WO2020065475A1

WO2020065475A1 - Title: process for the preparation of bilastine

Info

Publication number: WO2020065475A1
Application number: PCT/IB2019/057967
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Suresh Mahadev Kadam; Sachin Baban Gavhane; Sadeep Bandu KHANDAGALE; Ajit Shankar Mindhe; Rajesh Kumar DWIVEDI; Sukumar Sinha
Original assignee: Glenmark Life Sciences Limited; Glenmark Pharmaceuticals Limited
Priority date: 2018-09-25
Filing date: 2019-09-20
Publication date: 2020-04-02
Also published as: BR112021005403A2

Abstract

The present invention relates to a process for the preparation of bilastine, a compound of formula I. The present invention relates to p-xylene solvate of bilastine and process for its preparation. The present invention relates to a process for the preparation of bilastine form 2 via p-xylene solvate of bilastine.

Description

PROCESS FOR THE PREPARATION OF BILASTINE

PRIORITY

[0001] This application claims the benefit of Indian Provisional Applications 201821036024 filed on September 25, 2018 and 201821049313 filed on December 27, 2018, entitled“PROCESS FOR THE PREPARATION OF BILASTINE”, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of bilastine.

Description of the Related Art

[0003] Bilastine is a selective antagonist of Hl receptors, useful in the treatment of allergic reactions and pathological processes mediated by histamine, especially for treating rhinoconjunctivitis and urticaria. Bilastine is chemically known as 2-[4-(2-(4-(l- (2-ethoxyethyl)benzimidazol-2-yl)piperidin-l-yl)ethyl)phenyl]-2-methylpropanoic acid, and represented by formula (I):

Formula I

[0004] United States patent number US 5,877,187 discloses bilastine and its process for preparation. United States patent number US 7,612,095 discloses crystalline forms 1, 2 and 3 of bilastine.

[0005] The present invention provides a method for producing the crystalline p-xylene solvate of bilastine.

[0006] The present invention also provides an economical and efficient process for the preparation of stable crystalline form 2 of bilastine.

SUMMARY OF THE INVENTION

[0007] In one embodiment, the present invention provides a process for the preparation of crystalline form 2 of bilastine, the process comprising:

a) treating p-xylene solvate of bilastine with a solvent system comprising a C₆-Cis aromatic hydrocarbon and an alcohol to obtain a reaction mixture; b) heating the reaction mixture obtained in step (a), followed by cooling the reaction mixture;

c) optionally stirring the reaction mixture obtained in step (b); and

d) isolating the crystalline form 2 of bilastine.

[0008] In one embodiment, the present invention provides a p-xylene solvate of bilastine.

[0009] In one embodiment, the present invention provides a process for the preparation of p-xylene solvate of bilastine comprising:

e) treating bilastine with a solvent system comprising p-xylene and an alcohol to obtain a reaction mixture; and

f) isolating the p-xylene solvate of bilastine from the reaction mixture.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is the characteristic XRPD of p-xylene solvate of bilastine in crystalline form as obtained in Example 3

[0011] Figure 2 is the TGA thermogram of p-xylene solvate of bilastine in crystalline form as obtained in Example 3

[0012] Figure 3 is the DSC thermogram of p-xylene solvate of bilastine in crystalline form as obtained in Example 3

DETAILED DESCRIPTION OF THE INVENTION

[0013] In one embodiment, the present invention provides a process for the preparation of crystalline form 2 of bilastine, the process comprising:

g) treating p-xylene solvate of bilastine with a solvent system comprising a C₆-Ci8 aromatic hydrocarbon and an alcohol to obtain a reaction mixture;

h) heating the reaction mixture obtained in step (a), followed by cooling the reaction mixture;

i) optionally stirring the reaction mixture obtained in step (b); and

j) isolating the crystalline form 2 of bilastine.

[0014] In one embodiment, the C6-C18 aromatic hydrocarbon is selected from the group consisting of toluene, ethyl benzene, m-xylene and o-xylene, trimethylbenzenes, hemellitene, pseudocumene, mesitylene.

[0015] In one embodiment, the C6-C18 aromatic hydrocarbon is selected from the group consisting of toluene, ethyl benzene, m-xylene and o-xylene

[0016] In one embodiment, the C6-C18 aromatic hydrocarbon is toluene. [0017] In one embodiment, the alcohol is C1-C6 alcohol.

[0018] In one embodiment, the C1-C6 alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol and t-butanol.

[0019] In one embodiment, the C1-C6 alcohol is methanol.

[0020] In one embodiment, the volume ratio of C₆-Ci8 aromatic hydrocarbomalcohol in the solvent system is in the range of 95:5 to 60:40 volume/volume.

[0021] In one embodiment, the volume ratio of C6-C18 aromatic hydrocarbomalcohol in the solvent system is 85: 15 volume/volume.

[0022] In one embodiment, the C6-C18 aromatic hydrocarbon is toluene and C1-C6 alcohol is methanol.

[0023] In one embodiment, the volume ratio of toluene: methanol in the solvent system is in the range of 95:5 to 60:40 volume/volume.

[0024] In one embodiment, the volume ratio of toluene: methanol in the solvent system is 85:15 volume/volume.

