CN108727335A - A kind of purification method of bepotastine besilate - Google Patents

Abstract

The invention discloses a purification method of bepotastine besilate, which belongs to the technical field of drug separation and purification, and particularly adopts β -cyclodextrin bonded silica gel as an adsorbent, column chromatography silica gel is used for adsorbing impurities in a crude product of bepotastine besilate, and β -cyclodextrin is used for separating isomers, so that purified bepotastine is obtained.

Description

A kind of purification method of bepotastine besilate

technical field

The invention belongs to the technical field of separation and purification of medicines, and in particular relates to a purification method of bepotastine besilate.

Background technique

Bepotastine Beslilate, chemical name: 4-[4-[(S)-[(4-chlorophenyl)pyridin-2-yl]methoxy]piperidin-1-yl] Butyric acid monobenzenesulfonate, the molecular weight is 547.06, the CAS number is: 190786-44-8, and its structural formula is as follows:

.

Bepotastine bepotastine is a histamine H-1 receptor antagonist jointly developed by Japan's Tanabe Seiyaku and Japan's Ube Industries, which is highly selective for histamine H1 receptors. Other studies have found that bepotastine bepotastine can inhibit the infiltration of eosinophils into peripheral tissues, thereby alleviating the inflammatory response of the nasal mucosa. In addition, bepotastine besilate rarely enters the brain, has no sedative effect, the anticholinergic effect is separated from the antihistamine effect, and other adverse reactions are minimal. In ketotifen, terfenadine, cetirizine, epinadine, so the prospect of clinical application is broad.

Existing studies have shown that there are significant differences in the pharmacological effects of different isomers of bepotastine besilate, among which the pharmacological effect of the S isomer is more than 100 times stronger than that of the R isomer, and the plasma protein binding rate of the S isomer is higher than that of the R isomer. The R type is high, so the less the R isomer content in bepotastine bepotastine as an impurity, the better. There is no special report on the purification of bepotastine besilate in the existing literature, and recrystallization is often used for purification. Although the recrystallization method can obtain bepotastine bepotastine with a purity of 95%, it needs to be further purified to obtain bepotastine with a purity of more than 99.5%, while keeping the optical isomers below the detection limit. Not yet possible. Therefore, it is urgent to propose a new scheme to effectively purify bepotastine besilate.

Contents of the invention

Aiming at the problems existing in the prior art, the present invention provides a purification method that can effectively improve the purity of bepotastine besilate, has good operability and is suitable for large-scale industrial production.

To achieve the above object, the present invention adopts the following technical solutions:

A purification method of bepotastine besilate, which comprises the following steps:

1) Dissolving the crude product of bepotastine besilate in an organic solvent to form a bepotastine besilate solution;

2) Dissolve β-cyclodextrin bonded silica gel with an organic solvent to form a bonded silica gel solution;

3) Drop the bepotastine bepotastine solution into the bonded silica gel solution under stirring conditions, filter and wash with water, then take the organic layer and concentrate to dryness to obtain purified bepotastine bepotastine.

The purity of the crude bepotastine besilate is 95%-98%, and the optical purity is 0.5%-1%.

The weight ratio of the β-cyclodextrin-bonded silica gel to the crude product of bepotastine besilate is 3-4:1 to ensure sufficient removal of impurities and to avoid solvent contamination caused by excessive use of β-cyclodextrin-bonded silica gel. An increase in dosage and a decrease in yield.

Too much addition of organic solvent may cause impurities to be unable to absorb completely, and too little addition may cause yield reduction. Therefore, the weight ratio of organic solvent used in the operation to the crude product of bepotastine besilbestatin is 5-20:1; wherein, The organic solvent is one or more of n-butanol, ethyl acetate and dichloromethane, preferably ethyl acetate.

The time of dropping in step 3) is controlled within 1-2 hours.

Step 3) When filtration is used to remove the solid matter of adsorbed impurities, the filter cake can be washed with ethyl acetate to wash out the bepotastine besil in the filter cake; ethyl acetate at 0-5°C is preferred for cleaning, which can Effectively wash out bepotastine besilate without eluting impurities, achieving better separation effect.

The water washing in step 3) is to add 0.2-0.3 times the volume of water to the filtrate to wash twice, so as to remove impurities such as β-cyclodextrin that may be mixed in the organic phase.

After purification through the above steps, the purity of bepotastine bepotastine obtained can reach 99.5%, and it can be further purified by recrystallization. The specific steps are: heating and dissolving the obtained purified bepotastine in a solvent, Then lower the temperature to 0-20°C to precipitate solids, and then filter and dry to obtain high-purity bepotastine besilate.

The weight ratio of the solvent to the purified bepotastine bepotastine is 5-20:1; wherein the solvent is acetone, ethyl acetate, propyl acetate, methanol, ethanol, isopropanol, n-hexane, One or more of n-heptane.

Significant advantage of the present invention is:

(1) In the present invention, the crude product of bepotastine besilate is dissolved in an organic solvent, and then β-cyclodextrin-bonded silica gel is used to effectively adsorb most of the impurities in the solution without affecting the target product bepotastine Bepotastine bepotastine with a purity of more than 99.5% is obtained by filtering and concentrating. After further recrystallization and purification, the impurities and isomers in the crude product of bepotastine besylate can be effectively removed, and the purity of the obtained high-purity bepotastine besylate can reach 99.9%, and the R isomer impurity is lower than the detection limit .

