxy and the like.

"aryl" refers to an aromatic group having at least one conjugated pi-electron ring and includes carbocyclic aryl, heterocyclic aryl (also referred to as heteroaryl groups), and biaryl groups, all of which may be optionally substituted. The aryl group may include 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, non-limiting examples include phenyl, pyridyl, or naphthyl.

The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and the spirit and scope of the present invention are not limited thereto.