700173369
CROSS REFERENCE TO RELATED APPLICATION This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201641038857, filed on November 15, 2016, which is incorporated herein by reference in its entirety. 5
FIELD OF THE INVENTION The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Bilastine or a pharmaceutical^ acceptable salt thereof using novel intermediates, in high yield and purity. 10
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.
15 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-methylpropanoic acid, is a selective histamine H|
receptor antagonist used for treatment of allergic rhinoconjunctivitis and urticaria
20 (hives). Bilastine is represented by the following structural formula I:
(I)
Bilastine, a novel second-generation H[-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,
30 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
.. t - ^ojj^da^ydosing: wjsj AT . .14/ 1 '!../ 2 0 1 7 I."0:> 4.6 ..
2

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), llaxten® (in United Kingdom), and Blexten™
5 (in Canada).
Various processes for die 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.
10 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:
a
E-o
o
u
^&XEii:c—^
CO

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-5 (2-(4-( 1 -(4,4-dimethyl-A2-oxazoline-2-yl)-1 -(methylethyl)phenyl)ethyl)piperidine-4-yl]-lH-benzimidazole; b) the resulting dimethyl-oxazoline intermediate is reacted with 2-chloroethyl ethylether in dimethylformamide in presence of sodium hydride at a temperature of 80°C, followed by tedious work-up and isolation methods to produce the 1 -(2-ethoxyethyl)-2-1 -(2-(4-(l -(4,4-dimethyl-A2-oxazoline-2-yl)-1 -
10 methylethyl) phenyl)ethyl)piperidine-4-yl-lH-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
15 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-
20 dimethyl-A2-oxazoline-2-yl)-1 -(methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-
benzimidazole and 2-chloroethyl ethylether is performed under very stringent reaction condition and involves the use of dangerous, corrosive and explosive alkali metal hydrides such as sodium hydride; c) the use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view.
25 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.
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4

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.
5 The present inventors have found that Bilastine can be prepared in high purity
and with high yield, by reacting 2-methyl-2-phenyl-propanoic acid with chloroacetyl chloride in presence of a suitable Lewis acid to produce 2-[4-(2-chloroacetyl)phenyl]-2-methyl-propanoic acid, which is then reduced with a suitable reducing agent in presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-
10 methyl-propanoic acid, followed by condensation with 2-(4-Piperidinyl)-lH-benzimidazole to produce 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]: ethyl]phenyl]-2-methyl propanoic acid. The resulting intermediate is further condensed with 2-chloroethyl ethyl ether in presence of a suitable base and a suitable catalyst to produce Bilastine.
15 In one aspect, provided herein is an efficient, industrially advantageous and
environmentally friendly process for the preparation of Bilastine of formula I, in high yield and high purity, using a novel intermediate. The process disclosed herein avoids the tedious and cumbersome procedures of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which
20 is more convenient to operate at laboratory scale and on a commercial scale.
In another aspect, provided also herein is a novel compound, 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic acid, of formula VIII:
or a salt thereof.
In another aspect, provided also herein is a process for the preparation of the 30 novel compound of formula VIII.
Q n PPTi-F T. H -E NJ^J_l^^L'L^2_HLl_7_^lJ£Ll-4-S
5

The novel process for the preparation of Bilastine disclosed in the present invention may be represented by a schematic diagram as depicted in scheme-2:
ale
The process for the preparation of Bilastine described herein has the 5 following advantages over the processes described in the prior art:
i) the process of the present invention involves the use of novel intermediate
compound; ii) the overall process involves a reduced number of process steps, shorter reaction times and less expensive reagents, thereby making the process cost effective; 10 iii) the process avoids the use of highly inflammable, dangerous and difficult to handle reagents like Sodium hydride; iv) the process avoids the use of expensive Palladium catalysts like bis (dibenzylidene acetone) palladium (Pd(dba)2); and expensive ligands such as tri-tertiary butyl phosphine (t-Bu3P); and
lifflCE. CHENNAI 14 i \ 1 >„2 01 7 1 8 ; 4.8

v) the process avoids the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolations, additional and excess amounts of solvents.
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:
10
or a pharmaceutically acceptable salt thereof, which comprises: a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:
15
or a salt thereof, with chloroacetyl chloride of formula VI:
20
optionally in the presence of a Lewis acid, to produce 2-[4-(2-
25 chloroacetyl)phenyl]-2-methyl-propanoic acid compound of formula III:
VJ
30
or a salt thereof; E.IC1: .lO-RFTCF ;T;HTNN A..T. 14 / 1 T 7 2 U) 1. .7 l..B= 4.?-
7