[0025] In one embodiment, in step (a), p-xylene solvate of bilastine is stirred in a solvent system comprising a C6-C18 aromatic hydrocarbon solvent and an alcohol to obtain a reaction mixture.

[0026] In one embodiment, in step (a), p-xylene solvate of bilastine is stirred in a solvent system comprising a C6-C18 aromatic hydrocarbon solvent and methanol to obtain a reaction mixture.

[0027] In one embodiment, in step (a), p-xylene solvate of bilastine is stirred in a solvent system comprising toluene and methanol to obtain a reaction mixture.

[0028] In one embodiment, in step (a), p-xylene solvate of bilastine is stirred in a solvent system wherein the volume ratio of toluene: methanol is 85: 15 volume/volume to obtain a reaction mixture.

[0029] In one embodiment, in step (a), p-xylene solvate of bilastine is treated with a solvent system comprising C6-C18 aromatic hydrocarbon solvent and alcohol, wherein the treatment is carried out at room temperature.

[0030] In one embodiment, in step (b), the reaction mixture is heated at a temperature in the range of 40°C to l20°C.

[0031] In one embodiment, in step (b), the reaction mixture is heated at 60°C to 70°C. [0032] In one embodiment, in step (b), the reaction mixture is cooled at a temperature in the range of 0°C to 30°C.

[0033] In one embodiment, in step (c), the reaction mixture is optionally stirred.

[0034] In one embodiment, in step (c), the reaction mixture is optionally stirred for a time period in the range of 20 minutes to 40 minutes.

[0035] In one embodiment, in step (c), the reaction mixture is optionally stirred for 30 minutes.

[0036] In one embodiment, in step (d), the crystalline form 2 of bilastine is isolated from the reaction mixture.

[0037] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by filtration.

[0038] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by centrifugation.

[0039] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by solvent drying.

[0040] In one embodiment, in step (d), the isolated crystalline form 2 of bilastine is dried at a temperature in the range of 50°C to 90°C for a time period in the range of 4 hours to 15 hours.

[0041] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by filtration and dried at temperature in the range of 50°C to 90°C for time period in the range of 4 hours to 15 hours.

[0042] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by filtration and dried at temperature in the range of 80°C to 85°C for 12 hours.

[0043] In one embodiment, the crystalline form 2 of bilastine is isolated from the reaction mixture by filtration and dried at temperature in the range of 55°C to 65°C for 6 hours.

[0044] In one embodiment, the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is less than 1%.

[0045] In one embodiment, the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is less than 0.5%.

[0046] In one embodiment, the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is below detection limit.

[0047] In one embodiment, the present invention provides a p-xylene solvate of bilastine. [0048] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form.

[0049] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by X-ray powder diffraction (XRPD) spectrum as depicted in Figure 1.

[0050] In one embodiment, a p-xylene solvate of bilastine, in crystalline form is characterized by X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.3, 17.7, 21.1 and 24.0 ±0.2 degrees 20.

[0051] In one embodiment, a p-xylene solvate of bilastine, in crystalline form is characterized by X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.3, 12.8, 17.7, 18.5, 21.1 and 24.0 ±0.2 degrees 20.

[0052] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by TGA thermogram as depicted in Figure 2.

[0053] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by TGA thermogram, showing a weight loss of about 8 weight% to about 12 weight% up to l50°C determined over the temperature range of 0°C to 250°C and heating rate l0°C/min.

[0054] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by DSC thermogram as depicted in Figure 3.

[0055] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by DSC thermogram having three endothermic peaks with peak temperatures at about 130.5±2, l95±2 and 204. l±2°C.

[0056] In one embodiment, the present invention provides a p-xylene solvate of bilastine in crystalline form characterized by Hl NMR (400 MHz, DMSO-d6) having peak values l.0l(t,3H), l.46(s,6H), l.9l(m,4H), 2. l3(m,2H), 2.25(s,4H), 2.54(t,2H), 2.75(t,2H), 3.07(m,3H), 3.34(q,2H), 3.65(t,2H), 4.40(t,2H), 7.05(s,2H), 7.l4-7.28(m,6H), 7.51-7.57 (m,2H).

[0057] In one embodiment, the present invention provides a process for the preparation of p-xylene solvate of bilastine comprising:

k) treating bilastine with a solvent system comprising p-xylene and an alcohol to obtain a reaction mixture; and

l) isolating the p-xylene solvate of bilastine from the reaction mixture. [0058] In one embodiment, the alcohol is C1-C6 alcohol.

[0059] In one embodiment, the solvent system comprises p-xylene and C1-C6 alcohol.

[0060] In one embodiment, the C1-C6 alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol and t-butanol.

[0061] In one embodiment, the C1-C6 alcohol is methanol.

[0062] In one embodiment, the volume ratio of p-xylene:methanol in the solvent system is in the range of 95:5 to 60:40 volume/volume.

[0063] In one embodiment, the volume ration of p-xylene:methanol in the solvent system is 85: 15 volume/volume.

[0064] In one embodiment, the isolation of the p-xylene solvate of bilastine from the reaction mixture comprises:

(a) stirring the reaction mixture; and

(b) cooling the reaction mixture obtained in (a) at a temperature in the range of 0°C to 30°C followed by filtration to obtain p-xylene solvate of bilastine.