(2) The present invention does not need to adopt the silica gel column chromatography method which is difficult to operate and is not suitable for industrial production for purification, but only uses β-cyclodextrin-bonded silica gel adsorption and recrystallization methods for purification. The purification process is easy to operate and takes less time to operate. Short, low requirements for operators, and save the use of a large number of organic solvents, and the product yield is high, high purity, isomers are also reduced to near the detection limit, suitable for large-scale production of high-purity bepotastine besilate industrial production.

Detailed ways

In order to make the content of the present invention easier to understand, the technical solutions of the present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.

In a 50L reaction kettle, add 30L of anhydrous dimethylformamide and 0.5kg of dried β-cyclodextrin, and add 2.5g of sodium metal, stir and mix; weigh 5kg of silica gel for column chromatography, 0.05kg of dried Add the 3-glycidyloxypropyltrimethoxysilane to the reaction kettle, stir and mix; raise the temperature to 105°C, react for 12 hours, filter, and wash the filter cake with anhydrous dimethylformamide, acetone, and water Three times, drying under reduced pressure at 60° C. for 5 hours to obtain β-cyclodextrin-bonded silica gel.

Wherein, the column chromatography silica gel used is 100-300 mesh, preferably 200-300 mesh, and finer silica gel has better impurity adsorption effect, and is easier to separate and filter.

1. Purification of crude bepotastine besilate by adsorption on β-cyclodextrin bonded silica gel

Add ethyl acetate and crude bepotastine bepotastine into a glass bottle, stir and dissolve to obtain a solution of bepotastine besilate for later use; put β-cyclodextrin bonded silica gel and ethyl acetate into the reaction kettle, stir After dissolving, a bonded silica gel solution is obtained; drip bepotastine bepotastine solution into the bonded silica gel solution under stirring conditions, and the dropping time is 1-2 hours; then filter, the filter cake is washed with ethyl acetate and the filtrate is combined and washing solution, add 0.2-0.3 times the volume of water to wash twice, take the ethyl acetate layer and concentrate to dryness to obtain bepotastine besilate.

In the above operation, the amount of crude product of bepotastine bepotastine, purity, reaction kettle volume, solvent usage, dosage of β-cyclodextrin bonded silica gel and the amount of bepotastine obtained after adsorption and purification of β-cyclodextrin bonded silica gel The purification results of stastatin are shown in Table 1, Examples 1-5.

Table 1 Parameters and results of purification of crude bepotastine besilate by adsorption on β-cyclodextrin bonded silica gel

It can be seen from Table 1 that after the crude product of bepotastine bepotastine with a purity of 95.1%-97.6% and an isomer content of 0.82%-0.99% was purified by β-cyclodextrin-bonded silica gel, the purity of bepotastine besilate was greatly improved. Improvement, the purity reaches more than 99.5%, and the isomer content is also reduced to less than 0.3%, which meets the basic requirements of the quality standard of bepotastine besilate raw material.

2. Purification of bepotastine besilate by recrystallization

The bepotastine bepotastine prepared above was dissolved in an organic solvent under reflux, cooled to T°C to precipitate a solid, filtered, and dried to obtain high-purity bepotastine bepotastine. The purification effect is shown in Table 2.

Table 2 Parameters and results of further purification of bepotastine besilate

It can be seen from Table 2 that after further recrystallization and purification of the obtained bedastatin besylate, the purity of the obtained finished products all reached above 99.9%, and no isomers were detected in the finished products (below the minimum detection limit).

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (8)

1. a kind of purification process of benzene sulphur bepotastine, it is characterised in that：Include the following steps：

1）Benzene sulphur bepotastine crude product is dissolved in organic solvent, benzene sulphur bepotastine solution is formed；

2）Beta-cyclodextrin bonded silica gel is leached with organic solvent, forms bonded silica gel solution；

3）Benzene sulphur bepotastine solution is instilled in bonded silica gel solution under agitation, takes organic layer dense after filtering, washing It is reduced to dry, to be purified benzene sulphur bepotastine.

2. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：The benzene sulphur bepotastine crude product Purity be 95%-98%.

3. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：Beta-cyclodextrin bonded silica gel used Weight ratio with benzene sulphur bepotastine crude product is 3-4:1.

4. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：Organic solvent used is total in operation Amount and the weight ratio of benzene sulphur bepotastine crude product are 5-20:1；

Wherein, the organic solvent is one or more of n-butanol, ethyl acetate, dichloromethane.

5. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：Step 3）The time of middle dropwise addition is controlled System was at 1-2 hours.

6. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：Step 3）Described in washing be The water cleaning of 0.2-0.3 times of its volume is added in filtrate twice.

7. the purification process of benzene sulphur bepotastine according to claim 1, it is characterised in that：The benzene sulphur Beta that gained is purified Sting dissolves by heating in solvent, is then cooled to 0-20 DEG C, makes it that solid be precipitated, high-purity using filtering, being dried to obtain Spend benzene sulphur bepotastine.

8. benzene sulphur bepotastine purification process according to claim 7, it is characterised in that：The benzene of the solvent and purifying The weight ratio of sulphur bepotastine is 5-20:1；

Wherein, the solvent is in acetone, ethyl acetate, propyl acetate, methanol, ethyl alcohol, isopropanol, n-hexane, normal heptane It is one or more of.