b) reducing the compound of formula III obtained in step-(a) with a hydrosuane reagent in the presence of an acid to produce 2-[4-(2-chloroethyl)phenyl]-2-methy I-propanoic acid compound of formula IIIA:
or a salt thereof; c) condensing the compound of formula IIIA obtained in step-(b) with 2-(4-piperidinyl)-lH-benzimidazole of formula VII:
or a salt thereof, in a suitable solvent in the presence of a base, optionally in the presence of a phase transfer catalyst, to produce 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic acid compound of formula
VIII:
or a salt thereof; and d) reacting the compound of formula VIII obtained in step-(c) with 2-chloroethyl ethyl ether in a suitable solvent in the presence of a base, optionally in the presence of a phase transfer catalyst, to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine or a salt thereof 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 obtained by the processes described in the present
m^ntiG^Spsele^ted^^^ an
8

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 5 acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
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 of the
10 solvent used for at least 5 minutes, specifically at the reflux temperature of the solvent used; 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.
Unless otherwise specified, the term 'base' as used herein includes, but is not
15 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
20 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
25 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
30 chloride, tetrabutylammonium iodide, benzyltrimefhyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers
^ T - and.tncjjik^ C BE N N AI H f 1 1" ' 2 -Gl 1 7 1 GP 4 8
9

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,
5 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 10 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
"aT 15 pharmaceutically acceptable salt thereof obtained by the processes disclosed herein is
— about 99.5% to about 99.99% as measured by HPLC.
Q.
E As used herein, the term "reflux temperature" means the temperature at
O
O which the solvent or solvent system refluxes or boils at atmospheric pressure.
Q As used herein, the term "room temperature" refers to a temperature of about
"3. 20 20°C to about 35°C. For example, "room temperature" can refer to a temperature of
O about 25°C to about 30°C.
* Exemplary Lewis acids used in step-(a) include, but are not limited to,
h- aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, boron
§g trichloride, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc
O 25 chloride, titanium tetrachloride, and hydrates or solvates thereof. A most specific
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
^ Lewis acid used in step-(a) is aluminum chloride.
o
CN
CO
CO ketone, an ether, an ester, a hydrocarbon, and mixtures thereof.
O
30 Specifically, the solvent used in step-(a) is selected from the group consisting
O CN
of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, 4etrahydijefpanf2^
^p-A-T-Frcrtf^T'i o

CO

10

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 5 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, a 10 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.
In one embodiment, the compound of formula III or a salt thereof may be
15 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 20 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, trichlorosilane, and the like; and a most specific 25 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, trifluoroacetic acid and
30 methanesulfonic acid; and a most specific acid is titanium tetrachloride.
Exemplary solvents used in step-(b) include, but are not limited to, a
hydrGcarbor^solwp^-p!^
11

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 5 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
10 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 VIII, or the
compound of formula IIIA or a salt thereof may be isolated and/or recrystallized and
then used in the next step.
15 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 20 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.
25 Exemplary solvents used in step-(c) include, but are not limited, water,
acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, Toluene, xylene, ethyl acetate, butyl acetate, and mixtures thereof. A most specific solvent used in step-(c) is water.
Exemplary phase transfer catalysts used in step-(c) include, but are not 30 limited to, tetrabutyl ammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl {I. O-KriTF THFNNAT . 1 4 / 1 1 7 X Pit T. "1 8 '- * *
12

ammonium chloride, methyl tributyl ammonium chloride, crown ethers, or a combination thereof.
. In another embodiment, the reaction in step-(c) is optionally carried out in the
presence of sodium iodide or potassium iodide.
5 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 between about 10 hours to about 25 hours, and more specifically about 18 hours to 10 about 22 hours.
The reaction mass containing the compound of formula VIII 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. The reaction mass may 15 be used directly in the next step to produce the compound of formula I, or the compound of formula VIII or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula VIII or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods as 20 described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula VIII obtained by the process described herein is selected from the group as described hereinabove.
The base used in step-(d) is an organic base or an inorganic base selected
25 from the group as described hereinabove. Specifically, the base used in step-(d) is an
inorganic base selected from the group consisting of sodium hydroxide, calcium
hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, potassium carbonate and mixtures thereof; and a most specific base is
sodium hydroxide.
30 Exemplary phase transfer catalysts used in step-(d) include, but are not
limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, —tetrabutylfin^omuip^ip^
EK
13

