DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Bilastine using novel intermediates.

BACKGROUND OF THE INVENTION
Bilastine i.e. 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid is an active pharma ingredient (API) developed by FAES FARMA; which is a non-sedating, long-acting second-generation histamine antagonist used for treatment of allergic rhino-conjunctivitis & urticarial.

Bilastine
The first report for the synthesis of Bilastine was given in EP0818454B1. The synthetic scheme involved is given below (Scheme 1).

Scheme 1

Major challenge found in the process given in EP’454 was the deprotection of compound of Formula II using mineral acids such as HCl or H2SO4 to yield Bilastine, with low yield due to formation of impurities which are difficult to remove. For removing these impurities inventors have to compromise on yield as it requires multiple purification to achieve the desired purity. Thus, this procedure was not commercially viable.

Few publications have tried to address the challenges faced during deprotection of Compound of Formula II by changing the reagent used. In one publication i.e. CN103214455A discloses hypochlorite solution for deprotection. In another report i.e. CN103351380A deprotection was attempted using organic acids.

Bilastine a solid compound is known to exhibit “Polymorphism”. Polymorphism, the occurrence of different crystalline forms, is the property of some molecules and molecular complexes. It is generally known that various salts or polymorphs of pharmaceutically active substances may have different physico-chemical, and consequently pharmacological properties. Further, such salts and/or polymorphs can be used to obtain an ideal composition of pharmaceutical formulations containing the given active substance or its salt. This means that it is very important to keep looking for suitable salts or polymorphic forms of pharmaceutically active substances.

Polymorphism in Bilastine was first reported in EP1505066B1, which disclosed three different crystalline polymorphic forms of Bilastine i.e. Form I, Form II and Form III; and directed to the preparation the new polymorph Form I of Bilastine, its pharmaceutical formulation and its use for the treatment of allergic reactions. EP’066 further describes, Bilastine which was first reported in EP’454 generates a mixture of Form II and Form III and both crystalline forms i.e. Form II and Form III reportedly gets converted into Form I. Further, no commercially viable procedures were reported in literature for preparing crystalline Form III.

Thus, there was a need felt to overcome the above mentioned limitations such as excessive use of reagents, long reaction time, multi stage purification, tedious work up etc., and more specifically a low overall yield of the final product i.e. Bilastine. Thus, in view to overcome above mentioned drawbacks, the inventors of the present application have worked extensively to get a modified and improved process for the preparation of Bilastine and its polymorph.

OBJECTS OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Bilastine using novel intermediates in good yield and purity.

Another objective of the present invention is to provide novel intermediates of Formula III and IV and its process for the preparation.

Yet another objective of the present invention is to provide a process for the preparation of crystalline Form III of Bilastine.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Bilastine using novel intermediates of formula III and IV.

According to one aspect of the present invention, an improved process of preparing Bilastine comprising;
i) reacting compound of Formula II with an acid to give compound of Formula III;

ii) reacting compound of Formula III with nitrosating agents to give compound of Formula IV;

Where R= , , or its mixture thereof

iii) reacting compound of Formula IV with a base to give Bilastine.

Yet another aspect of the present invention provides the novel intermediates Formula III and Formula IV used in the preparation of Bilastine are,

Where R= , ,

Yet another aspect of the present invention provides a process of preparing novel intermediates of Formula III and IV used in preparation of Bilastine.

Yet another aspect of the present invention provides a process of preparing crystalline Form III of said Bilastine.

BRIEF DESCRIPTION OF FIGURES:

Figure 1: PXRD pattern of crystalline Form III of Bilastine obtained as per present invention

Figure 2: A synthetic scheme of preparing Bilastine as per present invention

DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.

All terms/definitions as used herein in this application shall be understood in their ordinary meaning as known in the art or according to the description herein.

