Claims:WE CLAIM:

1. An improved process for the preparation of Bilastine (I), comprising the steps of;

a) 4-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) propan-2-yl) phenyl ethyl 4-methylbenzene sulfonate (3) is reacted with 2-(piperidin-4-yl)-1Hbenzo[d]imidazole (2) in presence of base, water and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (4),

b) The compound of formula (4) is reacted with 2-ethoxyethyl 4-methyl benzenesulfonate (7) in presence of strong base, organic solvent and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydro oxazole (5),

c) The compound of formula (5) converts into Bilastine (I) in presence of organic acid/strong base /hydrochloric acid and water, and

d) Isolated Bilastine (I) with IPA and MeOH.

2. The process as claimed in claim 1, the organic solvents are selected from dimethyl formamide, acetone, ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dichloride, ethylene dichloride, dimethyl amino formamide, tetrahydrofuran, toluene, benzene and xylene.

3. The process as claimed in claim 1, the bases are selected from potassium carbonate, sodium carbonate, rubidium carbonate, caesium carbonate, potassium bicarbonate and sodium bicarbonate.

4. The process as claimed in claim 1, the strong bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide and cesium hydroxide.

5. The process as claimed in claim 1, the organic acids are selected from, trifluoro acetic acid, acetic acid, hydrochloric acid, methyl sulphonic acid and oxalic acid.

Dated this fifteenth (15th) day of June, 2020,
, Description:BACKGROUND OF THE INVENTION
Bilastine, sold under the brand name Bilaxten among others, is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria (hives). It exerts its effect as a selective histamine H1 receptor antagonist and has an effectiveness similar to cetirizine, fexofenadine, and desloratadine. It was developed in Spain by FAES Farma.

Bilastine is approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria, but it is not approved for any use in the United States. Bilastine meets the current European Academy of Allergy and Clinical Immunology (EAACI) and Allergic Rhinitis and its Impact of Asthma (ARIA) criteria for medication used in the treatment of allergic rhinitis.

Bilastine has been effective in the treatment of diseases of allergies, including rhinoconjuctivitis. Additionally, Bilastine has been shown to improve quality of life, and all nasal and eye symptoms related to allergic rhinitis

Bilastine chemically known as 4-[2-[4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl] ethyl ]-a,a-dimethylbenzeneacetic acid is a antihistamine having the following structural formula (I);

Bilastine is reported in US 5877187 by Fabrica Espanola. The synthetic process for Bilastine is reported in US 5877187. The compound of formula (2) is reacted with the compound of formula (3) in presence of Na2CO3 / DMF to obtain the compound of formula (4). The compound of formula (4) is reacted with 1-chloro-2-ethoxy-ethane in presence of NaH / DMF to obtain the compound of formula (5). The compound of formula (5) converts into Bilastine (I) in presence of 3N hydrochloric acid.

The above process is schematically shown as below:

The process for the preparation of Bilastine as described in the aforementioned prior art suffers from the major disadvantage is the reaction between 2-[1-(2-(4-(1-(4,4-dimethyl-oxazoline-2-yl)-1-methyl ethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole (4) with 2-chloroethyl ethyl ether is performed under very stringent reaction condition and involves the use of dangerous and explosive alkali metal hydride such as sodium hydride ; use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view.

Synthetic Communications 2011, 41 (9), 1394-1402 discloses process for preparing Bilastine, includes palladium catalyzed vinylation of aryl bromide (7) with vinyl tributylstannane or with vinylboronic anhydride followed by hydroboration of the resulting styrene (8). This alternative cross coupling approach uses in the first step high cost and low available vinyl synthons (and highly toxic in the case of the tin compound). Besides, the anti-Markovnikov hydroxylation step is performed using the well-known and undesirable borane (highly toxic and flammable gas), which also undermines its industrial applicability.
The above process is schematically shown as below:

The above aforementioned prior art process for preparing Bilastine includes palladium catalysed vinylation of aryl bromide (7) with vinyl tributylstannane or with vinylboronic anhydride followed by hydroboration of the resulting styrene (8). The alternative cross coupling approach uses in the first step high cost and low available vinyl synthons (and highly toxic in the case of the tin compound). Beside, the anti-markovnikov hydroxylation step is performed using the well-known and undesirable borane (highly toxic and flammable gas), which also undermines its industrial applicability.

