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Preparation method of succinic acid S-metoprolol

A technology of succinic acid and oil, which is applied in the field of preparation of S-metoprolol succinate, can solve the problem of low ee value of the product, and achieve the effects of low cost, low environmental pollution and low risk factor

Active Publication Date: 2014-08-13
ANHUI NEW STAR PHARMA DEV
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The Chinese patent application whose publication number is CN102295569A discloses a method for preparing (S)-metoprolol succinate, which involves pumping 4-hydroxyphenethyl methyl ether and (R)-epichlorohydrin into the reactor , during the reaction process, the external circulating water outlet system filled with water removal agent is used to circulate the water, and the prepared (S)-3-[4-(2-methoxyethyl)phenoxy]-1,2-epoxy Propane reacts with isopropylamine to obtain (S)-metoprolol, and (S)-metoprolol is mixed with succinic acid to obtain (S)-succinic acid metoprolol again, and the final yield is greater than 75%, but The ee value of the product is not high

Method used

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  • Preparation method of succinic acid S-metoprolol

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Experimental program
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Effect test

Embodiment 1

[0049] (1) 3.7kg of p-methoxyethylphenol, 7.4kg of anhydrous potassium carbonate, dissolved with 7.4kg of DMF (N,N-dimethylformamide), heated and stirred to 35°C, and 2.7kg of (R) -Epichlorohydrin, after dripping and keeping warm for 55 hours, TLC (ethyl acetate:dichloromethane=3:20) showed that the reaction was complete and the raw materials disappeared, and the reaction solution was poured into 30L of water and stirred evenly. The dichloromethane was extracted completely, the dichloromethane layer was washed with water and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, and the dichloromethane was concentrated at 40°C to obtain an etherified product, which was directly used for the next reaction.

[0050] (2) At 25°C, dissolve the etherification product obtained in step (1) with isopropyl ether (about 10 kg), drop it into 4.25 kg of isopropylamine, and keep it warm overnight, TLC (EA:DCM=3:20) shows After the reaction is completed, co...

Embodiment 2

[0056] Except that the dibenzoyl-D-tartaric acid in the resolution step (4) is replaced by an equimolar amount of p-methoxydibenzoyl-D-tartaric acid, step (5) obtains S-metoprolol oil 1.15 kg, the HPLC purity of S-metoprolol at this moment is 99.5%, and the ee value is 99.4%.

Embodiment 3

[0058] Except that the dichloromethane in the resolution step (4) is replaced by 12L, tetrahydrofuran is replaced by 20L, step (5) obtains S-metoprolol oily matter 1.31kg, and the HPLC purity of S-metoprolol is 99.0% , ee value is 93.6%.

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Abstract

The invention discloses a preparation method of succinic acid S-metoprolol. The preparation method of the succinic acid S-metoprolol comprises that methoxyl ethyl phenol is taken as an initial raw material, (R)-epoxy chloropropane is taken as a reaction agent, and etherification reaction and amination reaction are carried out, so that an S-metoprolol crude product is obtained; then the S-metoprolol crude product and succinic acid form salt, dissociation is carried out by virtue of alkali for obtaining oily metoprolol, dibenzoyl-D-tartaric acid is used for splitting, so that an S-metoprolol pure product is obtained, and the obtained S-metoprolol pure product and succinic acid form salt, so that the succinic acid S-metoprolol is obtained. The preparation method of the succinic acid S-metoprolol has the advantages that S-metoprolol is salified and then purified, then splitting is carried out, and purity and ee value of the succinic acid S-metoprolol product are increased, and quality requirement in the field of medicines can be met.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of S-metoprolol succinate. Background technique [0002] Metoprolol is an aminopropanol drug and a selective β1 receptor blocker. It competes with adrenaline and noradrenaline, protects the heart at the position of the receptor, inhibits cardiac contractility, and prevents nerve Impulse and avoid excessive excitement, it is one of the commonly used medicines for treating hypertension, coronary heart disease, chronic heart failure and arrhythmia, and it also has a good curative effect on angina pectoris caused by hypoxia. [0003] S-Metoprolol succinate (Metoprolol succinate), the structure is shown in formula (Ⅰ), Chinese alias: S-1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy] -2-Propanol succinate is a white or off-white crystalline powder. API for angina pectoris and hypertension treatment. S-metoprolol succinate sustained-release tablets have s...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/10C07C213/08C07C55/10C07C51/41
Inventor 李晓祥狄潘潘徐自奥赵永海刘海亮李德刚
Owner ANHUI NEW STAR PHARMA DEV
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