Field of Invention

The present invention relates to an improved process for the preparation of Azelastine and its pharmaceutically acceptable salts.

Background of Invention

Azelastine is chemically known as 4-(4-chlorobenzyl)-2[(4RS)-l-methylhexahydro-lH-azepin-4-yl)]phtalazin-l(2H)-one and is represented by the following structural formula-1

formula-1

Azelastine is used in the form of its hydrochloride salt. Azelastine and therapeutically acceptable salts thereof are well known as antihistamine and mast cell stabilizer. Different synthetic strategies for the preparation of azelastine and its salts are known. For instance, US3813384 discloses certain substituted benzyl phthalazone derivatives including azelastine and its salts, methods for their preparation and pharmaceutical compositions using these compounds. Several preparation processes of azelastine are reported in this patent. In particular, example-10 relates to the preparation of azelastine in analogous manner from P-chlorobenzylacetophenone-o-carboxylic acid by its reaction with hydrazine sulfate, followed by the reaction of the compound obtained with 4-(p-chlorobenzyl)-l-(2H)-phthalazinone. However the said process is not suitable for commercial scale as the purity and yields are satisfactory.

JP07-316137 disclose the preparation of N'-(l-methylazepin-4-ylidene) acetohydrazide using dioxane as solvent. The usage of dioxane is generally not recommended in commercial level as it difficult to handle and high cost. The present inventor surprisingly found that the usage of alcohol solvent in place of dioxane provides high yields and purity. Further usage of alcoholic solvents provides more advantages like low cost, easily recoverable and easy handling compare to dioxane.

The two different crystalline forms of azelastine were disclosed in Arch.pharm. 1988, vol.321, pp.205-208. This forms obtained crystallization of mixture of ethanol/water.

Crystal growth & Design 2009, vol.9, 517-524 discloses anhydrous and hydrated crystalline forms as well as the methanol and butanone solvated forms of azelastine hydrochloride. The said journal also disclosed process for their preparations and the physical characteristics. The crystalline azelastine hydrochloride obtained as per the process disclosed in US3813384 is similar to the anhydrous crystalline azelastine hydrochloride disclosed in this journal.

The prior art processes involves number of stages, including isolation and purification of intermediates, which further increases the cost of production. Hence it is necessary to have an improved process which avoids unnecessary isolation and purification of intermediates. The main aspect of the present invention is to provide one-pot process for the preparation of azelastine hydrochloride.

Brief Summary of the invention:

In one embodiment, the present invention provides one pot process for the preparation of azelastine hydrochloride compound of formula-la starting from N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3, which comprises of reducing the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3 with a suitable reducing agent in a suitable solvent provides the N'-(l-methylazepan-4-yl)acetohydrazide compound of formula-4, which on in-situ treatment with hydrochloric acid provides the 4-hydrazinyl-l-methylazepane hydrochloride compound of formula-5, which on in-situ reaction with the 2-(2-(4-chlorophenyl)acetyl)benzoic acid compound of formula-6 in the presence of base or aqueous base in a suitable solvent, followed by treatment of the obtained azelastine with suitable hydrochloric acid in a suitable solvent provides the azelastine hydrochloride compound of formula-la.

In another embodiment, the present invention provides an improved process for the preparation of N-(l-methylazepin-4-ylidene)acetohydrazide compound of formula-3, which comprises of reacting the 1 -methylazepan-4-one hydrochloride compound of formula-2 with acetohydrazide in the presence of base in alcoholic solvents.

Brief on Drawings of the invention:

Figure-1: PXRD of azelastine hydrochloride obtained as per the present invention

Figure-2: IR spectrum of azelastine hydrochloride obtained as per the present invention

Detailed Description of Invention:

The present invention relates to an improved process for the preparation of pure azelastine hydrochloride compound of formula-la.

Formula-la

Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvents selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; ammonia or their aqueous solution.

As used herein the term "suitable reducing agent" refers to the reducing agent selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrCO3, Pd/ AhO3, Pd/MgO, Pd/CaCO3, Pd/ BaSO4, PdO, Pd Black, PdCl2, Rh/C, Ru/C, PtO2, Rh/C, RuO2, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride etc; preferably sodium borohydride.

