DESC:FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of bilastine methyl ester, an intermediate of bilastine. More specifically, the present invention relates to a process for the preparation of pure bilastine methyl ester and its conversion into bilastine.
BACKGROUND OF INVENTION
Bilastine is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria. Bilastine is chemically known as 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2- methylpropanoic acid, and is represented by Formula I:

Formula I
Bilastine and its synthesis was first time described in the US Patent 5,877,187. As per the process exemplified, bilastine is prepared by reaction of 2-(4-piperidinyl)-1H-benzimidazole with 2-(4-(1-(4,4-dimethyl-?2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl p-toluenesulphonate in presence of sodium carbonate in dimethylformamide (DMF), the alkylation of resulting intermediate to prepare 1-(2-ethoxyethyl)-2-1-(2-( 4-(1-(4,4-dimethyl-2-oxazoline-2-yl)-1-methylethyl) phenyl) ethyl)piperidine-4-yl-lH–benzimidazole, followed by its hydrolysis with 3N hydrochloric acid at reflux temperature. The product is isolated by cooling the reaction mass and adjusting pH to 7 using 50% sodium hydroxide solution. The process is schematically shown below:

The major shortcoming of above-mentioned process is the introduction of 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.
Another US patent 8,367,704 discloses a process for preparing 2-methyl-2-phenylpropionic acid derivatives, comprising the step of reacting 2-methyl-2-propanoate intermediate with a benzo[d]imidazole moiety in the presence of an inorganic base in a suitable organic solvent. The schematic synthetic scheme is shown below:
wherein A is O, N; R1 is H or C1-C6 linear or branched alkyl, X is a common leaving group, preferably halogen and R2 is CH2CH2Oalkyl
Bilastine preparation has been exemplified using several leaving groups such mesyl or tosyl. However, the said patent does not explicitly provide any example wherein halogen is used as leaving group to prepare bilastine.
A PCT publication WO2014/188453 discloses and teaches a process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate. Thereafter, the said methylpropanoate moiety is reacted with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d]imidazole in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide bilastine methyl ester, which is converted to bilastine by hydrolyzing the ester moiety to the required carboxylic acid group. The whole process for synthesis of bilastine is depicted in said publication is shown below:

A Chinese patent CN102675101 unveils the process for synthesis of bilastine comprising the following steps, acylation reaction of 2,2-dimethylphenylacetate with halo acetyl halide is carried out under the action of a catalyst in the presence of a solvent to form 2-(4-haloacetyl)phenyl-2-methylpropionate. Thereafter, the resulting compound undergoes a reduction reaction to reduce the carbonyl group to generate 2-(4-haloethyl)phenyl-2-methylpropionate. Further, condensation of 2-(4-haloethyl) phenyl-2-methylpropionate with 1-ethoxyethyl-2-pyridin-4-yl benzimidazole under goes in the presence of a base and solvent to obtain bilastine methyl ester which is subjected for hydrolysis in the presence of a solvent and catalyst to form bilastine. The process is schematically shown below:

Another Chinese patent publication CN107365298 discloses a method for preparing 2-methyl-2-phenylpropionic acid derivative by using water as a solvent. The process is schematically shown below:

