FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process for preparation of Olopatadine Hydrochloride"
2. APPLICANT (S)
(a) NAME. Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur Pharmaceuticals Pvt. Ltd.
Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. Tel No. 91-22-66499144 Fax No. 91-22-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Process for preparation of Olopatadine Hydrochloride
Field of Invention:
The present invention mainly relates to an efficient process for preparation of {(11Z)-11-[3-
(Dimethylamino)propylidene]-6,ll-dihydrodibenzo[d,e]oxepin-2-yl}aceticacid
hydrochloride (Olopatadine hydrochloride), further this invention extends to the formation
of acid addition salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate, to avoid numerous by product, which further extend to hydrolysis of Methyl-2-[(l lZ-(3-DimethylaminopropyIidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, to selectively obtained Z-isomer of Olopatdine hydrochloride.
Background of Invention:
Olopatadine hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for the treatment of the signs and symptoms of allergic conjunctivitis. Olopatadine hydrochloride is the generic international denomination (DCI) for {(11Z)-11-[3-(Dimethylamino)propylidene]-6,l l-dihydrodibenzo[6,e]oxepin-2-yl}acetic acid

hydrochloride, (herein after referred as Olopatadine hydrochloride) represented by Formula I, below:

Formula-I I
Olopatadine hydrochloride is a known anti-allergy drug. In the United States, it is marketed under the name Patanol® and, in Europe it is marketed under the name Opatanol®. It has been approved for the treatment of the signs and symptoms of allergic conjunctivitis.US 5,1 16,863 describe preparation of Olopatadine hydrochloride by three different processes. In two of the process the side chain is introduced by "Grignard reaction" and in another, it is introduced using "Wittig reaction".
Process A:
6,1 1-dihydro-l 1 -oxodibenz[b,e]oxepin-2-acetic acid (II) is converted to its corresponding N-(l,l-dimethyl-2-hydroxyethyl)-l 1 -oxo-6, 1 l-dihydroxdibenz[b,e] oxepin-2-acetamide
(III) which is cyclised to obtain 2-(methyl(4,4-dimethyl-2-oxazoline-2yl))-l l-oxo-6,11-dihydrodibenz[b,e]oxepin (IV) (Scheme 1). Grignard reaction of oxazoline derivative
(IV) gave 1 l-(3-dimethylaminopropyl)-l l-hydroxy-2-(mefhyl(4,4-dimethyl-2-oxazoline-2yl))-6,l l-dihydrodibenz[b,e]oxepin (V), which is simultaneously dehydrated and

deprotected and then esterified to get ethyl 1 l-(3-dimethylaminopropylidine)-6,l 1-dihydrodibenz[b,e]oxepin-2-acetate (VI). Hydrolysis of the compound (VI) gave the corresponding Olopatadine hydrochloride (I).

The above process is a lengthy route involving protection and deprotection reactions. The steps leading to formation of amide (III) as well as oxazoline (IV) provides undesirable side products. Hence these steps require purification and thus result in reduced yields. Cis trans ratio of the dehydrated product (VI) is also not reported. Purity and overall yield of product (I) is not mentioned. On following the above process the obtained cis: trans ratio was 10-15:90-85.
Process B:
Methyl 1 l-oxo-6,1 l-dihydrodibenz[b,e] oxepin-2-acetate (VII) is reduced by lithium aluminum hydride to get 1 l-hydroxy-2(2-hydroxyethyl)-6,l 1 -dihydrodibenz[b,e] oxepin (VIII) (Scheme 2) which is then protected with trityl group to obtain 1 1 -hydroxy-2-(2-triphenylmethyloxy ethyl)-6,1 l-dihydrodibenz[b,e] oxepin (IX) which is oxidized to obtain 1 1 -oxo-2-(2-triphenylmethyloxyethyl)-6, 1 1 -dihydrodibenz[b,e]oxepin (X). Grignard reaction on (X) gave 1 l-(3-dimethylaminopropyl)-l 1 -hydroxy-2-(2-triphenylmethyloxy

ethyl)-6, 1 1 -dihydrodibenz[b,e]oxepin (XI), which is dehydrated to get 11 -(3-dimethylaminopropylidene)-2-(2-tripheny Imethy loxyethyI)-6, 1 1 -dihydrodibenz[b,e] oxepin (XH). The compound (XII) is deprotected to obtain 1 1 -(3-dimethylamino propylidene)-2-(2-hydroxyethyl)-6,l l-dihydrodibenz[b,e]oxepin (Xni). Oxidation of (XIII) gave the corresponding Olopatadine hydrochloride (I).

