阅读说明：本技术 一种琥珀酸美托洛尔异构体杂质的合成方法 (Method for synthesizing metoprolol succinate isomer impurity ) 是由 李宗涛 王孟 杨学谦 任中强 范立柱 冯宇 朱建益 宋迎春 翟民 刘素静 于 2020-05-14 设计创作，主要内容包括：本发明属于药物化学技术领域,具体涉及一种琥珀酸美托洛尔异构体杂质的合成方法。所述合成方法,以对甲氧基乙基苯酚为原料,经过缩合反应、开环反应、氧化反应、还原胺化反应、水解反应5步反应制得琥珀酸美托洛尔异构体杂质。本发明所述的合成方法,共5步反应,原料易得,总收率大于30％,对采用外标法来严格控制琥珀酸美托洛尔异构体杂质含量做出贡献；其合成方法操作简单,反应条件温和,产物纯度高,适用于药品质量研究,为提高琥珀酸美托洛尔原料药的质量提供保证。(The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing metoprolol succinate isomer impurities. The synthesis method comprises the steps of taking p-methoxyethyl phenol as a raw material, and carrying out 5-step reactions including condensation reaction, ring opening reaction, oxidation reaction, reductive amination reaction and hydrolysis reaction to obtain metoprolol succinate isomer impurities. The synthesis method disclosed by the invention has the advantages that 5 steps of reaction are carried out, the raw materials are easy to obtain, the total yield is more than 30%, and the method contributes to the strict control of the content of the metoprolol succinate isomer impurities by adopting an external standard method; the synthetic method is simple to operate, mild in reaction conditions and high in product purity, is suitable for medicine quality research, and provides guarantee for improving the quality of the metoprolol succinate bulk drug.)

1. A method for synthesizing metoprolol succinate isomer impurities is characterized by comprising the following steps: the method comprises the following steps:

(1) carrying out condensation reaction on p-methoxyethyl phenol and epoxy chloropropane in a solvent under the action of alkali to obtain a compound 1;

(2) the compound 1 and benzoic acid are subjected to ring-opening reaction in a solvent under the action of alkali to prepare a compound 2;

(3) carrying out oxidation reaction on the compound 2 in a solvent to obtain a compound 3;

(4) the compound 3 and isopropylamine are put into a solvent to prepare a compound 4 through reductive amination reaction;

(5) the compound 4 is put in a solvent, and isomer impurities are prepared through alkaline hydrolysis reaction;

wherein, the structural formulas of the compounds 1-4 and isomers are shown as follows:

2. the method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (1), the solvent is one or a mixture of several of methanol, ethanol, isopropanol, water, tetrahydrofuran or dioxane in any proportion.

3. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (1), the alkali is one of potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine.

4. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (1), the molar ratio of the epichlorohydrin to the p-methoxyethylphenol is 2-4: 1.

5. the method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (2), the solvent is one or a mixture of several of toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion.

6. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (2), the alkali is one of sodium bicarbonate, potassium carbonate or sodium carbonate.

7. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (3), the solvent is dichloromethane, and the oxidant adopted in the oxidation reaction is pyridinium chlorochromate.

8. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (4), the solvent is one or a mixture of several of dichloromethane, chloroform, dioxane, acetonitrile, tetrahydrofuran and toluene in any proportion.

9. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (4), the reducing agent used for the reduction is one of sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

10. The method for synthesizing metoprolol succinate isomer impurities according to claim 1, which is characterized in that: in the step (5), the solvent is a mixed solution of water and one of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane; in the step (5), the alkali is one of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing metoprolol succinate isomer impurities.

Background

Metoprolol succinate with the chemical name: 1-isopropylamino-3- [ p- (2-methoxyethyl) phenoxy ] -2-propanol succinate, trade name: betalaks, developed by the company astrazen, was approved by the FDA in 1992 for the treatment of hypertension and angina pectoris. It is a selective beta 1 receptor blocker, competes with adrenaline and noradrenaline, protects the heart at the position of the receptor, inhibits the contractility of the heart, prevents nerve impulses and avoids over-excitation, is one of the common medicines for treating hypertension, coronary heart disease, chronic heart failure and arrhythmia, and has good curative effect on angina caused by oxygen deficiency. The structural formula is as follows:

the preparation process of metoprolol succinate generally takes p-methoxyethyl phenol as an initial material, performs condensation reaction with epichlorohydrin to obtain an intermediate 3- [4- (2-methoxyethyl) phenoxy ] -1, 2-epoxypropane, and then performs ring opening reaction with isopropylamine to obtain metoprolol, wherein the ring opening reaction mainly takes the 1-position carbon atom attacked by the isopropylamine as a main component, and a trace amount of the isopropylamine can attack the 2-position carbon atom to generate the metoprolol isomer, as shown in the following:

in order to ensure the safety of clinical medication, the quality control of isomer impurities in the metoprolol succinate is required. Because only trace isomer impurities are generated in the preparation process of the metoprolol succinate, the metoprolol succinate is not easy to separate and purify and is used as an impurity reference substance. At the present stage, only one literature reports a synthetic route of the impurity analogue, but the literature reports that the reaction condition is harsh, and the reaction is carried out by raising the temperature to 190 ℃, and the literature is as follows: beta. -Adrenoceptor students.5. Proton NMR and dIR spectroscopic analysis of the transformation of the hydraulic salt.beta. -expression-blocking aryloxypropanolamines. evaluation for a sectional-recording structure with a differentiation of a to-hydrogen hydroxides bases "Journal of medical Chemistry,1979, Vol.22, No.4, p 441.

Therefore, it is necessary to develop a method for preparing metoprolol succinate isomer impurity mildly.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the method overcomes the defects of the prior art, provides a method for synthesizing metoprolol succinate isomer impurities, has the advantages of easily obtained raw materials, mild reaction conditions, high total yield and high product purity, and provides guarantee for improving the quality of metoprolol succinate bulk drug.

The metoprolol succinate isomer impurity is prepared by taking p-methoxyethyl phenol as a raw material and carrying out 5 steps of condensation reaction, ring opening reaction, oxidation reaction, reductive amination reaction and hydrolysis reaction.

The synthetic route is as follows:

the method for synthesizing the metoprolol succinate isomer impurity specifically comprises the following steps:

(1) carrying out condensation reaction on p-methoxyethyl phenol and epoxy chloropropane in a solvent under the action of alkali to obtain a compound 1;

(2) the compound 1 and benzoic acid are subjected to ring-opening reaction in a solvent under the action of alkali to prepare a compound 2;

(3) carrying out oxidation reaction on the compound 2 in a solvent to obtain a compound 3;

(4) the compound 3 and isopropylamine are put into a solvent to prepare a compound 4 through reductive amination reaction;

(5) the compound 4 is put in a solvent and subjected to alkaline hydrolysis reaction to prepare an isomer;

wherein, the structural formulas of the compounds 1-4 and isomers are shown as follows:

in the step (1), the solvent is one or a mixture of several of methanol, ethanol, isopropanol, water, tetrahydrofuran or dioxane in any proportion, preferably ethanol.

In the step (1), the alkali is one of potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, and preferably potassium carbonate or sodium hydroxide.

In the step (1), the molar ratio of the epichlorohydrin to the p-methoxyethylphenol is 2-4: 1.

in the step (2), the solvent is one or a mixture of several of toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, preferably acetonitrile.

In the step (2), the alkali is one of sodium bicarbonate, potassium carbonate or sodium carbonate, preferably sodium bicarbonate.

In the step (3), the solvent is dichloromethane, and the oxidant adopted in the oxidation reaction is pyridinium chlorochromate (PCC).

In the step (4), the solvent is one or a mixture of several of dichloromethane, chloroform, dioxane, acetonitrile, tetrahydrofuran and toluene in any proportion, preferably dichloromethane.

In the step (4), the reducing agent used for the reduction is one of sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

In the step (5), the solvent is a mixed solution of one of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and water, preferably methanol.

In the step (5), the alkali is one of sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.

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

1. the method for synthesizing the metoprolol succinate isomer impurity has 5 steps of reaction, easily obtained raw materials and more than 30% of total yield, and contributes to strictly controlling the content of the metoprolol succinate isomer impurity by adopting an external standard method.

2. The synthetic method disclosed by the invention is simple to operate, mild in reaction conditions, high in product purity, suitable for medicine quality research, and capable of providing guarantee for improving the quality of the metoprolol succinate bulk drug.

Drawings

FIG. 1 is a nuclear magnetic spectrum of metoprolol succinate isomer impurity prepared in example 10 of the present invention;

FIG. 2 is a mass spectrum of metoprolol succinate isomer impurity prepared in example 10 of the present invention;

FIG. 3 is a liquid phase purity profile of metoprolol succinate isomer impurity prepared in example 10 of the present invention.

Detailed Description

The present invention is further illustrated by, but is not limited to, the following examples.