This application claims priority to Indian patent application numbered 1253/CHE/2011 filed on Apr 11, 2011

FIELD OF THE INVENTION

The present invention is to provide an improved process for the preparation of Olopatadine or its hydrochloride salt.

The present invention also provides a process for increasing the (Z) / (E) ratio of Olopatadine or its hydrochloride.

BACK GROUND OF THE INVENTION

Olopatadine hydrochloride [(Z)-11-(3-dimethylaminopropylidene)-6, 11- dihydrodibenz [b, e] oxepin-2-acetic acid hydrochloride], of formula I
is a selective antagonist of HI receptors of histamine, which is used in the treatment of ocular symptoms typical of seasonal allergic conjunctivitis. It is also used in the symptomatic treatment of allergic rhinitis and of urticaria as well as in the treatment of eczema and dermatitis. Olopatadine hydrochloride can be administered in a solid oral pharmaceutical dosage form or as an ophthalmic solution.

Olopatadine and pharmaceutically acceptable salts thereof are described in patents EP 235796 and US 5116863. Patent US5116863 describes the production of Olopatadine hydrochloride by several different processes, two of which include a Grignard reaction for introducing the side chain in position 11 and a third process (called "Process C" in said patent) in which said side chain is introduced in position 11 by means of a Wittig reaction. In a specific embodiment (Example 9), the Wittig reaction is performed on the 6,11-dihydro-l I-oxodibenz[b,e]oxepin-2-acetic acid substrate, also known as Isoxepac, which is reacted with (3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide, in the presence of n-butyl lithium giving rise to a Z/E mixture of Olopatadine which, after purifying by means of transforming it into the methyl ester of Olopatadine and subsequent hydrolysis to provide Olopatadine.

Scheme 1
The process therefore having very low yields and being rather expensive. The Z/E isomer ratio obtained in said process is not described.

J. Med. Chem. 1992, 35, 2074-2084 also describes the process for the preparation of olopatadine Hydrochloride of formula I, which process includes the Wittig reaction of dibenz [b, e] oxepin-11-one to get the crude product. The obtained product was esterified for ease of purification. By this method the Z-isomer was preferentially obtained (E/Z=3/7, experimental section E/Z=l/2). So obtained ester is saponified without isomerization and converted into p-toluenesulfonate salt which was recrystallized from alcoholic solvent, neutralized, and treated with hydrochloric acid to furnish desired product.

Patent US7687646 describes the process for increasing the Z/E ratio of olopatadine or salt by taking diatereomeric mixture as an acid-addition salt in an n-butanol/water solvent.

The patent also describes the process for increasing the Z/E ratio of acid addition salt of olopatadine comprising the step of stirring a suspension of the diastereomeric mixture in n-

butanol containing from about 0.2% to about 4% water for an amount of time sufficient to increase tlie Z/E ratio of the mixture in suspension.

The patent further describes the process for increasing the Z/E ratio of diastereomeric mixture of olopatadine, comprising beginning with a slurry of a diatereomeric olopatadine or a salt thereof in water, adjusting the pH to about the isoelectric point of Olopatadine and maintaining the slurry for an amount of time sufficient to increase the Z/E ratio.

According to US'646 process, removal of n-butanol is very difficult and it requires drying of Olopatadine at higher temperature which leads to form other impurities. Based on prior art processes there is a need for alternate process to obtain pure olopatadine or its salts.

SUMMARY OF THE INVENTION

Main aspect of the present invention is to provide an improved process for preparation of Olopatadine or its hydrochloride salt.

One aspect of the present invention is to provide a process for increasing the (Z) / (E) ratio of Olopatadine or its hydrochloride salt, comprising the steps of;

a) suspending olopatadine salt in ketone solvent,
b) adding a base to step a),
c) filtering the obtained solid in step b),
d) adding alcohol solvent to step c),
e) adding acetic acid to get clear solution,
f) filtering the olopatadine freebase, and
g) optionally convering the Olopatadine base to its hydrochloride salt.

