WO2009081417A2

WO2009081417A2 - Process for preparation of olopat adine hydrochloride

Info

Publication number: WO2009081417A2
Application number: PCT/IN2008/000780
Authority: WO
Inventors: Ketan Dhansukhlal Vyas; Ranjeet Nair; Rajendra Vasantrao Chavan; Yogesh Vishwas Shelke; Aditi Milind Panandikar
Original assignee: Indoco Remedies Limited
Priority date: 2007-11-21
Filing date: 2008-11-20
Publication date: 2009-07-02
Also published as: WO2009081417A3

Abstract

Disclosed herein is a process for preparation of compound 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydrodibenz [b, e] oxepin -2 - yl - acetic acid (Olopatadine) and its pharmaceutically acceptable salt; comprising reacting carboxylic acid protected 11 - oxo - 6, 11 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid with 3 - dimethylaminopropyl triphenyl phosphonium halide in presence of a suitable base and an organic solvent.

Description

PROCESS FOR PREPARATION OF OLOPAT ADINE HYDROCHLORIDE Field of Invention:

The present invention relates to one pot process for preparation of (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b,e] oxepin - 2 - acetic acid and its pharmaceutical acceptable salts.

Background and Prior Art:

The compound (Z) - 1 1 - [(3 - Dimethylamino)propylidene] - 6, 1 1 - dihydrodibenz [b,e] oxepin - 2 - acetic acid hydrochloride of formula - 1 having International Non - Proprietary Name Olopatadine Hydrochloride

Formula - I is a selective histamine H l antagonist, which has mast cell stabilizing property and has been shown to affect the release of TNFα and various cytokines from conjuctival epithelial cell and is used for the treatment of allergic conjunctivitis.

Olopatadine hydrochloride was disclosed as dibenz [b, e] oxepin derivative in US Patent No 5, 1 16,863 (herein after "863') in 1992, assigned to Kyowa Hakko Kogyo Co., Ltd. The patent discloses the preparation of Olopatadine through Wittig reaction by reacting 1 1 - oxo - 6, 1 1 - dihydrodibenz [b, e] oxepin - 2 - acetic acid (Formula - 11) with 3 - dimethylaminopropyl triphenyl phosphonium bromide hydro bromide (Formula - III) in presence of base n - butyl lithium and solvent tetrahydrofuran. The crude compound is passed through column chromatography to isolate pure olopatadine. The reaction sequence is as shown in scheme - I.

Formula - II Formula - III Formula - 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, 1 1 - oxo - 6, 1 1 - Dihydrodibenz [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 1 l -(3-Dimethylamino-propyl) - 2 - (4, 4-dimethyl-4, 5-dihydro- oxazoI-2-ylmethyl) - 6, 1 1 - dihydrodibenz [b, e] oxepin- 1 l -ol (Formula - Vl), which on hydrolysis followed by dehydration with strong acid yields olopatadine (Formula - I). The reaction sequence is as per scheme - II.

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 HCl 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 Publication 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.

Formula - VIII Formula - VII

Scheme - III

PCT Publication 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 [( I I Z)- I l -(3-hydroxypropylidene)-6, l 1 - dihydrodibenz[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 Publication WO2007105234 discloses one pot process for the preparation of olopatadine hydrochloride using Grignard reaction. The compound 1 1 - oxo - 6, 1 I - Dihydrodibenz [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:

Formula - 1

Scheme - IV

WO20071 10761 A2 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 trifiuoroacetic acid and trifluoroacetic anhydride to give 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid; Wittig reaction of the acid with 3- Dimethylaminopropyl triphenylphosphonium bromide hydrobromide in presence of sodium hydride followed by treatment with hydrobromic acid to isolate olopatadine hydrobromide. The hydrobromide 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 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid; Wittig reaction of the acid formed with (3-dimethylaminopropyl) triphenyl phosphonium bromide hydrobromide 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 methylester 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.

