INTERMEDIATES USED IN THE PREPARATION OF

ANTIHISTAMINE AGENT

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of intermediate compounds used in the preparation of Antihistamine agents.

The present invention specifically relates to an improved process for the preparation of intermediate compounds of formula (I) used in the preparation of Bilastine or its pharmaceutically acceptable salts. Formula (I)

The present invention more specifically relates to an improved process for the preparation of intermediate compound of formula (la) used in the preparation of Bilastine or its pharmaceutically acceptable salts.

The present invention more specifically relates to an improved process for the preparation of intermediate compound of formula (lb) used in the preparation of Bilastine or its pharmaceutically acceptable salts. The present invention also relates to use of intermediate compounds in the preparation of Bilastine or its pharmaceutically acceptable salts having the following structure of Formula II.

BACKGROUND OF THE INVENTION

Bilastine is a nonsedating HI receptor antihistamine used in the symptomatic treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria.

Bilastine is chemically 2-[4-[2-[4-[l-(2-ethoxyethyl) benzimidazol-2- yl]piperidin-l-yl]ethyl]phenyl]-2-methylpropionic acid and has the following chemical structure.

Bilastine was first disclosed in US 5,877,187 and the process for the preparation of Bilastine disclosed in this patent is as shown below:

US 6,242,606 B1 discloses novel intermediates useful in the preparation of piperidine derivatives which are useful as antihistamines, anti allergy agents and broncholidators. The process generically disclosed for the preparation of these novel intermediates is shown below: wherein A is hydrogen or hydroxyl, B is halo or hydroxyl, Hal represents Cl, Br or I and n is an integer of from 1 to 5 and R ₆ and R ₇ are each independently H, Ci-C ₆ alkyl, C _r C ₆ alkoxy or R ₆ and R ₇ , taken together with the nitrogen atom for a pyrrolidine, piperidine or morpholine, with the proviso that R ₆ and R ₇ , cannot both be represented by Ci-C ₆ alkoxy.

US 8,633,223 B2 discloses a process for the preparation of Bilastine intermediate which is shown in the scheme given below: CN 102675101 B discloses a process for the preparation of Bilastine intermediate which is shown below :

CN 110698343 A claims a process for the preparation of Bilastine intermediate which is shown below:

This application neither enables or disclose use of halogen instead of benzyloxy group which requires difficult hydrogenation conditions to remove before further reactions. WO 2020/020873 A1 discloses a process for preparing a compound of formula (III) or a solvate thereof which comprises oxidative rearrangement of a compound of formula (II) or a solvate thereof which is shown in the scheme given below:

Oxidative rearrangement is carried out in the presence of trimethyl orthoformate (TMOF), an iodine oxidizing agent selected from I ₂ , ICI, HI0 ₃ and Phl(OAc) ₂ and an acid selected from HCI, H3PO4 , H ₂ SO _t , MsOH, pTsOH and TFA. Iodine oxidizing agent is a highly toxic and require harsh conditions such as anhydrous and inert conditions, difficult purification, expensive raw materials, expensive conditions, and it is difficult to handle in industrial bulk scale production. The process of the present invention does not involve use of iodine oxidizing agent

On the contrary, the present inventors have surprisingly found new improved process for the preparation of Bilastine intermediates. The present method uses less toxic and commercially available zinc bromide. Moreover, the zinc bromide is used in catalytic amount which results in faster reaction with excellent yield.

