Claims:1. A process for the preparation of isomerically pure Z-isomer of olopatadine or salt thereof, comprising the step of:
a) reacting alkyl ester of methyl 2-(11-oxo-6H-benzo[c][1] benzoxepin-2-yl) acetic acid of formula (III)

with dimethyl amine propyl magnesium halide of formula (IV)

at a temperature between -35 to -55°C in a suitable solvent to form compound of formula (II)
;
and
b) converting compound of formula (II) to olopatadine or salt thereof,
wherein R is selected (1-4C alkyl) and X is Cl, Br, or I.
2. The process as claimed in claim 1, wherein the solvent used in stage a) is selected from the group consisting of toluene, THF and mixture thereof.
3. The process as claimed in claim 1, wherein stage a) is carried out at a temperature between -40 to -45°C.
4. The process as claimed in claim 1, wherein in stage b) is carried out in presence of an acid selected from the group consisting of sulfuric acid and hydrochloric acid.
5. The process as claimed in claim 4, wherein the reaction is carried out in the presence of a solvent selected the group consisting of xylene and toluene.
6. The process as claimed in claim 4 and 5, wherein the reaction is carried out in the presence of hydrochloric acid and in toluene as a solvent.
7. The process as claimed in claim 1, wherein the reaction is carried out at a temperature between 80-120°C.
8. The process as claimed in claim 7, wherein the reaction is carried out at a temperature between 95-110°C.
9. The process as claimed in claim 1, wherein in stage b), water is removed azeotropically.
10. The process as claimed in claim 9, wherein the reaction mixture is heated at a temperature between 95-110°C for at least 24 hours for isomerization.
11. The process as claimed in claim 10, wherein in after isomerization, acetone is added and the reaction mixture is heated at a temperature between 55-60°C for at least 1 hour.
12. The process as claimed in claim 11, wherein the mixture is cooled to temperature between 25-30°C and stirred for at least on hour.
13. The process as claimed in claim 1, wherein the olopatadine is at least 99% isomerically pure Z-isomer.
14. Olopatadine or salt thereof having Z/E isomer ratio of about 99:1.
15. Olopatadine or salt thereof having enriched Z-isomer as obtained from the process as claimed in claim 1.
, Description:Field of the Invention
The present invention generally relates to the field of process chemistry, and more particularly relates to an improved process for the preparation of isomerically pure Z-isomer of olopatadine and salts thereof.

Background of the Invention
Olopatadine, structurally represented as

is an dibenzo[b,e]oxepin-2-yl}acetic acid derivative, approved for the treatment of allergic conjunctivitis and allergic rhinitis. Chemically referred as {(11Z)-11- [3- (dimethylamino) propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid, Olopatadine was first reported and disclosed in the US Patent No. 5,116,863 along with the process for preparing the same.

There are two processes reported in the literature for olopatadine, one involving Witting reaction and the other is Grignard reaction followed by dehydration step. However, none of these processes yields enriched Z-isomer of olopatadine, which is substantially free of E-isomer.

It would be desirable to provide process for preparing olopatadine, which contains more of a Z-isomer than an E-isomer.

Summary of the Invention
The present invention provides a process for the preparation of enriched Z-isomer of olopatadine. The present invention further provides a process for preparing isomerically pure Z-isomer of olopatadine comprising steps of: (a) reacting alkyl ester of 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl) acetic acid of formula (III) with dimethyl amino propyl magnesium chloride of formula (IV) at -35 to -55°C in a suitable solvent to form alkyl ester of 2-[11- [3-(dimethylamino) propyl]-11-hydroxy -6H-benzo[c][1]benzoxepin-2-yl]acetic acid of formula (II);

and (b) converting compound of formula (II) to Olopatadine or salt thereof.

Detailed Description of the Invention
In one embodiment, the present invention provides a process for the preparation of isomerically pure Z-isomer of olopatadine and salt thereof comprising,
a) reacting alkyl ester of methyl 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl) acetic acid of formula (III) with dimethyl amino propyl magnesium chloride of formula (IV) at -35 to -55°C in a suitable solvent to form compound of formula (II); and

