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Synthesis method of metoprolol succinate isomer impurities

A technology for the synthesis of metoprolol succinate and a synthetic method, which is applied in the field of synthesis of metoprolol succinate isomer impurities, can solve problems such as difficult separation and purification, and achieve simple operation, mild reaction conditions, and high product purity Effect

Inactive Publication Date: 2020-08-11
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since only a small amount of isomer impurities are produced during the preparation of metoprolol succinate, it is not easy to separate and purify as an impurity reference substance

Method used

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  • Synthesis method of metoprolol succinate isomer impurities
  • Synthesis method of metoprolol succinate isomer impurities
  • Synthesis method of metoprolol succinate isomer impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of compound 1

[0041] Dissolve p-methoxyethylphenol (1.5g, 9.9mmol) in 10mL ethanol, add it to a 25mL reaction flask, add sodium hydroxide (0.6g, 15.0mmol), stir, add epichlorohydrin (2.8g , 30.0mmol), heated to 60±2°C, stirred for 4 hours, TLC detected that the reaction was complete (petroleum ether:ethyl acetate=5:1, V / V), poured the reaction solution into purified water (30mL), and used Extracted with ethyl acetate (10 mL), kept the ethyl acetate phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain 1.6 g of a colorless oily substance, namely compound 1, with a yield of 77%.

Embodiment 2

[0043] Synthesis of compound 2

[0044] Compound 1 (1.6g, 7.7mmol) was dissolved in 10mL of acetonitrile, added to a 25mL reaction flask, benzoic acid (1.1g, 9.1mmol) was added, stirred, sodium bicarbonate (0.8g, 9.5mmol) was added, and the temperature was raised to 50±2°C, stirred for 6 hours, TLC detected the completion of the reaction (petroleum ether: ethyl acetate = 2:1, V / V), filtered to remove sodium bicarbonate and distilled under reduced pressure, the residue obtained was separated and purified by column chromatography, 2.1 g of a colorless viscous oil was obtained, which was compound 2, with a yield of 83%.

Embodiment 3

[0046] Synthesis of compound 3

[0047] Dissolve compound 2 (2.1g, 6.3mmol) in 10mL of dichloromethane, add it to a 25mL reaction flask, add pyridinium chlorochromate (2.0g, 9.4mmol), stir at room temperature, stir for 2 hours, TLC detects that the reaction is complete (petroleum ether: ethyl acetate = 2:1, V / V), the reaction solution was poured into purified water (10 mL), stirred for 5 minutes, left to stand and separated, the dichloromethane phase was retained, dried over anhydrous sodium sulfate, After concentrated under reduced pressure and separated by column chromatography, 1.8 g of a colorless oily substance was obtained, namely compound 3, with a yield of 87%.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a synthesis method of metoprolol succinate isomer impurities. According to the synthesis method, p-methoxyethyl phenol is used as a raw material, and the metoprolol succinate isomer impurity is prepared through five steps of reactions including a condensation reaction, a ring-opening reaction, an oxidation reaction, a reductive amination reaction and a hydrolysis reaction. The synthesis method provided by the invention comprises five steps of reactions, the raw materials are easy to obtain, the total yield is greater than 30%, and contribution is made to strict control of the impurity content of the metoprolol succinate isomer by adopting an external standard method; the synthesis method has the advantages of simple operation, mild reaction conditions and high product purity, is suitable for drug quality research, and provides a guarantee for improving the quality of metoprolol succinate bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method of metoprolol succinate isomer impurities. Background technique [0002] Metoprolol succinate, chemical name: 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate, trade name: Betalol Gram, developed by AstraZeneca, was approved by the FDA in 1992 for the treatment of high blood pressure and angina. It is a selective β1 receptor blocker, which competes with adrenaline and norepinephrine, protects the heart at the position of the receptor, inhibits cardiac contractility, prevents nerve impulses and avoids excessive excitement. One of the commonly used drugs for coronary heart disease, chronic heart failure and arrhythmia, it also has a good curative effect on angina pectoris caused by hypoxia. Its structural formula is as follows: [0003] [0004] The preparation process of metoprolol succinate generally takes p-meth...

Claims

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Application Information

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IPC IPC(8): C07C213/06C07C217/34C07C213/02C07C219/14C07C67/26C07C67/29C07C69/78C07D303/23
CPCC07C67/26C07C67/29C07C213/02C07C213/06C07D303/23C07C69/78C07C219/14C07C217/34
Inventor 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
Owner SHANDONG QIDU PHARMA
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