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...

Examples

Embodiment 27

[0070] Example 27, Example 28, and Example 29 are the data obtained by monitoring the same reaction at different reaction times. Therefore, there is no purity and yield data for Example 27 and Example 28.

Embodiment 30

[0071] Embodiment 30 and embodiment 31 are the data obtained by monitoring different reaction times for the same reaction. Therefore, there are no purity and yield data for Example 30.

[0072] From the results in Table 6, the conversion rate can reach about 96% in about 2 hours of reaction; the reaction can be considered as complete after reaction of 4 hours; there is no significant difference between the time extension of 8 hours and the reaction of 4 hours. Considering the above reasons, the reaction time should be between 3 and 5 hours.

Embodiment 32

[0081] Example 32. Synthesis of [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide

[0082]

[0083] Add 750kg of n-heptane into a 2000L reactor; then add 250kg of triphenylphosphine; 192kg of 1,3-dibromopropane; heat to reflux and react for about 60hr. After the reaction is complete, cool the reaction solution to 20-30°C; add 335 kg of 40% dimethylamine aqueous solution; raise the temperature to 45-50°C, and keep the reaction for about 5 hours; the solid in the reaction system gradually dissolves completely. After the reaction is completed, concentrate under reduced pressure, collect the azeotrope of n-heptane / water, add the separated n-heptane to the reaction system, and continue to concentrate until the water in the reaction system is basically concentrated to dryness; the reaction solution is cooled and centrifuged Shake filtration to collect the solids; heat the collected solids with absolute ethanol for beating; cool, centrifuge and shake them to colle...

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...

Examples

Embodiment 27

[0070] Example 27, Example 28, and Example 29 are the data obtained by monitoring the same reaction at different reaction times. Therefore, there is no purity and yield data for Example 27 and Example 28.

Embodiment 30

[0071] Embodiment 30 and embodiment 31 are the data obtained by monitoring different reaction times for the same reaction. Therefore, there are no purity and yield data for Example 30.

[0072] From the results in Table 6, the conversion rate can reach about 96% in about 2 hours of reaction; the reaction can be considered as complete after reaction of 4 hours; there is no significant difference between the time extension of 8 hours and the reaction of 4 hours. Considering the above reasons, the reaction time should be between 3 and 5 hours.

Embodiment 32

[0081] Example 32. Synthesis of [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide

[0082]

[0083] Add 750kg of n-heptane into a 2000L reactor; then add 250kg of triphenylphosphine; 192kg of 1,3-dibromopropane; heat to reflux and react for about 60hr. After the reaction is complete, cool the reaction solution to 20-30°C; add 335 kg of 40% dimethylamine aqueous solution; raise the temperature to 45-50°C, and keep the reaction for about 5 hours; the solid in the reaction system gradually dissolves completely. After the reaction is completed, concentrate under reduced pressure, collect the azeotrope of n-heptane / water, add the separated n-heptane to the reaction system, and continue to concentrate until the water in the reaction system is basically concentrated to dryness; the reaction solution is cooled and centrifuged Shake filtration to collect the solids; heat the collected solids with absolute ethanol for beating; cool, centrifuge and shake them to colle...

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