WO 2018/042305 discloses process for the preparation of Bilastine, the compound of formula (II) is reacted with 2-chloro acetyl chloride in presence of lewis acid to obtain the compound of formula (III). The compound of formula (III) undergoes reduction to obtain the compound of formula (IIIa). The compound of formula (IIIa) is reacted with the compound of formula (IV) in presence of sodium carbonate to obtain Bilastine (I).

The above process is schematically shown as below:

CN 109694367 A discloses process for preparing Bilastine, the compound of formula (6) is reacted with p-toluene sulfonyl chloride in presence of TBAB / NaOH and water to obtain the compound of formula (3). The compound of formula (3) is reacted with the compound of formula (2) in presence of TBAB / Na2CO3 and water to obtain the compound of formula (4). The compound of formula (4) is reacted with ethylene glycol monomethyl ether p-toluene sulfonate in presence of DMSO / TBAB and NaOH to obtain the compound of formula (5). The compound of formula (5) converts into Bilastine sodium salt (Ia) in presence of glacial acetic acid / NaOH / MDC and water, which is followed by converts into Bilastine (I) in presence of water and HCl.

The above process is schematically shown as below:

According to the above prior art processes which involves the condensation reaction of compound of formula (3) with compound of formula (2) and compound of formula (4) with ethylene glycol monoethyl ether p-toluenesulfonate in presence of phase transfer catalyst (PTC) causes low yield and high impurity profile.

Hence, the use of phase transfer catalyst (PTC) may not feasible and it is not economical for industrial scale for the preparation of Bilastine (I).

In view of the foregoing, the present inventors have result of extensive studies, the efficiency is extremely only the condensation reaction of formula (3) with compound of formula (2) and the compound of formula (4) with ethylene glycol monoethyl ether p-toluenesulfonate are carried out in absence of phase transfer catalyst (PTC), it was found that the corresponding Bilastine can be produced in high yield and purity with advantages of low consumption of solvents and cost effective process.

None of the above prior-art processes teaches nor suggests the use of base and solvents in absence of phase transfer catalyst (PTC) in the two condensation reactions.

SUMMARY OF THE INVENTION

The present invention relates to an improved, commercially viable, industrially advantageous and cost effective process for the preparation of Bilastine with good yield and purity.

In one aspect of the present invention, provides an process for the preparation of Bilastine (I), comprising the steps of;
a) 4-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) propan-2-yl) phenyl ethyl 4-methylbenzene sulfonate (3) is reacted with 2-(piperidin-4-yl)-1Hbenzo[d]imidazole (2) in presence of base, water and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (4),

b) The compound of formula (4) is reacted with 2-ethoxyethyl 4-methyl benzenesulfonate (7) in presence of strong base, organic solvent and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydro oxazole (5),

c) The compound of formula (5) converts into Bilastine (I) in presence of organic acid/strong base /hydrochloric acid and water.

d) Isolated Bilastine (I) with IPA and MeOH.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved, commercially viable, industrially advantageous and cost effective process for the preparation of Bilastine with good yield and purity.

In one embodiment of the present invention, provides an process for the preparation of Bilastine (I), comprising the steps of;

a) 4-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) propan-2-yl) phenyl ethyl 4-methylbenzene sulfonate (3) is reacted with 2-(piperidin-4-yl)-1Hbenzo[d]imidazole (2) in presence of base, water and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (4),

b) The compound of formula (4) is reacted with 2-ethoxyethyl 4-methyl benzenesulfonate (7) in presence of strong base, organic solvent and absence of Phase transfer catalyst (PTC) to obtain 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydro oxazole (5),

c) The compound of formula (5) converts into Bilastine (I) in presence of organic acid/strong base /hydrochloric acid and water, and

d) Isolated Bilastine (I) with IPA and MeOH.

