Title of Invention

A NOVEL PROCESS FOR PREPARATION OF 10-OXO-10,11-DIHYDRO-5H-DIBENZ[B,F]AZEPINR-5-CARBOXAMIDE (OXCARBAZEPINE)

Abstract

.An improved process for preparation of 10 - 0x0 -10,1 l-dihydro-5H-dibenz[b,fj azepine -5 - carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) comprising the following steps, a) reacting 10-methoxyiminostilbene with sodium cyanate and monochrloro acetic acid using a solvent at temperature below 20C for optionally completing an acid addition and allowed to complete reaction at room temperature , b) added reaction mixture obtained at step (a) in water and allowed to separate a layers containing the desired intermediate, c) reacting an organic layer obtained at step(b) containing 10-Methoxy-5H-dibenz(b,f) azepine-5-carboxamide with a non-mineral acid and water at temperature upto 80C depending on the solvent used, d) Isolation of crude oxcarbazepine obtained at step© at room temperature followed by pirufication.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) ORIGINAL 663-MUM-2004 COMPLETE SPECIFICATION (See Section 10) 1. TITLE OF INVENTION "Novel Process for preparation of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) A) Amoli Organics Pvt Ltd b) having administrative office at Plot no322/4,40 Shed area, GIDC.Vapi 396195, Gujarat c) an Indian Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed. GRANTED 24-03-2005 Field of the Invention The present invention relates to an improved process for preparation of 10-oxo-10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) Background and prior art Oxcarbazepine is an anticonvulsant drug used as an anti-epileptical agent in treatment of AIDS-related neural disorders and for treatment of Parkinson's disease Several processes for preparing Oxcarbazepine have been reported. US Patent 3462775 describes the preparation of oxcarbazepine from 10 -methoxy iminostilbene by phosgenation in toluene, followed by amidation (ethanol and ammonia) and hydrolysis in acidic medium to get the desired product (Scheme 1). The phosgenation is carried out at relatively high temperatures of around 95°C and the hydrochloric acid produced leads to the formation of undesirable impurities. The process uses phosgene gas, which is toxic and hazardous requiring extreme precaution making this process commercially unattractive. Scheme 1 Oxcarbazepine Canadian Patent 112 241 describes an alternate preparation of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbamazepine, prepared from carbamazepine by reaction with m-chloroperbenzoic acid (CPBA) (Scheme-2). Starting with Carbamazepine, which is an expensive raw material, the conversion to its epoxide is poor in quality and yield. -2- EP Patent Application 028028, discloses a process involving nitration of 5-cyanoiminostilbene followed by reduction and hydrolysis (Scheme-3). However, the drawback of the process is in the preparation of the 5-cyanoiminostilbene, which is prepared from iminostilbene and cyanogen chloride that is toxic, hazardous and difficult to handle. Swiss Patent No. 642 950 suggests hydrolysis of the 10-chloro-5H-dibenz [ b,f ] azepin-5-carboxamide using concentrated sulphuric acid to form the oxcarbazepine. However the yields are poor. Scheme 4 US patent 5,808,058 discloses a process involving direct carbomoylation of 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) with isocyanic acid generated insitu from cyanates and acids and then subjecting the product to acid hydrolysis of the enol ether. The problem with the above process is that 10-methoxy iminostilbene undergoes 2 types of competitive reactions when an alkali metal cyanate and an acid are added. The enol-ether moiety undergoes hydrolysis to give the corresponding ketone which does not undergo a carboxamidation reaction with HOCN, whereas the imino function does undergo a carboxamidation reaction resulting in the formation of impurities. Scheme 5 US Patent 0105076 discloses a process involving direct carbamoylation of 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) with isocyanic acid generated insitu from cyanates and mild acidic reagent and then subjecting to hydrolysis in a biphasic system. However the quantity of acid and sodium cyanate used are very high and the yields obtained are low. Further it may be noted that in all the processes disclosed in the prior art discussed above (Scheme 1 and Scheme 3) and US Patent 5808058, EP Application 1 302 464 A1 and PCT Publication WO 01/56992A2, the conversion of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to 10-oxo-10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) is effected using strong mineral acids or mixture of mineral acids and acetic acid in aqueous medium. This leads to degradation of oxcarbazepine Methods described in the prior art have severe limitations in terms of poor quality and yields and also in some cases with the use of hazardous materials such as phosgene that need extreme care during usage making them commercially unattractive. Moreover the HCI formed during the course of the reaction and the relatively higher temperatures used lead to formation of undesired impurities. There is a long standing need in the industry to provide cost effective, safe and easy operating processes for the production of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) without the use of mineral acids. Summary of the invention The main object of the invention is to provide a cost effective, and high yielding process for the production of 10- oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) The process (scheme 6) comprises steps • Preparation of intermediate 10 -Methoxy-5H-dibenz (b,f) azepine-5- carboxamide from 10-methoxyiminostilbine using sodium cyanate and controlled addition of monochloro acetic acid in an organic solvent Formation of oxcarbazepine from 10-Methoxy-5H-di benz (b,f) azepine-5-carboxamide in situ using non mineral acids in organic solvent. Detailed description of the invention (Scheme 6) Scheme 6 10 - methoxyiminostilbene is dissolved in a solvent followed by addition of sodium cyanate and cooled to below 20°C. Monochloro acetic acid in an organic solvent is slowly added to the above solution maintaining the temperature below 20 °C till the reaction goes to completion. Optionally on completion of the acid addition, the reaction mixture is allowed to warm up to around room temperature and maintained at this temperature till the completion of the reaction. On completion of the reaction, the reaction mixture is quenched in water and the layers are allowed to separate. The organic layer is separated and stirred in the presence of a non-mineral acid and water at temperatures up to 80°C depending on the solvent used. On completion of the reaction, the system is cooled to room temperature. The crude oxcarbazepine is separated and purified. The solvent used are preferably chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1,1,1,-trichloroethane, trichloroethylene or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene. Monochloroacetic acid is slowly added at temperature up to 20°C preferably below 15°C and most preferably