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Preparation method of metoprolol

A technology of methoxyethylphenol and reaction, applied in the field of metoprolol preparation, can solve the problems of prolonging the reaction time and increasing the by-product III, and achieve the effect of high purity and shortening the reaction time

Inactive Publication Date: 2012-03-21
YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA +1
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Problems solved by technology

[0011] 1. When preparing compound II: increasing the reaction temperature can shorten the reaction time, but the by-product III increases, and the product needs to be purified by vacuum distillation (as described in CN97199796.9); the reaction temperature decreases, and the by-product III reduces (15-20 %), but need to extend the reaction time (as described in US5082969)

Method used

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  • Preparation method of metoprolol
  • Preparation method of metoprolol
  • Preparation method of metoprolol

Examples

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Embodiment 1

[0025] Add 19.2L of purified water into the 50L reactor, slowly add 0.9kg of sodium hydroxide and stir until completely dissolved. Add 3Kg of p-methoxyethylphenol, raise the temperature to 60°C, stir until completely dissolved and continue the reaction for 1 hour. The temperature was lowered to 30°C, and 2L of epichlorohydrin was added. The temperature was controlled at 30°C to continue the reaction for 4 hours. Extract with 8L of ethyl acetate, wash the ethyl acetate layer with purified water and saturated sodium chloride solution successively, and dry over anhydrous sodium sulfate. Filter, wash with ethyl acetate, and collect the filtrate. The solvent was distilled off under reduced pressure to obtain 3.8Kg of compound II with a yield of 92.6%. Purity 79.78% ( figure 1 ).

[0026] Add isopropanol and compound II into a 20L reactor, add isopropylamine dropwise, stir, heat to reflux, and react for 1 hour. The solvent was distilled off under reduced pressure until nothing...

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Abstract

The invention relates to a preparation method of metoprolol. Reaction of methoxy ethyl phenol and sodium hydroxide liquor is carried out at the temperature ranging from 30 DEG C to 80 DEG C to generate methoxy sodium ethyl phenate. When the temperature is reduced to a range between 0 DEG C and 40 DEG C, epichlorohydrin is added for reaction to obtain compound II. Due to isopropyl alcohol, the compound II is reacted with isopropyl amine to obtain metoprolol. Compared with the prior art, fewer by-products are generated during preparation of the compound II, reaction time is short, and the obtained product can be reacted with the isopropyl amine to prepare the metoprolol without being purified.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, especially the preparation method of metoprolol. Background technique [0002] Metoprolol is a selective β1 receptor blocker and is commonly used in the treatment of hypertension, coronary heart disease and myocardial infarction. Metoprolol attenuates the effects of catecholamines associated with physical and mental stress, reducing heart rate, cardiac output, and blood pressure. [0003] The chemical name of metoprolol is (±) 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol, and the clinically acceptable salts mainly include hydrochloric acid Salt, tartrate, succinate. [0004] The preparation of metoprolol mainly includes two steps, p-methoxyethylphenol reacts with epichlorohydrin to prepare compound II, and then reacts with isopropylamine to prepare metoprolol (I). [0005] [0006] US5082969 discloses a synthesis method of compound II, which is prepared by reacting p-met...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/04
Inventor 张培龙薛为哲林卓石和鹏侯鹏李玉宽宋志涛
Owner YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA
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