b) converting compound of formula (II) to olopatadine or salt thereof,
wherein R is selected from (1-4C alkyl) and X is Cl, Br, or I,
wherein stage (a) of the embodiment is carried out in a solvent selected from toluene, THF (tetrahydro furan) and mixture thereof.
The reaction is carried out at -35 to -55°C, preferably at -40 to -45°C. The inventors of the present invention have carried out the reaction at various temperatures.
Table 1
Reaction Temperature Product Reactant Assay Conclusion
-60 to -50 7.54% 90.49% 4.41 Reaction at this temp is very slow. Could not go for completion.
-50 to -40 98.92 ND 99.93 Reaction at this temp is very fast. Complete within 15mins.
-50 to -40 98.94 ND 99.69 Reaction at this temp is very fast. Complete within 15mins
-50 to -40 99.69 ND 99.81 Reaction at this temp is very fast. Complete within 15mins.
-20 to -10 95.84 0.55 96.83 Reaction at this temp is very fast. Complete within 15 mins. But the HPLC purity/assay of the product has decreased.
-10 to -0 95.74 0.6 92.85 Reaction at this temp is very fast. Complete within 15mins. But HPLC purity/assay of the product has decreased.
25 to 30 50.46 46.95 46.77 Reaction stopped midway and did not go beyond 50%.

From the conclusions provided in the above table, it is clear that the conversion is complete at -40 to -50°C and the assay shows that purity is also more at this temperature range.

The Grignard reagent of formula (IV) can be outsourced or can be prepared in house by processes reported in the art.

Magnesium metal is heated to 75-80°C to dry the metal thoroughly. To this heated metal THF is added and the mixture is maintained at 75-80°C.

Dimethylaminopropyl halide hydrochloride salt is added to sodium hydroxide solution at 0-5°C after complete addition and the mass is stirred for 15 minutes at 0-5°C. The base is isolated in a suitable organic solvent and the layer is separated. The organic layer is thoroughly dried. A part of this organic layer is added to the previously heated magnesium metal in THF. The mixture is heated to 60-80°C and catalytic iodine and ethylene dibromide are added. The mixture was stirred for 20-30 minutes. After initiation of the reaction, the remaining part of the organic layer is added gradually over 2-3 hours at 75-80°C. After completion of reaction the mixture is maintained for 2 hours at 75-80°C and gradually cooled to room temperature. THF is added to this Grignard reagent, N,N-dimethylamino propyl magnesium halide at room temperature and chilled to -40 to -45°C. The Grignard reagent thus prepared can be used in stage (a) to form compound of formula (II).

The stage (b) is carried out by heating compound (II) in a solvent in presence of as acid. The acid is selected from hydrochloric acid and sulfuric acid, preferably hydrochloric acid. The hydrochloric acid used is in aqueous or gaseous form.

The solvent used in stage (b) is organic solvent or mixture of organic solvent and water.

The organic solvent is preferably aromatic hydrocarbon. Aromatic hydrocarbon is selected from toluene and xylene, preferably toluene.

The reaction is preferably carried out at 80-120°C, preferably at 95-105°C. The dehydration and de-esterification is carried out simultaneously and isomerization from E-isomer to Z-isomer of compound (I) proceeds.

The reaction proceeds in presence of an acid and water is azeotropically removed by distillation for acceleration of isomerization after heating.

After removal of water by azeotropic distillation the Z:E ratio is around 22:88. The mixture is heated to 95-100°C for about 24 hours. The ratio of E:Z isomer achieved is around 85:15.

To the residue obtained acetone is added and stirred for around 1 hour at 55-60° C. The mixture is cooled to 25-30°C and stirred for 1 hour at 25-30°C. The Z:E ratio obtained at this stage is around 99:1.

Thus, olopatadine hydrochloride obtained by the process of the present invention is with Z:E ratio of about 99:1. The ratio of Z:E isomer obtained by the process of the present invention is 99-99.5:1-0.5.

Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention.

Example 1
Preparation of methyl 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl)acetate
2-(11-Oxo-6H-benzo[c][1]benzoxepin-2-yl) acetic acid (150 gm) was charged to methanol (1500 ml) at 25-30°C under inert atmosphere. The mixture was stirred for 10 minutes. Thionyl chloride (50 ml) was charged drop wise to the mixture in 2-3 hours. Exotherm was observed and drop wise addition of thionyl chloride was continued. The mass was heated to 50-55°C and maintained 50-55°C for 1 hour. Methanol was distilled at 50-55°C under vacuum completely. The mass was cooled at 25-32°C.
MDC (900 ml) was charged to the mass and stirred for 15 minutes. MDC layer was extracted with water (750 ml). The layers were separated and MDC layer was extracted with 5% NaHCO3 (750 ml x 2). The layers were separated and MDC layer was washed with water (200ml x 2). MDC layer was dried and distilled out under vacuum below 32-35°C to get an oil.

