FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF OLOPATADINE HYDROCHLORIDE"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Field of Invention:
The present invention relates to one pot process for preparation of (Z) - 11 - [(3 -Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b,e] oxepin - 2 - acetic acid and its pharmaceutical acceptable salts.
Background and Prior Art:
The compound (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b,e] oxepin - 2 - acetic acid hydrochloride of formula - I having International Non -Proprietary Name Olopatadine Hydrochloride

Formula -1
is a selective histamine HI antagonist, which has mast cell stabilizing property and has been shown to affect the release of TNFa and various cytokines from conjuctival epithelial cell and is used for the treatment of allergic conjunctivitis.
Olopatadine hydrochloride was first time disclosed as dibenz [b, e] oxepin derivative in US Patent No 5,116,863 (herein after '863') 'in 1992, assigned to Kyowa Hakko Kogyo Co., Ltd. The patent discloses the preparation of Olopatadine through Wittig reaction by reacting 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid (Formula -II) with 3 - dimethylaminopropyl triphenyl phosphonium bromide hydro bromide (Formula - III) in presence of base n - butyl lithium and solvent tetra hydrofuran. The crude compound is passed through column chromatography to isolate pure olopatadine. The reaction sequence is as shown in scheme -1, Scheme I:

In the above method the preparation of olopatadine involves excess use of base and the Wittig reagent. The isolation of pure cis olopatadine employs the use of column chromatography. The final yield of the compound is low.
Another method disclosed in '863' is use of Grignard reagent for the preparation of Olopatadine hydrochloride. In this reaction, 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid (Formula - II) is converted to corresponding amide of Formula -IV by reacting the acid with thionyl chloride followed by reaction with 2- amino - 2 -methyl propanol, which is cyclised to get corresponding oxazoline derivative (Formula -V). Grignard reaction of the oxazoline derivative with 3-(dimethylamino) propylchloride yields the intermediate ll-(3-Dimethylamino-propyl) - 2 - (4, 4-dimethyl-4, 5-dihydro-oxazol-2-ylmethyl) - 6, 11 - dihydro - dibenzo [b, e] oxepin-1 l-ol (Formula- VI), which on hydrolysis followed by dehydration with strong acid yields olopatadine (Formula - I). The reaction sequence is as per scheme - II.


Formula -1 Formula - VI
Scheme - II
The major disadvantages of the above process are non - selectivity in the formation of the E / Z isomers, and also the preparation of olopatadine involves protection and deprotection of the carboxylic acid group increasing the number of steps. Further, the isolation of pure compound employs the use of column chromatography.
J. Med. Chem discloses the preparation of olopatadine HC1 as per the above scheme, wherein the separation of the Z / E diastereomer is disclosed. As per the disclosure, the diastereo selectivity of the dehydration step is poor and leads to the formation of predominantly undesired 'E' isomer.
PCT application WO2006010459 discloses the preparation of olopatadine hydrochloride
wherein (3 - formyl -4 - hydroxyl - phenyl) - acetic acid methyl ester ( Formula - VII)
is reacted with 1 - chloromethyl - 2 - iodo benzene ( Formula - VIII) to get [3 -
Formyl - 4 - (2 - iodo - benzyloxy) - phenyl] - acetic acid methyl ester (Formula - IX), which is further reacted with (3 - Dimethylamino - propyl) - triphenyl phosphonium iodide in presence of base and anhydrous toluene to isolate {3 - (4 - Dimethylamino -but - 1 - enyl) - 4 - (2 - iodo - benzyloxy) - phenyl] acetic acid methyl ester (Formula -X). This ester is cyclized in mixed solvent, in presence of palladium acetate and tetra

butyl ammonium chloride to obtain olopatadine methyl ester, which on hydrolysis and reaction with hydrochloric acid yields olopatdine hydrochloride (Formula - I). The reaction sequence is as per Scheme - III.

PCT application WO2006129781 discloses the preparation of olopatadine hydrochloride wherein Methyl 2-(4-(2-chlorobenzyloxy)phenyl)acetate is iodinated using iodine and silver sulfate to give methyl 2-(4-(2-chlorobenzyloxy)-3-iodophenyl)acetate; which is coupled with but-3-yn-l-ol in presence of Copper iodide and palladium catalyst results methyl 2-(4-(2-chlorobenzyloxy)-3-(4-hydroxybut-l-ynyl)phenyl)acetate; which on palladium catalyzed cyclization yields methyl [(HZ)-ll-(3-hydroxypropylidene)-6,ll-dihydrodibenzo[b,e]oxepin-2-yl]acetate; which is converted to Olopatadine via mesylate salt followed by treatment with dimethylamine followed by basic hydrolysis.
Another PCT application WO2007105234 discloses one pot process for the preparation of olopatadine hydrochloride using Grignard reaction. The compound 11 - oxo - 6, 11 -Dihydroxydibenz [b, e] oxepin - 2 - acetic acid is reacted with 1 - halo - 3 -dimethylamino propane which is heated with dilute hydrochloric acid (1:1) to get Olopatadine hydrochloride. The reaction sequence is as per scheme - IV:

WO2007110761A2 discloses the preparation of olopatadine hydrochloride wherein 4-Hydroxyphenylacetic acid is reacted with Phthalide in presence of sodium methoxide to give 4-(2-Carboxybenzyloxy) phenyl acetic acid; which is cyclized in presence of trifluoroacetic acid and trifluoroacetic anhydride to give 11 - oxo - 6, 11 -Dihydroxydibenz [b, e] oxepin - 2 - acetic acid , Wittig reaction of the acid with 3-Dimethylaminopropyl triphenylphosphonium bromide hydro bromide in presence of sodium hydride followed by treatment with hydrobromic acid to isolate olopatadine hydro bromide. The hydro bromide salt is neutralized with aqueous sodium hydroxide and treated with concentrated hydrochloric acid in acetone to get olopatadine hydrochloride.
Japanese application JP2007031363 describes the preparation of olopatadine hydrochloride wherein 2 -(Bromomethyl) benzonitrile is reacted with methyl 2-(4-hydroxyphenyl)acetate in presence of potassium carbonate followed by hydrolysis of the ester with sodium hydroxide to get methyl 2-(4-hydroxyphenyl)acetate; which is cyclized with acetic anhydride results in 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 -


acetic acid; Wittig reaction of the acid formed with (3-dimethylaminopropyl) triphenyl phosphonium bromide hydro bromide in presence of n-Butyl lithium gives Olopatadine; which is treated with hydrochloric acid and water to give Olopatadine hydrochloride.
The major drawbacks of the prior art processes include:
- poor stereo selectivity in the formation of required Z - isomer; the E / Z ratio is in the range of 9 : 1 to 3 : 7.
- Formation of the olopatadine methyl ester impurity which is formed during the wittig reaction and very difficult to separate;
- the use of column chromatography to isolate the pure form of the compound;
- involves additional step to deprotect the carboxylic acid group.
There remains a need for an improved process for preparing olopatadine and its pharmaceutically acceptable salt that eliminates or substantially reduces the impurities and reducing the number of steps in a convenient and cost efficient manner. The present inventors have come out with a one pot process which ameliorates the problems in the prior art with a one - pot process for the preparation of olopatadine starting with the protected 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid compound of Formula - II.
Objectives of the invention:
The present invention tackles the problem of providing process for the preparation of (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 -acetic acid and its pharmaceutically acceptable salt, which overcomes the problems in the prior art.
The objective of the present invention is to prepare (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b,e] oxepin - 2 - acetic acid of higher purity devoid of the prior art impurities.


Another objective of the present invention is to prepare (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 - acetic acid by an industrially useful and cost effective process.
Yet another objective of the present invention is to prepare (Z) - 11 - [(3 -Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 - acetic acid in a one pot process.
Yet another objective of the present invention is to prepare the pharmaceutically acceptable salt of (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 - acetic acid.
Description of the invention:
Formula-II Formula- III Formula-I
The present invention describes one pot process for the preparation of the compound (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 -acetic acid of Formula -1 and its pharmaceutically acceptable salt. In one embodiment of the present invention the compound (Z) - 11 - [(3 -Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 - acetic acid of Formula - I is prepared in a one pot process by carrying out Wittig reaction of the carboxylic acid protected 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid compound of Formula - II with 3 - dimethylaminopropyl triphenyl phosphonium bromide or its salt thereof (Formula - III) in presence of a suitable base and an etheral solvent. The reaction sequence can be represented as below in Scheme - V.


Scheme - V
Wherein 'R' is carboxylic acid protecting group selected from phenyl or phenyl substituted by one or more groups such as C1 - C4 alkyl, halogen, nitro, C1 - C4 halo alkyl, C1 - C4 alkoxy, or C1 - C4 haloalkoxy or tert butyl dimethylsilyl. The preferred carboxylic acid protecting groups are phenyl substituted by one or more groups such as C1 - C4 alkyl, nitro or halo alkyl and tert butyl dimethylsilyl group and the most preferred carboxylic acid protecting group is benzyl.
The compound 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid compound of Formula - II can be prepared as per the process disclosed in US patent US 4, 585,788; Daniel E. Aultz et al; J. Med. Chem. (1977), 20(1), 66 -70 and Daniel E. Aultz et al; J. Med. Chem. (1977), 20(11), 1499 - 1501.
The carboxylic acid protected Compound 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid compound of Formula - II is prepared as per disclosed process in US 4,107,322 and incorporated here as reference.
The advantage of using the aryl or substituted aryl protecting group is the increase in stereo selectivity during the formation of distereo isomer, wherein after the Wittig reaction the inventors have isolated predominantly 'Z' isomer having the 'E' isomer content less than 1%. The ratio of distereo isomer Z: E obtained is 8: 2, wherein the preferred ratio is 9: 1. Here before, the prior art had difficulty in carrying out the stereo selective reaction to isolate 'Z' isomer and has to carry out the chromatographic separation to prepare the pure Z isomer. The ratio of E: Z isomer obtained as per prior art processes varied from 3: 7 to 9: 1.
The compound, 3 - dimethylaminopropyl triphenyl phosphonium bromide or its salt thereof (Formula - III) is charged in solvent and suitable base to form phosphorous ylide. The solvent used is selected from tetrahydro furan, toluene, N, N - dimethyl formamide, N - methyl pyrrolidone. The preferred solvent is tetrahydro furan.