[0065] In one embodiment, the isolated p-xylene solvate of bilastine is dried at temperature in the range of 40°C to 80°C for a time period in the range of 2 hours to 12 hours.

[0066] In one embodiment, the p-xylene solvate of bilastine is isolated from the reaction mixture by filtration and may be dried at a temperature in the range of 40°C to 80°C for a time period in the range of 2 hours to 12 hours.

[0067] In one embodiment, the p-xylene solvate of bilastine is isolated from the reaction mixture by filtration and may be dried at temperature in the range of 60°C to 65°C for 8 hours.

[0068] In one embodiment, the present invention provides a process for crystalline bilastine form 2 without forming bilastine form 1.

[0069] In one embodiment, the present invention provides a process for crystalline bilastine form 2 via p-xylene solvate of bilastine without forming bilastine form 1.

[0070] In one embodiment, the present invention provides a process for crystalline bilastine form 2 directly from p-xylene solvate of bilastine without forming bilastine form 1 [0071] In one embodiment, the present invention provides a process for crystalline bilastine form 2, wherein the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is less than 1%.

[0072] In one embodiment, the present invention provides a process for crystalline bilastine form 2, wherein the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is less than 0.5%.

[0073] In one embodiment, the present invention provides a process for crystalline bilastine form 2, wherein the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is below detection limit.

[0074] In one embodiment, the present invention provides a process for preparation of bilastine a compound of formula I comprising:

m) treating a compound of formula IV-A with a compound of formula V to obtain a compound of formula III;

F ormula III F ormul a II

b) treating the compound of formula III with 2-Ethoxyethyl 4- Methylbenzenesulfonate to obtain a compound of formula II; and

c) converting the compound of formula II obtained in step (b); to bilastine.

[0075] In one embodiment, the present invention provides a process for preparation of bilastine a compound of formula I comprising:

n) treating a compound of formula IV with a compound of formula V to obtain a compound of formula III

Formula IV

c) converting the compound of formula II obtained in step (b); to bilastine.

[0076] In one embodiment, in step (a), the reaction of compound of formula IV with compound of formula V is carried out using a base.

[0077] In one embodiment, in step (a), the reaction of compound of formula IV with compound of formula V is carried out using inorganic or organic base.

[0078] In one embodiment, the inorganic base may be selected from the group consisting of alkali metal hydroxides, alkali metal carbonates or bicarbonates, alkali metal alkoxides and the like.

[0079] In one embodiment, alkali metal hydroxides may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

[0080] In one embodiment, alkali metal carbonates or bicarbonates may be selected from the group consisting sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0081] In one embodiment, alkali metal alkoxides may be selected from the group consisting sodium ethoxide, potassium ethoxide, potassium t-butoxide and the like.

[0082] In one embodiment, in step (a), the reaction of compound of formula IV with compound of formula V is carried out in the presence of a solvent.

[0083] In one embodiment, in step (a), the reaction of compound of formula IV with compound of formula V is carried out in the presence of an alcoholic solvent.

[0084] In one embodiment, the alcoholic solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like.

[0085] In one embodiment, in step (b), the reaction of compound of formula III with 2-

Ethoxyethyl 4-Methylbenzenesulfonate is carried out using base.

[0086] In one embodiment, in step (b), the reaction of compound of formula III with 2- Ethoxy ethyl 4-Methylbenzenesulfonate is carried out using inorganic or organic base.

[0087] In one embodiment, the inorganic base may be selected from the group consisting of alkali metal hydroxides, alkali metal carbonates or bicarbonates, alkali metal alkoxides and the like. [0088] In one embodiment, alkali metal hydroxides may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

[0089] In one embodiment, alkali metal carbonates or bicarbonates may be selected from the group consisting sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0090] In one embodiment, alkali metal alkoxides may be selected from the group consisting sodium ethoxide, potassium ethoxide, potassium t-butoxide and the like.

[0091] In one embodiment, in step (c), the conversion of compound of formula II to bilastine is carried out using an acid.

[0092] In one embodiment, in step (c), the conversion of compound of formula II to bilastine is carried out using an inorganic or organic acid.

[0093] In one embodiment, the inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and the like.

[0094] In one embodiment, in step (c), the conversion of compound of formula II to bilastine is carried out using a base.

[0095] In one embodiment, in step (c), the conversion of compound of formula II to bilastine is carried out using an inorganic or organic base.

[0096] In one embodiment, the inorganic base may be selected from the group consisting of alkali metal hydroxides, alkali metal carbonates or bicarbonates, alkali metal alkoxides and the like.

[0097] In one embodiment, alkali metal hydroxides may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

[0098] In one embodiment, alkali metal carbonates or bicarbonates may be selected from the group consisting sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

[0099] In one embodiment, alkali metal alkoxides may be selected from the group consisting sodium ethoxide, potassium ethoxide, potassium t-butoxide and the like.

[0100] In one embodiment, the bilastine obtained by converting the compound of formula II is not isolated from the reaction mixture and is used for preparing the p-xylene solvate.