The process of the present invention not only avoids the use of highly toxic reagents, unstable and/or expensive reagents, but also leads to the desire product, stage-4 in shorter reaction times and with higher productivity and 98% purity than prior art processes. These features make the process of the invention cost-efficient making the process highly suitable for industrial scale up production.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of intermediate compounds used in the preparation of Antihistamine agents. Another objective of the present invention is to provide an improved process for the preparation of intermediate compounds of formula (I) used in the preparation of Bilastine or its pharmaceutically acceptable salts. Formula (I)

Yet another preferred objective of the present invention is to provide an improved process for the preparation of intermediate compound of formula (la) used in the preparation of Bilastine or its pharmaceutically acceptable salts. Formula (la)

Still another preferred objective of the present invention is to provide use of intermediate compounds in the preparation of Bilastine or its pharmaceutically acceptable salts having the following structure of Formula II. Formula II

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of compound of Formula (I) Formula (I) wherein Lg represents leaving group and R is H, Ci-C ₄ alkyl; wherein the process comprising the steps of: a) providing Phenethyl compound of Formula (III) Formula (III) where Lg represents a leaving group and reacting with compound of Formula

(IV) Formula (IV) wherein X represents a halogen atom in the presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (V), Formula (V) b) converting the intermediate compound of Formula (V) using halogenating agent in suitable solvent to produce the intermediate compound of Formula (VI), Formula (VI) wherein Lg is as defined above and X represents halogen, c) oxidative rearrangement of intermediate compound of formula (VI) using oxidative rearrangement agent in presence of ZnX ₂ and a solvent to obtain compound of Formula (I).

In another embodiment, the present invention specifically provides an improved process for the preparation of intermediate compound of Formula (la) Formula (la) wherein X and R are as defined above, which comprises : a) providing Phenethyl halide compound of Formula (Ilia) Formula (Ilia) where X represents a halogen and reacting with compound of Formula (IV) Formula (IV) wherein X represents a halogen atom in the presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (Va), Formula (Va) b) converting the intermediate compound of Formula (Va) using halogenating agent in suitable solvent to produce the intermediate compound of Formula (Via), Formula (Via) wherein X represents halogen, c) oxidative rearrangement of intermediate compound of formula (Via) using oxidative rearrangement agent in presence of ZnX ₂ and a solvent to obtain compound of Formula (la).

In yet another embodiment, the present invention more specifically provides an improved process for the preparation of intermediate compound of Formula (lb) Formula (lb) which comprises : a) providing Phenethyl chloride compound of Formula (TTTb) Formula (Illb) and reacting with compound of Formula (IV) Formula (IVb) in the presence of a Lewis acid in suitable solvent to obtain an intermediate compound of Formula (Vb), Formula (Vb) b) converting the intermediate compound of Formula (Vb) using brominating agent in suitable solvent to produce the intermediate compound of Formula (VIb), Formula (VIb) c) oxidative rearrangement of intermediate compound of formula (VIb) using oxidative rearrangement agent in presence of ZnX ₂ and a solvent to obtain compound of Formula (lb). In still another embodiment, the present invention particularly provides an improved process for the preparation of intermediate compound of Formula (lb) Formula (lb) which comprises : a) providing Phenethyl chloride compound of Formula (Ilia) Formula (Illb) and reacting with compound of Formula (IVb) Formula (IVb) using AICI ₃ in a suitable solvent to obtain an intermediate compound of Formula (Vb), Formula (Vb) b) converting the intermediate compound of Formula (Vb) using brominating agent in suitable solvent to produce the intermediate compound of Formula (VIb), Formula (VIb) c) oxidative rearrangement of intermediate compound of formula (VIb) using TMOF or methanol in presence of ZnCl ₂ or ZnBr ₂ and a solvent to obtain compound of Formula (lb).

In still another embodiment, the present invention provides a process for the preparation of Bilastine or its pharmaceutically acceptable salts compound of Formula (II). Formula II using compound of Formula (I) prepared by a process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise. In a specific embodiment, the reaction of compound of Formula (III) with compound of Formula (IV) or compound of Formula (Ilia) with compound of Formula (IV) or compound of Formula (Illb) with compound of Formula (IVb) is carried out in presence of Lewis acid and in suitable organic solvent. After completion of the reaction, the compound of Formula (V) or (Va) or (Vb) is quenched with an acid and extracted with an appropriate solvent or mixture of solvents. The reaction may be carried out at a temperature in the range of 0 °C to room temperature for a duration of 1 to 5 hours.