The process as disclosed above involves a lengthy synthesis requiring protection and deprotection reactions. It employs hazardous reagents like lithium aluminum hydride and Jones reagent, which pose safety and disposal problems. Purification of the final product and intermediates require column chromatography, which makes the process tedious and time consuming and also increase the solvent requirement of the process. The purity and yield of the product is not mentioned. The cis-trans ratio of the product is also not reported.

Process C:
(II) n-butyl lithium
The Wittig reaction of 1 l-oxo-6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid (II) with (3-dimethy]aminopropyl)-triphenylphosphonium bromide hydrobromide provided methyl 1 1 -(3-dimethylaminopropylidine)-6, 1 1 -dihydrodibenz[b,e]oxepin-2-acetate (XIV). Hydrolysis of (XIV) provided Olopatadine hydrochloride (I). Scheme 3


Scheme- 3
The above process involves use of excess Wittig reagent (5 mole eq) and the n-butyl lithium employed is hazardous and causes safety problems. The process is very tedious and uneconomical. The cis trans ratio of the product is not reported. However, on following the
above process, the product results in very poor yield.

The preparations of olopatadine are also described in Ohshima, E., et al., J Med. Chem.
1992,35,2074-2084.
65% Ph3CCI
81% CIMgCH2CH2CH2NMe2

Scheme 4
Scheme 4:




Scheme 5:
A significant disadvantage of the synthetic route depicted in Scheme 4 is the diastereoselectivity of the dehydration step, which gives up to 90% of the undesired E-isomer. The last step (oxidation) is not described in this publication. Scheme 5 below depicts a prior art method disclosed in Ohshima, E., et al., supra.

Each of the prior art methods for synthesis of olopatadine have significant cost and feasibility disadvantages. Specifically with the respect to the method set forth in Scheme 5, the disadvantages include:
(1) the need for excess reagents, e.g. 4.9 equivalents Wittig reagent and 7.6 equivalents of BuLi as the base for the Wittig reaction, which can be expensive;
(2) the need to use Wittig reagent in its hydrobromide salt form, so that additional amounts of the expensive and dangerous butyl lithium reagent are necessary for the "neutralization" of the salt (i.e., excess butyllithium is required because of the neutralization);
(3) because 7.6 equivalents of the butlylithium are used (compared to 9.8 equivalents of the (Olo-IM4) Wittig reagent), the Wittig reagent is not converted completely to the reactive ylide form, and thus more than 2 equivalents of the Wittig reagent are wasted;
(4) the need for an additional esterification reaction after the Wittig reaction (presumably to facilitate isolation of the product from the reaction mixture) and the purification of the resulting oil by chromatography;
(5) the need to saponify the ester and to desalinate the reaction product (a diastereomeric mixture) with ion exchange resin, prior to separating the diastereomers;

(6) the need, after the separation of the diastereomers, and liberation of the desired diastereomer from its corresponding pTsOH salt, to desalinate the product (olopatadine) again with ion exchange resin;
(7) the formation of olopatadine hydrochloride from olopatadine is carried out using 8 N HC1 in 2-propanol, which may esterify olopatadine and give rise to additional impurities and/or loss of olopatadine; and
(8) the overall yield of the olopatadine, including the separation of the diastereomers, is only approximately 24%, and the volume yield is less than 1%.
Application WO 2006/010459 describes obtaining Olopatadine hydrochloride by means of a process in which a Wittig reaction is also performed but, this time, on an open substrate with final cyclization to form oxepin by means of Pd catalyst as can be seen in reaction
[R is an acid protecting group, especially C1-C4 alkyl]
Scheme 2.