The process comprises of reacting 2-methyl-2-propanoate intermediate with a benzo[d]imidazole moiety in the presence of water under the action of catalyst (sodium iodide) to obtain bilastine methyl ester, wherein A is oxygen or nitrogen; when A is oxygen, R1 is hydrogen, C1-C6 branched or linear alkyl. Further, bilastine methyl ester is hydrolyzed to form bilastine.
Most of the prior art cited as above have one or the other drawbacks. In our hands, when we have repeated the examples given in the literature, it has been found that when specifically the reaction of 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole with methyl 2-[4-(2-chloroethyl) phenyl]-2-methylpropanoate is carried out in the presence of base, in a suitable solvent, the reaction does not go to completion. Both the starting materials were found to be unreacted during reaction monitoring. Even after extending the reaction hours and by using the higher temperature too, the reaction does not go to completion. It becomes stagnant at one point and does not proceed further. To remove the said unreacted material or by-product needs extensive multiple purifications, which enhance the cost of process and even yield of the final product decreases. The reported processes need prolonged reaction time, drastic reaction conditions and tedious isolation procedures to prepare pure product, thereby making the processes commercially unviable.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Even though, in synthetic organic chemistry getting a single end product with 100% purity is seldom wherein there is always a chance of having by-products. Because by-products or impurities can be formed through variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, rearrangement or unwanted reactions between starting materials or intermediate with chemical reagents or catalysts. Such impurities that remain within the API or formulation even in the small amounts can influence quality, safety and efficacy (QSE) of the product, thereby causing serious health hazards. Therefore, the limits and threshold values of those impurities should comply with the limits set and specified by official bodies and legislation (Pharmacopoeias and International conference on Harmonization (ICH) guidelines).
In order to overcome the aforementioned drawbacks in the prior art processes mainly due to the incompletion of the reaction, there is a need in the art to provide an efficient industrially viable process for the preparation of bilastine methyl ester, wherein the condensation reaction reaches to its completion. Since this condensation step is the penultimate step in the synthesis of bilastine, mild conditions need to be opted to minimize the formation of the by-products.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an industrial advantageous process for the preparation of bilastine methyl ester that overcomes the limitations of the prior methods i.e., prolonged reaction time, drastic reaction conditions and tedious isolation procedures.
Another object of the present invention is to provide an effective process for the purification of bilastine methyl ester wherein the formation of impurities is controlled at different RRT (relative retention time) levels.
Yet one another object of the present invention is to provide a process for the preparation and purification of bilastine methyl ester using a mild reaction conditions.
SUMMARY OF INVENTION
The present invention provides an industrially viable process for the preparation of bilastine methyl ester in a pure form, wherein the known and unknown impurities at different RRT levels are controlled.
In an embodiment, the present invention provides an efficient process for the preparation of bilastine methyl ester of formula II,

Formula II
which comprises:
i. reacting 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of formula III,

Formula III
with methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV

Formula IV
in the presence of a phase transfer catalyst, a base, in a suitable solvent,

ii. isolating bilastine methyl ester.
In another embodiment, the present invention provides a novel process for the purification of bilastine methyl ester of formula II, which comprises the steps of:
i. adding crude bilastine methyl ester in a suitable organic solvent,
ii. heating the reaction mass obtained in step (i) to obtain a clear solution,
iii. cooling the reaction mixture to obtain solid,
iv. isolating pure bilastine methyl ester.
In another embodiment, the present invention provides an efficient process for the preparation of the bilastine compound of formula I,

Formula I
which comprises the steps of:
i. reacting 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of formula III,