The term Leaving group as used herein and is not limited to halogens like Cl, Br, F, Iodine, -OMs, -OTs, -OTf, -ONs.

Lewis acid as used herein is selected from the lewis acid used in the present invention is selected from A1C1 , ZnCl ₂ , ZnBr ₂ , FeCl , T1CI ₄ , Titanium tetraisopropoxide, BF ₃ etherate, and a halide or a trifluoromethanesulfonate of a transition metal of the lanthanide series.

The compound of Formula (V) or (Va) or (Vb) is converted to intermediate compound of (VI) or (Via) or (VIb) using a halogenating agent in a suitable solvent. The addition of halogenating agent should be done at low temperature, thereafter the temperature is raised to room temperature to reflux temperature of the solvent. After completed the reaction, the reaction mass was quenched with water.

Halogenating agent as used herein is selected from Br ₂ , Cl ₂ , specifically brominating agent, which is bromine.

The oxidative rearrangement of compound of (VI) or (Via) or (VIb) is carried out using oxidative rearrangement agent in presence of Zinc halide (ZnX ₂ ) and a solvent. The reaction is carried out a temperature of 80 °C to 130 °C for a period of 3 to 6 hours. After completion of the reaction, the reaction mass was quenched with a mixture of organic solvent and water.

The oxidative rearrangement agent is trimethyl orthoformate (TMOF) and methanol.

Zinc halide as used here is selected from zinc chloride, zinc bromide.

In yet another embodiment, the acid used in the present invention are not limited to acids inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

In yet another embodiment, solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert- butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1 ,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl- 2-pyrrolidone, N-methylformamide, 2-pyrrolidone, l-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof. The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene- 2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, p- toluenesulfonate, xylenesulfonate, tartarate, and the like.

In another preferred embodiment, a process for the preparation of compound of Formula (I) which yields the compounds with high chemical purity.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (I) in the preparation of Bilastine or its salts. The intermediates formed in the present invention may or may not be isolated. Any of the above reactions may be carried out in-situ reactions to obtain intermediate compound of Formula (I).

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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 l-(2-chloroethyl)benzene:

2-Phenyl ethanol (500 g, 4.09 mol), Pyridine (350 ml, 4.42mol), were added into the round bottom flask. To this thionylchloride was added (371.12g, 5.11 mol) slowly for lh at 0-5 °C. After completion of thionylchloride addition, slowly raise the temperature to 30 °C, stir for 30 min. After 30 min, raise the temperature to 80 °C. Stir for lhr at same temperature until completion of starting material on TLC. After completion of reaction, it was quenched in ice cold water and extracted with DCM. Organic layer concentrated under reduced pressure results l-(2-chloroethyl)benzene (544 g, 94% yield with 99 % HPLC purity )

Example-2: Preparation of l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l-one: Isobutyryl chloride (306.89 g, 2.88 mol)) was taken into the round bottom flask. To this Aluminium chloride(319g, 2.4 mol) was added at 10 °C, followed by slow addition of l-(2-chloroethyl)benzene(270 g, 1.920 mol) at same temperature. Stir the reaction mass at same temperature for lhr. After completion of reaction by monitoring on TLC, it was quenching in 1M HC1 and extracted with cyclohexane. Organic layer wash with 1M NaOH and concentrated under reduced pressure results l-(4-(2- chloroethyl)phenyl)-2-methylpropan-l-one(358g, 88.5% yield with 98 % HPLC purity)

Example-3: Preparation of 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan- 1-one :

1-(4-(2-chloroethyl)phenyl)-2-methylpropan-l-one(50g, 0.238 mol) and chloroform(250 mL) were taken in a R.B.flask. To this liquid bromine (42 g, 0.261 mol) was added slowly at 5 °C for 30 min. After completion of bromine addition, slowly raise the temperature to 25 °C. Stir the reaction mass for 30min at same temperature until starting material was absent. After completion of reaction, quench the reaction mass with water, followed by workup with sodium thiosulfate, concentrate the organic layer under reduced pressure results 2-bromo-l-(4-(2-chloroethyl)phenyl)-

2-methylpropan-l-one(58g, 85% yield with 99 % HPLC purity).