The process shown in reaction scheme 2 has several drawbacks: high number of synthesis steps, the use of palladium catalysts which increase the cost of the process, the obtained Z/E isomer ratio is only 2.5:1 in favor of the Z isomer, and, finally, the need of using ionic exchange resins and chromatography columns, together with the use of dangerous reagents such as lithium aluminium hydride, n-butyl lithium or Jones reagent, make the process unfeasible on an industrial scale.
It would be desirable to provide processes for preparing olopatadine on a large scale, e.g., on a commercial scale, in a manner that is cost efficient and provides olopatadine that has a low level of impurities, including a low level of the undesired diastereomer. It further would be desirable to eliminate the need to derivatize the olopatadine product of the Wittig reaction, e.g., by esterification, in order to separate the olopatadine from the reaction mixture. It would be especially desirable to provide a method for preparing olopatadine that allows for isolation of olopatadine directly from the reaction mixture. It would also be desirable to provide improved methods for preparing chemical intermediates used in the synthesis of olopatadine .
The invention takes on the problem of providing an alternative and efficient process for obtaining Olopatadine and salts thereof, which overcomes all or part of the problems existent in the different syntheses of Olopatadine and salts thereof, in particular, of the previously mentioned syntheses which involve performing a Wittig reaction, isolation by column chromatography etc. in relation to the state of the art. The solution provided by the invention is based on the fact that the inventors have observed that it is surprisingly

possible to efficiently obtain {(11Z)-ll-[3-(dimethylamino)propylidene]-6,ll-
dihydrodibenzo[b,e]oxepin-2-yl}acetic acid (Olopatadine) and salts thereof by means of a
process comprising depicted in reaction scheme, reacting Methyl-2-[(llZ-(3-
mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (I) with dimethyiamine
followed by organic acid addition salt to form acid addition salt of Methyl-2-[(llZ-(3-
Dimemylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (MDA oxalate II)
which preamble to eliminate numerous byproduct & basify using base to obtain Methyl-2-
[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (pure).
Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (pure) is then hydrolyzed in inorganic acid & stirred in water immiscible solvent to form selectively Z isomer of Olopatadine Hydrochloride which further crystallized in mixture of water and water miscible ketone solvent to obtain Z isomer of Olopatadine hydrochloride in purity 99.8% and E isomer less than 0.1% in order to complies the regulatory requirement for product.


Summery of Invention:
The present invention comprises the process for the preparation of {(HZ)-ll-[3-(Dimethylamino)propylidene]-6,11 -dihydrodibenzo[b,e]oxepiiv2-yl }acetic acid hydrochloride (Olopatadine hydrochloride), by reacting Methyl-2-[(llZ-(3-mesyloxypropylidene)-6H-benzo[c] [2] benzoxepin-2-yl]acetate, with dimethylamine followed by organic acid salt to form acid addition salt of Methyl-2-[(HZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, the formation of acid addition salt, which is one of the key step of this invention to avoid the undesired side

product formed during the reaction, further basify to obtain Methyl~2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c] [2]benzoxepin-2-yl]acetate (pure).
Hydrolyzing the Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate, by treating with inorganic acid to obtain selectively Z isomer of olopatadine hydrochloride by eliminating E isomer of olopatadine hydrochloride. And treated with water, optionally with water miscible solvent at reflux temperature to obtain with a desired purity of Z-isomer of olopatadine hydrochloride, which further crystallizes with water and water miscible ketone solvent to prepare purely Z isomer of olopatdine hydrochloride in purity 99.8% and E isomer less than 0.1% in order to comply the regulatory requirement for product.
Object of Invention:
An object of the invention is to provide the efficient process for preparation of olopatadine hydrochloride.
Another object of the said invention is to provide the novel intermediate and novel intermediate acid addition salt as well to avoid the undesired side product which concomitantly exerts the economical process.

