DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

PROCESS FOR THE PREPARATION OF BILASTINE

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a novel, commercially viable and industrially advantageous process for the preparation of Bilastine (1) by using novel intermediates, in high yield and purity.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Bilastine is an antihistamine medication used to treat hives and inflammation of the eye caused by an allergy. It is a second-generation antihistamine and takes effect by selectively inhibiting the histamine H1 receptor, preventing these allergic reactions. It was originally developed in Spain by FAES Farma.

Bilastine is sold by numerous pharmaceutical companies under the brand names Allertine (Australia), Bilargo (Bangladesh), Blexten (Canada), Bilaxten (Switzerland), Ilaxten (UK), or Nixar (Croatia, Georgia, Macedonia and Serbia).

Bilastine and its preparation was first described in the US5877187 of FAES Farma patent. The process disclosed in the said patent is schematically represented below. The disclosed process involves the reaction of the benzimidazole intermediate (2) with tosylated oxazole intermediate (3) in presence of base such as sodium carbonate or sodium hydride, followed by reaction of obtained intermediate compound (4) with l-chloro-2-ethoxyethane to provide oxazole protected Bilastine (5). Cleavage of the said oxazole ring by treating it with 3N HC1 provides Bilastine (1).

The process for the preparation of Bilastine as described in US`187 has several disadvantages associated such as:
i) preparation of an intermediate compound having oxazole group and then cleavage of oxazole ring by hydrolyzing the compound in presence of acid leads to the formation of several byproducts, thereby resulting in a poor product yield and quality and making the whole process tedious;
ii) usage of alkali metal hydrides such as sodium hydride as a base is not advisable for commercial scale operations from safety point of view as use of sodium hydride is dangerous and corrosive.

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 which will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The problem addressed by the present invention is therefore that of providing a technically superior process for preparing Bilastine (1), which permits to avoid above reported with reference to the known prior art.
In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of Bilastine of formula 1, in high yield and high purity, using a novel intermediate. The process disclosed herein avoids the tedious procedure of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate on a commercial scale.
In another aspect, provided also herein is a novel compound of formula (7):

In another aspect, provided also herein is a process for the preparation of the novel compound of formula (7).
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel and industrially advantageous process for the preparation of Bilastine (1),

comprising:
(a) reacting tosylated oxazole intermediate (3) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole of formula (6) in a solvent and in presence of a base to provide oxazole protected Bilastine (5);

(b) treating oxazole protected Bilastine (5) obtained in step (a) with an acid and then reacting with an amine protecting agent to provide a compound of formula (7), which may or may not be isolated;

(c) treating compound of formula (7) or alternately treating the reaction mixture of step (b) in-situ with a base to provide Bilastine (1);

(d) purifying the Bilastine obtained in step (c), as required, using a solvent to provide pure Bilastine (1), having purity of 99-100 %.

The present invention also relates to the process, wherein step (c) can be carried out without isolating the compound of formula (7) obtained in step (b).
The solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.
The base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxide selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide; or an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
The acid used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluoride in ether.

The amine protecting agent used in step (b) is selected from an di-tert-butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (Fmoc chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl haloformates selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates selected from methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride, trichloroethoxycarbonyl chloride, pivaloyl chloride, triphenylmethyl chloride (trityl chloride); trialkyl silyl halides selected from trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride (TIPSCl), tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl).

The base used in step (c) is an alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal alkoxide selected from sodium methoxide, sodium ethoxide, potassium tert butoxide; an alkali metal carbonate selected from potassium carbonate, sodium carbonate, cesium carbonate; or an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate.
In an embodiment, an aqueous base is used in step (c).
The solvent used for purification of Bilastine (1) in step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, n-butanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

In an embodiment, the solvent used for purification of Bilastine (1) in step (d) is an alcoholic solvent selected from methanol, ethanol, isopropanol, n-butanol, t-amyl alcohol, t-butyl alcohol or hexanol.

The whole synthetic scheme of preparation of Bilastine (1) according to the present invention can be represented as below:

According to the present invention, the purification of Bilastine (1) in step (d) comprises the steps of:
(i) concentrating the reaction mixture of step (c) to obtain a residue;
(ii) crystallizing obtained residue of step (i) in solvent; and
(iii) filtering the precipitate of step (ii) and drying it to obtain crystalline solid of Bilastine (1).

In an embodiment, the solvent used in step (ii) is an alcoholic solvent selected from methanol, ethanol, isopropanol, n-butanol, t-amyl alcohol, t-butyl alcohol or hexanol.