Another aspect of the present invention is to provide process for increasing the (Z)/(E) ratio of Olopatadine hydrochloride comprising the steps of;

a) suspending olopatadine hydrochloride in acetone solvent,
b) adding triethylamine to step a),
c) filtering the obtained solid in step b),
d) adding isopropyl alcohol solvent to step c),
e) heating the suspension to reflux temperature.
f) adding acetic acid to get clear solution,
g) cooling the solution to 20-30°C.
h) filtering the olopatadine base, and
i) optionally convering to hydrochloride salt.

The present invention for the preparation of olopatadine hydrochloride is as shown below synthetic schemes 2 and 3.

DETAILED DESCRIPTION OF THE INVENTION

Present invention is to provide an improved process for the preparation of Olopatadine or its liydrociiioride salt.

One embodiment of the present invention is to provide a process for increasing the (Z) / (E) ratio of Olopatadine or its hydrochloride salt comprising the steps of:

a) suspending olopatadine salt in ketone solvent,
b) adding a base to step a),
c) filtering the obtained solid in step b),
d) adding alcohol solvent to step c),
e) adding acetic acid to get clear solution,
f) filtering the olopatadine freebase, and
g) optionally convering the olopatadine base to its hydrochloride salt.

According to present invention, crude olopatadine hydrochloride is suspended in ketone solvent and the base is added at 10-15°C. After completion of reaction, temperature is raised to 25-35°G and maintaining the stirring at the same temperature for about 2-3 hours, the obtained solid is filtered. The obtained solid is suspended in alcohol solvent, the suspension is heated to 55-80°C and acetic acid is added at same temperature to get clear solution. Reaction mass temperature is cooled 25-35°C. The obtained solid is filtered to get pure desired cis- isomer of olopatadine free base.

According to present invention, ketone solvent is selected from acetone, methyltert-butyl ketone or methyl ethyl ketone. The base is used in the present invention is selected from trietylamine, N,N-diisopropyl ethyl amine or pyridine.

Another embodiment of the present invention is to provide process for increasing the (Z)/(E) ratio of Olopatadine hydrochloride comprising the steps of;

a) suspending crude olopatadine hydrochloride in acetone solvent,
b) adding triethylamine to step a),
c) filtering the obtained solid in step b),
d) adding isopropyl alcohol solvent to step c),
e) heating the suspension to reflux temperature.
f) adding acetic acid to get clear solution,
g) cooling the solution to 20-30°C.
h) filtering the olopatadine base, and
i) optionally convering to hydrochloride salt.

According to present invention, crude olopatadine hydrochloride is suspended in acetone solvent and triethylamine is added drop wise at 10-15°C. After completion of reaction, temperature is raised to 25-35°C and maintaining the stirring at the same temperature for about 2-3 hours, the obtained solid is filtered. The obtained solid is suspended in isopropyl alcohol, the suspension is heated to reflux temperature and acetic acid is added at same temperature to get clear solution. Reaction mass temperature is cooled 25-35°C. The obtained solid is filtered to get pure desired (Z)- isomer of olopatadine free base. The obtained pure olopatadine base is converted to its hydrochloride salt.

According to the present invention the crude olopatadine hydrochloride containing (Z)/(E) ratio is about 98.0/2.0 to 99.0/1.0,

According to the present invention, olopatadine freebase containing tiie desired cis isomer is more than 99%. The cis-trans ratio of olopatadine hydrochloride as obtained from the present process is 99.5:0.5, preferably 99.95:0.05.

The present invention is illustrated in more detail by the following examples but should not be construed to be limited thereto.