DIPE (200 ml) was added to the oil obtained and distilled out completely under vacuum below 32-35°C to get white solid. DIPE (200 ml) was charged and suspension was stirred for 15 minutes. The solution was filtered, dried by suction and further dried under vacuum at 50-55°C.
Yield: 143gm (90.50%)
HPLC Purity: 99.95%

Example 2
Preparation of methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H- benzo[c][1] benzoxepin-2-yl]acetate
a) Preparation of dimethylamino propyl chloride base
Dimethylamino propyl chloride hydrochloride salt (298.66 gm) was cooled to 0-5°C under inert atmosphere and 33% sodium hydroxide solution (210 ml) was charged gradually for half hour. The temperature of the mixture was maintained at 0-5°C. The mass was stirred for 15 minutes at 0-5°C and then the temperature was raised gradually to room temperature.

The organic layer was separated. Aqueous layer was extracted twice with 350ml of toluene & mixed with organic layer. Dried organic layer with sodium hydroxide pellets (11.5 gm) & then with anhydrous calcium chloride (11.5 gm) for next step.

b) Preparation of Grignard reagent (dimethylamino propyl magnesium chloride)
Magnesium metal (33 gm) was heated to 70-75°C for 30 minutes and THF (350 ml) was charged at 70°C. One fourth part of the organic layer of dimethyl amino propyl chloride base in toluene obtained in step a) was charged and maintained at 70-75°C for 10 minutes. Ethylene dibromide (2.5 ml) in THF (5 ml) was charged drop wise at 70°C. Iodine granules (2 mg) were charged to the mass at 70°C and maintained at 73-75°C for 20-30 minutes till the reaction initiates.

After initiation of the reaction, the remaining part of the organic layer was added drop wise at 73-75°C and the mass was maintained for 2 hours.

After completion of the reaction the mass was cooled at room temperature. THF (350 ml) was charged and the reaction was cooled at -40 to -45°C. This was utilized directly in step c).

c) Preparation of methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H-benzo[c] [1] benzoxepin-2-yl]acetate
Methyl 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl)acetate (140 gm) obtained in example 1 was charged to THF (700 ml) in an inert atmosphere. This solution was charged to the Grignard solution obtained in stage b) at -45 to -40° within 15 minutes. During complete addition, the temperature of the reaction mass was maintained below -40°C. After completion of the reaction, 10% acetic acid was charged to the mass. After complete addition, the mass was maintained for 15 minutes at -10°C. Addition of liquor ammonia (160 ml) was started at -10°C and maintained for 30 min. The mass was heated to room temperature and the organic layer was separated and washed with water (780 ml) and 20% brine solution (980 ml).

The organic layer was dried thoroughly and further distilled out under vacuum below 45°C to yield white solid.

DIPE (1620 ml) was charged to the white solid at room temperature and stirred. The mixture was heated to 65-70°C and stirred for 30 minutes. The clear solution obtained was filtered under vacuum. The hot filtrate was charged to a flask previously heated to 65-70°C, followed by addition of methanol (48.6 ml). The mixture was stirred and cooled to RT and solid material falls out at 35-40°C. The mass was chilled to 0-5°C and maintained at this temperature for 2 hours. The mass was filtered and washed with chilled DIPE (140 ml). The material was suck dried and further dried under vacuum for 12 hours at 35-40°C to obtain methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H- benzo[c][1]benzoxepin-2-yl]acetate (143 gm).
Yield: 135 gm (73.67%)
HPLC Purity: 97.28%

Example 3
Preparation of methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H- benzo[c][1] benzoxepin-2-yl]acetate
a) Preparation of dimethylamino propyl chloride base
Dimethylamino propyl chloride hydrochloride salt (54.34 kg) was cooled to 0-5°C under inert atmosphere and 33% sodium hydroxide solution (38.20 lit) was charged gradually for half an hour. The temperature of the mixture was maintained at 0-5°C. The mass was stirred for 15 minutes at 0-5°C and then the temperature was raised gradually to room temperature.

The organic layer was separated. Aqueous layer was extracted twice with 142 lit of toluene & mixed with organic layer. Dried organic layer with sodium hydroxide pellets (2.32 kg) & then with anhydrous sodium sulphate (2.32 kg) for next step.

b) Preparation of Grignard reagent (dimethylamino propyl magnesium chloride)
Magnesium metal (6.65 kg) was heated to 70-75°C for 30 minutes and THF (71 lit) was charged at 70°C. One fourth part of the toluene organic layer of dimethyl amino propyl chloride base obtained in step a) was charged and maintained at 70-75°C for 10 minutes. Ethylene dibromide (0.5 lit) in THF (1 lit) was added gradually at 70°C. Iodine granules (0.01 kg) were charged to the mass at 70°C and maintained at 73-75°C for 20-30 minutes till the reaction initiates.

