DESC:FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of intermediate compound of Formula II used in the preparation of Bilastine.

BACKGROUND OF THE INVENTION:
Bilastine is an antihistamine medication used to treat hives (urticaria) and inflammation of the eye (allergic conjunctivitis) caused by an allergy. It is a second-generation antihistamine and takes effect by selectively inhibiting the histamine H1 receptor, preventing these allergic reactions. Bilastine was originally developed in Spain by FAES Farma. Bilastine is marketing under the brand name of Ilaxten in UK and Bilanoa in Japan.

Bilastine is chemically named as 2-[42-{4-[1-2-Ethoxyethyl-1H-benzimidazol-2-yl] piperidin-1-yl}ethylphenyl]-2-methylpropanoic acid, and structurally represented by the following Formula I.

Formula I
Bilastine and its processes for the preparation were first reported in US 5877187. The disclosed process involves condensation of Compound A with Compound B in the presence of sodium carbonate in dimethylformamide (DMF) to provide a Compound (C). The obtained compound (C) was reacted with 2-chloroethylethylether in the presence of sodium hydride in DMF to provide Compound (D). Resulting Compound (D) was further converted into bilastine by treating with hydrochloric acid. The said process is schematically represented in the following scheme-1:

Scheme 1:

The compound of formula II and its use as an intermediate for the preparation of Bilastine was disclosed in US8487106. The preparation of compound of formula II and its intermediate has been described in various patents as detailed below.

WO2020020873A1 discloses a process for preparing Bilastine intermediate compound of formula-II and the disclosed process is schematically represented in the below scheme-2.
Scheme 2:

CN 102675101 discloses another process for the preparation of Bilastine intermediate compound of formula II and the disclosed process is schematically represented in the below scheme-3.
Scheme 3:

US8367743B2 discloses a process for an intermediate used for the preparation of Bilastine intermediate compound of formula II and the disclosed process is schematically represented in the below scheme-4.
Scheme 4:

WO2022214921A1 discloses a process for preparing Bilastine intermediate compound of formula-II and the disclosed process is schematically represented in the below scheme-5.
Scheme 5:

JP2023167001A discloses a process for preparing Bilastine intermediate compound of formula-II and the disclosed process is schematically represented in the below scheme-6.
Scheme 6:

The compound of formula II prepared by the prior-art processes involves the use of dangerous, corrosive and explosive reagents, contaminated with higher levels other isomers such as m-isomer, which results in lower yield and purity; hence not suitable for industrial scale production.

There remains a need in the art for an alternative process which reduces the other isomer levels, avoiding corrosive reagents and obtaining Bilastine and its intermediates with high yields and purity. Thus, the main objective of the present invention is to provide an improved process for the preparation of intermediate compounds used in the preparation of Bilastine and its conversion to Bilastine.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for the preparation of a compound of Formula II,

Formula II
wherein R is an alkyl group and X1 is a halogen;
which comprises,
oxidative rearrangement of a compound of formula III or a solvate thereof,

Formula III
wherein X1 and X2 are a halogen;
in the presence of trialkylorthoformate and zinc catalyst selected from Zinc nitrate, zinc oxide, zinc sulphate, zinc acetate or zinc phosphate to provide a compound of Formula II.

In another aspect, the present invention provides a process for the purification of a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
which comprises,
a) hydrolyzing a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
in the presence of an acid or a base to provide an acid compound of Formula IV; and

Formula IV
wherein X1 is a halogen;
b) esterification of the compound of Formula IV with an alcohol to provide a pure compound of Formula II.

In another aspect, the present invention provides a process for the preparation of Bilastine of formula I, which comprises;

Formula I
a) preparing a compound of formula II according to the present invention process; and
b) converting the compound of formula II into Bilastine of formula I.

DETAILED DESCRIPTION OF THE INVENTION:
The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.
The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl aminopyridine (DMAP), morpholine or mixture thereof.

In one aspect, the present invention provides a process for the preparation of a compound of Formula II,

Formula II
wherein R is an alkyl group and X1 is a halogen;
which comprises,
oxidative rearrangement of a compound of formula III or a solvate thereof,

Formula III
wherein X1 and X2 are a halogen;
in the presence of trialkylorthoformate and zinc catalyst selected from zinc nitrate, zinc oxide, zinc sulphate, zinc acetate or zinc phosphate to provide a compound of Formula II.

The compound of formula III is well known in the art and can be prepared by the known methods.

