Preparation method of rabeprazole chloride and intermediate thereof

Abstract

According to an existing method, acetic anhydride is adopted for a reaction when a formula III is synthesized from a formula IV, the reaction temperature is high, the reaction time is long, a large number of isomer byproducts can be generated in the reaction process, and the product purity is low. When the compound shown in the formula I is synthesized from free alkali of a compound shown in a formula II, halogenated alkane is used as a solvent and thionyl chloride is used as a chlorination reagent for reaction, alkali quenching, water washing extraction and salt formation after concentrationare needed for aftertreatment, the operation is complex, and the production period is long. According to the invention, p-toluenesulfonic acid is added for catalysis when the compound shown as the formula III is prepared, so that the reaction can be carried out at a relatively low temperature, the side reaction is greatly reduced, and the purity of the product is improved. When the compound shownin the formula I is prepared, ethyl acetate is used as a solvent, a product is gradually separated out along with the reaction, the product can be obtained through direct filtration after the reactionis completed, aftertreatment is simple, the product purity is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug 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 No.: 153259-31-5), is the raw material The key intermediate of the drug rabeprazole sodium, most of which are reported in the literature is 2,3-lutidine as the starting raw material, which is oxidized, nitrated, chlorinated, etherified, esterified, rearranged, hydrolyzed, Chlorine 2 and salt preparation. [0003] [0004] Esterification rearrangement can be obtained by reacting 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide (formula IV) w...

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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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