190730-42-8

The method comprises the following steps: (4 - chlorophenyl) (2 - pyridyl) - methanol as a starting raw material, and sequential addition reaction. Examples of the etherification reaction include a deprotection reaction, a chiral resolution, a condensation reaction, a hydrolysis reaction, and the like. The synthesis method has the advantages of cheap and easily available raw materials, no need of expensive chiral catalysts, simpler synthesis method, mild conditions, less side reactions and low cost.

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The present invention discloses a process for preparation of Bepotastine and its Besilate salt of formula I with good yield and purity. The invention also describes a process for recycle and reuse of the Ethyl-4-hydroxy piperidine-1-carboxylate from the aqueous medium after isolating the 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine, for subsequent batches in the production of Ethyl 4-[(4- Chlorophenyl)(pyridin-2-yl)methoxy]piperidine-1-carboxylate. The invention further discloses novel intermediates, viz., 2-[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride and bis{2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine} Dibenzoyl tartrate, useful in the preparation of Bepotastine and its Besilate salt.

A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric synthesis of bepotastine besilate in 51% total yield and 99.9% ee.

The invention discloses a stable bepotastine besilate crystal in novel crystal form through a recrystallization method. The obtained bepotastine besilate crystal is confirmed through X-ray powder diffraction and infrared spectrum. Stability contrast experiments prove that the provided bepotastine besilate crystal has extremely high stability, and both bulk drug and preparation of the bepotastine besilate crystal have stability obviously better than that of existing bepotastine besilate crystals.

The invention relates to an asymmetric synthesis method of an ophthalmologic drug pylistramine besylate. The method concretely comprises the following steps: oxidizing (4-chlorophenyl)(2-pyridyl)methanone to obtain (4-chlorophenyl)(2-pyridyl)ketone-N-oxide; carrying out asymmetric transfer hydrogenation reduction on the (4-chlorophenyl)(2-pyridyl)ketone-N-oxide through using a complex of monosulfonyl chiral diamine and metallic ruthenium, rhodium and iridium as a catalyst and a sodium formate or formic acid and triethylamine mixture or isopropanol as a hydrogen source in order to prepare (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide; reducing the (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide to prepare (S)-(4-chlorophenyl)(2-pyridyl)methanol; and condensing the (S)-(4-chlorophenyl)(2-pyridyl)methanol and ethyl 4-(4-bromopiperidine-1-yl)butyrate to obtain the ophthalmologic drug pylistramine besylate. The total yield is 61.6%.

The invention relates to an improved preparation method of bepotastine besilate.The improved preparation method of bepotastine besilate includes the following steps that firstly, 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine and a resolving agent a

PROBLEM TO BE SOLVED: To provide a benzene sulfonic acid salt of (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid, that is excellent in anti-histaminic activity and anti-allergic activity, is low in acid addition salt hygroscopic property, and is excellent in physicochemical stability, and to provide a preparation thereof. SOLUTION: Provided is a benzene sulfonic acid salt of an optically active piperidine derivative, represented by formula (I), whose absolute configuration is in (S) form. Also provided is a synthesis method in which an optically active (S)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine (IV) obtained by inducing an intermediate (±)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine into a diastereomeric salt and optically resolving the same by fractional crystallization method, is used as the intermediate. COPYRIGHT: (C)2016,JPOandINPIT

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.

The present invention refers to crystalline forms of formula (I) for (S)-4-[ 4-[ (4-chlorophenyl)-(2-pyridyl) methoxy] piperidine-1-one] butane acid and its novel manufacturing method is provided, more particularly amorphous (S)-4-[ 4-[ (4-chlorophenyl)-(2-pyridyl) methoxy] piperidine-1-one] butane compound 1) water, 2) methanol, ethanol, [...] ol, butanol, ISO oh wheat berry call , ethylene ethylene glycol, alcoholic solvent, 3) benzene, toluene, xylene such as aromatic hydrocarbon solvent, 4) methyl acetate, ether solvent of acetic acid such as ethyl acetate, 5) acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone such as ketone solvent, 6) ethyl ether, ISO [...] , dioxane, tetrahydrofuran, lime culling, d phenyl ether , 1-methoxy-2-(2-methoxyethoxy) ethane in an ether solvent such as, 7) the D maul the gun roentgen per hour at one meter amide which will bloom , dimethyl sulfoxide group selected from the group consisting of 1 in a solvent mixture of an aprotic or more species in contrast solvent [...] 10-30% weight ratio ground is prevented from being too small, room temperature to reflux under temperature , purity with refluxing to time 2-72 crystalline forms stable [...] and for preparing the compounds of formula (I) of method relates to.