Furthermore object of the said invention is to provide selective preparation of Z isomer of olopatdine hydrochloride in highly pure form by hydrolysis of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate.
Detail Description of the Invention:
In one aspect, process of the invention concerns towards the process for preparation of Olopatdine hydrochloride comprising:
a) reacting, Methyl-2-[(l lZ-(3-mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yljacetate (herein after referred as "Methane sulphonate ester"), with dimethylamine and quaternary ammonium salt as phase transfer catalyst at temperature 0 - 100 °C to obtain MethyI-2-[(ll-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl] acetate;
b) extracting, the Methyl-2-[(HZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, with water immiscible solvent and concentrate about to dry to get the solid of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate;
c) treating, Methyl-2-[(HZ-(3-Dimethylaminopropylidene)-6H benzo[c][2]benzoxepin-2-yl]acetate, with organic acid in C1-C4 alcohols as a solvent media to obtain acid addition salt of Methyl-2-[(llZ-(3-

Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (herein after refereed as "DMA oxalate"), for circumvent the side products or impurities form during the reaction period in step (b); and
d) Methyl-2-('(llZ-(3-DimethyIaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate Oxalate, treated with aqueous solution of base and extracted with water immiscible solvent and concentrate about to dry to form purified Methyl 2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate(herein after refereed as "MDAB acetate");
e) hydrolyzing, the Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, in aqueous inorganic acid about to temperature 0 - 80 °C up to the completion of hydrolysis to obtain selectively the Z isomer of {(11Z)-1 l-[3-(dimethylamino)propylidene]-6,ll-dihydrodibenzo[b,g]oxepin-2-yl}acetic acid hydrochloride (Olopatadine hydrochloride); and
f) refluxing, the solution or mixture of step e) with water immiscible solvent and
cooled about to 0-50 °C to form solid of {(11Z)-1l-[3-
(dimethylamino)propylidene]-6,ll-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid hydrochloride (Olopatadine hydrochloride), which further treated with ketone solvent at reflux temperature to selectively form Z- isomer of olopatadine hydrochloride;

f) crystallizing the olopatadine hydrochloride in a mixture of ketone solvent and water in ratio of 10:1 to 1:10 to obtain purely Z isomer of olopatadine hydrochloride by eliminating remaining E-isomer in order to comply the regulatory requirement for product.
The synthetic pathway of olopatadine hydrochloride has been depicted in scheme-I as below:

Scheme -I
The said description has been set forth with respect to comprehensive synthesis and purification of olopatadine hydrochloride with beginning from the Methyl-2-[(llZ-(3-

mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yI]acetate (methane sulphonate ester (I)) as protected carboxylic acid treated with dimethylamine to obtain Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate and concomitantly the formation of acid addition salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate as a key step of the invention in order to eliminated the undesired side product, and further hydrolysis to ensure the selectively purports the Z isomer of the olopatadine hydrochloride. The description for the same has been depicted in details below.
From said synthetic route, Methyl-2-[(llZ-(3-mesyloxypropylidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate (methane sulphonate ester (I)) with dimethylamine
and selected quaternary ammonium salt as a phase transfer catalyst selected from
benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide,
tetrabutylammonium bromide, methyltrioctylammonium chloride but preferably
tetrabutylammonium bromide at temperature 0-100 °C but more preferably at ambient
temperature to obtain Methyl-2-[(llZ-(3-DimethylaminopropyIidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate. Further extract Methyl-2-[(llZ-(3-
DimethylaminopropyJidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, with water
immiscible solvent organic solvent selected from methylene dichloride, ethylene dichloride, diethyl ether, cyclohexane, 1,4 dioxane, ethyl acetate or mixture thereof but preferably methylene dichloride and concentrate the solution about to dry to get the solid of Methyl- 2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate.