Techniques of separation or isolation of compounds can be done by conventional techniques known in the art and can be optionally purified. Separation or isolation techniques known in the art comprises but not limiting to crystallization, distillation, sublimation, or chromatography from the multi-phase extraction, solvent or solvent mixture. Chromatography can be of number of ways. For example, reverse phase and normal phase; Size exclusion, Ion exchange, High pressure, intermediate pressure and low pressure liquid chromatography methods and apparatus; Small scale analytical; simulated moving bed (SMB), preparative thin or thick-film chromatography, flash chromatography and like.

The term “Solvent” used in present invention refers but not limited to "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 (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane (DCM), dichloroethane (EDC), chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol (IPA), n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "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 (DIPE), methyl tert-butyl ether (MTBE), 1,2-dimethoxy ethane, tetrahydrofuran (THF), 1,4-dioxane and the like; "polar solvents" such as water; and their mixtures.

The term “Nitrosating agents” used in present invention refers but not limited to NaNO2, HNO2, KNO2 and like.

The term “Acid” used in present invention refers but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and like.

The term “Base” used in present invention refers but not limited to organic bases or inorganic bases.

Organic base include but not limited pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine), N-methylpiperidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and like.

Inorganic base includes but not limited to alkali and alkaline earth metal hydrides like sodium hydride, potassium hydride, lithium hydride etc; alkali and alkaline earth metal carbonates like potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate etc; alkali and alkaline earth metal hydrogen carbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and alkali and alkaline earth metal hydroxides such as, sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide etc; and like.

The present invention provides an improved process of preparing Bilastine comprising;
i) reacting compound of Formula II with an acid to give compound of Formula III;

ii) reacting compound of Formula III with nitrosating agents to give compound of Formula IV;
Where R= , , or its mixture thereof

iii) reacting compound of Formula IV with a base to give Bilastine.

The process of preparing a compound of formula II which is used in present invention can be prepared from any process known in prior art.

In an embodiment, the reaction of step i) is carried out by reacting compound of Formula II with an acid and optionally in presence of a solvent; the said acid used is selected from inorganic or organic acid, preferably acetic acid; and the said solvent used is selected from polar or non polar solvents solvent, preferably water.

In an embodiment, the reaction of step i) can be carried out at temperatures ranging from about 50-130 oC, preferably between 80-110 oC.

After the completion of the reaction, the compound of Formula III may optionally be isolated and purified as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula III may be taken forward for the next steps, without isolation.

In an embodiment, the reaction of step ii) is carried out by reacting a compound of formula III with a nitrosating agent and optionally in presence of an acid; the said nitrosating agents used in step ii) is selected from but not limited to NaNO2, HNO2, KNO2, preferably NaNO2; and acid used is selected from inorganic or organic acid, preferably acetic acid.

In an embodiment, the reaction of step ii) may be carried out at temperatures ranging from about 5-50 oC, preferably 10-30 oC.

After the completion of the reaction, the compound of Formula IV may optionally be isolated and purified as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula IV may be taken forward for the next steps, without isolation.

In an embodiment, the reaction of step iii) is carried out by reacting compound of formula IV with a base and optionally in presence of a solvent; the said base used in step iii) is selected from organic or inorganic base, preferably alkali and alkaline earth metal hydroxides; and solvent used in selected from polar or non polar solvents, preferably tetrahydrofuran.

In an embodiment, the reaction of step iii) may be carried out at temperatures ranging from about 50-100 oC, preferably 60-80 oC.

The said Bilastine obtained in the present invention is having a purity of more than 99.5% (w/w by HPLC).

The following impurities can be present in the said Bilastine in less than 0.1% (w/w by HPLC).