ammonium chloride, methyl tributyl ammonium chloride, crown ethers, or a
combination thereof.
In another embodiment, the reaction in step-(d) is optionally carried out in the
presence of sodium iodide or potassium iodide.
5 Specifically, the solvent used in step-(d) is selected from the group consisting
of acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylsulfoxide,
dimethylformamide, N-methylpyrrolidone, Toluene, xylene, ethyl acetate, butyl
acetate, and mixtures thereof. A most specific solvent used in step-(d) is toluene.
In one embodiment, the reaction in step-(d) is carried out at a temperature of 10 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 a temperature of about 90°C to the reflux temperature of the solvent
used. The reaction time may vary between about 10 hours to about 22 hours, and
more specifically about 16 hours.
15 The reaction mass containing the Bilastine of formula I or a salt thereof
obtained in step-(d) 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 20 isolated, purified and/or re-crystallized from a suitable solvent by conventional
methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization/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.
25 The crude Bilastine obtained in step-(d), 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 30 step-(d) is selected from the group consisting of water, acetone, methanol, ethanol,
isopropyl alcohol, ethyl acetate, butyl acetate, and mixtures thereof.
XrO'rrFir F_.CHFNN AT ' 1.4 / 11 V" 7 Pit 7" 1 .0. ■ 4-..S ...
14

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 5 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, provided also herein is a novel compound, 2-[4-
10 [2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic
acid, of formula VIII:
or a salt thereof.
According to another aspect, there is provided a process for the preparation of the novel compound, 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic acid, of formula VIII:
or a salt thereof, comprising: 25 a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:
(

30

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; 10 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 III A:
15
or a salt thereof; and c) condensing the compound of formula IIIA obtained in step-(b) with 2-(4-piperidinyl)-lH-benzimidazole of formula VII:
20
or a salt thereof, in a suitable solvent in the presence of a base, optionally in the
25 presence of a phase transfer catalyst, to produce 2-[4-[2-[4-(lH-Benzimidazol-2-
yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic acid compound of formula VIII or a salt thereof.
The preparation of 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-
ethyl]phenyl]-2-methyl propanoic acid compound of formula VIII or a salt thereof as
30 described in the above process steps-(a), (b) and (c) can be carried out by using the
suitable solvents, reagents, methods, parameters and conditions as described
■T--uE^lb£V&:.C.HENWAI.. 14/11/2017 1.0- "48
16

According to another aspect, there is provided a process for the preparation of highly pure Bilastine of formula I:
or a pharmaceutical^ acceptable salt thereof, which comprises:
a) reducing the 2-[4-(2-chloroacetyl)phenyl]-2-methyl-propanoic acid compound of
10 formula III:
15
or a salt thereof, 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:
20
or a salt thereof; b) condensing the compound of formula IIIA obtained in step-(a) with 2-(4-piperidinyl)-lH-benzimidazole of formula VII:
25
or a salt thereof, in a suitable solvent in the presence of a base, optionally in the
30 presence of a phase transfer catalyst, to produce 2-[4-[2-[4-(lH-Benzimidazol-2-
o y])-piperidin-l-yl]-ethyl]phenyl]-2-methyI propanoic acid compound of formula
17

5 or a salt thereof; and
c) condensing the compound of formula VIII obtained in step-(b) with 2-chloroethyl
ethyl ether, in a suitable solvent, in the presence of a base, optionally in the
presence of a phase transfer catalyst to produce to produce Bilastine of formula I
or a salt thereof, and optionally purifying the Bilastine or a salt thereof obtained
10 using a suitable solvent to produce highly pure Bilastine or a pharmaceutically
acceptable salt thereof.
The preparation of Bilastine of formula I or a pharmaceutically acceptable salt thereof as described in the above process steps-(a), (b) and (c) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as 15 described hereinabove.
According to another aspect, there is provided a process for the preparation of highly pure Bilastine of formula I:
20
or a pharmaceutically acceptable salt thereof, which comprises:
a) condensing 2-[4-(2-chloroethyl)phenyl]-2-methyl-propanoic acid compound of
25 formula IIIA:.
30 or a salt thereof, with 2-(4-piperidinyl)-lH-benzimidazole of formula VII:
1 r&F-F-T rrXHTJiFAT . . i 4 rt 1 / f 0 T 7 .18= 4.ft
M;
18

or a salt thereof, in a suitable solvent in the presence of a base, optionally in the presence of a phase transfer catalyst, to produce 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2:methyl propanoic acid compound of formula VIII:
10

or a salt thereof; and
b) condensing the compound of formula VIII obtained in step-(a) with 2-chJoroethyl
15 ethyl ether in a suitable solvent in the presence of a base, optionally in the
presence of a phase transfer catalyst, to produce Bilastine of formula I or a salt
thereof, and optionally purifying the Bilastine or a salt thereof obtained using a
suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable
salt thereof.
20 The preparation of 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.
The compounds obtained in any of the above process steps may be collected 25 by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
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
30 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
4 8
rr:BH.UF THfSKH - ■1V11.'7.»!'; .1.0':
19

