WO2018042305A1

WO2018042305A1 - Improved processes for preparation of bilastine using novel intermediates

Info

Publication number: WO2018042305A1
Application number: PCT/IB2017/055146
Authority: WO
Inventors: Dodda Mohan Rao; Bingi Venugopal
Original assignee: Symed Labs Limited
Priority date: 2016-08-29
Filing date: 2017-08-28
Publication date: 2018-03-08

Abstract

Provided herein are improved, commercially viable and industrially advantageous processes for the preparation of Bilastine or a pharmaceutically acceptable salt thereof using novel intermediates, in high yield and purity.

Description

IMPROVED PROCESSES FOR PREPARATION OF BILASTINE USING NOVEL

INTERMEDIATES

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to Indian Provisional Patent

Application No. 201641029306, filed on August 29, 2016, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of Bilastine or a pharmaceutically acceptable salt thereof using novel intermediates, in high yield and purity.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,877,187 (hereinafter referred to as the US '187 patent) discloses a variety of benzimidazole derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have high Hi antihistaminic and antiallergic activity and are devoid of effects on the central nervous and cardiovascular systems. Among them, Bilastine, chemically named 2- [4-[2-[4-[l-(2-ethoxyethyl)-benzimidazol-2-yl]piperidin-l-yl]ethyl]phenyl]-2-methyl propanoic acid, is a selective histamine Hi receptor antagonist used for treatment of allergic rhinoconjunctivitis and urticaria (hives). Bilastine is represented by the following structural formula I:

(I) Bilastine, a novel second-generation Hi-antihistamine, is approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children over 12 years of age. Bilastine has a favourable pharmacokinetic profile, being rapidly absorbed resulting in an onset of clinical effect within one hour of administration, and has a long duration of action, exceeding 24 hours, which allows for once-daily dosing. Bilastine was developed by FAES Farma and approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Bilastine is marketed under the trade names Bilaxten^® (in Spain, Colombia, Australia, and several other countries), Ilaxten^® (in United Kingdom), and Blexten™(in Canada).

Various processes for the preparation of Bilastine, its intermediates, and related compounds are described in U.S. Patent Nos. US 5,877,187 and US 8,367,704; PCT Publication Nos. WO 2014/188453, WO2014/026657; Chinese Patent Application Publication No. CN 102675101; and Journal Articles: Syn. Comm., 41(9), 1394-1402, 2011; and Drugs of future 35(2), 98-105, 2010.

The synthesis of Bilastine was first described in the US' 187 patent. According to the US' 187 patent, Bilastine is prepared by a process as depicted in scheme 1:

Scheme- 1:

Sodium carbonate

Dimethylformamide

ethyl ethyl ether

ydride

formamide

2-[l-(2-(4-(l-(4,4-Dimethyl-delta²-oxazoline-2-yl)- l-methylethyl)phenyl)ethyl)piperidine-4-yl]-lH- benzimidazole

-oxazoline-2-vl)-l-methvlethvl)phenvl)ethvl)piperid

Bilastine According to the synthetic route described in the US' 187 patent, Bilastine is prepared by the following main reaction steps: a) 2-(4-(l-(4,4-dimethyl-A -oxazoline-2- yl)-l-methylethyl)phenyl)ethylp-toluenesulphonate is reacted with 2-(4-piperidinyl)-lH- benzimidazole in the presence of sodium carbonate to produce 2-[l-(2-(4-(l-(4,4-dimethyl- Δ -oxazoline-2-yl)-l-methylethyl)phenyl)ethyl)piperidine-4-yl]-lH-benzimidazole; b) the resulting dimethyl-oxazoline intermediate is reacted with 2-chloroethyl ethylether in dimethylformamide in the presence of sodium hydride at a temperature of 80°C, followed by tedious work- up and isolation methods to produce the l-(2-ethoxyethyl)-2-l-(2-(4-(l-

(4,4-dimethyl-A -oxazoline-2-yl)- l-methylethyl)phenyl)ethyl)piperidine-4-yl- 1H- benzimidazole; and c) the resulting 2-ethoxyethyl compound is reacted with 3N

Hydrochloric acid to produce 2-4-(2-(4-(l-(2-ethoxyethyl)benzimidazole-2-yl)piperidine- l-yl)ethyl)phenyl-2-methylpropanoic acid (Bilastine).