[0101] In one embodiment, the bilastine obtained by converting the compound of formula II is isolated as a residue from the reaction mixture and is used with or without purification for preparing the p-xylene solvate. [0102] In one embodiment, the present invention provides a process for preparation of bilastine a compound of formula I comprising:

o) reacting a compound of formula IV-A with a compound of formula VI to obtain a compound of formula II; and

p) Formula IV-A Formula VI Formula II

q) converting the compound of formula II obtained in step (a) to bilastine.

[0103] In one embodiment, the present invention provides a process for preparation of bilastine a compound of formula I comprising:

r) reacting a compound of formula IV with a compound of formula VI to obtain a compound of formula II; and

Formula IV Formula VI s) Formula II

t) converting the compound of formula II obtained in step (a) to bilastine.

[0104] In one embodiment, the present invention provides a process for preparation of bilastine a compound of formula I comprising:

u) reacting a compound of formula IV with a compound of formula VI to obtain a compound of formula II;

v) converting the compound of formula II obtained in step (a) to bilastine; and w) converting the bilastine obtained in step (b) to p-xylene solvate of bilastine.

[0105] In one embodiment, in step (a), the reaction of compound of formula IV with compound of formula VI is carried out in the presence of a base.

[0106] In one embodiment, the base is as discussed supra.

[0107] In one embodiment, in step (b) conversion of compound of formula II to bilastine is carried out as discussed supra.

[0108] In one embodiment, in step (b) conversion of compound of formula II to bilastine is carried out by reacting the compound of formula II with an acid followed by a base. [0109] In one embodiment, the acid is selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid, hydrobomic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, phosphoric acid, perchloric acid and the like.

[0110] In one embodiment, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide and the like.

[0111] In one embodiment, the present invention provides a process for preparation of compound of formula VI comprising:

x) reacting a compound of formula IX with di-t-butyl-dicarbonate to obtain a compound of formula VIII;

y ) F ormu a I F orm a V F ormul a VII F ormul a VI z) reacting the compound of formula VIII with 2-ethoxy ethyl-toluene sulfonate to obtain a compound of formula VII; and

aa) converting the compound of formula VIII to compound of formula VI

[0112] In one embodiment, in step (a), reaction is carried out in the presence of a base.

[0113] In one embodiment, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium hydride and the like.

[0114] In one embodiment, in step (b), reaction is carried out in the presence of a base.

[0115] In one embodiment, the base is as discussed supra.

[0116] In one embodiment, the present invention provides a process for the preparation of bilastine, wherein the level of compound of formula A or compound of formula B or compound of formula C is less than 0.15% w/w relative to the amount of bilastine as determined by HPLC.

Compound B Compound C

[0117] In one embodiment, the present invention provides bilastine, wherein the level of compound of formula A or compound of formula B or compound of formula C is less than 0.15% w/w relative to the amount of bilastine as determined by HPLC.

[0118] In one embodiment, the present invention provides a process for the preparation of bilastine, wherein the level of compound of formula D or compound of formula E or compound of formula F is less than 0.15% w/w relative to the amount of bilastine as determined by HPLC.

bb) Compound E Compound F

[0119] In one embodiment, the present invention provides bilastine, salt or solvate thereof obtained by the processes herein described, having D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 30 microns, still more preferably less than about 10 microns.

[0120] In one embodiment, the present invention provides bilastine, salt or solvate thereof obtained by the processes herein described, having D50 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 30 microns, still more preferably less than about 10 microns.

[0121] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state bilastine or salt, solvate thereof into any of the foregoing desired particle size range.

[0122] Instrumental settings for XRPD: X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 20 range of 2-50° with a“time-per-step” optimized to 50 sec.

[0123] Measurement Parameters for quantification of form 1 in form 2: Scan axis Gonio; Scan mode Continuous; Start angle (°) 2.5; End angle (°) 5.0; Step size (°) 0.0167; Time per step (s) 7000

[0124] Prepare a mixture of bilastine form 1 standard and bilastine form 2 standard with ratio of 1.5: 98.5(%w/w). Perform three replicates of standard and single replicate of test sample. Derive the peak area corresponding to form 1 at 2 theta 3.7°±0.2°. Using the equation mentioned below, calculate bilastine form 1 in test sample.

Area of peak at 3.7±0.2° in Test sample

Percentage of Form 1= - * 1.5

Average Area of three replicates of peak at 3.7±0.2° in standard

[0125] Instrumental settings for TGA: Instrument Name: TGA Q 500; Method: 5-8 mg of sample was taken in platinum pan and heated at l00°C/minute from 0 to 4000C.

[0126] Instrumental settings for DSC: Instrument name: TA DSC250; Temperature range is 30°C to 350°C and heating rate is l0°C/minute.

[0127] Instrumental settings for proton NMR: Instrument Name: Bruker-400 MHz; 1H NMR spectra were recorded in DMSO-d6. [0128] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages. EXAMPLES

[0129] Example 1: Preparation of 2-(2-(4-(2-(4-(lH-benzo[d]imidazol-2- yl)piperidin-l- yl)ethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (compound of formula III):

2-Piperdin-4-yl-lH-Benzimidazole, sodium carbonate and 2-[4-[l-(4,4-dimethyl-5H- oxazol-2-yl)-l-methyl-ethyl]phenyl]ethyl4-methylbenzenesulfonate were added to methanol and the reaction mass was refluxed for about 8 hours. The solvent was removed under reduced pressure and the acetone was added to the obtained residue. The reaction mass was stirred. The reaction mass was then filtered and the obtained product is washed with acetone. Water was added to the wet solid and the reaction mass was stirred; followed by filtration. The wet product was then dried to obtain title compound.

