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Preparation method of high-purity ebastine

An ebastine and high-purity technology, which is applied in the field of high-purity ebastine preparation, can solve the problems of low melting point, easy oxidation of intermediates, unfavorable storage and transportation of intermediates, etc., and achieves a promising industrialization prospect. Effect

Pending Publication Date: 2022-06-28
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The intermediate produced by this method has a low melting point and is easily oxidized, which is not conducive to the storage and transportation of the intermediate in industrial production.

Method used

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  • Preparation method of high-purity ebastine
  • Preparation method of high-purity ebastine
  • Preparation method of high-purity ebastine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A preparation and purification method of ebastine, comprising the following steps:

[0036] 1) 20kg 4-chloro-1-(4-tert-butylphenyl)-1-butanone is added in 90kg toluene solution, 4-hydroxypiperidine 8.0kg, 14.2kg sodium bicarbonate and 2.0kg potassium iodide are added respectively, The temperature was raised to reflux for 10h, cooled to room temperature, washed once with 40kg of saturated brine, extracted with 40kg of 3N hydrochloric acid, and the aqueous layer was adjusted to pH 10-11 with 10% sodium hydroxide, extracted with 54kg of ethyl acetate, The organic layer was evaporated to dryness, 26kg of n-hexane was added, and 19.6kg of 4-chloro-1-(4-(1,1-dimethylethyl)phenyl-4-(4-hydroxy-1-piperidine) was obtained by centrifugal rejection. base)-butanone).

[0037] 2) 19.6kg of 4-chloro-1-(4-(1,1-dimethylethyl)phenyl-4-(4-hydroxy-1-piperidinyl)-butanone), toluenesulfonic acid 13.5kg, 59kg of methyl isobutyl ketone was heated to reflux, and the methyl isobutyl ketone sol...

Embodiment 2

[0040] A preparation and purification method of ebastine, comprising the following steps:

[0041] 1) 20kg 4-chloro-1-(4-tert-butylphenyl)-1-butanone is added in 95kg methyl isobutyl ketone solution, 4-hydroxy piperidine 8.0kg, 14.2kg sodium bicarbonate and 2.0kg potassium iodide was heated to reflux for 10h, cooled to room temperature, washed once with 40kg of saturated brine, extracted with 40kg of 3N hydrochloric acid, the aqueous layer was adjusted to pH 10-11 with 10% sodium hydroxide, and 54kg of ethyl acetate was used. After the ester extraction, the organic layer was evaporated to dryness, 26 kg of n-hexane was added, and 20.2 kg of 4-chloro-1-(4-(1,1-dimethylethyl) phenyl-4-(4-hydroxyl- 1-piperidinyl)-butanone).

[0042]2) 20.2kg of 4-chloro-1-(4-(1,1-dimethylethyl)phenyl-4-(4-hydroxy-1-piperidinyl)-butanone), p-toluenesulfonic acid 14.1 kg of acid, 59 kg of methyl isobutyl ketone were heated to reflux, and the methyl isobutyl ketone solution of 25.3 kg of benzyl al...

Embodiment 3

[0045] A preparation and purification method of ebastine, comprising the following steps:

[0046] 1) 20kg 4-chloro-1-(4-tert-butylphenyl)-1-butanone is added in 90kg toluene solution, 4-hydroxypiperidine 8.0kg, 14.2kg sodium bicarbonate and 2.0kg potassium iodide are added respectively, The temperature was raised to reflux for 10h, cooled to room temperature, washed once with 40kg of saturated brine, extracted with 40kg of 3N hydrochloric acid, and the aqueous layer was adjusted to pH 10-11 with 10% sodium hydroxide, extracted with 54kg of ethyl acetate, The organic layer was evaporated to dryness, 26kg of n-hexane was added, and 20.0kg of 4-chloro-1-(4-(1,1-dimethylethyl)phenyl-4-(4-hydroxy-1-piperidine) was obtained by centrifugal rejection. base)-butanone).

[0047] 2) 4-chloro-1-(4-(1,1-dimethylethyl)phenyl-4-(4-hydroxy-1-piperidinyl)-butanone) 20.kg, p-toluene 14.0kg of sulfonic acid, 59kg of methyl isobutyl ketone are heated to reflux, add dropwise the methyl isobutyl...

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Abstract

The invention provides a preparation method of high-purity ebastine, which comprises the following steps: condensing 4-chloro-1-(4-tert-butylphenyl)-1-butanone serving as an initial raw material with 4-hydroxypiperidine to obtain 4-chloro-1-(4-(1, 1-dimethyl ethyl) phenyl-4-(4-hydroxy-1-piperidyl)-butanone), adding benzhydrol into methyl isobutyl ketone or methylbenzene serving as a solvent, and reacting at the temperature of 60-80 DEG C for 2-3 hours to obtain the high-purity ebastine. Ebastine is obtained through condensation, the obtained ebastine is purified through salification and then free, the purity of the obtained ebastine finished product is larger than 99.9%, the single impurity content is smaller than 0.1%, and the ebastine finished product meets the quality standard of ebastine pharmacopeia.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of high-purity ebastine. Background technique [0002] Ebastine is a new type of long-acting, non-sedative second-generation histamine H1 receptor antagonist of chloropiperidine, which is used for the treatment of seasonal, allergic rhinitis and chronic idiopathic urticaria. , long-acting and highly selective, it has no antagonistic effect on cholinergic receptors in the central nervous system, and its metabolites have stronger antihistamine effects. In addition, recent foreign studies have also shown that it has an anti-angiogenesis effect. , is expected to be used in the treatment of asthma and bronchitis. [0003] There are mainly two methods for preparing ebastine in industrial production that have been disclosed at present: [0004] The first: 4-chloro-1-(4-tert-butylphenyl)-1-butanone and 4-hydroxypiperidine are condensed to for...

Claims

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Application Information

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IPC IPC(8): C07D211/46
CPCC07D211/46
Inventor 张泉盛王冬军吕磊任欢辉
Owner JIANGSU LIANHUAN PHARMA
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