The acid addition salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, was prepared by using the organic acid selected from lactic acid, oxalic acid, acetic acid, formic acid , citric acid but preferably oxalic acid in Cj-C4 alcohol as a solvent media selected from methanol, ethanol, propanol, iso- propanol, butanol or mixture thereof but preferably in methanol to form the oxalate salt of Methyl-2-[(llZ-(3-Dimemylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate.
The preparation of acid addition salt such as oxalate salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, is an added advantages of the said invention. We invented that, the formation of oxalate salt of Methyl-2-[(llZ-(3-Dimemylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (DMA oxalate), accountable for the elimination of numerous byproducts from during the reaction and the removal of this numerous byproduct in converse, the removal of byproduct is very tedious and extravagant process in view of large scale preparation, so we invented the oxalate salt formation in our proficient process for preparation of olopatadine hydrochloride to conquer this problem.
Further, Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yfjacetate oxalate, treated with aquous solution of base selected from sodium hydroxide, ammonia, triethylamine, sodium carbonate or a mixture thereof but preferably sodium carbonate and extracted with in water immiscible solvent selected form methylne dichloride, ethylene dichloride, diethyl ether, cyclohexane, 1,4 dioxane, ethyl acetate or
mixture thereof but preferably methylene dichloride and concentrate about to dry to obtain
1

pure Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-
yl] acetate, without any undesired side product.
Hydrolyzing the Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate in aqueous inorganic acid selected from hydrochloric acid, sulphuric acid, nitric acid or mixture thereof but preferably hydrochloric acid at 40-45 QC up to the completion of reaction, which is monitored by TLC and extract the reaction mass with water immiscible solvent selected from methylene dichloride, ethylene dichloride, diethyl ether, cyclohexane,l,4 dioxane, ethyl acetate or mixture thereof but preferably methylene dichloride at reflux temperature and concomitantly cooled to 25-30 °C to obtain the solid of olopatadine hydrochloride, which further purified with ketone solvent selected from ethyl isopropyl ketone, methyl isobutyl ketone, acetone, methyl isobutyl ketone , ethyl methyl ketone or mixture thereof but preferably acetone at reflux temperature for 30 minutes to selectively obtain the Z- isomer of oloptadine hydrochloride. The added advantage of this hydrolysis stage is that, to eliminate the E isomer of olopatadine hydrochloride from product and insitu hydrochloride salt formation of olopatadine.
Crystallization of olopatadine hydrochloride preferably done in a combination of water and ketone solvent selected from methyl isobutyl ketone, acetone, methyl isobutyl ketone , ethyl methyl ketone or mixture thereof but preferably a mixture of water and acetone in parts 1: 10 to 10:1 v/v but more preferably 4:1 v/v (acetone: water) to eliminate the

remaining E isomer of olopatadine hydrochloride after hydrolysis in order to complies the regulatory obligation for the product.
The another aspect of present invention is to provide the novel intermediate in form of acid
addition salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-
benzo[c][2]benzoxepin-2-yl]acetate. It has been observed that, to obtain the pure olopatadine hydrochloride it is necessary to eliminate the numerous side product formed during the reaction so, in order to overcome this disadvantage we invented the acid addition salt of Methyl-2-[(l lZ-(3-Dimethylammopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate.
In further aspect of the invention the complete eliminating the undesired E isomer of
olopatadine hydrochloride by hydrolysis of Methyl-2-[(llZ-(3-
DimethyIaminopropylidene)-6H-benzo[c] [2]benzoxepin-2-yl]acetate, to obtain
olopatadine hydrochloride and isolation by preferred water immiscible solvent and concomitantly crystallize in preferred combination of water and ketone solvent in order to obtain pre z-isomer of olopatadine hydrochloride about to 99.8% and E isomer is about to less than 0.1% to complies the regulatory obligation for product.
Another aspect of the invention is to be used the enantiomerically resolved material at the earliest stage such as starting stage for preparation of olopatadine hydrochloride in respect to resolved in final stage is economical to achieve the utmost yield is lucrative towards the commercial point of view so, in connection to this, we have been use the enantiomerically