The process for the preparation of Bilastine as described in the aforementioned prior art suffers from the following major disadvantages and shortcomings: (a) the introduction of the oxazoline group and its subsequent hydrolysis inevitably comprised in the process leads to the formation of several by-products, thereby resulting in a poor product yields and quality and making the whole process lengthy and cumbersome; b) the reaction between 2-[l-(2-(4-(l-(4,4-dimethyl-A -oxazoline-2-yl)-l-methylethyl)phenyl) ethyl)piperidine-4-yl]-lH-benzimidazole and 2-chloroethyl ethylether is performed under very stringent reaction condition and involves the use of dangerous and explosive alkali metal hydrides such as sodium hydride; c) use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view.

A need remains for novel, commercially viable and environmentally friendly processes for the preparation of Bilastine and its intermediates with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION

The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Bilastine and its intermediates in high yields and purity.

The present inventors have found that Bilastine or a pharmaceutically acceptable salt thereof can be prepared, in high purity and with high yield, by reacting 2-methyl-2- phenyl-propanoic acid with an acylating agent in the presence of a suitable Lewis acid to produce 2- [4-(2-chloroacetyl)phenyl]-2-methyl- propanoic acid, followed by reduction with a suitable reducing agent in the presence of a Lewis acid to produce 2-[4-(2- chloroethyl)phenyl]-2-methyl-propanoic acid, which is then condensed with l-(2- ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole in the presence of a suitable base to produce Bilastine or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a novel intermediate compound, 2-[4-(2- chloroethyl)phenyl]-2-methyl-propanoic acid, of formula IIIA:

or a salt thereof.

In another aspect, provided also herein is a process for the preparation of the novel intermediate compound, 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid, of formula

IIIA.

The novel process for the preparation of Bilastine disclosed in the present invention is represented by a schematic diagram as depicted in scheme-2:

Scheme 2:

(I)

Bilastine

The process for the preparation of Bilastine described herein has the following advantages over the processes described in the prior art: i) the process involves the use of novel intermediate compounds;

ii) the overall process involves a reduced number of process steps, shorter reaction times and less expensive reagents, thereby making the process cost effective;

iii) the process avoids the use of the explosive and difficult to handle reagents like Sodium hydride;

iv) the process avoids the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications and additional purifications or isolations.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a novel and industrially advantageous process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with chloroacetyl chloride of formula VI:

optionally in the presence of a Lewis acid, to produce 2-[4-(2-chloroacetyl)phenyl]-2- methyl-propanoic acid of formula III:

in

or a salt thereof;

b) reducing the compound of formula III obtained in step-(a) with a hydrosilane reagent in the presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid compound of formula IIIA:

or a salt thereof; and

c) condensing the compound of formula IIIA obtained in step-(b) with l-(2-ethoxyethyl)- 2-(piperidin-4-yl)benzimidazole of formula IV:

or an acid addition salt thereof, in the presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained using a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.

Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds of formula I, III and IIIA obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

Unless otherwise specified, the term 'base' as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.

Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.

Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, 4- dimethylaminopyridine (DMAP), and mixtures thereof.

Unless otherwise specified, the term 'phase transfer catalysts' as used herein include, but are not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers and the like.

Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.

Acid addition salts may be derived from organic and inorganic acids. Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt.

Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.

The highly pure Bilastine or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein has a purity of greater than about 99.5%, specifically greater than about 99.8%, more specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure Bilastine or a pharmaceutically acceptable salt thereof obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.

As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

As used herein, the term "room temperature" refers to a temperature of about 20°C to about 35°C. For example, "room temperature" can refer to a temperature of about 25°C to about 30°C. Exemplary Lewis acids used in step-(a) include, but are not limited to, aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, boron trichloride, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, titanium tetrachloride, and hydrates or solvates thereof. A most specific Lewis acid used in step-(a) is aluminum chloride.

The reaction in step-(a) is carried out in a suitable solvent. Exemplary solvents used in step-(a) include, but are not limited to, a halogenated hydrocarbon, a ketone, an ether, an ester, a hydrocarbon, and mixtures thereof.

Specifically, the solvent used in step-(a) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is dichloromethane.

Specifically, the reaction in step-(a) is carried out at a temperature of about -10°C to about 50°C, and more specifically at a temperature of about -5°C to about 35°C. The reaction time may vary between about 30 minutes to about 5 hours, and specifically about 1 hour to about 3 hours.