S. No Impurity Name IUPAC Name Structure
1. Impurity-A
1-{2-[4-(1-carboxy-1-methylethyl)phenyl]ethyl}-4-
[1-(2-ethoxyethyl)-1H-1,3-benzodiazol-2-yl]piperidin-1-ium-1-olate

2 Impurity-B
2-(4-{2-[4-(1H-1,3-benzodiazol-2-yl)piperidin-1-yl]ethyl}phenyl)-2-methylpropanoic acid

3 Impurity-C
2-(4-{2-[4-(1-{2-[4-(1-carboxy-1-methylethyl) phenyl]ethyl}-1H-1,3-benzodiazol-2-yl)piperidin-1-yl]ethyl}phenyl)-2-methylpropanoic acid

4 Impurity-D
2-[4-(2-{2-[1-(2-ethoxyethyl)piperidin-4-yl]-1H-1,3-benzodiazol-1-yl} ethyl)phenyl]-2-methylpropanoic acid

5 Impurity-E
2-[4-(2-{4-[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid

According to another embodiment of the present invention, novel intermediates used in the preparation of Bilastine are Formula III and Formula IV.

Where R= , ,

In yet another embodiment of the present invention provides a process of preparing the said intermediates Formula III and Formula IV used in the preparation of Bilastine comprising; i) reacting the said compound of Formula II with an acid to give compound of Formula III; ii) reacting the said compound of Formula III with nitrosating agents to give compound of Formula IV.

In yet another embodiment of the present invention, the said Bilastine can be further converted to its desired polymorphic form i.e. crystalline Form III by dissolving the Bilastine in a solvent and isolating crystalline Form III.

In an embodiment, crystalline Form III of Bilastine is prepared from ether solvent, polar solvent or mixture thereof.

In a particular embodiment, ether solvents used is selected from dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and like and polar solvent used is preferably water.
Techniques of separation or isolation of Bilastine crystalline Form III can be done by conventional techniques known in the art, preferably filtration.

The general techniques used for the characterization of compounds are given below for reference.

I. Prep HPLC
The Shimadzu's Prominence preparative HPLC system was used to isolate compound of formula IVb and IVc using Reprosil Gold C18 (250 x 20) mm, 5 µm as column and Acetonitrile & Ammonium acetate in water as mobile phase.

II. IR
The Infrared spectrum was recorded using a Shimadzu Affinity-1 FT-IR spectrophotometer over the range of 4000-400 cm-1 with a resolution of 4.0 cm-1. The spectrum was obtained using KBr pellet and are given in cm-1.

III. NMR
NMR spectrum was recorded in a BRUKER-400 MHz instrument using CDCl3 and given in ppm.

IV. MASS
Atmospheric pressure chemical ionization (APCI) mass spectrum of was recorded using Thermo Scientific Velospro mass spectrometer and given as m/z.

V. PXRD
X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: PanAlytical X'pert Pro powder diffractometer, CuKa radiation, ? = 1.5405980 A. X’Celerator detector active length (2 theta) = 3.3473mm, laboratory temperature 22-25 °C.

Certain specific aspects and embodiments of this invention are described in further detail by the examples given below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

Examples:
Example 1: Preparation of compound of Formula III (2-Amino-2-methylpropyl 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-1,3-benzo[d]imidazole-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoate): Molecular Formula: C32H46N4O3; Molecular Weight: 534.73 g/mol

A Compound of formula II (9 g) and acetic acid solution (6 ml of acetic acid in 20 ml water) was taken in a round bottomed flask and contents were heated together at 90-95 °C. After 4 hours, contents were cooled and pH was adjusted between 7-7.5 using aqueous ammonia. The product was extracted using DCM and further purified using ethyl acetate.

FT-IR [Band (cm-1)]: 3383 (-N-H stretching); 3051, 2974 & 2943 (-C-H stretching); 1732 (-C=O stretching); 1614 & 1558 (-C=C stretching); 1252 & 1146 (-C-N stretching); 1123 (-C-O-C stretching).

1H-NMR (ppm): 1.04 (s, 6H); 1.12 (t (J = 6.8 Hz), 3H); 1.62 (s, 6H); 2.05-2.07 (m, 2H); 2.17-2.25 (m, 2H); 2.36-2.47 (m, 2H); 2.76-2.80 (m, 2H); 2.87-2.91 (m, 2H); 3.10-3.15 (m, 1H); 3.28-3.31 (m, 2H); 3.37-3.43 (q, 2H); 3.73 (t (J = 5.2 Hz), 2H); 3.86 (s, 2H); 4.34 (t (J = 5.2 Hz), 2H); 4.89 (bs, 2H); 7.20-7.34 (m, 7H); 7.77-7.79 (m, 1H).