According to another aspect, there is provided a novel intermediate of formula (7):

According to yet another aspect, there is provided a process for preparing the compound of formula (7),

comprising steps of:

(a) reacting tosylated oxazole intermediate (3) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole of formula (6) in a solvent and in presence of a base to provide oxazole protected Bilastine (5); and

(b) treating oxazole protected Bilastine (5) obtained in step (a) with an acid and then reacting with an amine protecting agent to provide a compound of formula (7), which may or may not be isolated.

The present invention has several advantages over prior art methods reported in the literature which include:
(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;
(v) obtaining Bilastine with a purity greater than or equal to 99.9 %;
(vi) no formation of Bilastine hydroxy impurity and Bilastine amide impurity in the final active pharmaceutical ingredient (API);
(vii) robustness of the developed process from plant operations perspective.

Thereby, the practicability of the reaction is greatly enhanced both at the laboratory scale and the industrial scale. In an embodiment, the present invention results into purity of Bilastine greater than or equal to 99.9 % by HPLC, thereby, making the process ef?cient, economic and industrially viable. In an embodiment, the present invention results into purity of Bilastine (1) to be 100 % by HPLC,

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of oxazole protected Bilastine of formula 5
Tosylated oxazole intermediate of formula 3 (5.0 g), N,N-dimethylformamide (DMF) (10 ml), 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole of formula 6 (3.9 g) and potassium carbonate (3.3 g) were charged in a round bottom flask at 25-30 °C. The reaction mixture was stirred for 36-40 h at 25-30 °C and then demineralized water (DM water, 20 mL) was added. The reaction mixture was stirred for 1 h at 25-30 °C. The solid was filtered, washed using DM water (5 ml) and was suck dried. The obtained wet solid and acetone (15 mL) were charged in the round bottom flask at 25-30 °C, reaction mixture was heated to 55 - 60 °C, maintained for 15-20 minutes and DM water (15 ml) were added in the round bottom flask at 55 - 60 °C. The reaction mixture was stirred for 1 h at 55-60 °C, then cooled to 20-25 °C and stirred for 2-3 h. The solid was filtered, washed with acetone: water (5 ml) solution and dried at 45-50 °C for 10 h under vacuum to offer oxazole protected Bilastine of formula 5.
Results:
Practical Yield (%): 4.6 g
Yield (%): 74.19%
HPLC Purity: 97.6%

Example 2
Preparation of Bilastine by using compound of formula (7) [Acetyl Intermediate; P= C(O)CH3]
Oxazole protected Bilastine of formula 5 (5.0 g), 1N HCl Solution (25 ml) were charged in a round bottom flask at 25-30 °C and reaction mixture was heated to 95-100 °C. Reaction mixture was stirred for 1 h at 95-100°C, cooled to 25-30 °C and pH was neutralised by using 50% aqueous NaOH solution. Reaction mass was extracted with 10 % triethylamine (TEA) in methylene dichloride (MDC) (30 mL). Aqueous layer was again extracted with 10 % TEA in MDC (20 mL) and layer was separated. Combined MDC layer was washed with DM water (25 mL) and charged in the round bottom flask at 25-30 °C. Triethyl amine (1.7 mL), Acetic anhydride (1.08 g) were charged in the round bottom flask at 25-30°C and stirred for 3-4 h. The reaction mass was distilled out under vacuum at 40-45 °C and Methanol (20 mL), NaOH (1.0 g) and DM water (20 mL) were charged in the round bottom flask at 25-30 °C, which was heated to 70 - 75 °C and maintained for 8-10 h. Reaction mixture was cooled at 25-30 °C and pH was neutralised by using concentrated. HCl solution. The solid was filtered, washed with DM water (10 ml) and dried at 50-60 °C for 14 h under vacuum to give Bilastine (1).
Results:
Practical Yield (%): 3.8g
Yield (%): 86%
HPLC Purity: 99.90%

