Salt-forming method of bepotastine besilate

A technology of shellfish benzenesulfonate and water benzenesulfonic acid, which is applied in the field of pharmaceutical raw materials and its synthesis, can solve the problems of unsuitability for industrial production, long crystallization time, and difficulty in removal, and achieve high product yield and long crystallization time The effect of shortening and high production efficiency

Active Publication Date: 2016-10-26
HANGZHOU HEZE PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The crystallization time of this method is still relatively long, and the product tends to form an oily substance during the stirring and crystallization process, and then solidifies after a long period of stirring. In the process, it is easy to wrap organic impurities and inorganic salts in the product and it is difficult to remove, so further steps are needed. Refined, not suitable for industrial production

Method used

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  • Salt-forming method of bepotastine besilate
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  • Salt-forming method of bepotastine besilate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment one: the preparation of bepotastine besilate

[0029] Add benzenesulfonic acid monohydrate (35.51g) into isopropanol (35ml), stir until completely dissolved, and set aside. Then (+)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidinyl}n-butyric acid (80.00g) was dissolved in 240ml of isopropanol In the process, the temperature is controlled at 0° C. and the stirring speed is 120 rpm, a small amount of bepotastine benzenesulfonate seed crystals are added, and the above-mentioned isopropanol benzenesulfonate solution is added dropwise. After dropping, continue to insulate and stir for 3 hours before filtering, and the filter cake is rinsed with isopropanol. The wet product was dried under reduced pressure at 50-60°C to obtain 102.30 g of bepotastine besilate, yield: 93.49%. Submitted for inspection, the purity is 99.51%, the maximum impurity is 0.07%, and the residue on ignition is not more than 0.2%.

Embodiment 2

[0030] Embodiment two: the preparation of bepotastine besilate

[0031] Add benzenesulfonic acid monohydrate (35.48g) into ethanol (35ml), stir until completely dissolved, set aside. Then (+)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxyl]piperidinyl}n-butyric acid (80.03g) was dissolved in 240ml of ethanol, Control the temperature at 0° C. and the stirring speed at 120 rpm, add a small amount of bepotastine benzenesulfonate seed crystals, and add the above ethanol benzenesulfonate solution dropwise. After dropping, continue to insulate and stir for 3 hours before filtering, and the filter cake is rinsed with ethanol. The wet product was dried under reduced pressure at 50-60°C to obtain 100.67g of bepotastine besilate, yield: 92.01%. Submitted for inspection, the purity is 99.21%, the maximum impurity is 0.10%, and the residue on ignition is not more than 0.2%.

Embodiment 3

[0032] Embodiment three: the preparation of bepotastine besilate

[0033] Add benzenesulfonic acid monohydrate (35.55g) into methanol (35ml), stir until completely dissolved, and set aside. Then (+)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxyl]piperidinyl}n-butyric acid (80.01g) was dissolved in methanol 240ml, Control the temperature at 0° C. and the stirring speed at 120 rpm, add a small amount of bepotastine benzenesulfonate seed crystals, and add the above-mentioned methanol solution of benzenesulfonate dropwise. After dropping, continue to insulate and stir for 3 hours before filtering, and the filter cake is rinsed with ethanol. The wet product was dried under reduced pressure at 50-60°C to obtain 98.70 g of bepotastine besilate, yield: 90.21%. Submitted for inspection, the purity is 99.28%, the maximum impurity is 0.09%, and the residue on ignition is not more than 0.2%.

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Abstract

The invention discloses a salt-forming method of bepotastine besilate, wherein the method includes the steps of: 1) adding benzenesulfonic acid monohydrate to organic alcohol, stirring the solution until the benzenesulfonic acid is completely dissolved for later use; 2) dissolving (+)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxyl]piperidyl}n-butyric acid in organic alcohol, controlling the temperature at -20 - 20 DEG C and stirring speed at 50-200 rpm, adding a less amount of bepotastine besilate crystal seeds, dropwisely adding the benzenesulfonic acid organic alcohol solution, and then continuously stirring the solution with temperature maintained; and 3) performing crystallization for 1-5 h and filtering the solution, pour-washing a filter cake with the organic alcohol, and performing pressure reduced drying to obtain the bepotastine besilate. The method can form uniform granules in the product, is high in yield, has good impurity removal effect and excellent operability, is low in production cost and high in efficiency, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical raw material drug and a synthesis method thereof, and specifically discloses a method for forming a salt of bepotastine besilate. Background technique [0002] The chemical name of bepotastine benzenesulfonate is (+)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidinyl}n-butyric acid-benzene Sulfonate, the structural formula is as follows: [0003] . [0004] Bepotastine besilate was developed by Ube Corporation of Japan and licensed by Tanabe Corporation. Its tablet was listed in Japan for the first time in October 2000 under the trade name of Talion, and has been imported domestically. For the treatment of allergic rhinitis, urticaria, itching caused by skin diseases (eczema, dermatitis, prurigo, pruritus), nervous deafness. [0005] In 2006, ISTA Pharmaceuticals obtained the authorization of Bepotastine Besylate Eye Drops from Senshou Company in North America, and in 2007, the company obtained the a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 倪晟周英雷陈鸿翔林立波姜维斌赵航姜建胜许建明楼小丽周亮
Owner HANGZHOU HEZE PHARMA TECH
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