In one embodiment, the present invention provides one-pot process for the preparation of azelastine hydrochloride compound of formula-la, which comprises of reducing the N'-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3

Formula-3

with a suitable reducing agent in a suitable solvent provides the N'-(l-methylazepan-4-yl)acetohydrazide compound of formula-4,

Formula-4

4 which on in-situ treatment with hydrochloric acid in presence or absence of solvent provides the 4-hydrazinyl-l-methylazepane hydrochloride compound of formula-5,

Formula-5

which on further in-situ reaction with the 2-(2-(4-chlorophenyl)acetyl)benzoic acid compound of formula-6

Formula-6

in the presence of base or aqueous base in a suitable solvent, followed by treating the compound formula-1 in-situ with hydrochloric acid in a suitable solvent provides the azelastine hydrochloride compound of formula-la.

Further the azelastine hydrochloride obtained above optionally purified the using a suitable solvent to provide pure azelastine hydrochloride compound of formula-la.

The suitable reducing agent used in the present invention is selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrCO3, Pd/ AI2O3, Pd/MgO, Pd/CaCO3, Pd/ BaSO4, PdO, Pd Black, PdCl2, Rh/C, Ru/C, PtO2, Rh/C, RuO2, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride etc; preferably sodium borohydride; and the suitable solvent used is selected from alcoholic solvents, chloro solvents, ether solvents, polar solvents or mixtures thereof; preferably alcoholic solvent; and the suitable base used is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates preferably sodium hydroxide or organic bases like triethylamine; and hydrochloric acid in suitable solvent is selected from alcohol or ester solvents, preferably methanolic hydrochloride.

In a preferred embodiment of the present invention, one-pot process for the preparation of azelastine hydrochloride compound of formula-la comprises of reducing the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3 with sodium borohydirde in aqueous methanol to provide the N'-(l-methylazepan-4-yl)acetohydrazide compound of formula-4, which on in-situ reaction with dilute hydrochloric acid in methanol provides the 4-hydrazinyl-l-methylazepane hydrochloride compound of formula-5, which on further in-situ reaction with the 2-(2-(4-chlorophenyl) acetyl)benzoic acid compound of formula-6 in the presence of aqueous sodium hydroxide in methanol, followed by treating the obtained compound of formula-1 with methanolic hydrochloric acid in methanol provides the azelastine hydrochloride compound of formula-1 a.

The present embodiment of the present invention schematically represented by the following scheme:

In another embodiment, the present invention provides an improved process for the preparation of N-(l-methylazepin-4-ylidene)acetohydrazide compound of formula-3,

Formula-3

which comprises of reacting the 1-methylazepan-4-one hydrochloride hydrochloride compound of formula-2

Formula-2

with acetohydrazide in the presence of base in alcoholic solvents, and optionally purifying the obtained compound in a suitable solvent provides the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3.

In a preferred embodiment, improved process for the preparation of the N-(l-methylazepin-4-ylidene)acetohydrazide compound of formula-3 comprises of reacting the l-methylazepan-4-one hydrochloride compound of formula-2 with acetohydrazide in
the presence of sodium bicarbonate in methanol at room temperature for 6 to 10 hours and purifying the obtained compound in cyclohexane provides the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3.

The azelastine hydrochloride compound of formula-la prepared as per the present invention is having purity greater than 99%, preferably 99.5% and more preferably 99.8% by HPLC.

The N-(l-methylazepin-4-ylidene)acetohydrazide compound of formula-3 prepared as per the present invention is having purity greater than 98%, preferably 99% and more preferably 99.5% by GC.

The PXRD of crystalline azelastine hydrochloride prepared by the present invention is similar to the PXRD anhydrous crystalline azelastine hydrochloride disclosed in Crystal growth & Design 2009, vol.9, 517-524.

Azelastine hydrochloride prepared as per the present invention can be further micronized or milled to get the desired particle size to meet the formulation requirements.

The following are the possible impurities which were observed in the synthesis of azelastine hydrochloride are illustrated below:

In the present invention, the above impurities are controlled to well within the limits as per ICH guidelines.

Related substances of the azelastine hydrochloride were analyzed by HPLC using the following conditions:

Column: Zorbax SB CN, 250 x 4.6 mm, 5 μm;
Flow rate: 1.0 ml/min;
Wavelength: 210 nm;
Temperature: 50°C;
Injection volume 10 μL;
Run time 50 min;
Elution: gradient; and using buffer:acetonitrile in 90:10 v/v ratio and acetonitrile:water in
90:10 v/v as mobile phases.

