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Preparation method for metoprolol salt

A technology of Trolol salt and Trolol base, which is applied in the field of chemistry, can solve the problems of many organic solvents, large environmental pollution, and high cost, and achieve the effects of less organic solvents, less environmental pollution, and a short preparation cycle

Active Publication Date: 2012-06-20
SHANDONG JINHE DRUG RES DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Over the years, there have been a lot of preparation methods about metoprolol, U.S. Patent US2005107635, US5082969, US20050107635A and CN97199796.9 have all described the preparation methods of metoprolol, they use p-(2-methoxyethyl) Phenol is used as the starting material, and the target product is obtained by vacuum distillation. Industrial production is not easy to operate, and more organic solvents such as toluene and isopropanol are used, causing greater environmental pollution.
European patent EP0041760A takes acetylated 3-[4-(2-methoxyethylphenoxy)]-1,2-propylene oxide as the starting material to react with isopropylamine in toluene, and then catalyzes hydrogenation to obtain the Troll base, environmental pollution is big, and yield is low, and cost is very high, is not suitable for large-scale production
The preparation method described in Chinese patent CN101607918A also takes p-(2-methoxyethyl)phenol as starting material, but adds a phase transfer catalyst, uses a large amount of organic solvents such as isopropanol, methylene chloride, etc. Production will generate a large amount of waste liquid, resulting in higher costs and greater environmental pollution

Method used

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  • Preparation method for metoprolol salt
  • Preparation method for metoprolol salt

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Embodiment 1

[0032] The preparation of embodiment 1,3-[4-(2-methoxyethyl) phenoxy]-1,2-propylene oxide (intermediate I)

[0033] Add 500ml of purified water to a 3000ml reaction bottle, start stirring, add 304g of p-(2-methoxyethyl)phenol, 158ml of epichlorohydrin (1.0 equivalent), stir for 0.5h until completely dissolved; Sodium 64g (0.8 equivalent), was added to 412ml of purified water to dissolve, after it was completely dissolved, it was lowered to room temperature, and slowly added dropwise to the mixture, the temperature was controlled at 60°C, and the drop rate was controlled, and the dropwise addition was completed in 1.5h; 60 ℃ insulation reaction for 16h. Treatment after completion of the reaction: standing for stratification, retaining the lower organic phase, washing with purified water three times, 600ml of water / time; adding 30g of anhydrous sodium sulfate to dry for 0.5h, filtering, and retaining the filtrate to obtain intermediate I 3-[4-( 400 g of 2-methoxyethyl)phenoxy]-...

Embodiment 2

[0034] Embodiment 2, the preparation of 3-[4-(2-methoxyethyl) phenoxy]-1,2-propylene oxide

[0035] Add 500ml of purified water to a 3000ml reaction flask, start stirring, add 304g of p-(2-methoxyethyl)phenol, 173ml of epichlorohydrin (1.1 equivalent), stir for 0.5h until completely dissolved. Weigh 48g (0.6 equivalent) of sodium hydroxide, add it to 412ml of purified water and dissolve it, cool it down to room temperature after it is completely dissolved, slowly add it dropwise to the mixture, control the temperature at 70°C, and control the rate of addition, and complete the dropwise addition in 1.5h. After the dropwise addition, keep the reaction at 70°C for 16h. Treatment after completion of the reaction: standing for stratification, retaining the lower organic phase, washing with purified water 600ml×3 for three times; adding 30g of anhydrous sodium sulfate to dry for 0.5h, filtering, and retaining the filtrate to obtain intermediate I: 3-[4-(2 -380 g of -methoxyethyl)ph...

Embodiment 3

[0036] Embodiment 3, the preparation of 3-[4-(2-methoxyethyl) phenoxy]-1,2-propylene oxide

[0037] Add 500ml of purified water to a 3000ml reaction flask, start stirring, add 304g of p-(2-methoxyethyl)phenol, 141ml of epichlorohydrin (0.9 equivalent), stir for 0.5h until completely dissolved. Weigh 64g (0.8 equivalent) of sodium hydroxide, add it to 412ml of purified water and dissolve it, cool it down to room temperature after it is completely dissolved, slowly add it dropwise to the mixture, control the temperature at 50°C, and control the rate of addition, and complete the dropwise addition in 1.5 hours. After the dropwise addition was completed, the reaction was incubated at 50° C. for 16 hours. Treatment after completion of the reaction: standing for stratification, retaining the lower organic phase, washing with purified water 600ml×3 for three times; adding 30g of anhydrous sodium sulfate to dry for 0.5h, filtering, and retaining the filtrate to obtain intermediate I: ...

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Abstract

The invention discloses a preparation method for metoprolol salt, which includes the steps of utilizing p-(2-methoxyethyl) phenol and epoxy chloropropane as raw materials and water or ethanol as dissolvent, and obtaining 3-[4-(2-methoxyethyl phenoxy)]-1,2-epoxypropane under the action of strong alkali; and utilizing water as dissolvent, carrying reaction between the 3-[4-(2-methoxyethyl phenoxy)]-1,2-epoxypropane and isopropylamine so that metoprolol alkali is obtained, and then carrying out reaction between the metoprolol alkali and saturated monohydric alcohol liquor of organic acid or saturated monohydric alcohol liquor of hydrochloric acid, so that the metoprolol salt is obtained. Clinically, hydrochloride, succinate, fumarate or tartrate of the compound is utilized as common medicinefor treating hypertensive disease, coronary disease, congestive heart failure and arrhythmia. The raw materials of the preparation method are cheap and easy to obtain, the water and the ethanol are utilized as the dissolvent so as to hardly cause pollution, the method is convenient in operation, high in purity of the prepared metoprolol salt, high in yield, lower in cost and extremely suitable for mass production.

Description

technical field [0001] The invention relates to a preparation method of metoprolol salt, which belongs to the technical field of chemistry. Background technique [0002] Metoprolol (metoprolol) is an aminopropanol drug, a selective β-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. And it also has a good curative effect on angina pectoris caused by hypoxia. [0003] Metoprolol is also known as Metoprolol, Betaloc, and Metoprolol. Its English name is metoprolol. Chemical name: 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol. Molecular formula is C 15 h 25 NO 3 , clinically mainly use its hydrochloride, tartrate, fumarate and succ...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/08C07C213/04C07C55/10C07C57/15C07C59/255C07C51/41
Inventor 张义智常建晖王振彭坤杨敬燕
Owner SHANDONG JINHE DRUG RES DEV
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