Examples:

Example 1: Preparation of 4-(2-carboxybenzyloxy) phenyl acetic acid of formula IV:
To the mixture of dimethylformamide (500ml) and 4-hydroxyphenyl acetic acid (100gm) of fomiula V, sodium hydroxide (65gm) and toluene (1000ml) was added and the reaction mass was heated to 110-115°C, water was removed azeotropicaliy by using dean-stark, to the obtained reaction mass phthalide of formula V! (114.62gm in 200ml dimethylformamide) solution was added at the same temperature followed by toluene removed simultaneously. Maintained the reaction mass at 150-155°C for about 3-4hours, after completion of reaction the mass was cooled to 85-90°C and water (3.5lit) was added. The reaction mass further cooled to 25-30°C and sodium hydroxide (92.73gm) was added, stirred for 30-45minutes. Then the aqueous reaction mass was washed with ethyl acetate (2x1.0 lit) followed by acidify with aqueous hydrochloric acid (35%, 0.5 lit) at 25-35°C and the reaction mass stirred for 1-2hours at the same temperature. The obtained solid was filtered and washed with water (1.0 lit), dried to get title compound (100gm).

Example 2: Preparation of Isoxepac of formula III.
The mixture of dichloromethane (2.0 lit), 4-(2-carboxybenzyloxy) phenyl acetic acid (100 gm) of formula IV was stirred for 15-30 minutes. To the mixture trifluoroacetic anhydride (110 gm) was added over a period of about 15-30 minutes at 25-35°C and the temperature was raised to 40-45minutes, maintained the reaction temperature for 30-45minutes at the same temperature. Boron trifluoride etherate (1.24 gm in dichloromethane 0.5lit) solution was added over a period of 10-15minutes at 40-45°C. After completion of reaction the reaction mass was cooled to 20-25°C and sodium hydroxide solution (70gm in 1000ml water) was added, stirred for 30-45minutes at 25-30°C. Separated the organic layer and washed with aqueous sodium hydroxide solution (70gm in 1000ml water), combined the both alkaline aqueous layers, then acidify with aqueous hydrochloric acid (0.5lit) to pH 1-2. Maintained the stirring fori-1.5 hours and the obtained solid was filtered. Obtained solid was taken in to methanol (0.425lit), aqueous ammonia (85ml) was added to get clear solution and the resultant solution was subjected to charcoal (10gm) treatment. To the obtained solution water {2.5lit) was added and adjusted the pH with aqueous hydrochloric acid (0.120 lit) to 2-3, mass was stirred for about 2-3 hours and filtered the obtained solid. The obtained wet solid was further purified by dissolving in ethyl acetate (O.Slit) at 55-60°C and to the resulting solution n-hexane (1.5lit) was added followed by stirred for 30-45 minutes. The obtained solid was filtered and dried the solid at 60-65°C to get title compound (83gm, 90%yield, purity 99.95%).

Example 3: Preparation of 11-(3-Dimethylaminopropyl)-11-hydroxy-6,11-dihydrobenz [b, e] oxepin -2-acetic acid of formula II.
To a stirred solution of magnesium (27.21g,1.119moles) and iodine (1.22g,0.0048mole) in tetrahydrofuran (200.0 ml.) , 10% w/w solution of 3-dimethylaminopropyl chloride (273.0g, 2.238 moles diluted with 300ml of tetrahydrofuran) was added at 25-30°C under nitrogen atmosphere. Further reaction mixture was heated for 40-45°C for 10-15.0 minutes. 1,2 dibromoethane was added slowly into reaction mixture. Remaining solution of 3-dimethyaminopropyl chloride was added slowly within 1.0 hr. the reaction mixture was refluxed for 2 hrs at 65-70°C and cooled to 25-30 °C.To the solution of 6, 11-dihydro-11-oxo-dibenz [b, e] oxepin-2-acetic acid of formula 111 (lOO.Og, 0.3731 moles) in tetrahydrofuran (500ml, 5.0 vol.),the above 3-dimethylaminopropyl magnesium chloride was added at 0-5 °C for 1.0 hr. Reaction mass temperature was raised to 25-30 °C and stirred for 15-18 hours for completion of reaction .After completion of reaction, acetic acid (150ml) followed by water (400ml) was added slowly at 10-15 °C. Reaction mixture was further stirred for 10-15 minutes to get a clear solution. To a clear solution ethyl acetate (500 ml) was added and stirred for 10-15 minutes. Aqueous layer was separated and pH of the aqueous layer was adjusted to 7 with aqueous NH3 Further, the mass was stirred for 2-3 hours. The resultant solid was filtered and washed with toluene (500ml). Product was dried at 45-50°C for 6.0 hours to get 11-(3-Dimethylaminopropyl)-11-hydroxy-6, 11-dihydrobenz [b, e] oxepin -2-acetic acid of formula II (yield 125gm, HPLC purity 98%).