Buffer: 0.92 grams of potassium dihydrogen orthophosphate and 2.92 grams of 1-octane
sulfonate sodium salt monohydrate in 1000 ml of water, adjust pH to 3.0 with diluted
orthophosphoric acid. Filtered this solution through 0.45 μm Nylon membrane filter
paper and sonicate to degas it.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of N -(l-methylazepin-4-ylidene)acetohydrazide:

52.5 grams of sodium bicarbonate was added to a solution of 1 -methylazepin-4-one hydrochloride (l00gms) and methanol (1000 ml) at 25-30°C. 42.6 grams of acetohydrazide was added to the reaction mixture at 25-35°C and stirred for 8 hours. After completion of the reaction, the unwanted solid was removed by the filtration from the reaction mixture. 100 grams of silica gel was added to the filtrate and distilled off the solvent from the filtrate. Cyclohexane (200 ml) was added to the obtained residue and distilled off the solvent under vacuum below 45°C. Repeated cyclohexane distillation procedure for two to three times and then cyclohexane (2200 ml) was added to the obtained residue, heated to reflux temperature and azeotropically reflux for 4 hours. The reaction mixture was cooled to 30-40°C, the reaction mixture was filtered and silica gel was washed with cyclohexane. The filtrate was distilled off under reduce pressure at <50°C and cyclohexane was added to the obtained residue. The mixture was heated to 70°C and stirred for 1 hour at 70°C. The reaction mixture was cooled to 25-35°C and stirred for 1 hour, then further cooled to 10-15°C. The reaction mixture was stirred for 3 hours, the precipitated compound was filtered and washed with cyclohexane and dried to provide the title compound.

Yield: 68 grams,

Melting Point: 85-90°C,

Purity by GC: 99.57%.

Example-2: Preparation of Azelastine hydrochloride compound of formula-la:

10 ml methanol was added to the mixture of 100 grams of N-(l-methylazepin-4-ylidene) acetohydrazide and 350 ml of water at 25-30°C. The reaction mixture was cooled to l0-15°C and then 31 grams of sodiumborohydride was slowly added to the reaction mixture and stirred for 2 hours. The temperature of the reaction mixture was raised to 25-35°C and stirred for 30 minutes and then the reaction mixture was heated to 40-45°C, stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C and 400 ml of methanol was added to the reaction mixture. The reaction mixture was further cooled to 10-15°C and then 200 ml of hydrochloric acid was added and stirred for 1 hour at the same temperature. The temperature of the reaction mixture was raised to 25-35°C and stirred for 30 minutes. Heated the reaction mixture to 75-80°C and maintain for 8 hours at 75-80°C. The reaction mixture was cooled to 25-35°C and 100 ml of hydrochloric acid was added at the same temperature. The reaction mixture was further heated to 75-80°C and stirred for 8 hours at the same temperature. After completion of the reaction the reaction mixture was cooled to 25-35°C and then 135 gms of 2-(2-(4-chlorophenyl)acetyl)benzoic acid followed by 200 ml of methanol was added to the reaction mixture and stirred for 30 minutes at 25-30°C. The reaction mixture was cooled to 10-15°C and adjusted the reaction mixture pH to 6.5-7 using 5% Sodium hydroxide solution. The reaction mixture was stirred for 45 minutes at 10-15°C and further stirred for 60 minutes at 25-30°C. The reaction mixture was heated to 80-85°C and stirred for 17 hours at the same temperature. The reaction mixture was cooled to 25-35°C and 600 ml of dichloromethane was added to the reaction mixture and stirred for 20 minutes. The both organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane and combined the organic layers. The organic layer was washed with 5% sodiumhydroxide solution followed by water. Distilled off the solvent from the organic layer and 1000 ml of methanol was added the obtained residue at 25-30°C. Adjusted the pH of the reaction mixture to 2.0 using methanolic HC1 and stirred it for 60 minutes at 25-30°C. The reaction mixture was heated to 60-65°C and stirred for 45 minutes. 10 grams of Carbon was added to the reaction mixture at 60-65°C and stirred for 30 minutes. The reaction mixture was filtered through hiflow and washed with methanol. Distilled off the solvent from the filtrate and then 300 ml of methanol was added to the obtained residue at 25-30°C. The solution was heated to 60-65°C and stirred for 60 minutes. The reaction mixture was cooled to 25-35°C and stirred for 4 hours. The precipitated compound was filtered and washed with methanol, dried the material to provide the title compound. PXRD of the obtained compound is similar to the X-Ray diffractogram shown in figure-1.