[0130] Example 2: Preparation of (2-(2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5- dihydrooxazole (compound of formula II):

The solution of 2-(2-(4-(2-(4-(lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl) propan-2-yl) -4,4-dimethyl-4,5-dihydrooxazole(36gm.0.0809mmol) in DMF was stirred and potassium tertiary butoxide and 2-Ethoxyethyl 4-Methylbenzenesulfonate were added to the reaction mass. The reaction mass was heated to in the temperature range of 60°C to 65°C for about 2 hours to about 3 hours. The reaction mass was then cooled at temperature in the range of 25°C to 30°C and water was added to the reaction mass and stirred. The reaction mass was then filtered and the title compound was obtain by filtration followed by drying.

[0131] Example 3: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid p- xylene solvate (p-xylene solvate of bilastine) (2-(2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl) phenyl)propan-2-y l)-4,4-dimethy 1-4, 5 -dihy drooxazole(37gm, 0.071 mmol) was mixed with 50% hydrochloric acid and the reaction mass was heated to reflux temperature for about 5h to about 6h and then reaction mass cooled to about 25°C to about 30°C. 20% methanol in dichloromethane was then added to the reaction mass and 20% aqueous sodium hydroxide solution was added to the reaction mass to adjust the pH of the reaction mass to 7. The aqueous and organic layers were separated. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulphate and solvent was removed under reduced pressure to obtained semisolid residue. The p-xylene and methanol solvent mixture (volume ratio p-xylene: methanol is 85: 15 V/V) was added to the obtained residue and the reaction mass was heated in the temperature range of 65°C to 70°C for about 30min. The reaction mass was then cooled in the temperature range of 25°C to 30°C and the reaction was further cooled in the temperature range of l5°C to 20 °C. Then the reaction mass was stirred followed by filtration and the product was dried to obtained title compound. The obtained title compound was characterized by

Hl NMR (400 MHz, DMSO-d6): l .0l(t,3H), l .46(s,6H), l .9l(m,4H), 2. l3(m,2H), 2.25(s,4H), 2.54(t,2H), 2.75(t,2H), 3.07(m,3H), 3.34(q,2H), 3.65(t,2H), 4.40(t,2H), 7.05(s,2H), 7. l4-7.28(m,6H), 7.51-7.57 (m,2H).

XRPD 2Q values for obtained compound are listed in the below table

TGA thermogram, showing a weight loss of about 8 weight% to about 12 weight% up to l50°C determined over the temperature range of 0°C to 250°C and heating rate lO°C/min. DSC thermogram having three endothermic peaks with peak temperatures at about 130.5±2, l95±2, and 204. l±2°C.

[0132] Example 4: Preparation of form 2 of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo [d] imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid

The toluene and methanol solvent mixture (volume ratio of toluene: methanol is 85 : 15 V/V) was added to 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoic acid p-xylene solvate and the reaction mass was refluxed for about 30min. the reaction mass was cooled to temperature in the range of 25°C to 30°C. The reaction was further cooled to temperature in the range of 5°C to 10

°C. The reaction mass was then stirred and filtered. The solid obtained was dried to obtain title compound. The obtained title compound was characterized by

IR peak values at (cm ¹): 3431, 3053, 2968, 2934, 2868, 2803, 1697, 1614, 1505, 1458, 1379, 1352, 1330, 1255, 1198, 1156, 1121, 1049, 994, 822, 767, 743, 723, 628.

XRPD 2Q values for obtained compound are listed in the below table

[0133] Example 5: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo [d] imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid p- Xylene solvate (p-xylene solvate of bilastine)

The p-xylene and methanol solvent mixture (volume ratio of p-xylene:methanol is 85: 15 V/V) was added to 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoic acid form 1 and the reaction mass was heated to temperature in the range of 65 °C to70°C for about 30min. The reaction mass was cooled to temperature in the range of 25°C to 30°C. The reaction mass was further cooled to temperature in the range of l5°C to 20°C. The reaction mass then stirred followed by filtration and drying to obtain title compound.

Hl NMR (400 MHz; DMSO-d6): l .00(t,3H), l .46(s,6H), l .9l(m,4H), 2. l3(m,2H), 2.25(s,4H), 2.54(t,2H), 2.75(t,2H), 3.07(m,3H), 3.34(q,2H), 3.65(t,2H), 4.40(t,2H),

7.05(s,2H), 7. l4-7.28(m,6H), 7.51-7.57 (m,2H)

XRPD 2Q values for obtained compound are listed in the below table

[0134] Example 6: Preparation of form 2 of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo [d] imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid

The o-xylene and methanol solvent mixture (volume ratio o-xylene: methanol is 80:20 V/V) was added to the crude 2-(4-(2-(4-(l -(2-ethoxy ethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid. The reaction mass was heated at temperature in the range of 65 °C to70°C for about 30min. The reaction mass was cooled to temperature in the range of 25°C to 30°C. The reaction mass was then further cooled to temperature in the range of 0°C to 5°C. The reaction mass was then stirred followed by filtration. The residue was dried to obtain the title compound. The obtained titled compound was characterized by

IR peak values at (cm ¹): 3444, 3052, 2968, 2934, 2869, 2802, 1703, 1613, 1505, 1458, 1379, 1352, 1328, 1254, 1198, 1155, 1121, 1048, 995, 821, 767, 742, 723,627.