resolved material as a starting material such as Methyl-2-[(llZ-(3-mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate (methane sulphonate ester (I)).
Example: 1
Preparation of Methyl-2-[(llZ-(3-DimethylaminopropyIidene)-6H-
benzo[c][2]benzoxepin-2-yI]acetate Oxalate. (DMA Oxalate; One pot synthesis)
Methyl 2-[(HZ-(3-mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, 5.0 Kg
was treated with dimethylamine, 24.0 Lit and Tetrabutylammonium bromide, 0.5 Kg as
phase transfer catalyst and maintained the reaction for 12 hours at room temperature and
completion of reaction monitored by TLC/ HPLC. Extracted the reaction mass with
methylene dichloride and washed the organic layer by water, concentrate about to dry to
get the solid. In the same solid added methanol 20 lit. and treated with oxalic acid 1.5 kg
at room temperature up to the completion of reaction . The white solid was filtered and
dried to obtain Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-
benzo[c] [2]benzoxepin-2-yl]acetate Oxalate. Dry wt: 3.4 Kg
Example: 2
Preparation of Methyl-2-[(ll-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yI]acetate pure (MDAB acetate pure).
3.4 kg DMA oxalate salt obtained from example 1 was treated with aqueous sodium carbonate, 1.5 Kg. The product was isolated by extraction with methylene chloride, 50 Lit

and distilled the solvent under reduced pressure to obtain pure Methyl-2-[(ll-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate without any undesired side product which can be used for next stage without any purification .
Example: 3
Preparation of Olopatadine hydrochloride crude.
Pure Methyl-2-[(ll-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-
yl]acetate, obtained from example 2 was dissolved in hydrochloric acid, 10 lit for hydrolysis. The reaction mixture was heated to 40-45 °C till to the completion of hydrolysis then the reaction mixture was cooled to 25-30°C and methyl chloride 16.3 lit. added further reflux the mixture for 30 minutes and concomitantly cooled the reaction mixture about to ambient temperature to obtain solid of crude olopatadine hydrochloride. Further purified by acetone in 50 lit. at reflux temperature and cooled to ambient temperature respectively and filter to get solid of olopatadine hydrochloride. Dry wt: : 1.75 kg
Z isomer of Olopatadine hydrochloride 99.5 %. E isomer of Olopatadine hydrochloride 0.5%.
Example: 4
Preparation of Olopatadine hydrochloride pure.
The Olopatadine hydrochloride crude, 1.75 Kg obtained from example 3 was further purified by crystallization in a mixture of Acetone, 20 Lit, water, 5.0 Lit. at ambient

temperature to get the pure olopatadine hydrochloride in order to comply the regulatory requirement for the product.
Dry wt: 1.5 Kg
Z isomer of Olopatadine hydrochloride 99.8 %.
E isomer of Olopatadine hydrochloride less than 0.1%.

Claims:
1) A process for preparing olopatadine or salt thereof comprising:
a) reacting Methyl-2-[(l lZ-(3-mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, with dimethylamine and quaternary ammonium salt as a phase transfer catalyst at temperature 0-100°C to obtain Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate;
b) extracting the Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, from reaction mixture or mass with water immiscible solvent organic solvent and concentrate about to dry to get the solid of Methyl-2-[(llZ-(3-Dimethy]aminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl] acetate;
c) treating Methyl-2-[(l lZ-(3-Dimethylarainopropylidene)-6H-benzo[c][2]benzoxepin-2-yl] acetate, with organic acid in C1-C4 alcohol as a solvent media to form selectively acid addition salt of Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c] [2]benzoxepin-2-yl]acetate; and
d) acid addition salt of Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, treated with aqueous solution of base and extracted with water immiscible solvent and concentrate about to dry to form