Yield: 149 grams,

Purity by HPLC: 92.5%; Impunity-C: 0.02% (0.33 RRT); Impunity-D: 5.29% (0.86 RRT), Impunity-E: 0.01% (1.57 RRT).

Example-3: Purification of Azelastine hydrochloride compound of formula-la:

The mixture of 100 grams of crude azelastine hydrochloride and 1000 ml was heated to 60-65°C. Stirred for 45 minutes and then cooled to 0-5°C. The reaction mixture was stirred for 4 hours at 0-5 °C. The precipitated compound was filtered, washed with methanol and 900 ml of methanol was added to the wet compound at 25-30°C. The mixture was heated to 60-65°C and stirred for 45 minutes. The reaction mixture was filtered through Inflow bed and washed with methanol; the filtrate was cooled to 0-5°C. The reaction mixture was stirred for 4 hours at 0-5 °C and the precipitated compound was filtered. Washed the obtained compound with methanol and dried to get pure azelastine hydrochloride. PXRD of the obtained compound is similar to the X-Ray diffractogram shown in figure-1. IR spectrum of the obtained compound is similar to the IR-spectrum shown in figure-2.

Yield: 74 grams

Melting Point: 225-228°C

Purity by HPLC: 99.83%, unknown impurity: 0.07% (0.63 RRT)

We Claim:

1. One-pot process for the preparation of Azelastine hydrochloride compound of formula-la,

Formula-la
which comprises of reducing the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3

Formula-3
with a suitable reducing agent in the presence of suitable solvents, provides the N'-(l-methylazepan-4-yl)acetohydrazide compound of formula-4,

Formula-4
which on in-situ treatment with hydrochloric acid in presence or absence of solvent provides the 4-hydrazinyl-l-methylazepane hydrochloride compound of formula-5,

Formula-5
which on further in-situ reaction with the 2-(2-(4-chlorophenyl)acetyl)benzoic acid compound of formula-6

Formula-6
in the presence of base or aqueous base in a suitable solvent, followed treating the compound formula-1 in-situ with hydrochloric acid in a suitable solvent provides the azelastine hydrochloride compound of formula-la.

2. One pot process according to claim 1, wherein in the suitable reducing agent is sodium borohydride and the solvent used is selected from alcoholic solvent, chloro solvents, ester solvents, polar solvent, or mixtures thereof, the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethyl amine,

3. One pot process for the preparation of Azelastine hydrochloride compound of
formula-la, which comprises of reducing the N'-(l-methylazepin-4-ylidene)
acetohydrazide compound of formula-3

Formula-3
with sodium borohydride in aqueous methanol to provide the N'-(l-methylazepan-4-yl)acetohydrazide compound of formula-4,

Formula-4
which on in-situ treatment with dilute hydrochloric acid in methanol provides the 4-hydrazinyl-l-methylazepane hydrochloride compound of formula-5,

Formula-5
which on further in-situ reaction with the 2-(2-(4-chlorophenyl)acetyl)benzoic acid compound of formula-6

Formula-6 followed by treating the obtained compound of formula-1 with methanolic hydrochloric acid in methanol provides the azelastine hydrochloride compound of formula-la.

4. A process for the preparation of the N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3,

Formula-3
which comprises of reacting the l-methylazepan-4-one hydrochloride compound of formula-2

Formula-2
with acetohydrazide in the presence of suitable base in alcoholic solvents provides the compound of formula-3 and optionally purifying the compound of formula-3 using a suitable solvent provides N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3.

5. The process according to claim 4, wherein the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic baseslike triethyl amine.

6. The process according to claims 5, wherein the suitable base is alkali metal bicarbonate, preferably sodium bicarbonate.

7. The process according to claims 4, wherein the suitable solvent is methanol and the reaction is carried out at room temperature for 6 to 8 hours.

8. A process for the purification of N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3, which comprises of purifying the compound of formula-3 using hydrocarbon solvents, preferably cyclohexane.

9. A process according to claim 8, wherein obtained N-(l-methylazepin-4-ylidene) acetohydrazide compound of formula-3 is having purity greater than 99.50% by GC.

10. A process according to claims 1-3, wherein the obtained Azelastine hydrochloride is having purity greater than 99 % by HPLC, preferably 99.50% and more preferably 99.80% by HPLC.