XRPD 2Q values for obtained compound are listed in the below table

[0135] Example 7: Preparation of form 2 of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo [d] imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid

The m-xylene and methanol solvent mixture (volume ratio m-xylene:methanol is 80:20 V/V) was added to the crude 2-(4-(2-(4-(l -(2-ethoxy ethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid. The reaction mass was heated at temperature in the range of 65°C to 70°C for about 30min. The reaction mass was cooled at temperature in the range of 25°C to 30°C. The reaction mass was then further cooled at temperature in the range of 0°C to 5°C. The reaction mass was then stirred followed by filtration. The residue was dried to obtain the title compound. The obtained titled compound was characterized by

IR peak values at (cm ¹): 3052, 2968, 2934, 2868, 2802, 1698, 1613, 1505, 1458, 1379, 1352, 1328, 1254, 1198, 1155, 1121, 1048, 995, 821, 767, 742, 723, 627.

XRPD 2Q values for obtained compound are listed in the below table

[0136] Example 8: Preparation of Form 2 of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo [d] imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid

The ethyl benzene and methanol solvent mixture (volume ratio ethyl benzene:methanol is 80:20 V/V) was added to the crude 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid. The reaction mass was heated at temperature in the range of 65°C to 70°C for about 30min. the reaction mass was cooled at temperature in the range of 25°C to 30°C. The reaction mass was then further cooled to temperature in the range of 0°C to 5°C. The reaction mass was then stirred followed by filtration. The residue was dried to obtain the title compound. The obtained titled compound was characterized by

IR peak values at (cm ¹): 3052, 2968, 2934, 2869, 2802, 1690, 1614, 1505, 1457, 1379, 1352, 1328, 1254, 1198, 1155, 1121, 1048, 995, 821, 767, 742, 723, 627

XRPD 2Q values for obtained compound are listed in the below table

[0137] Example 9: Preparation of amorphous type of Bilastine

Bilastine was added to methanol and the reaction mass was stirred followed by heating the reaction mass at temperature in the range of 60°C to 65°C for 30 min. The reaction mass was then cooled at temperature in the range of 25°C to 30°C. The reaction mass was then stirred followed by filtration; the obtained residue was dried to get of new form of Bilastine. IR peak values at (cm ¹): 3052, 3022, 2970, 2931, 2868, 2804, 2767, 2586, 2504, 1934, 1711, 1613, 1570, 1508, 1460, 1381, 1351, 1331, 1288, 1248, 1201, 1156, 1119, 1046, 1035, 1020, 1009, 996, 944, 932, 823, 767, 746, 724, 631, 566, 534, 513, 484.

XRPD 2Q values for obtained compound are listed in the below table

[0138] Example 10: Preparation of tert-butyl 4-(lH-benzimidazol-2-yl) piperidine- 1-carboxylate compound of formula (VIII)

To a solution of 2-(Piperidin-4 yl)-lH benzimidazole in tetrahydrofuran; aqueous sodium carbonate solution and di t-butyl dicarbonate was added. The reaction mass was stirred for about 1.5 hour at about 25°C-30°C. Water was added to reaction mass and stired. The reaction mass was then filter and dried at about 45°C-50°C to get t-butyl 4-(lH- benzimidazol-2-yl) piperidine- l-carboxylate.

[0139] Example 11: Preparation of l-(2-Ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d] imidazole dihydrochloride (compound of formula VI)

To a solution of t-butyl 4-(lH-benzimidazol-2-yl) piperidine- l-carboxylate in tetrahydrofuran potassium hydroxide and 2-Ethoxyethyl p-toluene sulfonate was added. The reaction mass was heated at about 55°C-60°C for about 2-3 hours. The reaction mass was cooled to about 25°C-30°C and water was added to reaction mass. Reaction mass was extracted with ethyl acetate .The combined organic layer was washed with water, brine and dried over sodium sulphate. To the organic layer added 20-25% IPA:HCl solution and reaction mass was heated at about 60°C-65°C for about 3hours.The reaction mass was cooled to about 25°C-30°C and stired for about 12 hours. The white solid was isolated by filtration and washed with ethyl acetate. The product was dried in vacuum at about 40°C-45°C to obtain 1 -(2 -Ethoxy ethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole dihydrochloride. [0140] Example 12: Preparation of (2-(2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5- dihydrooxazole (compound of formula II)

To a solution of 1 -(2-Ethoxy ethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole dihydrochloride in methyl ethyl ketone; potassium carbonate and 2-[4-[l-(4,4-dimethyl- 5H-oxazol-2-yl)-l -methyl-ethyl] phenyl]ethyl 4-methylbenzenesulfonate was added and the reaction mass was refluxed for about 5 hours. The reaction mass was cooled and filtered; filtrate was distilled to obtain the solid n-heptane was added to the obtained soild and the reaction mass was stirred. The reaction mass was filtered to obtain the solid and the solid was then dried to obtain (2-(2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5- dihydrooxazole.