between 10°C to 15°C. The reaction period may vary from about 3 hours to about 10 hours. The molar ratio of 10-methoxy iminostilbene to sodium cyanate is 1:2 - 1:3. The molar ratio of the 10-methoxy iminostilbene verses Monochloroacetic acid is 1:1.5 to 1:2. The solvents used in the final oxo preparation step are preferably chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1,1,1-trichloroethane, trichloroethylene or aromatic hydrocarbon solvent such as toluene, xylene, chlorobenzene, or aprotic solvents including dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and acetonitrile. The non mineral acids are preferably methane sulfonic acids, para toluene sulfonic acids, cationic resins and aluminum chloride. The temperature at which the hydrolysis for conversion of the enol-ether is carried out is 25 to 80 ° C, preferably between 50 to 80° C. The invention is now illustrated with a few non-limiting examples. Example 1 100 gms of 10- methoxy iminostilbene is dissolved in 300 ml chloroform & cooled to 10 °C and 80 gms sodium cyanate is added. This is followed by addition of 80 gms of monochloroacetic acid in 300 ml chloroform over a period of 6 hours maintaining temperature at 10°C - 15°C. The temperature is then increased to 25°C - 30°C and maintained for 8 hours. The reaction mixture is poured into 300 ml water and the layers are separated. Chloroform is evaporated and 10-methoxy-5H-di benz (b, f) azepine-5-carboxamide obtained is dissolved in 500 ml of toluene. P-toluene sulfonic (66gms in 800ml of water) is added and the reaction mixture is heated to 75°C - 80 °C till reaction goes to completion. The reaction mixture is cooled to 20 °C. Oxcarbazepine is separated by filtration and purified in acetone-water system to yield 75 gms of pure oxcarbazepine. Example 2 100 gms of 10- methoxy iminostilbene is dissolved in 300 ml chloroform & cooled to 10 °C and 60 gms sodium cyanate is added. This is followed by addition of 60 gms of monochloroacetic acid in 300 ml chloroform over a period of 6 hours maintaining temperature at 10°C - 15 °C. The temperature is then increased to 25°C - 30°C and maintained for 8 hours. The reaction mixture is poured into 300 ml water and the layers are separated. Chloroform is evaporated and 10-methoxy-5H-di benz (b, f) azepine-5-carboxamide obtained is dissolved in 500 ml of toluene. P-toluene sulfonic (66gms in 800ml of water) is added and the reaction mixture is heated to 75°C - 80 °C till reaction goes to completion. The reaction mixture is cooled to 20 °C. Oxcarbazepine is separated by filtration and purified in acetone-water system to yield 65 gms of pure oxcarbazepine Example 3 100 gms of 10- methoxy iminostilbene is dissolved in 300 ml methylene chloride & cooled to 10 °C and 80 gms sodium cyanate is added. This is followed by addition of 80 gms of monochloroacetic acid in 300 ml methylene chloride over a period of 6 hours maintaining temperature at 10°C - 15°C. The temperature is then increased to 25°C - 30°C and -7- maintained for 8 hours. The reaction mixture is poured into 300 ml water and the layers are separated. Methylene chloride is evaporated and 10-methoxy-5H-di benz (b, f) azepine-5-carboxamide obtained is dissolved in 500 ml of toluene. P-toluene sulfonic (66gms in 800ml of water) is added and the reaction mixture is heated to 75°C - 80°C till reaction goes to completion. The reaction mixture is cooled to 20°C. Oxcarbazepine is separated by filtration and purified in acetone-water system to yield 75 gms of pure oxcarbazepine. The present invention provides a cost effective, and high yielding process for the production of 10- oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) that is carried out with controlled addition of mono chloro acetic acid at temperatures below 20°C and subsequent hydrolysis carried out in the presence of non-mineral acids to avoid the formation of any undesirable impurities using easily available raw materials. -8- We Claim, 1 .An improved process for preparation of 10 - 0x0 -10,1 l-dihydro-5H-dibenz[b,fj azepine -5 - carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) comprising the following steps, a) reacting 10-methoxyiminostilbene with sodium cyanate and monochrloro acetic acid using a solvent at temperature below 20C for optionally completing an acid addition and allowed to complete reaction at room temperature , b) added reaction mixture obtained at step (a) in water and allowed to separate a layers containing the desired intermediate, c) reacting an organic layer obtained at step(b) containing 10-Methoxy-5H-dibenz(b,f) azepine-5-carboxamide with a non-mineral acid and water at temperature upto 80C depending on the solvent used, d) Isolation of crude oxcarbazepine obtained at step© at room temperature followed by pirufication. 2. An improved process for preparation of 10 - 0x0 -10,11 -dihydro-5H-dibenz[b,f] azepine -5 - carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,fjazepine (10-methoxy iminostilbene),as claimed in claim 1, wherein the solvent used is selected from chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1,1,1, -trichloroethane, trichloroethylene or aromatic hydrocarbon such as toluene, xylene,chlorobenzene, An improved process for preparation of 10-oxo-IO, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) as claimed in claims 1-2 wherein the molar ratio of 10-methoxy iminostilbene to sodium cyanate is 1:2 - 1:3 and the molar ratio of the 10-methoxy iminostilbene to monochloroacetic acid is 1:1.5 to 1:2. An improved process for preparation of 10-oxo-IO, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) as claimed claims 1-2 wherein the monochloroacetic acid is added at temperature up to 20°C, preferably below 15°C and most preferably between 10°C to 15°C. An improved process for preparation of 10-oxo-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) as claimed in claims 1-2 wherein the reaction period varies from about 3 hours to about 10 hours. An improved process for preparation of 10-oxo-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) as claimed in claims 1- 2, wherein the solvent used in the oxo preparation are selected from chlorinated aliphatic hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, 1,1,1 ,-trichloroethane,trichloroethylene or aromatic hydrocarbons such as toluene, xylene, chlorobenzene, or aprotic solvents including dimethyl formamide, dimethyl acetamide, methyl pyrrolidine and acetonitrile. An improved process for preparation of 10-oxo-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[bazepine (10-methoxy iminostilbene) as claimed in claim 1 wherein the non mineral acid is selected from methane sulfonic acids, para toluene sulfonic acids, cationic resins and aluminum chloride. An improved process for preparation of 10-oxo-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) from 10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) as claimed in claims 1-2 wherein the temperature at which the hydrolysis for conversion of the enol-ether is carried out at 25 to~80 ° C, preferably between 50 to 80° C. Dated 17th Feb 2005 Applicant (Parenky Chandrashekar)