purified, Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, without any undesired side product;
e) hydrolyzing the Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, in aqueous inorganic acid about to temperature 0 - 80 °C up to the completion of hydrolysis monitored by TLC ; and
f) refluxing the solution or mixture prepared in step e) with water immiscible solvent and cooled about to 0-50 °C to obtain solid of {(llZ)-ll-[3-(Dimethylamino)propylidene]-6,11 -dihydrodibenzo[b, e]oxepin-2-yl} acetic acid hydrochloride (Olopatadine hydrochloride), which further treated with ketone
solvent at reflux temperature to selectively form Z- isomer of olopatadine
hydrochloride;
f) crystallizing the olopatadine hydrochloride in a mixture of ketone solvent and water in ratio of 10:1 to 1:10 v/v to obtain the pure Z isomer of olopatadine hydrochloride in order to eliminate E isomer of olopatadine hydrochloride.
2) A process according to claim 1 wherein, step (a), quaternary ammonium salt as a phase
transfer catalyst selected from benzyltrimethylammonium chloride,
hexadecyltributylphosphonium bromide, tetrabutylammonium bromide,
methyltrioctylammonium chloride, but preferably tetrabutylammonium bromide.
3) A process according to claim 1 wherein, step (a), the reacting the mefhyl-2-[(HZ-(3-
mesyloxypropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, with dimefhylamine and

quaternary ammonium salt is carried out at temperature 0 - 100 °C but preferably at ambient temperature to obtain Methyl-2-[(l lZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yI]acetate.
4) A process according to claim 1 wherein, step (b), isolation of solid Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, by extracting from reaction mass in water immiscible solvent selected form methylne dichloride, ethylene dichloride, diethyl ether, cyclohexane, 1,4 dioxane, ethyl acetate or mixture thereof but preferably methylene dichloride.
5) A process according to claim 1 wherein, step (c), the formation of acid addition salt of Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate, by treating with organic acid selected from lactic acid, oxalic acid, acetic acid, formic acid , citric acid but preferably oxalic acid to form oxalate salt.
6) A process according to claim 1 wherein, step (c), the formation of Methyl-2-[(HZ-(3-Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate oxalate, carried out in C1-C4 alcohol as a solvent media selected from methanol, ethanol, propanol, iso-propanol, butanol or mixture thereof but preferably methanol.
7) A process according to claim 1 wherein, step (d), Methyl-2-[(llZ-(3-
Dimethylaminopropylidene)-6H-benzo[c][2]benzoxepin-2-yl]acetate oxalate, treated with
aqueous solution of base and extracted with water immiscible solvent selected form

methylne dichloride, ethylene dichloride, diethyl ether, cyclohexane, 1,4 dioxane, ethyl acetate or mixture thereof but preferably methylene dichloride to obtain selectively Methyl-2-[(llZ-(3-Dimethylaminopropylidene)-6H-benzofcJ[2]benzoxepin-2-yl]acetate without any numerous side product.
8) A process according to claim 1 wherein, step (e), the hydrolysis of Methyl-2-[(llZ-(3-
Dimethylaminopropylidene)-6H-benzo[c][2]benZOxepin-2-yl]acetate, is carried out in
aqueous inorganic acid selected from hydrochloric acid, sulphuric acid or nitric acid but
preferably hydrochloric acid about to temperature 0 - 80 °C but preferably 40-45 °C.
9) A process according to claim 1 wherein, step (f), refluxing the mixture obtained from
step (e) with water immiscible solvent selected from methylene dichloride, ethylene
dichloride, diethyl ether, cyclohexane, 1,4 dioxane, ethyl acetate or mixture thereof but
preferably methylene dichloride and concomitantly cooled to obtain solid of {(HZ)-ll-[3-
(Dimethylamino)propylidene]-6,ll-dihydrodibenzo[i,e]oxepin-2-yl}aceticacid
hydrochloride (Olopatadine hydrochloride),
10) A process according to claim 1 wherein, step (f), {(HZ)-ll-[3-
(Dimethylamino)propylidene] -6, ll-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid
hydrochloride (Olopatadine hydrochloride), treated with ketone solvent selected from ethyl
isopropyl ketone, methyl isobutyl ketone, acetone, methyl isobutyl ketone , ethyl methyl
ketone or mixture thereof but preferably acetone at reflux temperature to form selectively
Z-isomer of olopatadine hydrochloride.

11) A process according to claim 1, wherein step (g), crystallization of olopatadine hydrochloride is carried out in a mixture of acetone and water in ratio of 10:1 to 1:10 v/v but preferably in 4:1 v/v (acetone: water) order to eliminate E isomer of olopatadine hydrochloride.