The reaction mass containing the compound of formula III or a salt thereof obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula IIIA, or the compound of formula III or a salt thereof may be isolated and/or recrystallized and then used in the next step.

Unless otherwise specified, the carbon treatment is carried out by methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.

In one embodiment, the compound of formula III or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof. The solvent used for work up, isolation and/or recrystallization of the compound of formula III obtained by the process described herein is selected from the group as described hereinabove.

In one embodiment, the hydrosilane reducing agent used in step-(b) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichloro silane, and the like; and a most specific reducing agent is triethylsilane.

In another embodiment, the acid used in step-(b) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoro acetic acid and methanesulfonic acid. A most specific acid used is titanium tetrachloride.

Exemplary solvents used in step-(b) include, but are not limited to, a hydrocarbon solvent, a chlorinated hydrocarbon solvent, and mixtures thereof.

Specifically, the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and a most specific solvent is dichloromethane.

In another embodiment, the reaction in step-(b) is carried out at a temperature of about -10°C to 50°C; and specifically at a temperature of about 10°C to about 40°C. The reaction time may vary between about 2 hours to 8 hours, and more specifically about 4 hours to 6 hours.

The reaction mass containing the compound of formula IIIA or a salt thereof obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula IIIA or a salt thereof may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the compound of formula IIIA or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.

The solvent used for work up, isolation and/or recrystallization of the compound of formula IIIA obtained by the process described herein is selected from the group as described hereinabove. In one embodiment, the base used in step-(c) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step- (c) is an inorganic base. A most specific base used in step-(c) is sodium carbonate or potassium carbonate.

In another embodiment, the reaction in step-(c) is carried out in the presence of a phase transfer catalyst. The phase transfer catalyst can be selected from the group as described hereinabove.

Exemplary solvents used in step-(c) include, but are not limited, water, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and mixtures thereof. A most specific solvent used in step-(c) is water.

In one embodiment, the reaction in step-(c) is carried out at a temperature of about 10°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary from about 15 hours to about 25 hours.

The reaction mass containing the Bilastine of formula I or a salt thereof obtained in step-(c) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.

In one embodiment, the Bilastine of formula I or a salt thereof may be isolated, purified and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.

The solvent used for work up, isolation, recrystallization and/or purification of the Bilastine of formula I or a salt thereof obtained by the process described herein is selected from the group as described hereinabove.

The crude Bilastine obtained in step-(c) is, optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by methods known in the art, for example, as per the methods described hereinabove.

In one embodiment, the solvent used for purification of Bilastine obtained in step- (c) is selected from the group consisting of water, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, butyl acetate, and mixtures thereof.

The term "anti- solvent" refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance. Exemplary anti-solvents include, but are not limited to, water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ester, a nitrile, an ether, a polar aprotic solvent, and mixtures thereof.

Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere to obtain highly pure Bilastine or a salt thereof.

According to another aspect, there is provided a novel compound, 2-[4-(2- chloroethyl)phenyl]-2-methyl-propanoic acid, of formula IIIA:

or a salt thereof.

According to another aspect, there is provided a process for the preparation of 2- [4- (2-chloroethyl)phenyl]-2-methyl-propanoic acid of formula IIIA:

or a salt thereof, comprising:

a) reacting the 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with chloroacetyl chloride of formula VI:

optionally in the presence of a Lewis acid, to produce 2-[4-(2-chloroacetyl)phenyl]-2- methyl-propanoic acid compound of formula III:

or a salt thereof; and

b) reducing the compound of formula III obtained in step-(a) with a hydrosilane reagent in the presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid of formula IIIA or a salt thereof.

The preparation of the 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid compound of formula IIIA or a salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.

According to another aspect, there is provided a process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:

a) reducing the 2-[4-(2-chloroacetyl)phenyl]-2-methyl-propanoic acid compound of formula III:

or a salt thereof, with a hydrosilane reagent in the presence of an acid to produce the 2- [4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid compound of formula IIIA:

or a salt thereof; and b) condensing the compound of formula IIIA obtained in step-(a) with l-(2-ethoxyethyl)- 2-(piperidin-4-yl)benzimidazole of formula IV:

or an acid addition salt thereof, in the presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained with a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.