In view of the above, there remains a need for an improved process for preparing olopatadine and its pharmaceutically acceptable salt that eliminates or substantially reduces the impurities and 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 for the preparation of olopatadine starting with the protected 1 1

- oxo - 6, 1 1 - dihydrodibenz [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)

- 1 1 - [(3 - Dimethylamino)propylidene] - 6, I I - dihydrodibenz [b, e] oxepin - 2 - acetic acid and its pharmaceutically acceptable salt, which overcome the problems in the prior art.

The objective of the present invention is to prepare (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [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) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [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) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, I I - dihydrodibenz [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) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b, e] oxepin - 2 - acetic acid.

Summary of the invention:

The present invention provides a process for the preparation of compound (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b,e] oxepin - 2 - acetic acid of Formula I and its pharmaceutically acceptable salt;

Formula - 1 comprising reacting compound of Formula - I I,

Formula - I I where R is phenyl or phenyl substituted carboxylic acid protecting group; with triphenyl phosphonium halide or its salt of Formula - III

Formula - III where X is iodine, chlorine or bromine; wherein;

1. the compound of Formula - II reacts with triphenyl phosphonium halide of Formula - III a. undergoing Wittig reaction in presence of solvent and base to form reaction mixture containing olopatadine; b. quenching the reaction mixture in water and adjust the pH of aqueous layer with suitable acid to isolate olopatadine salt; c. purifying isolated olopatadine salt.

2. The process further provides stereoselective Wittig reaction predominantly forming 'Z' or Cis Olopatadine.

Description of the invention:

The present invention describes one pot process for the preparation of the compound (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b, e] oxepin - 2 - acetic acid of Formula - I and its pharmaceutically acceptable salt.

In one embodiment of the present invention, the compound (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [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 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid compound of Formula - II with 3 - dimethylaminopropyl triphenyl phosphonium halide selected from bromine, chlorine and iodine or its salt thereof (Formula - III) in presence of a suitable base and an organic solvent. The reaction sequence can be represented as below in Scheme - V,

Formula - 111

Scheme - V wherein 'R' is carboxylic acid protecting group selected from phenyl or phenyl substituted by one or more groups such as Ci - C4 alkyl, halogen, nitro, Ci - C4 halo alkyl, C, - C₄ alkoxy, or C, - C₄ haloalkoxy or tert butyl dimethylsilyl. The preferred carboxylic acid protecting groups are phenyl substituted by one or more groups such as Ci - C₄ alkyl, nitro or halo alkyl and tert butyl dimethylsilyl group and the most preferred carboxylic acid protecting group is benzyl. The term Ci - C₄ alkyl means a linear or branched chain of 1 - 4 carbon atoms, for example methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert - butyl.

The compound 1 1 - oxo - 6, I l - Dihydrodibenz [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. Che^'m. ( 1977), 20( 1 ), 66 -70 and Daniel E. Aultz et al; J. Med. Chem. (1977), 20(1 1 ), 1499 - 1501.

The carboxylic acid protected Compound 1 1 - oxo - 6, 1 1 - Dihydrodibenz [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 to 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 halide or its salt thereof (Formula - III) is charged in solvent containing suitable base to form phosphorous ylide, wherein the preferred 3 - dimethylaminopropyl triphenyl phosphonium halide used is 3 - dimethylaminopropyl triphenyl phosphonium bromide and its salt. The solvent used for the preparation of phosphorous ylide is selected from tetrahydrofuran, toluene, N, N - dimethylformamide and N - methyl pyrrolidone. The preferred solvent used is tetrahydrofuran.

The suitable base used during the formation of phosphorous ylide and the reaction 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 preferred base used for the reaction is sodium hydride, potassium hydride, lithium hydride, potassium tertiary butoxide and sodium tertiary butoxide. The most preferred base used is sodium hydride.

