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Preparation method of metoprolol intermediate

A technology of metoprolol and intermediates, applied in the field of drug synthesis, can solve the problem of high price, achieve the effect of low price, simple reaction steps, and reduce production cost

Pending Publication Date: 2020-05-08
江西美晶科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method uses p-bromophenol and reacts with methyl vinyl ether, it needs to use palladium catalysts, and the price is relatively high.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] S1. Pump 500kg of toluene and 200kg of p-chlorophenol into the reaction kettle, pump in 150kg of dimethyl sulfate after completely dissolving, slowly add 150kg of caustic soda dropwise, and complete the dropwise addition in 5 hours. The reaction temperature is 40°C. After the dropwise reaction 1 hour; stand still, remove the water layer to recover sodium sulfate; after the toluene is evaporated from the organic layer, cool, add 500 kg of methyl tetrahydrofuran, dissolve, and pack into barrels to obtain 786 kg of p-chloroanisole-methyl tetrahydrofuran solution;

[0042] S2. Put 48kg of magnesium chips into the nitrogen-protected reaction kettle, immerse it in 600kg of ether, add p-chloroanisole-methyltetrahydrofuran solution dropwise under stirring, after the dropwise addition, react for 1h, control the reaction temperature at 15°C, and maintain the reaction Liquid steady slight reflux. Suction filter the above reaction solution into another reaction kettle, add 240kg of...

Embodiment 2

[0053] S1. Pump 500kg of toluene and 200kg of p-chlorophenol into the reaction kettle, pump in 150kg of dimethyl sulfate after completely dissolving, slowly add 150kg of caustic soda dropwise, and complete the dropwise addition in 5 hours. The reaction temperature is 40-45°C. Afterwards, react for 1 hour; let stand, remove the water layer to recover sodium sulfate; evaporate the toluene from the organic layer, cool, add 500 L of methyl tetrahydrofuran, dissolve, and put it in barrels to obtain 786 kg of p-chloroanisole-methyl tetrahydrofuran solution;

[0054] S2. Put 45kg of magnesium chips into the nitrogen-protected reaction kettle, immerse it in 600kg of ether, and add p-chloroanisole-methyl tetrahydrofuran solution dropwise under stirring. After the dropwise addition, react for 1.5h. The reaction solution was slightly refluxed steadily. Suction filter the above reaction solution to another reaction kettle, add 240kg of hydrochloric acid, under cooling condition, control t...

Embodiment 3

[0066] S1. Pump 500kg of toluene and 200kg of p-chlorophenol into the reaction kettle, pump in 150kg of dimethyl sulfate after completely dissolving, slowly add 150kg of caustic soda dropwise, and complete the dropwise addition in 5 hours. The reaction temperature is 40°C. After the dropwise reaction 1 hour; stand still, remove the water layer to recover sodium sulfate; evaporate the toluene from the organic layer, cool, add 500 L of methyl tetrahydrofuran, dissolve, put in barrels, and obtain 786 kg of p-chloroanisole-methyl tetrahydrofuran solution;

[0067] S2. Put 50kg of magnesium chips into the nitrogen-protected reaction kettle, immerse it in 600kg of ether, add p-chloroanisole-methyl tetrahydrofuran solution dropwise under stirring, after the dropwise addition, react for 1.5h, control the reaction temperature at 20°C, and maintain The reaction solution was slightly refluxed steadily. Suction filter the above reaction solution into another reaction kettle, add 240kg of ...

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Abstract

The invention provides a preparation method of a metoprolol intermediate, and belongs to the field of drug synthesis. The preparation method specifically comprises the following steps: etherifying p-chlorophenol under the action of dimethyl sulfate and sodium hydroxide to obtain p-chloroanisole; reacting the p-chloroanisole with ethylene oxide under the condition of magnesium catalysis to obtain p-methoxyphenylethanol; and reacting the p-methoxyphenylethanol with dimethyl carbonate in a toluene solvent, and adding dilute sulfuric acid for hydrolysis to obtain the metoprolol intermediate p-(2-methoxy)ethyl phenol. The preparation method has the advantages of cheap and easily available raw materials, simple process steps, and convenience in operation, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a metoprolol intermediate. Background technique [0002] Metoprolol is a β-receptor blocker that selectively blocks β1 receptors. It is mainly used clinically to treat various arrhythmias, hypertension, angina pectoris, Myocardial infarction, heart failure, hypertrophic cardiomyopathy, aortic dissection. [0003] Metoprolol chemical name is 1-[4-(2-methoxyethyl)phenoxy]-3-(isopropylamino)-2-propanol, CAS No. 51384-51-1, its structural formula as follows. [0004] [0005] P-(2-methoxy)ethylphenol, also known as p-methoxyethylphenol and p-4-(2-methoxyethyl)phenol, is an important intermediate for the synthesis of metoprolol. The method for synthesizing p-(2-methoxy)ethylphenol in the prior art still has the use of stoichiometric metal reagents, such as aluminum trichloride, etc., or the use of high toxicity, high operating requirements, unfavorable for in...

Claims

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Application Information

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IPC IPC(8): C07C41/26C07C43/178C07C41/16C07C43/205
CPCC07C41/26C07C41/16C07F3/02C07C41/30
Inventor 夏铁红夏铁平夏治海
Owner 江西美晶科技有限公司
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