Formula III
with methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV

Formula IV
in the presence of a phase transfer catalyst, a base, in a suitable solvent,
ii. isolating bilastine methyl ester,
iii. converting the bilastine methyl ester obtained in step (ii) into bilastine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous process for the preparation of bilastine methyl ester wherein the use of specific catalyst leads to the completion of reaction thereby minimizing the possibilities of by-products formation.
As used herein, the term “pure” represents a compound having purity greater than 98.0% w/w by HPLC, preferably greater than 98.5% w/w by HPLC, more preferably greater than 99.0% w/w by HPLC and any individual impurity [known] present in an amount less than 0.50% w/w by HPLC, any unknown impurity present in an amount of less than 0.50% w/w by HPLC and total impurities present in an amount less than 1.00% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature 25?± 5?.
In the first aspect the present invention provides a process for the preparation of bilastine methyl ester. The process comprises condensation of 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of formula III with methyl 2-[4-(2-chloroethyl) phenyl]-2-methylpropanoate of formula IV in the presence of a phase transfer catalyst, a base, in a suitable solvent.
The inventors of present application have surprisingly found that the condensation of 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of the formula III with methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV in the presence of a phase transfer catalyst reaches to completion thereby minimizing the prolonged reaction time, drastic reaction conditions and tedious isolation procedures and enhancing the yield and purity of bilastine methyl ester as compared to the prior art processes performed in absence of phase transfer catalyst.
Generally, the condensation of benzoimidazole intermediate of formula III and methylpropanoate intermediate of formula IV, in the presence of phase transfer catalyst, a base in a suitable solvent can be carried out at a temperature of 95 to 115°C preferably at a temperature between 100-110°C for few minutes to few hrs. Specifically, the reaction can be completed at 16-24 hrs, more preferably in 20-24 hrs.
The phase transfer catalyst used herein may include but not limited to tetraalkylammonium salts and crown ethers. In some embodiments, the phase transfer catalyst can be chosen from crown ethers, such as 18-crown-6 and 15-crown-5 phase transfer catalysts. In some embodiments, the phase transfer catalyst can be chosen from tetraalkylammonium salts. In some embodiments, the phase transfer catalyst can be chosen from tetraalkylammonium halides. In some embodiments, the at least one phase transfer catalyst can be chosen from tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI), tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TOAB), tetraoctylammonium chloride (TOAC), tetraoctylammonium iodide (TOAI), trioctylmethylammonium chloride, and trioctylmethylammonium bromide.
Optionally, the mixture of phase transfer catalysts with an additive can be also utilized for the condensation reaction.
The additive can be chosen from metal halide. In some embodiments, the at least metal halide can be chosen from sodium iodide, potassium iodide, sodium bromide, potassium bromide or mixture thereof. Preferably, the additive may be potassium iodide.
The base used herein may include an organic base, inorganic base or mixture thereof. The organic bases include, but are not limited to, amines such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, dimethylaminopyridine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethyl aniline, N-methyl morpholine (NMM), N,N-dimethyl amino pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO), tetramethylpiperidine, tetramethylguanidine, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.
Inorganic bases include, but are not limited to alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, hydride such as sodium hydride, lithium hydride or potassium hydride, alkoxide such as sodium or potassium methoxide or ethoxide, tertiary butoxide, alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like or mixtures thereof. Preferably, the inorganic base may be potassium carbonate, sodium carbonate or a mixture thereof.
The “suitable solvent” used in above reaction can be selected from but are not limited to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "polar solvents" such as water; acetic acid, formic acid or their mixtures.
The completion of reaction can be monitored by HPLC. After completion of reaction, the reaction mass containing the bilastine methyl ester of formula II can be subjected to usual work up methods such as quenching, an extraction, a pH adjustment, acid base treatment, evaporation, a layer separation, decolourization, a carbon treatment, filtration, washing a combination thereof.
Specifically, after completion of reaction, the reaction mass can be cooled and subjected for extraction with a solvent, preferably from water. The reaction mixture can be stirred, and layers may be separated. The organic layer can be acidified to pH 2-3 with an acid solution such as hydrochloric acid or any similar acid. Thereafter, layers are separated, and the aqueous layer can be neutralized to pH 6.5-7.5 with basic solutions such as ammonia.