The preparation of the Bilastine of formula I or a pharmaceutically acceptable salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.

or a pharmaceutically acceptable salt thereof, comprising condensing the 2-[4-(2- chloroethyl)phenyl]-2-methyl-propanoic acid compound of formula IIIA:

or a salt thereof, with l-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula IV:

or an acid addition salt thereof, in the presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained with a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof. The preparation of the Bilastine of formula I or a pharmaceutically acceptable salt thereof can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.

The highly pure Bilastine or a salt thereof obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 75°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours.

Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.

The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of 2-[4-(2-Chloroacetyl)phenyl]-2-methyl-propanoic acid

Aluminum chloride (122 g) was slowly added to a mixture of 2-methyl-2-phenyl- propanoic acid (25 g) and dichloro methane (250 ml) at room temperature. The resulting mixture was cooled to -5 to -10°C, followed by drop wise addition of chloroacetyl chloride (34.5 g) at the same temperature. The temperature of the reaction mass was raised to 25-30°C and then stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mass was poured into water (1300 ml), ice (160 g) and hydrochloric acid (220 ml) at 10-15°C. The layers were separated and the aqueous layer was extracted twice with dichloro methane (250 ml x 2). The organic layers were combined and then washed with 1 N HC1 solution (250 ml x 2), followed by water (250 ml x 2). The solvent was removed from the organic layer by distillation under vacuum to produce 35 g of 2-[4- (2-chloroacetyl)phenyl]-2-methyl-propanoic acid. Example 2

Preparation of 2-[4-(2-Chloroethyl)phenyl]-2-methyl-propanoic acid

Dichloro methane (700 ml) was added to 2-[4-(2-chloroacetyl)phenyl]-2-methyl-propanoic acid (35 g) and the mixture was cooled to 0-5°C, followed by slow addition of titanium tetrachloride (140 g) at the same temperature. The temperature of the resulting mass was raised to 20-25°C, followed by the addition of triethylsilane (64.4 g) and then stirring the reaction mixture at 25-30°C for 4 hours. The reaction mass was cooled to below 10°C and then water (980 ml) was added at the same temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 ml x 2). The resulting organic layers were combined, followed by removal of the solvent completely by distillation under vacuum to produce a crude compound. Aqueous NaOH solution was added to the resulting crude compound while adjusting the pH to 9-10, and then washed with toluene (75 ml x 2). The layers were separated, followed adjusting the pH of the aqueous layer to 1-2 with dilute hydrochloric acid at 10-15°C. The resulting acidic aqueous layer was extracted thrice with ethyl acetate (100 ml x 3). The combined organic layers were washed with water (100 ml), and then distilled-off the solvent completely under vacuum to produce 31 g of 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid.

Example 3

Preparation of 2-(4-Piperidinyl)-lH-benzimidazole

Orthophenylenediamine (20 g), polyphosphoric acid (120 g) and isonipecotic acid (26.5 g) were taken into a reaction flask and the resulting mixture was heated to 115-120°C, followed by stirring for 20 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to 90°C, quenched with distilled water (260 ml) and then cooled to room temperature (25-30°C). The resulting mass was further cooled to 10-15°C, followed by adjusting the pH of the reaction mass to 9-10 with dilute sodium hydroxide solution, and then stirring for 30 minutes at 10-15°C. The separated solid was filtered and washed with distilled water. The wet material was dried at 40-45°C. Methanol (720 ml) was added to the resulting material and stirred for 1 hour at room temperature. The resulting mass was filtered and washed with methanol (250 ml). The resulting filtrate was concentrated under reduced pressure to give 36 g of 2-(4-Piperidinyl)-lH-benzimidazole.

Example 4

Preparation of Ethyl 4-(lH-Benzimidazol-2-yl)-piperidine-l-carboxylate

2-(4-Piperidinyl)-lH-benzimidazole (36 g) and chloroform (720 ml) were taken into a reaction flask and then triethylamine (45 g) was added at room temperature. The resulting mass was cooled to 0-5°C, followed by drop-wise addition of a solution of ethyl chloroformate (21.5 g) in chloroform (80 ml) at the same temperature for 30-45 minutes. After completion of the reaction, water (360 ml) was added to the reaction mass at the same temperature and then stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with chloroform (250 ml). The chloroform layers were combined and then washed twice with water (250 ml x 2). The chloroform was distilled off under reduced pressure from the resulting organic layer to give 46 g of crude 4-(lH- benzimidazol-2-yl)-piperidine-l-carboxylic acid ethyl ester. The crude compound was added to cyclohexane (157.5 ml) and then heated to reflux temperature. The resulting mass was stirred for 30-45 minutes at reflux temperature for 30-45 minutes and then cooled the reaction mass to room temperature, followed by stirring for 1 hour at the same temperature. The separated solid was filtered and washed with cyclohexane (45 ml) to give 44 g of pure ethyl 4-(lH-benzimidazol-2-yl)-piperidine-l-carboxylate.

