Synthesis method for preparing metoprolol intermediate

Abstract

A synthesis method for preparing a metoprolol intermediate comprises the following steps: 1, dissolving phenol and chloroacetyl chloride in a dichloroethane solvent, adding aluminum trichloride as a catalyst, stirring for reaction to generate 4-chloracetyl phenol; 2, dissolving the 4-chloracetyl phenol generated by the reaction of the step 1 in methanol, adding methanol sodium, starting a stirrer for stirring for reaction to generate 4-(2'-methoxy acetyl) phenol; 3, adding the 4-(2'-methoxy acetyl) phenol generated by the reaction of the step 2 into a reactor, adding a catalyst, adding a reductant, starting stirring, and heating for reaction to generate intermediate 4-(2 '-methoxy ethyl) phenol. The advantages are as follows: the method for preparation of the 4-(2 '-methoxy ethyl) phenol is simple in operation, mild in conditions, environmental friendly, low in cost, and is suitable for industrial production, Raney nickel can be reused, the reaction yield reaches 86%, and the purity reaches 98% or above.

Description

technical field [0001] The present invention relates to the technical field of preparation methods of pharmaceutical intermediates, in particular to a low-cost and easy-to-industrial preparation method for the key intermediate 4-(2'-methoxyethyl)phenol of the drug metoprolol for treating cardiovascular diseases . Background technique [0002] Cardiovascular disease seriously endangers human health, and its morbidity and mortality rank first among all diseases, becoming the "number one killer" of human life. All countries in the world have invested huge manpower, material and financial resources in the research and development of cardiovascular drugs. Among the "world's top ten best-selling drugs" ranked every year by the world pharmaceutical market, drugs for the treatment of cardiovascular diseases account for the most, accounting for about half. Among cardiovascular drugs, β-blockers (also known as β-adrenergic receptor blockers) occupy a large market share and are commo...

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Problems solved by technology

[0004] Regarding the chemical synthesis of metoprolol, there have been many reports in domestic and foreign literature, mostly using phenylethyl alcohol or p-nitrotoluene as the starting material, which is obtained through methylation, nitration, reduction, diazotization, and hydrolysis, but phenylethyl alcohol The price is more expensive, the current domestic supply is very limited, and the reaction steps are long, resulting in high cost; according to the report of US5107034, p-hydroxyacetophenone is used as raw material and prepared by bromination, methylation, palladium carbon catalytic hydrogenation reduction p-Hydroxyacetophenone is expensive, and liquid bromine needs to be used in the reaction, which is very harmful to operators, and the high price of palladium carbon also limits its industrial use; according to Zhou Yong [1] It is reported that 4-(2′-methoxyethyl)phenol was synthesized by chloroacetylation, etherification and Clemmensen reduction using phenol as the starting material

The price of phenol as the starting material of this reaction is low, but the last step of reaction is reduced by Clemmensen method. Although the effect is good, highly toxic waste mercury is produced, causing environmental pollution, and the total yield is only 37%.

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