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Method for preparing metoprolol succinate on scale

A technology of metoprolol succinate and compound, which is applied in the field of preparation technology of metoprolol succinate, can solve the problems of reducing the yield of the compound of formula I, the low purity of the compound of formula II, and the increase of production cost, and achieves simplified The effect of operation, faster response speed, and easy operation

Inactive Publication Date: 2012-05-02
湖南康普医药研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The low purity of the compound of formula II will eventually reduce the yield of the compound of formula I, and the production cost will increase significantly. Therefore, it is necessary to develop a method for preparing the compound of formula I that is easy to operate and cost-effective

Method used

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  • Method for preparing metoprolol succinate on scale
  • Method for preparing metoprolol succinate on scale
  • Method for preparing metoprolol succinate on scale

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 45.6g of p-methoxyethylphenol, 200mL of tetrahydrofuran, and 7.2g of sodium hydride into a 500mL three-necked flask, and stir at 50°C for 30min. 50 g of epichlorohydrin was added dropwise, and the reaction was stirred at 50° C. for 1 h after the drop was completed. The reaction was detected by TLC. After the reaction was completed, it was distilled under reduced pressure, and the residue was extracted with 200 mL of toluene and washed twice with 200 mL of water.

[0025] Add isopropylamine dropwise to the toluene solution of 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene in a 500mL three-neck flask in an ice-water bath (0-15°C) 90g, stirred for 10min and then heated to reflux, stirred and reacted for 2h. The reaction was detected by TLC. After the reaction was completed, distilled under reduced pressure, added 300mL of absolute ethanol and 20g of succinic acid to the residue, stirred and reacted at 50°C for 2h, cooled to room temperature, filtered with suction, wa...

Embodiment 2

[0027] Add 45.6g of p-methoxyethylphenol, 200mL of toluene, and 7.2g of sodium hydride into a 500mL three-necked flask, and stir at 45°C for 30min. 50 g of epichlorohydrin was added dropwise, and the reaction was stirred at 45° C. for 1.5 h after the drop was completed. The reaction was detected by TLC. After the reaction was completed, it was cooled to room temperature and washed twice with 200 mL of water.

[0028] Add isopropylamine dropwise to the toluene solution of 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene in a 500mL three-neck flask in an ice-water bath (0-15°C) 90g, stirred for 10min, heated to 50°C, refluxed, and stirred for 2h. The reaction was detected by TLC. After the reaction was completed, it was distilled under reduced pressure. Add 300mL of absolute ethanol and 20g of succinic acid to the residue, stir and react at 60°C for 2h, cool to room temperature, filter with suction, wash the filter residue with 300mL of absolute ethanol, and dry it under vacuum ...

Embodiment 3

[0030] Add 45.6g of p-methoxyethylphenol, 200mL of tetrahydrofuran, and 21g of sodium ethoxide into a 500mL three-necked flask, and react at 30°C for 30min. 50 g of epichlorohydrin was added dropwise, and the reaction was stirred at 50° C. for 2 h after the drop was completed. TLC detects the reaction. After the reaction is completed, it is distilled under reduced pressure, and the residue is extracted by adding 200mL of toluene, washed twice with 200mL of water, and the organic phase is distilled under reduced pressure to obtain 1-(2,3-epoxypropoxy)-4-(2-methanol) Oxyethyl)-benzene 60.5g, yield 97.0%.

[0031] Add 60.5g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene and 100mL of isopropanol into a 500mL three-necked flask, and put Add 90 g of isopropylamine, stir for 10 min, then raise the temperature to 50° C., reflux, and stir for 2 h. The reaction was detected by TLC. After the reaction was completed, the heating was stopped, distilled under reduced pressure, 300 mL ...

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Abstract

The invention relates to a preparation method of metoprolol succinate, which comprises the following steps: reacting para-methoxylethylphenol with sodium hydride or sodium ethylate in tetrahydrofuran to obtain para-methoxyl sodium phenate; reacting para-methoxylethyl sodium phenate with epoxy chloropropane in toluene or the tetrahydrofuran to obtain 1-(2, 3-epoxy propoxyl)-4-(2-methoxylethyl)-benzene, and then, reacting the 1-(2, 3-epoxy propoxyl)-4-(2-methoxylethyl)-benzene with isopropylamine in isopropanol or the toluene to obtain metoprolol alkali; and in absolute ethyl alcohol or chloroform, reacting the metoprolol alkali with succinic acid to obtain the metoprolol succinate.

Description

1. Technical field [0001] The invention belongs to the field of production of fine chemical products, in particular to a preparation process of metoprolol succinate. 2. Background technology [0002] Metoprolol (metoprolol) is an aminopropanol drug, a selective D-receptor blocker, and is the drug of choice for the treatment of hypertension in the world in recent years. It competes with excitatory epinephrine and norepinephrine, and protects the heart at the receptor's site, inhibits cardiac contractility, prevents hyperexcitability, and blocks nerve impulses. It also ensures the contraction of the smooth muscle of the heart wall by itself. According to the "Journal of the American College of Cardiology" published in August 2001, both high-dose and low-dose metoprolol controlled-release / sustained-release dosage forms (CR / XL) can improve the clinical prognosis of patients with chronic heart failure. And it also has a good curative effect on angina pectoris caused by hypoxia....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/32C07C213/04
Inventor 杨俊吴锋张静谷陟欣陈腊梅余小娟郝芳朱敏陈敏
Owner 湖南康普医药研究院
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