The suitable base used is selected from sodium hydride, potassium hydride, Lithium hydride, potassium tertiary butoxide, sodium tertiary butoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropyl amide and butyl lithium.
The reaction mixture maintained in the temperature range of 25°C to reflux temperature of the used solvent. The mixture is cooled to 10 to -10°C and the solution of carboxylic acid protected compound of Formula - II in solvent selected from tetrahydro furan, toluene, N, N - dimethyl formamide, N - methyl pyrrolidone is added to the phosphorous ylide. After complete addition the reaction is further maintained at 0°C to 40°C for 3 to 10 hours to provide a reaction mixture containing olopatadine.
The reaction mass is cooled to 10 to -10 °C and charged water 1400 ml to 2000 ml to the reaction mixture maintaining the temperature in the range of 10 to -10°C. The organic layer is separated and the aqueous layer washed with organic solvent selected from ethyl acetate, toluene, diethyl ether and diisoprpyl ether. Aqueous layer is further taken for pH adjustment to 1 - 3 with an appropriate acid. The preferred acid for the pH adjustment is hydrochloric acid.
The acidified aqueous solution is extracted with chlorinated solvent selected from dichloromethane, trichloroethane, or tetrachloro ethane. The organic layer is separated and taken for concentration under vacuum yields crude olopatadine hydrochloride containing the cis isomer, having the purity by HPLC of more than 98%.
The crude olopatadine hydrochloride is taken in either single or mixed organic solvent selected from a group consisiting of polar aprotic solvent, polar protic solvent, ketones, ether, chlorinated solvent and hydrocarbons to purify the product. The polar protic solvents used are selected from methanol, ethanol, propanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate. The polar aprotic solvents used are selected from acetonitrile, N, N - Dimethyl formamide, Dimethyl sulfoxide and dimethyl acetamide. The ketones used are selected from acetone, methyl ethyl ketone, and methyl isobutyl


ketone. The chlorinated solvents selected from dichloromethane and tetrachloro ethane. The ethers are selected from diethyl ether, diisopropyl ether, methyl tertiary butyl ether and the hydrocarbons are selected from toluene, hexane and tetrahydro furan.
The pure cis olopatadine hydrochloride so obtained has purity by HPLC more than 99.0%.
Yet another embodiment of the present invention is to prepare the pharmaceutically acceptable acid addition salt of the compound (Z) - 11 - [(3 - Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin - 2 - acetic acid of Formula -1. The acid used for the salt preparation is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, paratoluene sulphonic acid and acetic acid.
The present invention is further illustrated in detail with reference to the following example. It is desired that the example be considered in all respect as illustrative and non restrictive to the invention.
Example:
Preparation of Olopatadine Hydrochloride:
Charged 238 gms [3 - (Dimethylamino) propylamine] triphenyl phosphonium bromide hydrobromide in 1400 ml tetrahydro furan under nitrogen atmosphere. Slowly charged 130.5 gms sodium hydride and raised the temperature to reflux to maintain for 3.0 hrs. The suspension cooled and chilled to 0°C and charged solution of 100 gms benzyl ester of 11 - oxo - 6, 11 - Dihydroxydibenz [b, e] oxepin - 2 - acetic acid in 400 ml tetrahydro furan and stirred the reaction mass at 25 - 30°C for 3.0 hours. Cooled the reaction mass to -10 to 5°C and quenched in 1700 ml water. The organic layer separated and washed with water. Combined aqueous layer washed with diisopropyl ether and acidified with dilute hydrochloric acid to pH 2. The acidified aqueous layer extracted with dichloromethane 2500 ml. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was taken in the mixture of 500 ml dichloromethane


and diethyl ether solvent. The product was filtered and dried. The HPLC purity of the product Olopatadine hydrochloride obtained; Cis / Z Isomer = > 99.0%; Trans / E Isomer = < 0.5%.
Dated this 21st day of November 2007