Documents:

663-mum-2004-cancelled page(24-3-2005).pdf

663-mum-2004-cancelled pages(24-03-2005).pdf

663-mum-2004-claim(granted)-(24-3-2005).doc

663-mum-2004-claim(granted)-(24-3-2005).pdf

663-mum-2004-claims(granted)-(24-03-2005).doc

663-mum-2004-claims(granted)-(24-03-2005).pdf

663-mum-2004-correspondence(08-08-2008).pdf

663-mum-2004-correspondence(27-10-2005).pdf

663-mum-2004-correspondence(ipo)-(11-09-2008).pdf

663-mum-2004-form 1(18-06-2004).pdf

663-mum-2004-form 1(18-6-2004).pdf

663-mum-2004-form 13(08-08-2008).pdf

663-mum-2004-form 19(18-06-2004).pdf

663-mum-2004-form 19(18-6-2004).pdf

663-mum-2004-form 2(granted)-(24-03-2005).doc

663-mum-2004-form 2(granted)-(24-03-2005).pdf

663-mum-2004-form 2(granted)-(24-3-2005).doc

663-mum-2004-form 2(granted)-(24-3-2005).pdf

663-mum-2004-form 3(18-06-2004).pdf

663-mum-2004-form 3(18-6-2004).pdf

663-mum-2004-form 5(18-06-2004).pdf

663-mum-2004-form 5(18-6-2004).pdf

663-mum-2004-power of attorney(13-05-2006).pdf