The present invention relates to a novel method of synthesizing bepotastine or its benzenesulfonic acid salt and novel intermediates used therein. The present invention uses L-α-hydroxy acid for chiral resolution to form an L-α-hydroxy acid salt of a compound represented by the following formula (VII-1), so as to synthesize bepotastine or its benzenesulfonic acid salt in high optical purity.

An efficient and alternative synthesis of enantiomerically pure (+)-(S)-4-(4-((4-chlorophenyl)(pyrid-2-yl)methoxy]piperidin-1-yl)butanoic acid, bepotastine (1) is described. The key resolution of (R/S)-bepotastine l-menthyl ester (3) is achived via diastereomeric salt crystallization using N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA) as the resolving agent to provide (S)-bepotastine l-menthyl ester (S)-3. Hydrolysis of (S)-bepotastine l-menthyl ester (S)-3 afforded the desired bepotastine (1) with good yields and enantiopurity (> 99%). Finally, bepotastine besilate (4) and bepotastine calcium (5) are achived by salt formation of bepotastine (1) with benzene sulfonic acid and calcium salt respectively. The reaction conditions were optimized to make suitable for commercial scale production.

The present invention discloses a non-hygroscopic crystalline bepotastine metal salt hydrate, a method for preparing same, and a pharmaceutical composition comprising same for treating or preventing a histamine-mediated disease or an allergic disease.

A process for stereospecific preparation of bepotastine of formula (I) and novel intermediates used therein having formulae (II) to (IV) are provided. The inventive process comprises subjecting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine to a reaction with a 4-halobutanoic acid l-menthyl ester, halo being chloro, bromo or iodo, in an organic solvent in the presence of a base to produce (RS)-bepotastine l-menthyl ester of formula (II), conducting a reaction of the compound of formula (II) with N-benzyloxycarbonyl L-aspartic acid in an organic solvent to induce selective precipitation of bepotastine l-menthyl ester.N-benzyloxycarbonyl L-aspartate of formula (III), filtering the precipitates formed in step 2) to isolate the compound of formula (III), treating the compound of formula (III) with a base to liberate bepotastine l-menthyl ester of formula (IV), and hydrolyzing the compound of formula (IV) in the presence of a base. The inventive process can provide bepotastine having a high optical purity of not less than 99.5% in a high yield, and thus, is useful in the development of anti-histamines and anti-allergic agents.

The present invention provides an optically stable and non-hygroscopic crystalline form of (S)-4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidin-1-yl]butyric acid (bepotastine) p-toluenesulfonate; a method for preparing said compound, and an anti-histamin

The present invention discloses a non-hygroscopic crystalline bepotastine metal salt hydrate, a method for preparing same, and a pharmaceutical composition comprising same for treating or preventing a histamine-mediated disease or an allergic disease.

A process for stereospecific preparation of bepotastine of formula (I) and novel intermediates used therein having formulae (II) to (IV) are provided. The inventive process comprises subjecting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine to a reaction with a 4-halobutanoic acid l-menthyl ester, halo being chloro, bromo or iodo, in an organic solvent in the presence of a base to produce (RS)-bepotastine l-menthyl ester of formula (II), conducting a reaction of the compound of formula (II) with N-benzyloxycarbonyl L-aspartic acid in an organic solvent to induce selective precipitation of bepotastine l-menthyl ester?N-benzyloxycarbonyl L-aspartate of formula (III), filtering the precipitates formed in step 2) to isolate the compound of formula (III), treating the compound of formula (III) with a base to liberate bepotastine l-menthyl ester of formula (IV), and hydrolyzing the compound of formula (IV) in the presence of a base. The inventive process can provide bepotastine having a high optical purity of not less than 99.5% in a high yield, and thus, is useful in the development of anti-histamines and anti-allergic agents.