Example 3
Preparation of Bilastine by using compound of formula (7) [Boc Intermediate, P=t-butyl oxycarbonyl]
Oxazole protected Bilastine of formula 5 (5.0 g), 1N HCl Solution (25 ml) were charged in a round bottom flask at 25-30 °C and reaction mixture was heated to 95-100 °C. Reaction mixture was stirred for 1 h at 95-100 °C, cooled to 5-10 °C and pH was adjusted to 10-11 by using 50 % aqueous NaOH solution. Di-tert-butyl dicarbonate (DIBOC) (3.3 g) were charged in the round bottom flask at 25-30 °C and reaction mixture was stirred for 3-4 h at 25-30 °C. Methanol (20 mL), 50 % aq. NaOH (15 mL) were charged into the reaction mass at 25-30 °C, which was heated to 70-75 °C and maintained for 12-16 h at 70-75 °C. Reaction mixture was cooled to 25-30 °C and pH of reaction was neutralized by using concentrated HCl solution. The solid was filtered, washed with DM water (10 ml) and dried at 50-60 °C for 14 h under vacuum to give Bilastine (1).
Results:
Practical Yield (%): 3.9g
Yield (%): 87.64%
HPLC Purity: 99.92%

Example -4
Purification of Bilastine
Bilastine (1) prepared in example 2 or example 3 (25.0 g), n-Butanol (250 ml) were charged in a round bottom flask at 25-30°C and reaction mixture was heated to 120-125 °C. Charcoal (2.5 g) was added into the reaction mass and maintained for 0.5 h at 120-125 °C which was then cooled to 85-95 °C. The reaction mass was filtered through hyflow bed, washed with hot n-Butanol (25.0 mL) and then again filtered through micron filter at 85-95 °C, which was then cooled to 25-30 °C and maintained for 2-3 h at 25-30 °C. The solid was filtered, washed with n-Butanol (25.0 mL) and dried at 50-60 °C for 14 h under vacuum to give Bilastine (Pharma).

Results:
Practical Yield (%): 22.6g
Yield (%): 90%
HPLC Purity: 100%

,CLAIMS:We claim:

1. A process for the preparation of Bilastine (1),

comprising:
(a) reacting tosylated oxazole intermediate (3) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole of formula (6) in a solvent and in presence of a base to provide oxazole protected Bilastine (5);

(b) treating oxazole protected Bilastine (5) obtained in step (a) with an acid and then reacting with an amine protecting agent to provide a compound of formula (7), which may or may not be isolated;

(c) treating compound of formula (7) or alternately treating the reaction mixture of step (b) in-situ with a base to provide Bilastine (1);

(d) purifying the Bilastine obtained in step (c), as required, using a solvent to provide pure Bilastine,(1) having purity of 99-100 %.

2. The process as claimed in claim 1, wherein the solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

3. The process as claimed in claim 1, wherein the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxide selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide; or an organic amine selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. The process as claimed in claim 1, wherein the acid used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluoride in ether.

5. The process as claimed in claim 1, wherein the amine protecting agent used in step (b) is selected from di-tert-butyl dicarbonate (DIBOC); benzyl chloroformate; fluorenylmethyloxy carbonyl chloride (Fmoc chloride); acetyl chloride; acetic anhydride; benzoyl halides; benzyl halides; alkyl haloformates selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate; tosyl halides; tosyl anhydrides; alkyl trifluoroacetates selected from methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate; trifluoroacetic acid; trifluoroacetyl chloride; trichloroethoxycarbonyl chloride; pivaloyl chloride; triphenylmethyl chloride (trityl chloride); trialkyl silyl halides selected from trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride (TIPSCl), tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl).

6. The process as claimed in claim 1, wherein the base used in step (c) is an alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal alkoxide selected from sodium methoxide, sodium ethoxide, potassium tertiary butoxide; an alkali metal carbonate selected from potassium carbonate, sodium carbonate, cesium carbonate; or an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate.

7. The process as claimed in claim 1, wherein the purification of Bilastine (1) in step (d) comprises the steps of:
(i) concentrating the reaction mixture of step (c) to obtain a residue;
(ii) crystallizing obtained residue of step (i) in a solvent; and
(iii) filtering the precipitate obtained in step (ii) and drying it to obtain crystalline solid of Bilastine (1).

8. The process as claimed in claim 1, wherein the solvent used in step (d) for purification of Bilastine (1) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, n-butanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

9. The process as claimed in claim 1, wherein the compound of formula (7),

is prepared by a process comprising steps of:

(c) reacting tosylated oxazole intermediate (3) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole of formula (6) in a solvent and in presence of a base to provide oxazole protected Bilastine (5); and

(d) treating oxazole protected Bilastine (5) obtained in step (a) with an acid and then reacting with an amine protecting agent to provide a compound of formula (7), which may or may not be isolated.

10. The process as claimed in claim 1, wherein the Bilastine (1) obtained has purity greater than or equal to 99.9 %.