A kind of preparation method of rabeprazole chloride and intermediate thereof

Abstract

In the existing method, acetic anhydride is used for reaction when synthesizing formula III from formula IV, the reaction temperature is high, the time is long, and a large number of isomer by-products are produced in the reaction process, resulting in low product purity. When synthesizing the compound of formula I from the free base of the compound of formula II, the halogenated alkane is used as a solvent, and thionyl chloride is used as a chlorinated reagent to carry out the reaction, and the post-treatment needs to be quenched with a base, washed with water, extracted, concentrated, and then formed into a salt. The operation is complicated. Long production cycle. The invention discloses adding p-toluenesulfonic acid for catalysis when preparing the compound of formula III, so that the reaction can be carried out at a lower temperature, the side reaction is greatly reduced, and the purity of the product is improved. When preparing the compound of formula I, ethyl acetate is used as a solvent. As the reaction proceeds, the product will gradually separate out. After the reaction is complete, the product can be obtained by direct filtration. The post-processing is simple and the product purity is high, which is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to a preparation method of rabeprazole chloride and an intermediate thereof. Specifically, the chemical name of rabeprazole chloride is 2-chloromethyl-3-methyl-4- (3-methoxypropoxy)pyridine hydrochloride, the chemical name of the intermediate is 3-methyl-2-acetoxymethyl-4-(3-methoxypropoxy)pyridine. Background technique [0002] Rabeprazole chloride, chemically named 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride, (CAS number: 153259-31-5), is the raw material The key intermediate of the drug rabeprazole sodium, the literature reports more take 2,3-lutidine as the starting material, after oxidation, nitration, chlorination, etherification, esterification rearrangement, hydrolysis, Chlorinated 2 and its salts were prepared. [0003] [0004] The esterification rearrangement can be obtained by reaction of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitroxid...

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Problems solved by technology

[0006] Patent WO2009116072 discloses the esterification rearrangement reaction, using glacial acetic acid as an acylating reagent, and reacting at a high temperature of 90°C. It is found that there are a large number of isomer impurities in the reaction solution after 6 hours of reaction, and the purity of the target product is less than 85%; However, in the esterification rearrangement reaction disclosed in patent EP1795195, a small amount of concentrated sulfuric acid is added, and the reaction time is shortened, but high temperature reaction is still required. It is found that after 3 hours of reaction, the reaction solution is detected, and there are a large amount of isomer impurities. less than 85%

[0007] For the chlorination reaction, as disclosed in patents WO2009116072 and EP1795195, it is generally 3-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine (the free base of the compound of formula II) and chlorine The reaction reagent is reacted under the conditions of halogenated alkanes, such as dichloromethane and chloroform. After the reaction, the pH is adjusted, extracted, and then salted to prepare 2-chloromethyl-3-methyl-4-(3-methoxypropoxy Base) pyridine hydrochloride (compound of formula I), this reaction operation is loaded down with trivial details

[0008] That is, the esterification rearrangement reaction in the existing method has a high reaction temperature and a long time, and a large amount of isomer by-products will be produced in the reaction process, or the reaction temperature is low and the conversion is incomplete, resulting in low product purity; The reaction uses halogenated alkanes as solvents, the post-treatment is cumbersome, the period of industrial production is long, and the cost is high

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