[0141] Example 13: Preparation of p-xylene solvate of bilastine

To a solution of compound of formula II as obtained in Example 12 in methanol; 25 % aqueous hydrochloric acid was added and reaction mass was refluxed for about 1-2 hours. The reaction mass was cooled to 25°C-30°C. 50% Potassium hydroxide solution was added to the reaction mass and refluxed for about 24 hours. The reaction mass was cooled to about 25°C-30°C and dichloromethane was added. The pH of reaction mass was adjusted to 7 by using hydrochloric acid; the layers were separated and aqueous layer was extracted with dichloromethane. The organic layer washed with saturated sodium chloride solution and dried over sodium sulphate and solvent was removed under reduced pressure to obtain semisolid residue. 15% methanol in p-xylene was added to the obtained semi solid and reaction mixture heated at about 65°C-70°C for about 30 minutes and then cooled to about 25°C-30°C and the reaction mass was further cooled to about l5°C-20 °C. The reaction mass was stirred for about 1.0 hour and filtered and dried to obtain p- xylene solvate of bilastine.

[0142] Example 14: Preparation of bilastine Form 2

The toluene and methanol solvent mixture (volume ratio of toluene: methanol is 85: 15 V/V) was added to bilastine p-xylene solvate obtained in Example 13 and the reaction mass was refluxed for about 30 minutes. The reaction mass was cooled to about 25°C - 30°C. The reaction mass was further cooled to about 5°C-l0°C. The reaction mass was then stirred and filtered. The solid obtained was dried to obtain title compound.

Purity >99%; compound of formula A< 0.15%; compound of formula B< 0.15%; compound of formula C< 0.15%.

[0143] Example 15: Preparation of bilastine Form 2

To a solution of compound of formula II as obtained in Example 12 in methanol; 25 % aqueous hydrochloric acid was added and reaction mass was reflux for about 1-2 hours. The reaction mass was cooled to 25°C-30°C. 50% Potassium hydroxide solution was added to the reaction mass and refluxed for about 24 hours. The reaction mass was cooled to about 25°C-30°C and dichloromethane was added. The pH of reaction mass was adjusted to 7 by using hydrochloric acid; the layers were separated and aqueous layer was extracted with dichloromethane. The organic layer washed with saturated sodium chloride solution and dried over sodium sulphate and solvent was removed under reduced pressure to obtain semisolid residue. 15% methanol in toluene was added to the obtained residue and reaction mass was heated to about 65°C-70°C for about 30 minutes. The reaction mass was cooled to about 25°C-30°C and further cooled to about 5°C-l0 °C and reaction mass was stirred for about 1.0 hour, filtered and dried under vacuum at 80-85°C to obtain bilastine form 2. HPLC Purity: 98%; compound of formula A: 0.2%; compound of formula B: 0.2%; compound of formula C: 0.2% by HPLC.

[0144] Example 16: Preparation of tert-butyl 4-(lH-benzimidazol-2-yl) piperidine- 1-carboxylate

To a stirred solution of 2-(piperidin-4 yl)-lH-benzimidazole (lOg) in methanol (85mL) was added di-tert-butyl dicarbonate (l l .05g), and the reaction mixture was stirred for about 60min at about l0°C to about l5°C. Water was added to the reaction mixture. The reaction mixture was stirred and filtered. Cyclohexane was added to the wet solid and the mixture was heated to about 65°C to about 70°C. The mixture was cooled to about 25°C to about 30°C and filtered. The solid was dried at about 45°C to about 50°C. Yield: 13.6g [0145] Example 17: Preparation of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo [d] imidazole dihydrochloride

To a stirred solution of tert-butyl 4-( l//-benzimidazol-2-yl) piperidine- l-carboxylate (lOg) in toluene (lOOmL), was added potassium hydroxide (3.72g), 2-ethoxyethyl p- toluene sulfonate (9.8g) and tetrabutyl ammonium bromide (l.07g) and the reaction mixture was heated to about 85°C to about 90°C for about 2-3 hours. The reaction mixture was cooled to about 25°C to about 30°C and water was added to it. The reaction mixture was stirred and the two layers were separated. To the organic layer was added isopropyl alcohol and 20-25% isopropyl alcohol-hydrochloric acid solution and the reaction mixture was heated to about 60°C to about 65°C for about 90min. The reaction mixture was cooled to about 25°C to about 30°C and stirred for about 4-5 hours. The solid obtained was filtered and dried in vacuum at about 45°C to about 50°C. Yield: 9.4g