13C-NMR (ppm): 15.13, 26.42, 26.67, 30.00, 32.35, 33.50, 43.88, 46.42, 49.98, 52.69, 59.57, 67.00, 68.67, 73.51, 109.32, 119.53, 122.07, 122.26, 125.89, 128.92, 134.76, 138.34, 142.47, 142.62, 158.01, 176.59.

Mass [m/z]: 535.45 [M+H]+

Example 2: Preparation of compound of formula IV
The product obtained in previous step was further reacted acetic acid (1 ml) followed by the addition of sodium nitrite (1 g) at 0-5 °C and stirred. After completion of reaction, pH was adjusted using sodium hydroxide and contents were extracted using ethyl acetate. After distilling out the solvent an oily mass was obtained. The obtained reaction mixture was subjected to column chromatography using ethyl acetate and cyclohexane to isolate compound of formula IVa and residue obtained was further subjected to Prep HPLC to isolate compound of Formula IVb and IVc. Structure characterizations of these compounds are given below.

Formula IVa (R = ): 2-Hydroxy-2-methylpropyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate: Molecular Formula: C32H45N3O4; Molecular Weight: 535.72 g/mol

FT-IR [Band (cm-1)]: 3391 (-O-H stretching); 3053 & 2974 (-C-H stretching); 1728 (-C=O stretching); 1614 & 1514 (-C=C stretching); 1252 & 1145 (-C-N stretching); 1123 (-C-O-C stretching).

1H-NMR* (ppm): 1.05-1.11 (m, 9H); 1.60 (s, 6H); 2.00-2.15 (m, 4H); 2.27 (t (J = 11.2 Hz), 2H); 2.63-2.67 (m, 2H); 2.83-2.87 (m, 2H); 3.18-3.21 (m, 3H); 3.36-3.41 (q, 2H); 3.75 (t (J = 4.8 Hz), 2H); 3.89 (s, 2H); 4.45 (t (J = 4.8 Hz), 2H); 7.22-7.27 (m, 4H); 7.33 (d (J = 8.0 Hz), 2H); 7.48 (d (J = 7.2 Hz), 1H); 7.63 (d (J = 8.0 Hz), 1H)
*Exchangeable proton (-OH) was not observed.

13C-NMR (ppm): 15.44, 26.41, 26.92, 31.77, 33.58, 35.36, 44.81, 47.47, 54.57, 61.63, 67.69, 69.77, 70.30, 73.07, 111.16, 119.19, 123.21, 123.44, 126.93, 129.73, 135.78, 139.86, 143.13, 143.78, 159.93, 178.04.

Mass [m/z]: 536.37 [M+H]+

Formula IVb (R = ): 2-Methylprop-2-en-1-yl 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-1,3-benzodiazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoate: Molecular Formula: C32H43N3O3; Molecular Weight: 517.70 g/mol

FT-IR [Band (cm-1)]: 2974 & 2932 (-C-H stretching); 1730 (-O=C-O stretching); 1508 & 1460 (-C=C stretching); 1144 (-C-N stretching (Aliphatic)); 1248 (-C-N stretching (Aromatic)); 1123 (-C-O-C stretching).

1H-NMR (ppm): 1.14 (t (J = 7.2 Hz), 3H); 1.63 (s, 6H); 1.66 (s, 3H); 2.01-2.06 (m, 2H); 2.16-2.21 (m, 4H); 2.68 (bs, 2H); 2.85 (m, 2H); 3.03 (bs, 1H); 3.19 (bs, 2H); 3.39-3.44 (q, 2H); 3.75 (t (J = 5.6 Hz), 2H); 4.35 (t (J = 5.6 Hz), 2H); 4.50 (s, 2H); 4.86 (s, 2H); 7.21-7.35 (m, 7H); 7.77-7.79 (m, 1H).