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
5 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 10 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. 15 However, they should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1
20 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 dichloromethane (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
25 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 dichloromethane (250 ml x 2). The organic layers were combined and then washed with IN HC1 solution
30 (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-
cJilnroacetylSphenylJ-Sj-r^qthy^ -Q 1- / ■*- ■* '
20

Example 2
Preparation of 2-[4-(2-Chloroethyi)phenyl)-2-methyl-propanoic acid
Method-(A):
Dichloromethane (700 ml) was added to 2-[4-(2-chloroacetyl)phenyl]-2-methyl-
5 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
10 the same temperature. The organic layer was separated and the aqueous layer was
extracted with dichloromethane (500 ml). 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
"aT 15 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 mass
E was cooled to 0-5°C for 30 minutes. The separated solid was filtered and then
O
O washed with cold water (50 ml) to produce 20 g of 2-[4-(2-chloroethyl)phenyl]-2-
C O
methyl-propanoic acid. 20 Method-(B):
O Dichloromethane (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
r^ addition of titanium tetrachloride (140 g) at the same temperature. The temperature
IO
of the resulting mass was raised to 20-25°C, followed by the addition of
CO
CO
CO
O 25 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
o
CN
the same temperature. The organic layer was separated and the aqueous layer was
extracted with dichloromethane (500 ml). The resulting organic layers were
CO
CO combined, followed by removal of the solvent completely by distillation under
o
t; 30 vacuum to produce a crude compound. Aqueous NaOH solution was added to the
Q resulting crude compound while adjusting the pH to 9-10, and then washed with
j[_ „ . _J$Mig475-ml-X£2^ of the
Z ■
CO
*~ 21

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-5 propanoic acid.
Example 3 Preparation of 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-mcthyl propanoic acid
10 2-[4-(2-Chloroethyl)phenyl]-2-methyl propanoic acid (46 g), water (460 ml) and 2-(4-piperidinyl)-lH-benzimidazole (64.5 g) and sodium carbonate (44 g) were taken into a reaction flask, the resulting mixture was heated to reflux temperature and then maintained for 20-22 hours at reflux. The reaction mass was cooled to 20-25°C, followed by addition of water (918 ml) at the same temperature. The resulting mass
15 was neutralized while adjusting the pH to 6-7 with dilute hydrochloric acid (120 ml) at 20-25°C, followed by the addition of n-butanol (250 ml) and then stirring for 10-15 minutes at the same temperature. The solid obtained was filtered and washed with water (50 ml) to produce 42 g of 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic acid.
20
Example 4 Preparation of Pure Bilastine Step-(a): Preparation of Crude Bilastine 2-[4-[2-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-ethyl]phenyl]-2-methyl propanoic
25 acid (37 g) was taken in toluene (370 ml) and the mixture was heated to 40-45°C, followed by the addition of sodium hydroxide (15 g), potassium iodide (3.7 g), 2-chloroethyl ethyl ether (37 ml) and tetrabutyl ammonium bromide (7.4 g). The resulting mass was heated to 95-100°C and then stirred for 16 hours at the same temperature. The resulting mass was cooled to room temperature and water (1850
30 ml) was added at the same temperature. The organic layer was separated and the aqueous layer was washed twice with toluene (740 ml x 2). The aqueous layer was
.. neutralized-with (aqqtrc taqidj^ZO ml)lwriile adjusting^ the pH to 6-7, followed by
N 1. . 0 r. 1.1- A~. *-. *""
22

extracting with dichloromethane (500 ml x 2). Activated Carbon (7 g) was added to the organic layer and stirred for 10 minutes. The resulting mixture was filtered through hyflo-bed and then washed the bed with dichloromethane (40 ml). The resulting filtrate was distilled-off under vacuum to remove the solvent completely. Acetone (186 ml) was added to the crude compound and then stirred for 10-15 minutes at room temperature. The solvent was distilled-off completely from the resulting mass, acetone (140 ml) was added again and then stirred for 1 hour at room temperature. The separated solid was filtered and washed with acetone (40 ml) to produce 23 g of crude Bilastine.
Step-(b): Purification of crude Bilastine:
Crude Bilastine (23 g) was added to n-butyl acetate (690 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 (40 ml). Butyl acetate (650 ml) was added to the resulting wet material and then repeated the above re-crystallization process. The resulting wet material was taken in methanol (460 ml) and then heated to reflux, followed by stirring the reaction mass for 30 minutes at reflux temperature. Activated carbon (2.0 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 (20 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 (20 ml) and then dried the material at 60-70°C to give 18 g of pure Bilastine (Purity by HPLC: 99.9%).