Example-4: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate :

To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726), Zinc bromide(5 g, 0.1 w/w) and Trimethyl orthoformate(640 mL, 12.8v) were taken. Slowly heat the reaction mass at 120 °C, Keep the reaction at same temperature for 4h by monitoring on HPLC. After completion of reaction, to the reaction mass ethyl acetate and water were added sequentially. After separation of both layers, organic layer concentrated under reduced pressure results methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate(35.2g, 85% yield with HPLC purity 98%).

Example-5: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate : To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726), Zinc bromide(5 g, 0.1 w/w) and Trimethyl orthoformate(400 mL, 8 v) were taken. Slowly heat the reaction mass at 120 °C, Keep the reaction at same temperature for 4h by monitoring on HPLC. After completion of reaction, to the reaction mass ethyl acetate and water were added sequentially. After separation of both layers, organic layer concentrated under reduced pressure results methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate(34.3 g, 83% yield with HPLC purity 97%).

Example-6: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate :

To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726), Zinc bromide (5 g, 0.1 w/w) and Trimethyl orthoformate(300 mL, 6 v) were taken. Slowly heat the reaction mass at 120 °C, Keep the reaction at same temperature for 4h by monitoring on HPLC. After completion of reaction, to the reaction mass ethyl acetate and water were added sequentially. After separation of both layers, organic layer concentrated under reduced pressure results methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate(34.7g, 84% yield with HPLC purity >96%).

Example-7: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate :

To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726), Zinc bromide(5 g, 0.1 w/w) and Trimethyl orthoformate(150 mL, 3 v) were taken. Slowly heat the reaction mass at 120 °C, Keep the reaction at same temperature for 4h by monitoring on HPLC. After completion of reaction, to the reaction mass ethyl acetate and water were added sequentially. After separation of both layers, organic layer concentrated under reduced pressure results methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate(35.2g, 85% yield with HPLC purity >97%).

Example-8: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate : To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726 moles), Zinc bromide(427.5 g, 1.898 moles) and Methanol (250 mL,

5 v) were taken. Slowly heat the reaction mass at 100 °C, Keep the reaction at same temperature for 3h by monitoring on HPLC. After completion of reaction, the reaction mixture was diluted with ice-cold water (300 ml) and extracted with CH ₂ C1 ₂ (3 x 250 ml). The organic phases were combined and distilled under reduced pressure results methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate (4.1 g, 10 % yield with HPLC purity 70%) and more unidentified products was observed.

Example-9: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate :

To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726), Zinc chloride(5 g, 0.1 w/w) and Trimethyl orthoformate(150 mL, 3.0 v) were taken. Slowly heat the reaction mass at 120 °C, Keep the reaction at same temperature for 8h by monitoring on HPLC. After completion of reaction, to the reaction mass ethyl acetate and water were added sequentially. After separation of both layers, organic layer concentrated under reduced pressure results methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate(35.2g, 85% yield with HPLC purity 97%).

Example-10: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2- methylpropanoate :

To a round bottom flask, 2-bromo-l-(4-(2-chloroethyl)phenyl)-2-methylpropan-l- one(50g, 0.1726 moles), Zinc chloride(258.6 g, 1.898 moles) and Methanol (250 mL,

5 v) were taken. Slowly heat the reaction mass at 100 °C, Keep the reaction at same temperature for 4h by monitoring on HPLC. After completion of reaction, the reaction mixture was diluted with ice-cold water (300 ml) and extracted with CH ₂ C1 ₂ (3 x 250 ml). The organic phases were combined and distilled under reduced pressure results methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate (28.9 g, 70 % yield with HPLC purity 97%).