13C-NMR (ppm): 15.17, 19.50, 26.60, 31.03, 33.12, 34.56, 43.84, 46.39, 53.66, 60.52, 67.05, 67.98, 68.77, 109.31, 112.58, 119.62, 121.97, 122.15, 125.89, 128.87, 134.93, 138.99, 140.16, 142.38, 142.88, 158.49, 176.56.

Mass [m/z]: 518.36 [M+H]+

Formula IVc (R = ): 2-Methylprop-1-en-1-yl 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-1,3-benzodiazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoate: Molecular Formula: C32H43N3O3; Molecular Weight: 517.70 g/mol

FT-IR [Band (cm-1)]: 2930 & 2970 (-C-H stretching); 1736 (-O=C-O stretching); 1614 & 1462 (-C=C stretching); 1142 (-C-N stretching (Aliphatic)); 1252 (-C-N stretching (Aromatic)); 1121 (-C-O-C stretching).

1H-NMR (ppm): 0.99 (t (J = 6.8 Hz), 3H); 1.42-1.50 (m, 12H); 1.87-1.96 (m, 2H); 2.01-2.08 (m, 4H); 2.53 (m, 2H); 2.69-2.72 (m, 2H); 2.88 (m, 1H); 3.04 (m, 2H); 3.24-3.293 (q, 2H); 3.60 (t (J = 5.6 Hz), 2H); 4.20 (t (J = 5.6 Hz), 2H); 6.67 (s, 1H); 7.06-7.20 (m, 7H); 7.62-7.64 (s, 1H).

13C-NMR (ppm): 15.16, 15.63, 19.69, 26.51, 31.12, 33.19, 34.56, 43.83, 46.40, 53.78, 60.54, 67.05, 68.78, 109.30, 118.81, 119.62, 121.95, 122.12, 125.85, 128.92, 130.31, 134.95, 139.11, 142.05, 142.90, 158.52, 174.18.

Mass [m/z]: 518.35 [M+H]+

Example 3: Preparation of crude Bilastine
The compound of Formula IV was taken in tetrahydrofuran and water solvent mixture in 1:1 ratio. To this reaction mixture, potassium hydroxide (8 g) was added and heated at 60-65 °C. After completion of the reaction, contents were cooled and pH was adjusted between 6 and 7 using acetic acid solution. Filtered the solid obtained and dried to obtain crude Bilastine.

Example 4: Purification of Bilastine
The crude Bilastine obtained in previous step was dissolved in MTBE and water mixture (in a ratio of 1:2) and stirred for ~1 hour. Filtered the solid obtained, washed with water (30 ml) and dried to obtain purified Bilastine.

Example 5: Preparation of Form III of Bilastine
Bilastine (1 g) was taken in a flask and dissolved in a mixture of THF (20 ml) and water (5 ml) and cooled. After ~1 hour, solid obtained was filtered, washed with pre cooled THF (5 ml) and dried to obtain crystalline Form III of Bilastine.
,CLAIMS:1) An improved process of preparing Bilastine comprising;
i) reacting compound of Formula II with an acid to give compound of Formula III;

ii) reacting compound of Formula III with nitrosating agent to give compound of Formula IV;

Where R= , , or its mixture thereof

iii) reacting compound of Formula IV with a base to give Bilastine.

2) The process as claimed in Claim 1, acid used is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid and benzenesulfonic acid or combinations thereof.

3) The process as claimed in Claim 1, nirosating agents is selected from NaNO2, HNO2 and KNO2 or combinations thereof.

4) The process as claimed in Claim 1, base used is selected from potassium hydride, lithium hydride, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide or combinations thereof.

5) The process as claimed in Claim 1, solvent used in any steps is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, water or their mixtures.

6) A compound of Formula III

7) A compound of Formula IV

Where R= , ,

8) The process as claimed in Claim 1, further comprising converting Bilastine to Crystalline Form III by dissolving in organic solvent and isolating the solid.

9) The process as claimed in claim 8, organic solvent used is selected from ether solvent, polar solvent or mixture thereof.