According to the embodiment of the present invention process for the preparation of Bilastine which comprises, 4-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) propan-2-yl) phenyl ethyl 4-methylbenzene sulfonate (3) is reacted with 2-(piperidin-4-yl)-1Hbenzo[d]imidazole (2) in presence of base/water and absence of Phase transfer catalyst (PTC) at 60-100ºC for 3 to 6 hrs, preferably 75-80ºC for 4 to 5 hrs to obtain crude product of 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (4), which was recrystallized with ethyl acetate to obtain a pure product. The compound of formula (4) is reacted with 2-ethoxyethyl 4-methyl benzenesulfonate (7) in presence of strong base and organic solvent at room temperature to obtain crude product of 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydro oxazole (5), which was recrystallized with organic solvent/water to obtain pure product. The compound of formula (5) is reacted with organic acid and strong base to obtain sodium salt of Bilastine (Ia), which is converts into crude Bilastine (I) in presence of HCl (hydrochloric acid) and water and the crude Bilastine is recrystallized with IPA (isopropyl alcohol) /MeOH (methanol) to obtain Pure Bilastine.

In an embodiment of the present invention provides, wherein the organic solvents are selected from dimethyl formamide, acetone, ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dichloride, ethylene dichloride, dimethyl amino formamide, tetrahydrofuran, toluene, benzene and xylene.

In an another embodiment of the present invention provides, wherein the bases are selected from potassium carbonate, sodium carbonate, Rubidium carbonate, Caesium carbonate, potassium bicarbonate and sodium bicarbonate.

In an embodiment of the present invention provides, wherein the strong bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide and cesium hydroxide.

In an embodiment of the present invention provides, wherein the acids are selected from, Trifluoro acetic acid, acetic acid, hydrochloric acid, methyl sulphonic acid and oxalic acid.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1:

Preparation of 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole

Charge 4-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl) propan-2-yl) phenyl ethyl 4-methylbenzene sulfonate (100 gm) and 2-(piperidin-4-yl)-1Hbenzo[d]imidazole (96.6 gm) in presence of water (500 ml) as a solvent, add sodium carbonate (101.7 gm) as a base. Heat the mixtures to 75-80°C and maintain for 4-5 hrs to gives 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole BILStage-1 as a crude product was recrystallized in Ethyl acetate (500 ml) solvent to gives the pure 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole product, dry weight: 90.0gm, HPLC Purity: 98.2%.

Example-2:

Preparation of 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole

Charge 2-(2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-di methyl-4,5-dihydrooxazole (100 gm) and add 2-ethoxyethyl 4-methylbenzenesulfonate (88.0 gm) in the presence of DMF (200 ml) as a solvent, sodium hydroxide (25.19) as a base at 25-35°C.Maintain for 4-5 hrs at 25-35°C to gives 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole as a crude product. The crude product was Re-crystalized in Acetone (300 ml), water (300 ml). Obtained pure 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole product, dry weight: 88.0 gm, HPLC Purity :99.11%.

Example-3

Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl)-2-methylpropanoic acid (Bilastine):

Charge 2-(2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl) propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (100 gr) in the presence of acetic acid (46.5 gr) and water (100 ml) mixture. temperature raise 90-100°C and maintain for 1-2 hrs to gives the Bilastine hydrolysate and it is further reacts with sodium hydroxide (270.0 gm) at 90-100°C for 2-3 hrs to gives Bilastine. add DCM (800 ml) and adjust pH with 5 N HCl gives 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl)-2-methylpropanoic acid as a crude product. The crude was Recrystallized in Methanol (800 ml) & IPA (500 ml) solvent to gives the pure 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl) ethyl) phenyl)-2-methyl propanoic acid product, dry weight:75.0gm, HPLC Purity:99.92%.