The resulting mixture can be cooled to 10-20°C and stirred at the same temperature for few hrs for complete precipitation. Thereafter the reaction mixture can be filtered and washed with a suitable solvent. The solvent used for washing can be selected from water or mixture of water with suitable solvent which can be same as of reaction solvent as given above. Finally, the resulting solid can be dried at 50-70°C for 15-20 hours to obtain bilastine methyl ester having HPLC purity more than 98.60% [w/w]. The preferable drying temperature can be 55- 65°C and preferably, the solid can be dried for 15-20 hours and more preferably for 16-18 hours.
In an embodiment the bilastine methyl ester may be purified and/or recrystallized from a suitable organic solvent, if desired, by any conventional method reported in the literature or a process as described in the present specification.
Particularly, the crude bilastine methyl ester can be added in a suitable organic solvent. The suitable organic solvent used herein can be selected from "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like or mixtures thereof. Preferably, the solvent may be isopropyl alcohol.
The dissolution of bilastine methyl ester in the organic solvent can be achieved by heating the reaction mixture to reflux temperature of the solvent. Specifically, the heating can be done 65-95°C, preferably at 75-85°C. Subsequently, after dissolution of bilastine methyl ester, the reaction mass can be allowed to attain ambient temperature and further cooled the reaction mass at -5 to 15°C. Preferably, the reaction mass can be cooled at -5 to 8°C.
After cooling, the resulting reaction mass may be subsequently stirred and then filtration step can be applied at the same temperature.
The filtration can be performed, amongst other methods, by passing the solution, dispersion, or slurry through a filter paper, sintered glass filter or other membrane material, by centrifugation, or using Buchner style filter, rosenmund filter or plates, or frame press. Preferably, in-line filtration or safety filtration may be advantageously intercalated in the process disclosed above, to increase the purity of the resulting mass.
Thereafter, the resulting mass can be dried at 50-60? at 5-25 hours to obtain highly pure bilastine methyl ester substantially free from impurities as per ICH guidelines. The preferable drying temperature can be 45- 55 °C and preferably, the solid can be dried for 12-18 hours, and more preferably for 16-18 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.
Bilastine methyl ester prepared by using process of present invention is pure and has purity more than 99.00% by HPLC [w/w] and starting materials benzoimidazole intermediate of formula III and methylpropanoate intermediate of formula IV are not detected in final compound. Using this intermediate, bilastine can be prepared having purity of greater than 99.5%.
In another preferred embodiment, the present invention provides conversion of pure bilastine methyl ester of formula II into bilastine of formula I by hydrolyzing bilastine methyl ester in presence of a suitable base in a suitable solvent. The suitable solvent and base as used herein are same as defined in the first aspect of the present invention. Further, the reaction can be carried out at a temperature of about 10°C to the reflux temperature of the solvent.
The crude bilastine obtained above can be further purified using the same solvent system as used for purification of bilastine methyl ester. In particular, bilastine can be purified and/or recrystallized from a suitable solvent by conventional methods as reported in the literature.
In another preferred embodiment, the present invention provides an environmentally friendly and economically profitable process for the preparation of bilastine methyl ester or bilastine.
In another embodiment of the present invention, the starting compound of formula III and IV can be prepared by the methods reported in the literature or by the process as given in the present specification. The process for the preparation of compound of formula III comprises deprotection of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate with aqueous hydrochloric acid. The resulting mixture can be neutralized using ammonia solution. Thereafter, the reaction mixture can be extracted with n-butanol and distilled off completely. Finally, the solid can be filtered, washed with petroleum ether and dried to get the compound 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole of formula III.
The process of compound formula IV comprises the reaction of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate with titanium tetrachloride in the presence of dichloromethane at 0-5°C. The temperature of the reaction mixture can be raised to 25- 30°C followed by the addition of triethylsilane and the reaction mixture can be stirred and quenched with water. Thereafter, layer can be separated and then solvent of organic layer can be completely distilled off under reduced pressure to get the compound methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Preparation of bilastine methyl ester of formula II
Methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate (100 g) was taken in toluene (500 ml) and 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride (120 g) was added in it. Thereafter, the mixture was stirred followed by addition of sodium carbonate (120 g), potassium iodide (10 g) and tetrabutylammonium bromide (10 g). The reaction mixture was heated at 100-110°C for 18 hours till completion of the reaction as monitored by HPLC [reaction monitoring=80.54%; unreacted formula III =6.65%; unreacted formula IV =6.56%; other single highest impurity=1.11%]. After the reaction completion, the reaction mass was cooled at 30-40°C and slowly water (500 ml) was added to the mass followed by addition of toluene (200 ml). The reaction mixture was stirred, and layers were separated. The organic layer was charged and acidified (pH 2-3) with hydrochloride solution (500 ml). Thereafter, the aqueous layer was neutralized to pH 6.5-7.5 with ammonia solution (100 ml). The resulting mixture was cooled at 10-20°C followed by filtration and washing with water (200 ml). Finally, the resulting residue was dried at 55-65°C for 15-20 hours to obtain bilastine methyl ester (163 g) having HPLC purity [w/w] = 98.80%; one impurity= 0.54% at RRT 0.12; other impurity= 0.50% at RRT 1.4.
Example 2: Preparation of bilastine methyl ester of formula II
Methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate (100 g) was taken in toluene (500 ml) and 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride (120 g) was added in it. Thereafter, the mixture was stirred followed by addition of sodium carbonate (120 g), potassium iodide (10 g) and tetrabutylammonium bromide (10 g). The reaction mixture was heated at 100-110°C for 24 hours till completion of the reaction as monitored by HPLC [reaction monitoring=84.36%; unreacted formula III =4.60%; unreacted formula IV =6.23%; other single highest impurity=0.12%]. After the reaction completion, the reaction mass was cooled at 30-40°C and water (500 ml) was added to the mass followed by addition of toluene (200ml). The reaction mixture was stirred, and layers were separated. The organic layer was charged and acidified with hydrochloride solution (500 ml). Thereafter, the aqueous layer was neutralized with ammonia solution (100 ml). The resulting mixture was cooled at 10-20°C followed by filtration and washing with water (200 ml). Finally, the resulting residue was dried at 55-65°C for 15-20 hours to obtain bilastine methyl ester (159 g) having HPLC purity [w/w] = 99.09%; one impurity= 0.41% at RRT 0.12; other impurity= 0.41% at RRT 1.4.
Example 3: Preparation of bilastine methyl ester of formula II
Methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate (100 g) was taken in toluene (500 ml) and 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride (120 g) was added in it. Thereafter, the mixture was stirred followed by addition of sodium carbonate (120 g), potassium iodide (10 g) and tetrabutylammonium bromide (10 g). The reaction mixture was heated at 100-110°C for 17 hours till completion of the reaction as monitored by HPLC [reaction monitoring=84.30%; unreacted formula III =Not detected; unreacted formula IV =7.27%; other single highest impurity=3.39%]. After the reaction completion, the reaction mass was cooled at 30-40°C and slowly water (500 ml) was added to the mass followed by addition of toluene (200 ml). The reaction mixture was stirred, and layers were separated. The organic layer was charged and acidified (pH 2-3) with hydrochloride solution (500 ml). Thereafter, the aqueous layer was neutralized to pH 6.5-7.5 with ammonia solution (100 ml). The resulting mixture was cooled at 10-20°C followed by filtration and washing with water (200 ml). Finally, the resulting residue was dried at 55-65°C for 15-20 hours to obtain bilastine methyl ester (162 g) having HPLC purity [w/w] = 98.87%; one impurity = 0.57% at RRT 0.12, other impurity= 0.27% at RRT 1.4.
Example 4: Preparation of bilastine methyl ester of formula II
Methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate (100 g) was taken in toluene (500 ml) and 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride (120 g) was added in it. Thereafter, the mixture was stirred followed by addition of sodium carbonate (120g), potassium iodide (10 g) and tetrabutylammonium bromide (10 g). The reaction mixture was heated at 100-110°C for 18 hours till completion of the reaction as monitored by HPLC [reaction monitoring=83.02%; unreacted formula III =2.87%; unreacted formula IV =7.21%; other single highest impurity= 1.32%]. After the reaction completion, the reaction mass was cooled at 30-40°C and slowly water (500 ml) was added to the mass followed by addition of toluene (200ml). The reaction mixture was stirred, and layers were separated. The organic layer was charged and acidified (pH 2-3) with hydrochloride solution (500 ml). Thereafter, the aqueous layer was neutralized to pH 6.5-7.5 with ammonia solution (100 ml). The resulting mixture was cooled at 10-20°C followed by filtration and washing with water (200 ml). Finally, the resulting residue was dried at 55-65°C for 15-20 hours to obtain bilastine methyl ester (160 g) having HPLC purity [w/w] = 98.71%; one impurity = 0.77% at RRT 0.12, other impurity = 0.42% at RRT 1.4.
Comparative example 1: Preparation of bilastine methyl ester of formula II
Methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate (20 g) was taken in toluene (100 ml) and 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride (24 g) was added in it, Thereafter, the mixture was stirred followed by addition of sodium carbonate (24 g), potassium iodide (2 g). The reaction mixture was heated at 100-110°C for 19 hours till completion of the reaction as monitored by HPLC [reaction monitoring has bilastine methyl ester of formula II =40.36%; unreacted compound of formula IV =25.21%; unreacted compound of Formula III =12.50%; other single highest impurity=10.82%]. After the reaction completion, the reaction mass was cooled at 30-40°C and slowly water (100 ml) was added to the mass followed by addition of toluene (40 ml). The reaction mixture was stirred, and layers were separated. The organic layer was charged and acidified (pH 2-3) with hydrochloride solution (100 ml). Thereafter, the aqueous layer was neutralized to pH 6.5-7.5 with ammonia solution (20 ml). The resulting mixture was cooled at 10-20°C followed by filtration and washing with water (40 ml). Finally, the resulting residue was dried at 55-65°C for 15-20 hours to obtain bilastine methyl ester (13.6 g).
Example 5: Purification of bilastine methyl ester of formula II
Bilastine methyl ester of formula II (50 g) [having HPLC purity= 98.71%; one impurity = 0.77% at RRT 0.12; other impurity= 0.42% at RRT 1.4] was taken in isopropyl alcohol (250 ml) and the reaction mixture was stirred at 10-30°C. Afterwards, the reaction mass was heated to reflux temperature of the solvent at 75-85°C and stirred for 0.5-1 hour. The reaction mass was then allowed to attain ambient temperature followed by slow cooling at -5-5°C. Further, the reaction mass was stirred for 1-3 hours at the same temperature and filtered to obtain resulting material. Finally, the resulting material was washed with isopropyl alcohol (15 ml) and dried at 55-65°C for 10-20 hours to get desired pure bilastine methyl ester (42 g) having HPLC purity[w/w]: 99.16%; compound of formula IV =0.07%; compound of formula III = Not detected; other single highest impurity = 0.28% at RRT 1.4; other impurities = 0.17% at RRT 0.12.
Example 6: Purification of bilastine methyl ester of formula II
Bilastine methyl ester of formula II (50 g) [having HPLC purity= 98.71%; one impurity = 0.77% at RRT 0.12; other impurity= 0.42% at RRT 1.4] was taken in isopropyl alcohol (250 ml) and the reaction mixture was stirred at 10-30°C. Afterwards, the reaction mass was heated to reflux temperature of the solvent at 75-85°C and stirred for 0.5-1 hour. The reaction mass was then allowed to attain ambient temperature followed by slow cooling at -5-5°C. Further, the reaction mass was stirred for 1-3 hours at the same temperature and filtered to obtain resulting material. Finally, the resulting material was washed with isopropyl alcohol (15 ml) and dried at 55-65°C for 10-20 hours to get desired pure bilastine methyl ester (45 g) having HPLC purity[w/w]: 99.69%; one impurity = 0.24% at RRT 1.4.
Comparative example 2: Purification of bilastine methyl ester of formula II
Bilastine methyl ester of formula II (10 g) [having HPLC purity= 98.71%; one impurity = 0.77% at RRT 0.12; other impurity= 0.42% at RRT 1.4] was taken in cyclohexane (30 ml) and the reaction mixture was stirred at 10-30°C. Afterwards, the reaction mass was heated to reflux temperature of the solvent at 75-85°C and stirred for 0.5-1 hour. The reaction mass was then allowed to attain ambient temperature followed by slow cooling at -5-5°C. Further, the reaction mass was stirred for 1-3 hours at the same temperature and filtered to obtain solid. Finally, the resulting solid was washed with cyclohexane (15 ml) and dried at 55-65°C for 10-20 hours to get desired pure bilastine methyl ester (7 g) having HPLC purity[w/w]: 99.09%; one impurity = 0.71% at RRT 0.12; other impurity= 0.28% at RRT 1.4).
Comparative example 3: Purification of bilastine methyl ester of formula II
Bilastine methyl ester of formula II (50 g) [having HPLC purity= 98.71%; one = 0.77% at RRT 0.12; other impurity= 0.42% at RRT 1.4] was taken in isopropyl alcohol (150 ml) and water (100 ml), the reaction mixture was stirred at 10-30°C. Afterwards, the reaction mass was heated to reflux temperature of the solvent at 75-85°C and stirred for 0.5-1 hour. The reaction mass was then allowed to attain ambient temperature followed by slow cooling at -5-5°C. Further, the reaction mass was stirred for 1-3 hours at the same temperature and filtered to obtain solid. Finally, the resulting solid was washed with isopropyl alcohol (15 ml) and dried at 55-65°C for 10-20 hours to get desired pure bilastine methyl ester (34 g) having HPLC purity[w/w]: 98.97%; one impurity= 0.11% at RRT 1.4 and other impurity-0.45%.
Example 7: Preparation of bilastine of formula I
Bilastine methyl ester of Formula II (50 g) was taken in methanol (125 ml) followed by addition of sodium hydroxide solution (50 ml) and stirred at 10-30°C. The reaction mixture was heated at 60-70°C and stirred for 1-3 hours till completion of the reaction [reaction monitoring=97.73%; single highest impurity=1.63%]. After the reaction completion, carbon (2.5 g) was added in the reaction mixture followed by stirring for 0.5 hrs. Thereafter, the mixture was filtered through hyflo bed and washed with methanol (25 ml) to obtain solid. The resulting solid was cooled at 25-35°C followed by slow addition of water (300 ml). The reaction mixture was stirred, and layers were separated. The aqueous layer was then neutralized to pH 6.5-7.5 with acetic acid (50 ml). Afterwards, the reaction mass was cooled at 10-20°C followed by filtration at the same temperature. Finally, the resulting slurry was given washing with water (100 ml) and the resulting solid was dried at 55-65°C for 10-20 hours to get bilastine (44 g) having HPLC purity[w/w] = 99.70%.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the preparation of bilastine methyl ester of formula II,

