Preparation of 1-(4-hydroxyphenyl)-2-bromopropan-1-one and application thereof

Abstract

Preparation of ifenprodil bromo-intermediate 1-(4-oxyphenyl)-2-bromopropane-1-ketone and its use in preparation ifenprodil and its salt are disclosed. The process is carried out by taking 4-hydroxy-phenyl-ketone as initial material, taking copper bromide as bromo-reagent, bromo-reacting under organic solvent back flow, removing copper ion in mixed liquid, and condensing to obtain solid final product.

Description

technical field [0001] The invention relates to a preparation method of 1-(4-hydroxyphenyl)-2-bromopropan-1-one, a brominated intermediate of Ifendil, and the application of the compound in the preparation of Ifendil and its medicinal salts. technical background [0002] The compound 1-(4-hydroxyphenyl)-2-bromopropan-1-one is an important intermediate for the preparation of ifendil and its pharmaceutically acceptable salts. Ifendil mainly uses 4-hydroxypropiophenone (I) as the starting material, and then prepares the intermediate 1-(4-hydroxyphenyl)-2-bromopropan-1-one (II) through bromination, Its condensation with 4-benzylpyridine produces the intermediate 1-(4-hydroxyphenyl)-2-(4-benzylpyridyl)propan-1-one hydrobromide (III), which is catalyzed by metal ions Reduction of intermediate (III) by hydrogenation produces ifendil (IV). Ifendil tartrate is obtained by salifying Ifendil with tartaric acid. Among them, the key steps are bromination, condensation and hydrogenatio...

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Problems solved by technology

However, these patents also have their shortcomings: ① When preparing brominated intermediates, some use 1.4-dioxane or related mixed solvents, and some use benzene as a solvent, which are all prohibited or strictly prohibited in pharmaceutical production. Limited solvent; ②During the condensation reaction, piperidine derivatives are used to condense with bromide, due to the high cost of piperidine raw materials, which leads to an increase in production costs; ③During the hydrogenation reaction, some patents use palladium-carbon and other precious metal catalysts also increase the production cost

[0008] Japan's Toyo Pharma K.K. company has applied for a patent JP60188344 specifically on the preparation of brominated intermediates. It has adopted a solid brominating reagent copper bromide. Although copper bromide has avoided some shortcomings of bromine, it has a certain Solubility, while copper ions can complex with another starting material 4-benzylpyridine or piperidine in the later condensation reaction to affect the reaction

[0009] There are many methods for the preparation of key brominated intermediates. Most of the above-mentioned patents use bromine as the brominated reagent. Pure bromine is highly irritating. It not only has a strong corrosive effect on equipment, but also has high toxicity and is prone to produce dibromine generation of side reactions, the yield is not high, the product is impure, and the post-treatment is more difficult, and only when 1.4-dioxane is used as the reaction solvent, the reaction can achieve better results, but the problem of 1.4-dioxane solvent residue is difficult has been solved

Although bromodioxane or pyridine: hydrobromic acid: bromine complexes are used for monobromination reaction, the selectivity is slightly better, but it still cannot solve the problems of solvent residue, corrosion and toxicity

Using copper bromide as the bromination reagent can carry out the bromination reaction well, but if the copper ions cannot be effectively removed, it will seriously affect the later reaction

There are still many shortcomings in the existing patents, and new preparation methods need to be further studied

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