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Method for preparing metoprolol succinate

A technology for metoprolol succinate and metoprolol, which is applied in the field of preparing metoprolol succinate, can solve the problems of metoprolol salt recrystallization and purification, increase production cost, unfavorable solvent recovery and the like, and achieves The process is stable, easy to operate, and the effect of good practical value

Pending Publication Date: 2020-09-08
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the method is low, only 72-75%, and the operation is relatively cumbersome, and the obtained metoprolol salt also needs to be recrystallized and purified, the process is cumbersome, and the production cost is increased.
[0007] CN 106083614A has reported a kind of preparation method of metoprolol salt, tartaric acid or succinic acid is dissolved in the mixed solvent of acetone and water under reflux, under reflux condition, metoprolol acetone solution is added to tartaric acid or succinic acid Salt formation in the mixed solvent of acetone and water, filter, dry, get metoprolol salt; The description of this invention also describes that the salt forming process selects acetone / water mixed solvent system, and this system is stronger than acetone to the dissolving ability of organic acid A single system is conducive to the full dissolution and reaction of organic acids, and the amount of acetone used in the examples is very large. The mass ratio of the amount of metoprolol to the total amount of acetone has reached 1:5.5, and in the reflux state The reaction requires cooling and then crystallization. This method is cumbersome and uses an acetone / water mixed solvent system, which is unfavorable for solvent recovery. The amount of solvent used is large, which increases the cost.

Method used

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  • Method for preparing metoprolol succinate
  • Method for preparing metoprolol succinate
  • Method for preparing metoprolol succinate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0036] Example 1: Metoprolol (I) preparation

[0037] Add 200g of 2% aqueous caustic soda solution, 11.1g of epichlorohydrin, and 15.2g of 4-(2-p-methoxyethyl)phenol into the four-necked bottle, control the temperature at 30-40°C, keep the temperature for 10 hours, and the reaction ends , the water phase was separated, the organic phase was washed twice with water, and distilled to dryness under reduced pressure at 60-70°C to obtain the phenol ether mixture (Ⅳ).

[0038] Add 11.8g of isopropylamine to 41.6g of drinking water, control the temperature at 30-40°C, slowly add the phenol ether mixture (Ⅳ) obtained in the previous step, after the feeding is completed, keep it warm at 0-10°C for 8 hours, and the reaction is over, 30-40°C Evaporate the isopropylamine to dryness under reduced pressure at 40°C, add 41.6 g of methyl tert-butyl ether to the reaction flask, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase to dryness under redu...

example 2

[0039] Example 2: Metoprolol (I) preparation

[0040] Add 600 g of 2% liquid caustic soda aqueous solution, 27.7 g of epichlorohydrin, and 15.2 g of 4-(2-p-methoxyethyl)phenol into the four-necked flask, and keep the reaction at 60-70° C. for 2 hours. After the reaction is completed, the water phase is separated, the organic phase is washed twice with water, and the organic phase is distilled to dryness under reduced pressure at 90-100° C. to obtain the phenol ether mixture (IV).

[0041] Add 20.8g of isopropylamine to 124.8g of drinking water, control the temperature at 30-40°C, slowly add the phenol ether mixture (Ⅳ) obtained in the previous step, after feeding is completed, keep the temperature at 30-40°C for 2 hours, and the reaction is completed, 30-40°C Evaporate the isopropylamine to dryness under reduced pressure at 40°C, add 166.4 g of ethyl acetate to the reaction bottle, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase ...

example 3

[0042] Example 3: Metoprolol (I) preparation

[0043] Add 67g of 12% aqueous caustic soda solution, 18.5g of epichlorohydrin, and 15.2g of 4-(2-p-methoxyethyl)phenol into the four-necked bottle, and keep the reaction at 30-40°C for 5 hours. Remove the water phase, wash the organic phase twice with water, and distill the organic phase to dryness under reduced pressure at 90-100°C to obtain the phenol ether mixture (IV).

[0044]Add 20.8g of isopropylamine to 83.2g of drinking water, control the temperature at 20-30°C, slowly add the phenol ether mixture (Ⅳ) obtained in the previous step, after the feeding is completed, keep the temperature at 20-30°C for 5 hours, and when the reaction is over, control the temperature 20-30°C, evaporate the isopropylamine to dryness under reduced pressure. Add 166.4 g of methyl tert-butyl ether into the reaction flask, stir to dissolve, wash the organic phase twice with drinking water, evaporate the organic phase to dryness under reduced pressu...

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Abstract

The invention relates to a method for preparing high-purity metoprolol succinate, which adopts a single solvent system to prepare the metoprolol succinate in a reverse dropping mode. The method is simple and convenient to operate, stable in process, high in salifying yield and purity, low in process cost, and has good practical value. A single conventional solvent is adopted, so that post-treatment and solvent recovery are facilitated, and the method is environment-friendly.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for preparing metoprolol succinate. Background technique [0002] Metoprolol (trade name: Betaloc) is a drug for the treatment of angina pectoris and antiarrhythmia developed by AstraZeneca LP. Metoprolol is a selective β1 receptor blocker . Its chemical name is 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol (I). Metoprolol is used in the form of salts, mainly including metoprolol Lolol tartrate and metoprolol succinate (II). Metoprolol succinate, the structure is shown below: [0003] [0004] CN 102503843 discloses a method for preparing metoprolol succinate. Metoprolol is dissolved in anhydrous ethanol or methanol solvent, then ethanol or methanol solution of organic acid is added dropwise, and the reaction is carried out at 40-45°C for 4 -6 hours, lower the temperature to 0-5°C, stir for 1.5-2 hours, crystallize, filter with...

Claims

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Application Information

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IPC IPC(8): C07C213/04C07C217/34C07D303/23C07C41/03C07C43/205C07C51/41C07C51/43C07C55/10
CPCC07C213/04C07D303/23C07C41/03C07C51/412C07C51/43C07C43/2055C07C217/34C07C55/10
Inventor 朱晓仁向浪朱元勋颜峰峰
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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