The forgoing process involving the oxidative rearrangement of a compound of formula III, wherein X1 & X2 are a halogen selected from Br, F, Cl or I; preferably Cl & Br; is carried out in the presence of trialkyl orthoformate selected from trimethyl orthoformate (trimethoxymethane), triethyl orthoformate, tripropyl orthoformate, or triisopropyl orthoformate; preferably trimethyl orthoformate; and a zinc catalyst selected from zinc nitrate, zinc oxide, zinc sulphate, zinc acetate or zinc phosphate; preferably zinc nitrate; optionally in the presence of an acid selected from sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, succinic acid or tartaric acid in a suitable solvent to provide a compound of formula II, wherein X1 is a halogen selected from Br, F, Cl or I; preferably Cl; and R is an alkyl group selected from methyl, ethyl, propyl, isopropyl, t-butyl etc; preferably methyl. The said reaction is carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used over a period of about 5 to 8 hours, preferably carried out at about 80°C to about 120°C for 8 hrs. The obtained compound of Formula II is isolated from the reaction mass by the methods known in the art and optionally purified using a suitable solvent or mixture of solvents.

In a specific embodiment, the present invention provides a process for the preparation of a compound of Formula IIa,

Formula IIa
which comprises,
oxidative rearrangement of a compound of formula IIIa or a solvate thereof,

Formula IIIa
in the presence of trimethyl orthoformate and zinc nitrate to provide a compound of Formula IIa.

In another aspect, the present invention provides a process for the purification of a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
which comprises,
a) hydrolyzing a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
in the presence of an acid or a base to provide an acid compound of Formula IV; and

Formula IV
wherein X1 is a halogen;
b) esterification of the compound of Formula IV with an alcohol to provide a pure compound of Formula II.

The step a) of the forgoing process involves the hydrolyzing a compound of formula II, wherein X1 is a halogen selected from Br, F, Cl or I; preferably Cl; and R is an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; preferably methyl; with an acid selected from sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid; or a base selected from inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide; preferably an acid and more preferably sulfuric acid, hydrochloric acid, acetic acid; in a suitable solvent to provide an acid compound of Formula IV, wherein X1 is a halogen selected from Br, F, Cl or I; preferably Cl. The step a) reaction can be carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used for a suitable period of time till formation of acid compound, preferably carried out at about 100°C to about 120°C for 12-16 hrs. The compound of formula IV can be isolated as a solid or proceeds in-situ to the next step without isolation. Preferably, the compound of formula IV is isolated as a solid and purified using a suitable solvent or mixture of solvents such as n-Heptane or cyclohexane or mixtures thereof.

The step b) of the forgoing process involves esterification of the compound of formula IV, wherein X1 is a halogen selected from Br, F, Cl or I; preferably Cl with a suitable alcohol selected from methanol, ethanol, propanol, isopropanol, n-butanol or t-butanol; preferably methanol; in a suitable solvent to provide a pure compound of formula II. The step b) reaction can be carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used for a suitable time period till completion of the reaction, preferably carried out at about 50°C to about 70°C for 4-6 hrs. The obtained compound of Formula II is isolated from the reaction mass by the methods known in the art and optionally purified by recrystallizing or slurring in a suitable solvent or mixture of solvents.

The compound of formula II (wherein X1 is a chloro and R is methyl group) obtained by the reported processes having low purity of 83.2% by HPLC and contaminated with higher levels of 9.66% of m-isomer impurity of formula V

m-isomer Impurity Formula V
and other impurity at 0.988 RRT with the level of 2.87%, which in-turn, results in lower yield; its further required additional yield losing purifications to get the required purity. The present inventors working on improving yield, purity and reducing the m-isomer impurity and other unknown impurities content in the compound of formula II, surprisingly found that subjecting the compound of formula II containing higher levels of m-isomer and other impurities mentioned above to hydrolysis in the presence of an acid followed by esterification with suitable alcohol results in the compound of formula II with the purity more than 97% and controlling the m-isomer impurity to 0.3% and 0.988 RRT impurity to 0.01% levels.

In another aspect, the present invention provides a process for the preparation of Bilastine of formula I, which comprises;

Formula I
a) preparing a compound of formula II according to the present invention processes; and
b) converting the compound of formula II into Bilastine of formula I.

The step b) of forgoing process involving the conversion of compound of formula II into formula I is carried out by reacting the compound of formula II with a compound of Formula VI or a salt thereof; specifically hydrochloride monohydrate or hydrochloride sesquihydrate or hydrochloride dihydrate or dihydrochloride hydrate

Formula VI
under appropriate reaction conditions to provide Bilastine of formula I.

The obtained Bilastine of formula I is isolated by the methods known in the art; for example, recrystallization from a suitable solvent or by dissolving Bilastine in a suitable solvent followed by isolating pure compound by addition of anti-solvent followed by filtration and drying of the solid.

Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example-1: Preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propionate (Formula II, wherein R is methyl; X1 is chloro):
To a clean and dry RBF, trimethoxymethane (300 ml) and 2-bromo-1-[4-(2-chloroethyl)-phenyl]-2-methyl-propan-1-one (100 g) (Formula III, wherein X1 is chloro and X2 is bromo) were added at 20-30°C and stirred for 10 minutes. To this, zinc nitrate hexahydrate (30 g) was added at 20-30°C and stirred for 5 minutes. The reaction mass was heated to 90-105°C and maintained for 8 hrs. After the reaction completion, the reaction mass was cooled to 20-30°C and quenched into water at 20-30°C. Ethyl acetate was added to the reaction mass at 20-30°C and stirred for 15 mins. The organic and aqueous layers were separated; the organic layer was dried over sodium sulfate and distilled off under vacuum at below 55°C to get the title compound.