Example 4: Preparation of Olopatadine hydrochloride
11-(3-Dimethylaminopropyl)-11-hydroxy-6, 11-dihydrobenz[b,e]oxepin -2-acetic acid (120.0g,0.3370moles) of formula II was taken in concentrated hydrochloric acid and water (1:1, 900ml) under nitrogen atmosphere . A clear pale yellow solution was heated at 90-95 °C for 10-15 minutes. The reaction mixture was cooled to 25-30°C and extracted with dichloromethane [(2X 1.0 liter, 2X8.3 vol.)]. Dichloromethane layer was dried over sodium sulphate and distilled at 35 - 40 °C under vacuum to get a crude olopatadine hydrochloride as a residue. Above operation of heating, cooling, extraction and distillation was repeated six times. The obtained residue was further stirred in acetone (240ml, 2.0 vol.) at 40-45°C for 30-45 minutes. The obtained solid was filtered and washed with acetone (60 ml, 0.5 vol.) to get Olopatadine hydrochloride (30. Og) HPLC chromatographic purity: 98.28 %. Z (Cis) isomer: 98.28 %, E - (trans) isomer: 1.5 %.

Example 5: preparation of Olopatadine hydrochloride
Under nitrogen atmosphere (3-(dimethylamino) propyl) triphenylphosphonium bromide hydro bromide (166.5gm) was taken in tetrahydrofuran (5.0 lit) and the mass was stirred for 5-lOminutes. The solution was cooled to 0 to -5°C. To the cooled solution, n-butyl lithium was added slowly for 30-45 minutes and stirred for 45-60 minutes. Isoxepac of formula III (25.0 gm in 125.0 ml of tetrahydrofuran) solution was added for 20-30minutes and the reaction mass was maintained at 0-5°C for 30-45minutes. The reaction mass temperature was raised to 25-30°C again maintained the reaction mass for 23-24hours at the same temperature. After completion of reaction the mass temperature was cooled to 5-10°C, the reaction mass was quenched with water and stirred for 15-30minutes, again maintained the stirring at 25-30°C for 30-45minutes. Separated the layers and organic layer was extracted with water (twice 45.0ml), combined the aqueous layers and washed with toluene (twice 45,0vol). The aqueous layer was cooled to 10-15°C and acidify with concentrated hydrochloric acid till pH 2, the acidic aqueous layer was washed with toluene (twice 45.0 vol), to the aqueous layer sodium chloride was added. Extracted the aqueous layer with dichloromethane (4times 45.0 vol), dichloromethane layer was dried with sodium sulphate (100 gm) and then distilled out the solvent completely at 35-40°C under vacuum. The obtained residue was stirred with mixture of acetone (5.0 vol), dichloromethane (1.0 vol) and isopropanol hydrogen chloride (0.5vol). Filtered the obtained solid and washed with acetone (I.Ovol), the product was dried at 45-50°C to get Olopatadine hydrochloride (Yield 50% (w/w) HPLC purity 98.5 %

