Method for simply and conveniently preparing high-purity olopatadine hydrochloride intermediate

Abstract

The invention provides a simple and convenient method which is more suitable for industrial large-scale production and preparation of high-purity [3-(dimethylamine) propyl] triphenylphosphonium bromide hydrobromide. According to the preparation method, with triphenylphosphine and 1, 3-dibromopropane adopted as starting materials, reflux reaction is carried out in n-heptane to obtain (3-bromopropyl) triphenylphosphonium bromide; the obtained (3-bromopropyl) triphenylphosphonium bromide does not need to be separated, and directly reacts with a dimethylamine aqueous solution by means of a one-potmethod; after the reaction is finished, the n-heptane is concentrated, water in a system is taken out, so that a [3-(dimethylamine) propyl] triphenylphosphonium bromide hydrobromide crude product canbe obtained; and the crude product is thermally pulped with absolute ethyl alcohol, so that the high-purity [3-(dimethylamine) propyl] triphenylphosphonium bromide hydrobromide can be obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing a key intermediate of olopatadine hydrochloride. The olopatadine hydrochloride intermediate structure that the present invention relates to is as follows: [0002] Background technique [0003] Olopatadine hydrochloride was developed by Kyowa Hakko, Japan. It was first approved for marketing by the U.S. Food and Drug Administration (FDA) on December 18, 1996; on December 22, 2000, it was approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA); on May 17, 2002, it was approved for marketing. Approved by the European Medicines Agency (EMA) for marketing; the approval for import registration was completed in China on July 23, 2002, and the applicant manufacturer is Alcon (China) Ophthalmic Products Co., Ltd. [0004] Olopatadine hydrochloride mainly has a selective antagonistic effect on histamine H1 receptors, and inhibits the gener...

AI Technical Summary

Problems solved by technology

However, 1,3-dibromopropane is a good alkylating agent, which belongs to genotoxic compounds and has certain penetration power to plastics. During the production process, even if protective clothing is worn, the During the process of aerosol, centrifugal discharge, drying material, packaging, etc., it is inevitable that personnel will come into contact with residual 1,3-dibromopropane, causing operators to be allergic to it and other problems: such as eye stinging, tearing, skin allergies , hand and foot fatigue and other symptoms

[0011] 2. Compound 123B1-10 itself is also a good alkylating agent, and it also has potential risks such as sensitization and genotoxicity

[0012] 3. In the current production process, in order to avoid excessive by-product 123B1-X2 in the intermediate 123B2-10, resulting in the final transfer to olopatadine hydrochloride In the salt product, the intermediate 123B1-10 is usually separated by centrifugation, and the by-product 123B1-X2 is dissolved in toluene to achieve the purpose of removing most of the 123B1-X2, but because 1,3-dibromopropane also exists Due to the residue, it is difficult to eliminate the harm to the operator

[0013] 4. In the process of preparing 123B2-10, the mixture of dimethylamine aqueous solution and ethanol is used to react with 123B1-10 at 70-80°C under severe reflux, and the molar ratio of dimethylamine is about 6-8 during the reaction. Because the boiling point of dimethylamine aqueous solution is about 50°C, it is inevitable that dimethylamine will volatilize from the system during the violent reflux process, causing waste and increasing the difficulty of waste gas treatment

Even under reduced pressure conditions, when a single batch of feed is large, it is necessary to raise the temperature to at least 90°C in order to better evaporate the last remaining water in the material, resulting in increased energy consumption; at the same time , if the amount of residual water is too small, the residue in the kettle will form a very hard block, which is very easy to cause the stirring and locking of the reaction kettle to stop. Even if absolute ethanol is added and heated to reflux, the agglomeration can no longer be removed. the material is dispersed

It is difficult to control the concentration of solvent in the process of post-processing concentrated solvent

[0015] From the perspective of environmental health and safety (EHS), there are many problems in the current process: it is not very friendly to the environment; there is more waste of materials; it is easy to cause harm to personnel Unnecessary injury; prone to damage to equipment

Therefore, it is not suitable for industrial scale production

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