190786-44-8

Usage

Uses

Used in Pharmaceutical Industry:
Bepotastine besilate is used as an antihistamine for the treatment of allergic rhinitis, chronic urticaria, and pruritus associated with skin conditions such as eczema/dermatitis, prurigo, or pruritus cutaneus. It suppresses some allergic inflammatory processes by acting as a histamine H1 receptor antagonist.
Used in Respiratory Disorders:
Bepotastine besilate is used as a PAF antagonist and inhibits LTD4 in tracheal smooth muscle and ileum, IL-5 production by human peripheral blood mononuclear cells, and eosinophil infiltration in the airway and peripheral blood. It is currently being developed against other allergic and respiratory disorders.
Used in Ophthalmology:
Bepotastine besilate is used as a topical, selective, and non-sedating histamine (H1) receptor antagonist for the treatment of itching associated with allergic conjunctivitis. It prevents conjunctival vascular hyperpermeability in a guinea pig model of conjunctivitis in a dose-dependent manner.
Used in Allergy Treatment:
Bepotastine besilate is used as an anti-allergic agent due to its potent and long-acting activity in models of allergic rhinitis and its ability to reduce dye leakage from the nasal passages of rats acutely sensitized to an antigen. It also inhibits histamine-induced bronchoconstriction in anesthetized dogs.

Originator

UBE (Japan)

Manufacturing Process

Manufacturing process for BEPOTASTINE BESILATE includes these steps as follows: Step A: Synthesis of Methyl 2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro- 1H-5-cyclopenta[b]benzofurancarboxylate,Step B: Synthesis of Methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7- dioxin o[5,4-a]cyclopenta[b]benzofurancarboxylate,Step C: Synthesis of 3-Methyl-trans-4a-cosoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7- dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol,Step D: Synthesis of 7-Chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydrodioxino[5,4-a]cyclopenta[b]benzofuran,Step E: Synthesis of 4-[3-Methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7- dioxino[5,4-a]cyclopenta[b]benzofuranyl]butyric acid, Step F: Synthesis of Methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5- cyclopenta[b]benzofuranyl]butyrate, Step G: Synthesis of Methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5-cyclopenta[b]benzofuranyl]butyrate, Step H: Synthesis of Methyl ester of 11,15-dideoxy-11-acetoxy-16-methyl-15-oxo-18,19- tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2,Step I: Synthesis of 11-Deoxy-11-acetoxy-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2.To a solution of 54 mg of methyl ester of 11-deoxy-11-acetoxy-16-methyl- 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in 4.5 ml of anhydrous methanol was added 0.001 ml of 4.8 N sodium methoxide under argon, and the reaction mixture was stirred for 1.5 hours at room temperature. After addition of acetic acid to the reaction mixture and concentration of the mixture, the residue was dissolved in 20 ml of ethyl acetate, and the solution was washed with aqueous saturated solution of sodium hydrogen carbonate, water and aqueous saturated solution of sodium chloride, dried and concentrated to afford 55 mg of an oily material. This oily material was purified by column chromatography using ethyl acetate and cyclohexane (3:1) as eluent to give 48 mg of the methyl ester of 16- methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2.

Therapeutic Function

Antiallergic

InChI:InChI=1/C21H25ClN2O3.C6H6O3S/c22-17-8-6-16(7-9-17)21(19-4-1-2-12-23-19)27-18-10-14-24(15-11-18)13-3-5-20(25)26;7-10(8,9)6-4-2-1-3-5-6/h1-2,4,6-9,12,18,21H,3,5,10-11,13-15H2,(H,25,26);1-5H,(H,7,8,9)/t21-;/m1./s1

Upstream product

• 1415692-17-9 bepotastine besilate 
• 98-11-3 benzenesulfonic acid 
• 125602-71-3 Bepotastine 
• 26158-00-9 benzene-sulfonic acid monohydrate 
• 210095-55-9 (S)-(-)-2-((4-chlorophenyl)(piperidin-4-yloxy)methyl)pyridine 
• 2969-81-5 Ethyl 4-bromobutyrate 
• 176022-47-2 (S)-(+)-(4-chlorophenyl)-(2-pyridyl)methanol 
• 6318-51-0 2-(4-chlorobenzoyl)pyridine 
• 1563017-46-8 (4-chlorophenyl)(1-oxido-2-pyridinyl)methanone 
• 207726-35-0 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine-1-carboxylic acid ethyl ester 
• 106-39-8 bromochlorobenzene 

Downstream Products

• 125602-71-3 [14C]-Bepotastine besilate 

Relevant academic research and scientific papers

Total synthesis method of bestatin

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.

IMPROVED PROCESS FOR THE MANUFACTURE OF BEPOTASTINE AND ITS BESILATE SALT

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.

Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of Aryl N-Heteroaryl Ketones with N-Oxide as a Removable ortho-Substituent

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.

A stable besylate bepotastine crystal and its preparation method

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.

Asymmetric syntheses method of ophthalmologic drug bepotastine besilate

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%.

Salt-forming method of bepotastine besilate

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.

Improved preparation method of bepotastine besilate

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

OPTICALLY ACTIVE PIPERIDINE DERIVATIVE ACID-ADDITION SALT AND PREPARATION THEREOF

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

Crystalline Bepotastine and it's process for the preparation

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.