After initiation of the reaction, the remaining part of the organic layer was added gradually at 73-75°C and the mass was maintained for 2 hours.

After completion of the reaction the mass was cooled at room temperature. THF (71 lit) was charged and the reaction was cooled at -40 to -45°C. This was utilized directly in step c).

c) Preparation of methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H- benzo[c][1]benzoxepin-2-yl]acetate
Methyl 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl)acetate (28.30kg) obtained in example 1 was charged to THF (141 lit) in an inert atmosphere. This solution was charged to the Grignard solution obtained in stage b) at -45 to -40° within 15 minutes. During complete addition, the temperature of the reaction mass was maintained below -40°C. After completion of the reaction, 10% acetic acid was charged to the mass. After complete addition, the mass was maintained for 15 minutes at -10°C. Addition of liquor ammonia (32.30 lit) was started at -10°C and maintained for 30 min. The mass was heated to room temperature and the organic layer was separated and washed with water (158 lit) and 20% brine solution (198 lit).

The organic layer was dried thoroughly and further distilled out under vacuum below 45°C to yield white solid.

DIPE (328 lit) was charged to the white solid at room temperature and stirred. The mixture was heated to 65-70°C and stirred for 30 minutes. The clear solution obtained was filtered under vacuum. The hot filtrate was charged to a flask previously heated to 65-70°C, followed by addition of methanol (9.82 lit). The mixture was stirred and cooled to RT and solid material falls out at 35-40°C. The mass was chilled to 0-5°C and maintained at this temperature for 2 hours. The mass was filtered and washed with chilled DIPE (28.3 lit). The material was suck dried and further dried under vacuum for 12 hours at 35-40°C to obtain methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6H- benzo[c][1]benzoxepin-2-yl]acetate (143 gms).
Yield: 28.70 (77.52%)
HPLC Purity: 98.92%

Example 4
Preparation of crude Olopatadine hydrochloride
Charge toluene (1000 ml) to methyl 2-[11-[3-(dimethylamino)propyl]-11-hydroxy- 6H-benzo[c][1] benzoxepin-2-yl]acetate obtained in example 2 (100 gm) at room temperature and the mixture was stirred to obtain clear yellow solution. The solution was maintained for 15 min at RT.

35-37% conc. HCl (30 ml) was charged to the solution and the mixture was maintained for 15 minutes. The mixture was heated to 95°C and around 10 ml of water was removed azeotropically to obtain a white to off white sticky solid.

The mass was maintained at 95°C ± 3°C for 24 hours. The mass was cooled to 65-70°C.

Acetone (100 ml) was charged and the mass was stirred at 65-70°C for 1 hr. The reaction mass was cooled to 25-30°C & maintain at 25-30°C for 1 hr.

The mass was suction filtered and washed with chilled acetone (200ml) & suck dried well for half an hour. Off white amorphous solid obtained was charged to acetone (500 ml). The mass was stirred & heated at 55-57°C and maintained for 1 hr.

The reaction mass was cooled to 25-30°C & maintained at 25-30°C for 2 hrs.

The reaction mass was suction filtered & washed with chilled acetone (200 ml) and sucked dry well.

Off white solid obtained was dried at 50-55°C for 10 hrs. to obtain Olopatadine hydrochloride (Dry wt. = 90 gm) with LOD NMT 0.5%.

HPLC purity: Olopatadine hydrochloride 99.07%, Olopatadine E-isomer 0.23%
Yield: 82.22%

Example 5
Preparation of pure Olopatadine hydrochloride
Charge acetone (1485 ml) to crude Olopatadine hydrochloride obtained in example 3 (90 gm) at room temperature and the mixture maintained for 15 min at RT.

The mixture was heated to 65-70°C and added DM water 108ml dropwise. Reaction mass becomes clear. More water is added if reaction mass does not become clear.

The reaction was maintained at 65-70°C for 20min. Charged activated charcoal 9gm and maintained for 1hr. Filtered hot at suction on a hyflo bed, washed with hot acetone 270ml & sucked dry well for half an hour. Filtrate was heated to 65-70°C & added acetone 630ml dropwise. Cooled to 25-30°C. A white colored solid obtained was chilled to 0-5°C, filtered at suction, washed with chilled acetone 135ml & sucked dry well.

White crystalline solid obtained was dried at 55-60°C for 12 hrs to obtain Olopatadine hydrochloride (Dry wt. = 68 gm) with LOD NMT 0.3%.
HPLC purity: Olopatadine hydrochloride 99.87%, Olopatadine E-isomer 0.04%,
Yield: 68gm