The reaction mixture is maintained in the temperature range of 25°C to reflux temperature of the used solvent. The mixture is cooled to 10 to - 10⁰C and the solution of carboxylic acid protected compound of Formula - Il is added to the phosphorous ylide. The solvent for the solution preparation of the carboxylic acid protected compound of Formula - II is the same, which is used for the phosphorous ylide preparation and is selected from tetrahydrofuran, toluene, N, N - dimethylformamide and N - methyl pyrrolidone. After complete addition of the solution, reaction is further maintained at temperature of O⁰C to 40⁰C to provide a reaction mixture containing olopatadine. The preferred temperature for the reaction is 20 to 3O⁰C.

The reaction mass is cooled further to 10 to - 10 ⁰C and water is charged to the reaction mixture maintaining the temperature in the range of 10 to - 1 O⁰C. The quantity of water used is 10 volume to 20 volume of the carboxylic acid protected compound used. The preferred quantity of water used is 14 volume to 18 volume. The organic layer is separated and the aqueous layer is washed further with organic solvent selected from ethyl acetate, toluene, diethyl ether and diisopropyl ether. The Aqueous layer is acidified further to pH of 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 tetrachloroethane. The organic layer is separated and dried over anhydrous sodium sulphate. Dried organic layer is taken for concentration under vacuum, yields crude olopatadine hydrochloride containing the cis isomer, having purity by HPLC of more than 98%.

The crude olopatadine hydrochloride is further taken for purification in either single or mixed organic solvent selected from a group consisting of polar aprotic solvent, polar protic solvent, ketones, ether, chlorinated solvent and hydrocarbons. 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 are selected from dichloromethane and tetrachloro ethane. The ethers are selected from diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and the hydrocarbons are selected from toluene and hexane.

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) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b, e] oxepin - 2 - acetic acid of Formula - I. 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 tetrahydrofuran 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 0⁰C and charged solution of 100 gms benzyl ester of 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid in 400 ml tetrahydrofuran and stirred the reaction mass at 25 - 30⁰C for 3.0 hours. Cooled the reaction mass to -10 to 5⁰C 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%.

Claims

We claim,

A process for preparation of compound (Z) - 1 1 - [(3 - Dimethylamino) propylidene] - 6, 1 1 - dihydrodibenz [b,e] oxepin - 2 - acetic acid of Formula I and its pharmaceutically acceptable salt;

Formula - 1 comprising reacting compound of Formula - 11

Formula - II where R is phenyl or phenyl substituted carboxylic acid protecting group; with triphenyl phosphonium halide and its salt of Formula - III

Formula - III where X is iodine, chlorine or bromine.

2. The process as claimed in claim I , wherein said process comprises the following steps: a. reacting compound of formula II with formula III in presence of base and solvent; b. quenching the reaction mixture in water and adjust the pH of aqueous layer with suitable acid to isolate olopatadine salt; and c. purifying isolated olopatadine salt.

3. The process as claimed in claim 2, wherein the solvent is selected from tetrahydrofuran, toluene, N, N - dimethyl formamide, N - methyl pyrrolidone.

4. The process as claimed in claim 3, wherein the preferred solvent is tetrahydrofuran.

5. The process according to claims 1 and 2, wherein the carboxylic acid protecting group is selected from phenyl or phenyl substituted by one or more groups such as C| - C4 alkyl, nitro or halo alkyl and tert butyl dimethylsilyl group.

6. The process according to claim 5, wherein the carboxylic acid protecting group is benzyl.

7. The process according to claim 2, wherein the 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.

8. The process according to claim 7, wherein the preferred base used is sodium hydride.

9. The process according to claims 1 and 2, wherein the acid for pharmaceutically acceptable salt is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, or phosphoric acid.

10. The process according to claim 9, wherein the acid for the pharmaceutically acceptable salt preparation is hydrochloric acid.

1 1 . The process as claimed in any one of preceding claims, wherein the compound of Formula - II is reacted with triphenyl phosphonium halide of Formula - III through Wittig reaction, stereoselectively, to form predominantly 'Z' or Cis Olopatadine.

12. The process according to any of the preceding claims, wherein the compound is cis - olopatadine hydrochloride.