Formula II
which comprises:
i. reacting 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of formula III,

Formula III
with methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV

Formula IV
in the presence of a phase transfer catalyst, a base, in a suitable solvent,
ii. isolating bilastine methyl ester.

2. The process as claimed in claim 1, wherein phase transfer catalyst in step (i) is selected from tetraalkylammonium salts such as tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI), tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TOAB), tetraoctylammonium chloride (TOAC), tetraoctylammonium iodide (TOAI), trioctylmethylammonium chloride, and trioctylmethylammonium bromide and crown ethers such as 18-crown-6 and 15-crown-5 and optionally, the mixture of phase transfer catalysts with an additive such as metal halide is selected from sodium iodide, potassium iodide, sodium bromide, potassium bromide or mixture thereof.

3. The process as claimed in claim 1, wherein base in step (i) is selected from organic base such as amines such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, dimethylaminopyridine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethyl aniline, N-methyl morpholine (NMM), N,N-dimethyl amino pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO), tetramethylpiperidine, tetramethylguanidine, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof, and inorganic base alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, hydride such as sodium hydride, lithium hydride or potassium hydride, alkoxide such as sodium or potassium methoxide or ethoxide, tertiary butoxide, alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like or mixtures thereof.

4. The process as claimed in claim 1, wherein solvent in step (i) is selected from hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcohol solvents such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; polar solvents such as water; acetic acid, formic acid or their mixtures.

5. The process as claimed in claim 1, wherein reaction in step (i) is carried out at a temperature of 95 to 115°C.

6. A process for the purification of bilastine methyl ester of formula II, which comprises the steps of:
i. adding crude bilastine methyl ester in a suitable organic solvent,
ii. heating the reaction mass obtained in step (i) to obtain a clear solution,
iii. cooling the reaction mixture to obtain solid,
iv. isolating pure bilastine methyl ester.

7. The process as claimed in claim 6, wherein organic solvent in step (i) is selected from alcohol solvents such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like or mixtures thereof.

8. The process as claimed in claim 6, wherein heating of reaction mass in step (ii) is carried out at 65-95°C.

9. The process as claimed in claim 6, wherein cooling of reaction mass in step (iii) is carried out at -5 to 15°C.

10. A process for the preparation of bilastine of formula I,

Formula I
which comprises the steps of:
i. reacting 1-(2-ethoxy-ethyl)-2-(piperidin-4-yl)-1H-benzoimidazole hydrochloride of formula III,

Formula III
with methyl 2-[4-(2-chloroethyl)phenyl]-2-methylpropanoate of formula IV

Formula IV
in the presence of a phase transfer catalyst, a base, in a suitable solvent,
ii. isolating bilastine methyl ester of formula II,
iii. converting the bilastine methyl ester obtained in step (ii) into bilastine.

Dated this 17th day of January 2024