Example-2: Preparation of pure methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propionate (Formula II, wherein X1 is chloro and R is methyl):
Step A: Preparation of 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoic acid (Formula IV, wherein X1 is chloro):
To a clean and dry RBF, acetic acid (300 ml) and hydrochloric acid (100 ml) were added at 20-30°C; the reaction mass was cooled to 0-5°C and sulfuric acid (100 ml) was added it at 0-10°C. To this, methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propionate (100 g) were added at 20-30°C, heated to 105-115°C and maintained for 16 hrs. After the reaction completion, the reaction mass was cooled to 20-30°C; water and dichloromethane was added to the reaction mixture at 20-30°C and stirred for 15 mins. The organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. The organic layer was combined, washed with water followed by sodium bicarbonate solution, dried over sodium sulfate and distilled off under vacuum at below 45°C. n-Heptane was added to the obtained crude at 20-30°C and maintained for 1 hr. The solid obtained was filtered; washed with n-heptane and dried. Cyclohexane was added to the obtained wet material at 20-30°C and maintained for 1 hr. The obtained solid was filtered; washed with cyclohexane and dried to get the title compound.
Step B: Preparation of pure methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propionate (Formula II):
To a clean and dry RBF, methanol (400 ml) and 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoic acid (100 g) (Formula IV, wherein X1 is chloro) were added at 20-30°C and cooled to 0-5°C. To this, thionyl chloride (70 g) was slowly added at 0-5°C; heated to 60-65°C and maintained for 5 hours. After the reaction completion, the reaction mass was distilled off under vacuum at below 50°C and cooled to 20-30°C. Dichloromethane and water were added to the reaction mixture at 20-30°C and stirred for 20 mins. The organic and aqueous layers were separated; and the aqueous layer was extracted with dichloromethane. Combined organic layer was washed sodium bicarbonate solution followed by water. The organic layer was subjected to carbon treatment, filtered through hyflow bed and washed with dichloromethane. The filtrate was dried over sodium sulfate and distilled off under vacuum at below 45°C to get the title compound. Purity by HPLC: >97%; m-isomer: 0.3%.
,CLAIMS:1. A process for the preparation of a compound of Formula II,

Formula II
wherein R is an alkyl group and X1 is a halogen;
which comprises,
oxidative rearrangement of a compound of formula III or a solvate thereof,

Formula III
wherein X1 and X2 are a halogen;
in the presence of trialkylorthoformate and zinc catalyst selected from zinc nitrate, zinc oxide, zinc sulphate, zinc acetate or zinc phosphate to provide a compound of Formula II.

2. The process as claimed in claim 1, wherein X1 and X2 are a halogen selected from Br, F, Cl or I; trialkylorthoformate is selected from trimethyl orthoformate (trimethoxymethane), triethyl orthoformate, tripropyl orthoformate, or triisopropyl orthoformate and R is an alkyl group selected from methyl, ethyl, propyl, isopropyl and/or t-butyl.

3. The process as claimed in claim 1 is carried out in a suitable solvent selected from water, alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof.

4. The process as claimed in claim 1, wherein the X1 is Cl; the X2 is Br; R is methyl and the trialkylorthoformate is trimethyl orthoformate.

5. A process for the preparation of a compound of Formula IIa,

Formula IIa
which comprises,
oxidative rearrangement of a compound of formula IIIa or a solvate thereof,

Formula IIIa
in the presence of trimethyl orthoformate and zinc nitrate to provide a compound of Formula IIa.

6. A process for the purification of a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
which comprises,
a) hydrolyzing a compound of Formula II,

Formula II
wherein X1 is a halogen and R is an alkyl group;
in the presence of an acid or a base to provide an acid compound of Formula IV; and

Formula IV
wherein X1 is a halogen;
b) esterification of the compound of Formula IV with an alcohol to provide a pure compound of Formula II.

7. The process as claimed in claim 6, wherein X1 is a halogen selected from Br, F, Cl or I and R is an alkyl group selected from methyl, ethyl, propyl, isopropyl and/or t-butyl.

8. The process as claimed in claim 6, wherein the acid in step a) is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and/or mixtures thereof; and the base is selected from inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and/or mixtures thereof.

9. The process as claimed in claim 6, wherein the suitable alcohol in step b) is selected from methanol, ethanol, propanol, isopropanol, n-butanol and/or t-butanol.
10. The process for the preparation of Bilastine of formula I, which comprises;

Formula I
a) preparing a compound of formula II according to any of the preceding claims; and
b) converting the compound of formula II into Bilastine of formula I.