Example 5

Preparation of Ethyl 4-[l-(2-Ethoxyethyl)-benzimidazol-2-yl]-piperidine-l- carboxylate

Ethyl 4-(lH-benzimidazol-2-yl)-piperidine-l-carboxylate (42 g) and toluene (210 ml) were taken into a reaction flask and then heated to 40-45°C. To the reaction mass, sodium hydroxide (18.5 g), potassium iodide (4.6 g), 2-chloroethyl ethyl ether (25 ml) and tetrabutylammonium bromide (10 g) were added. The resulting mixture was heated to 95- 100°C and then stirred for 16 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to room temperature, followed by the addition of water (210 ml) and then stirring for 10 minutes at room temperature. The resulting mass was neutralized with dilute hydrochloric acid. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (200 ml x 2). The toluene layer and ethyl acetate layers were combined and washed with distilled water (250 ml). The solvents were distilled off completely under reduced pressure to give 51 g of ethyl 4-[l-(2-ethoxyethyl)- benzimidazol-2-yl] -piperidine- 1 -carboxylate.

Example 6

Preparation of l-(2-Ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole

Ethyl 4- [l-(2-ethoxyethyl)-benzimidazol-2-yl] -piperidine- 1 -carboxylate (50 g) and isopropyl alcohol (350 ml) were taken into a reaction flask and then potassium hydroxide (100 g) was added at room temperature. The resulting mixture was heated to reflux and then maintained for 10 hours at reflux temperature. The solvent was distilled off completely from the reaction mass under reduced pressure to obtain crude product. Water (850 ml) was added to the crude product and then neutralized with dilute hydrochloric acid. The resulting mass was extracted with 1-butanol (600 ml) and again extracted with 1- butanol (300 ml x 2) twice. The solvent was distilled off under reduced pressure, followed by co-distillation with toluene (100 ml). The resulting crude was cooled to room temperature and then toluene (135 ml) was added, followed by stirring for 20-30 minutes. The separated solid was filtered and washed with toluene (40 ml) to give 41 g of crude 1- (2-ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole. The crude compound was added to acetone (410 ml) and then heated to reflux, followed by stirring the reaction mass at reflux temperature for 30 minutes. The reaction mass was cooled to 25-30°C, filtered the material and then washed with acetone (30 ml) to give 32.5 g of pure l-(2-ethoxyethyl)-2- (piperidin-4-yl)-benzimidazole.

Example 7

Preparation of Pure Bilastine

Step-(a): Preparation of Crude Bilastine

2-[4-(2-Chloroethyl)phenyl]-2-methyl-propanoic acid (20 g), water (200 ml), l-(2- ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole (26 g) and sodium carbonate (28 g) were taken into a reaction flask at room temperature. The resulting mixture was heated to reflux temperature and maintained for 22 hours at the same temperature. After completion of reaction, the resulting mass was cooled to room temperature, followed by addition of water (960 ml) at the same temperature. The layers were separated and the aqueous layer was washed with toluene (640 ml x 2). The aqueous layer was separated and then neutralized with acetic acid, followed by extracting thrice with dichloromethane (800 ml x 3). Activated carbon (12 g) was added to the resulting organic layers and then stirred for 10 minutes. The resulting mixture was filtered through hyflo-bed and then washed the bed with dichloro methane (50 ml). The resulting filtrate was distilled-off under vacuum to remove the solvent completely. Acetone (110 ml) was added to the resulting crude compound and then stirred for 10-15 minutes at room temperature. The solvent was distilled-off completely from the resulting mass, acetone (85 ml) was added again and then stirred for 1 hour at room temperature. The separated solid was filtered and washed with acetone (30 ml) to produce 19 g of crude Bilastine.