[0146] Example 18: Preparation of p-xylene solvate of bilastine

To a stirred solution of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole dihydrochloride (40.4lg) in methyl ethyl ketone (400mL) added potassium carbonate (99.77g) and 2-[4-[l-(4,4-dimethyl-5H-oxazol-2-yl)-l-methyl-ethyl]phenyl]ethyl 4- methylbenzenesulfonate (50g) and the reaction mixture was refluxed for about 20 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum to obtain a solid. Methanol and 25% aqueous hydrochloric acid was added to the solid and the reaction mixture was heated to about reflux temperature for about 2 hours. The reaction mixture was cooled to about 25°C to about 30°C and aqueous 50% sodium hydroxide solution was added to it. The reaction mixture was heated to about reflux temperature for about 20 hours. The reaction mixture was cooled to about 25°C to about 30°C and dichloromethane and water were added to it. The pH of the reaction mixture was adjusted to about 7 using concentrated hydrochloric acid. The two layers were separated and the organic layer was washed with 5% sodium chloride solution and concentrated under reduced pressure. To the residue was added 20% methanol in p-xylene (500.0ml) and the reaction mixture was heated to about 65°C to about 70°C for about 30min. The reaction mixture was cooled to about 25°C to about 30°C, further cooled to about 20°C to about 25°C and stirred for about 1 hour. The solid obtained was filtered and dried under vacuum at about 60°C for about 6 hours. Yield: 43g; Purity: 99.65%

[0147] Example 19: Preparation of bilastine form 2

A stirred solution of bilastine p-xylene solvate (42g) in 15% methanol in toluene (420mL) was refluxed for about 30 min. The reaction mixture was cooled to about 25°C to about 30°C, further cooled to about 5°C to about l0°C and stirred for about 1 hour. The solid obtained was filtered and dried in vacuum tray dryer at a temperature of 55°C to about 60°C for about 6 hours. Yield: 24g; Purity: 99.82%; compound of formula A <0.1%; compound of formula B <0.1%; compound of formula C <0.1%; content of bilastine form 1 : <0.5%

[0148] Comparative Example:

A stirred solution of bilastine (3g) in below listed solvents was refluxed for about 30 min. The reaction mixture was cooled to about 25°C to about 30°C, stirred and filtered.

There was no formation of solvates with below listed solvents.

Claims

CLAIMS:

1. A process for the preparation of crystalline form 2 of bilastine, the process comprising:

a) treating p-xylene solvate of bilastine with a solvent system comprising a C6-Ci8 aromatic hydrocarbon and an alcohol to obtain a reaction mixture;

b) heating the reaction mixture obtained in step (a), followed by cooling the reaction mixture;

c) optionally stirring the reaction mixture obtained in step (b); and

d) isolating the crystalline form 2 of bilastine.

2. The process of claim 1, wherein the C6-C18 aromatic hydrocarbon is selected from the group consisting of toluene, ethyl benzene, m-xylene and o-xylene.

3. The process of claim 2, wherein the C6-C18 aromatic hydrocarbon is toluene.

4. The process of claim 1, wherein the alcohol is C1-C6 alcohol.

5. The process of claim 4, wherein the C1-C6 alcohol is selected from the group consisting of methanol, ethanol propanol, isopropanol, butanol, isobutanol and t-butanol.

6. The process of claim 5, wherein the C1-C6 alcohol is methanol.

7. The process of claim 1, wherein the volume ratio of C6-C18 aromatic hydrocarbon: alcohol in the solvent system is in the range of 95 :5 to 60:40 volume/volume.

8. The process of claim 7, wherein the volume ratio of C6-C18 aromatic hydrocarbon: alcohol in the solvent system is 85: 15 volume/volume.

9. The process of claim 8, wherein the C6-C18 aromatic hydrocarbon is toluene and the alcohol is methanol.

10. The process of claim 1, wherein in step (a), the treatment is carried out at room temperature.

11. The process of claim 1, wherein in step (b), the reaction mixture is heated at a temperature in the range of 40°C to l20°C.

12. The process of claim 1, wherein in step (b), the reaction mixture is cooled at a temperature in the range of 0°C to 30°C.

13. The process of claim 1, wherein in step (d), the isolated crystalline form 2 of bilastine is dried at a temperature in the range of 50°C to 90°C for a time period in the range of 4 hours to 15 hours.

14. The process of claim 1, wherein the level of crystalline form 1 of bilastine in the isolated crystalline form 2 of bilastine is less than 1%.

15. A p-xylene solvate of bilastine.

16. The p-xylene solvate of bilastine of claim 15, in crystalline form characterized by X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.3, 17.7, 21.1 and 24.0 ±0.2 degrees 2Q.

17. The p-xylene solvate of bilastine of claim 15, in crystalline form characterized by a TGA thermogram, showing a weight loss of about 8 weight% to about 12 weight% up to l50°C determined over the temperature range of 0°C to 250°C and heating rate l0°C/min.

18. The p-xylene solvate of bilastine of claim 15, in crystalline form characterized by DSC thermogram having three endothermic peaks with peak temperatures at about 130.5±2, l95±2, and 204. l±2°C.

19. A process for the preparation of p-xylene solvate of bilastine comprising:

a) treating bilastine with a solvent system comprising p-xylene and an alcohol to obtain a reaction mixture; and

b) isolating the p-xylene solvate of bilastine from the reaction mixture.

20. The process of claim 19, wherein in step b), the isolation of the p-xylene solvate of bilastine from the reaction mixture comprises:

a) stirring the reaction mixture; and

b) cooling the reaction mixture obtained in (a) at about 0°C to about 30°C; followed by filtration.

21. The process of claim 19, wherein the isolated p-xylene solvate of bilastine is dried at temperature in the range of 40°C to 80°C for a time period in the range of 2 hours to 12 hours.