Preparation method of azelastine hydrochloride

A technology of azelastine hydrochloride and hydrochloric acid, which is applied in the field of synthesis of raw materials, can solve the problems of unqualified raw material content, loss on drying, difficult to reach pharmaceutical standards, poor stability of raw materials, etc., and the product quality is easier to control and reduce The effect of quality risk and stability improvement

Active Publication Date: 2021-06-29
WUHAN LEADPHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Another preparation process of azelastine hydrochloride described in this journal document, the intermediate prepared is a hydrochloride solid, which is also less stable , and it is very easy to absorb water and deliquescence, and it is not easy to store, which makes it difficult to post-process in production
The azelastine hydrochloride prepared by it is very easy to absorb water to form crystal water in the solution state, and it is basically impossible to achieve absolute anhydrous conditions in conventional solvents, so the azelastine hydrochloride precipitated from conventional solvents must partially contain crystal water , the water of crystallization is extremely difficult to remove in the post-treatment. The water of crystallization will not only lead to unqualified indicators such as content in the raw material and weight loss on drying, but also affect the crystal form of the raw material medicine, making it difficult for the raw material medicine to meet the pharmaceutical standard

Method used

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  • Preparation method of azelastine hydrochloride
  • Preparation method of azelastine hydrochloride
  • Preparation method of azelastine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0040] A preparation method of azelastine hydrochloride, the steps are as follows:

[0041] 1) Put 1.7g of potassium hydroxide and 50mL of drinking water into the reaction flask at room temperature, stir until it dissolves, then add 3.9g of 1-methylhexahydroazepin-4-one and 4.2g of benzohydrazide, 25~ React at 35°C for 1 hour. After the reaction is complete, cool down to 0-10°C. Add 3g of sodium borohydride in batches. After the addition, keep the temperature at 0-10°C for 2 hours. Potassium carbonate solution to adjust the pH to 10-11, add 50mL of dichloromethane, separate the liquid to take the organic phase, extract the water phase with 50mL of dichloromethane once, combine the organic phase, wash twice with 50mL*2 drinking water, and then use 50mL After washing once with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain 7.4 g of ...

Embodiment 2

[0046] A preparation method of azelastine hydrochloride, the steps are as follows:

[0047] 1) Put 1.7g of potassium hydroxide and 50mL of drinking water into the reaction bottle at room temperature, stir until it dissolves, then add 3.9g of 1-methylhexahydroazepine-4-one and 4.2g of benzohydrazide, 25 React at ~35°C for 1 hour. After the reaction is complete, cool down to 0-10°C. Add 3g of sodium borohydride in batches. After the addition, keep the temperature at 0-10°C for 2 hours. After the reaction is complete, add hydrochloric acid to quench the excess sodium borohydride, and then add 50 % potassium carbonate solution to adjust the pH to 10-11, add 50mL of dichloromethane, separate the liquid to take the organic phase, extract the water phase with 50mL of dichloromethane once, combine the organic phase, wash twice with 50mL*2 drinking water, and then use 50 mL of saturated sodium chloride solution was washed once, the organic phase was dried over anhydrous sodium sulfate,...

Embodiment 3

[0052] A preparation method of azelastine hydrochloride, the steps are as follows:

[0053] 1) Put 1.7g of potassium hydroxide and 50mL of drinking water into the reaction bottle at room temperature, stir until dissolved, then add 3.9g of 1-methylhexahydroazepine-4-one and 4.2g of benzohydrazide, 25 React at ~35°C for 1 hour. After the reaction is complete, cool down to 0-10°C. Add 3g of sodium borohydride in batches. After the addition, keep the temperature at 0-10°C for 2 hours. After the reaction is complete, add hydrochloric acid to quench the excess sodium borohydride, and then add 50 % potassium carbonate solution to adjust the pH to 10-11, add 50mL of dichloromethane, separate the liquid to take the organic phase, extract the water phase with 50mL of dichloromethane once, combine the organic phase, wash twice with 50mL*2 drinking water, and then use 50 mL of saturated sodium chloride solution was washed once, the organic phase was dried over anhydrous sodium sulfate, fi...

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Abstract

The invention relates to the technical field of synthesis of raw material medicines, and particularly discloses a preparation method of azelastine hydrochloride. The method comprises the following steps: condensing benzoyl hydrazine and 1-methylhexahydroazepine-4-one serving as raw materials, reducing with sodium borohydride, and reacting to obtain a compound 1; preparing a solid intermediate compound 2 from the compound 1 and organic binary weak acid; hydrolyzing the compound 2, and cyclizing with a compound 3 to form a compound 4; and salifying the compound 4 by hydrochloric acid, and separating water by toluene to obtain a compound 5, namely azelastine hydrochloride. The intermediate compound 2 prepared by the invention is a solid, the stability of the intermediate compound 2 is greatly improved compared with that of hydrochloride obtained in other literatures, the intermediate compound 2 is free of hygroscopicity, the purity can reach 99% or above, the quality risk of subsequent bulk drugs can be greatly reduced, and the process production operation space is larger; and the obtained azelastine hydrochloride does not contain water and meets related quality standards, the yield is increased to 80% or above compared with other literatures, and the purity can reach 99% or above.

Description

technical field [0001] The invention relates to the technical field of synthesis of crude drugs, in particular to a preparation method of azelastine hydrochloride. Background technique [0002] Azelastine hydrochloride is an antihistamine drug, which acts as an anti-allergic agent by antagonizing certain receptors in our body, blocking allergic reactions, and thus relieves rhinitis-related symptoms caused by allergies. Its structure as follows: [0003] [0004] European Patent EP2072510A1 reports the synthesis process of azelastine, and its reaction process is as follows: [0005] [0006] This patent describes the synthesis process of azelastine hydrochloride: benzohydrazide is used as raw material, and 1-methylhexahydroazepine-4-one hydrochloride undergoes condensation reaction, and then reduced by sodium borohydride to obtain intermediate N'-(1-methylhexahydroazepine-4-yl)benzohydrazide hydrochloride, then use 36% hydrochloric acid as solvent, hydrolysis reaction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04Y02A50/30
Inventor 刘念陈蔚江谢树伟
Owner WUHAN LEADPHARM TECH CO LTD
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