Step-(b): Purification of crude Bilastine:

Crude Bilastine (19 g) was added to butyl acetate (570 ml) and then heated to reflux temperature while stirring, followed by maintaining the reaction mass for 15 minutes at the same temperature. The resulting mass was cooled to room temperature and then stirred for 30 minutes at the same temperature. The separated solid was filtered and washed with butyl acetate (30 ml). Butyl acetate (540 ml) was added to the resulting wet material and then repeated the above re-crystallization process. The resulting wet material was taken in methanol (320 ml) and then heated to reflux, followed by stirring the reaction mass for 30 minutes at reflux temperature. Activated carbon (1.6 g) was added to the reaction mass and then stirred for 10 minutes. The resulting mixture was filtered through hyflo-bed and then washed the bed with hot methanol (16 ml). The resulting filtrate was cooled to 20-22°C and then stirred for 40 minutes at the same temperature. The separated solid was filtered, washed with cold methanol (16 ml) and then dried the material at 60-70°C to give 15 g of pure Bilastine (Purity by HPLC: 99.6%).

Claims

We Claim:

1. A process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:

a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with chloroacetyl chloride of formula VI:

optionally in the presence of a Lewis acid, to produce 2-[4-(2-chloroacetyl)phenyl]- 2-methyl-propanoic acid of formula III:

or a salt thereof;

b) reducing the compound of formula III obtained in step-(a) with a hydrosilane reagent in the presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-methyl- propanoic acid compound of formula IIIA:

or a salt thereof; and c) condensing the compound of formula IIIA obtained in step-(b) with l-(2- ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula IV:

The process of claim 1, wherein the Lewis acid used in step-(a) is selected from the group consisting of aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, boron trichloride, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, titanium tetrachloride, and hydrates or solvates thereof; wherein the reaction in step-(a) is carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran,

2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert- butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the hydrosilane reducing agent used in step-(b) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; wherein the acid used in step-(b) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoro acetic acid and methanesulfonic acid; wherein the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(c) is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the phase transfer catalyst used in step-(c) is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, and crown ethers; and wherein the solvent used in step-(c) is selected from the group consisting of water, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and mixtures thereof.

3. The process of claim 2, wherein the Lewis acid used in step-(a) is aluminum chloride; wherein the solvent used in step-(a) is dichloro methane; wherein the hydrosilane reducing agent used in step-(b) is triethylsilane; wherein the acid used in step-(b) is titanium tetrachloride; wherein the solvent used in step-(b) is dichloro methane; wherein the base used in step-(c) is sodium carbonate or potassium carbonate; and wherein the solvent used in step-(c) is water.

4. A compound, 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid, of formula IIIA:

or a salt thereof.

A process for the preparation of 2-[4-(2-chloroethyl)phenyl]-2-methyl-propano of formula IIIA:

or a salt thereof, comprising:

a) reacting the 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with chloroacetyl chloride of formula VI:

optionally in the presence of a Lewis acid, to produce 2-[4-(2-chloroacetyl)phenyl]- 2-methyl-propanoic acid compound of formula III:

or a salt thereof; and

b) reducing the compound of formula III obtained in step-(a) with a hydrosilane reagent in the presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-methyl- propanoic acid of formula IIIA or a salt thereof.

6. The process of claim 5, wherein the Lewis acid used in step-(a) is selected from the group consisting of aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, boron trichloride, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, titanium tetrachloride, and hydrates or solvates thereof; wherein the reaction in step-(a) is carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert- butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the hydrosilane reducing agent used in step-(b) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; wherein the acid used in step-(b) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoroacetic acid and methanesulfonic acid; and wherein the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

A process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:

or a salt thereof, with a hydrosilane reagent in the presence of an acid to produce the 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid compound of formula IIIA:

or a salt thereof; and

b) condensing the compound of formula IIIA obtained in step-(a) with l-(2- ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula IV:

The process of claim 7, wherein the hydrosilane reducing agent used in step-(a) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; wherein the acid used in step-(a) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoro acetic acid and methanesulfonic acid; wherein the solvent used in step-(a) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(b) is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the phase transfer catalyst used in step-(b) is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, and crown ethers; and wherein the solvent used in step-(b) is selected from the group consisting of water, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and mixtures thereof.

9. A process for the preparation of highly pure Bilastine of formula I:

ΠΙΑ

or a salt thereof, with l-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula

IV:

The process of claim 9, wherein the base used in the reaction is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, sodium amide, potassium amide, lithium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the phase transfer catalyst used in the reaction is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, and crown ethers; and wherein the solvent used in the reaction is selected from the group consisting of water, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and mixtures thereof.