Example 6: Preparation of olopatadine base from olopatadine hydrochloride.
Olapatadine hydrochloride (25.Og) was taken in acetone (125.0 ml 5.0vol.) and the obtained white suspension was cooled to 10-15°C. To the suspension triethyl amine (7.08g) was added over 15minutes. After completion of addition temperature was raised to 25-30''C.The obtained slurry was stirred at 25-30°C for 3.0 hours, the solid was filtered and washed with acetone (50 ml. 2.0 vol.), dried the compound to get Olapatadine free base (wt 21.5) HPLC chromatographic purity: 99.61 % Z/E ratio by HPLC 99.81 / 0.19

Example 7: Crystallization of Olopatadine base.
Olapatadine base (22.5 gm) was taken in isopropyl alcohol (225.5ml, 10.0 vol.) The obtained white suspension was heated at 75-80 °C for 1-2hours. To the resulting suspension acetic acid (22.5 ml) was added to get a clear solution. The clear solution was further stirred for 20-30 minutes at 75-80 °C. The mass temperature was gradually cooled to 25-30°C and stirred for 2-3 hours. The obtained solid was filtered and washed with isopropyl alcohol (45.0 ml). Product was dried at 45-50 °C for 5.0 hours to get pure Olopatadine free base (wt 17.0 gm). HPLC chromatographic purity: 99.93 %. Z/E ratio by HPLC analysis: 99.97 / 0.03

Example 8: Stage 4:- Preparation of Olopatadine Hydrochloride
Olapatadine base (16.8 g) was suspended in acetone (84.0 mi, of 5.0 vol.), The suspension was heated at 45-5G°C for 15 -30 minutes. Water (16.80 ml, 1.0 vol.) was added to get a clear solution. To a clear solution Hydrochloric acid (6.72 ml) and acetone (336.0 ml, 20.0 vol.) were added at 40-45°C, reaction mixture was gradually cooled to 25-30°C and stirred at 25-30 °C for 1 -2 hours. The mass temperature was cooled to 0-5°C, stirred for 1-1.5 hours. The obtained solid was filtered, washed with acetone (33.6 ml,2.0 vol.) and dried at 45-50 °C for 6 -7hours. (13. 5 gm) HPLC chromatographic purity: 99.98 %. Z/E ratio by HPLC analysis: - 99.99 / 0.01 %.

WE CLAIM:

1. A process for increasing the (Z) / (E) ratio of Olopatadine or its hydrochloride salt comprising the steps of:

a) suspending olopatadine salt in ketone solvent,

b) adding a base to step a),

c) filtering the obtained solid in step b),

d) adding alcohol solvent to step c),

e) adding acetic acid to get clear solution,

f) filtering the olopatadine, and

g) optionally convering the olopatadine base to its hydrochloride salt

2. The process according to claim 1, wherein the ketone solvent used in step a) is selected form acetone, methyltert-butyl ketone, methyl ethyl ketone or mixture thereof.

3. The process according to claim 1, wherein and base is used in step b) is selected from trietylamine, N,N-diisopropyl ethyl amine or pyridine.

4. The process according to claim 1, wherein the alcoholic solvent used in step d) is selected from methanol, ethanol, isopropanol, n-butanol or isobutanol.

5. The process according to claim 1, wherein acetic acid is added in step e) at about 60°C to about 80°C,

6. The process according to claim 1, wherein the filtration temperature of olopatadine in step f) is about 0°C to 30°C.

7. A process for increasing the (Z) / (E) ratio of Olopatadine hydrochloride comprising the steps of:

a) suspending crude olopatadine hydrochloride in acetone solvent,
b) adding triethylamine to step a),
c) filtering the obtained solid in step b),
d) adding isopropyl alcohol solvent to step c),
e) heating the suspension to reflux temperature.
f) adding acetic acid to get clear solution.
g) cooling the solution to 20-30°C.
h) filtering the olopatadine base, and
i) optionally convering to hydrochloride salt.

8. The process according to claim 1 and 7, wherein Olapatadine or Olapatadine hydrochloride having Z-isomer more than 99.95.

9. The process according to claim 1 and 7, wherein Olopatadine or Olopatadine hydrochloride having the purity is not less than 99%.