PROCESS FOR PRODUCING OXCARBAZEPINB VIA AN ll-ALKOXY-l 0-HALO-DIHYDROIMINOSTILBENE INTERMEDIATE

Field of the Invention

This invention in general relates to the process for producing 10-oxo-10,l l-dihydro- 5H-dibenz[έ,/]azepine-5-carboxamide (oxcarbazepine). In particular the present invention provides a novel intermediate to produce oxcarbazepine.

Background of the Invention lO-Oxo-10,1 l-dihydro-5H-dibenz[ό,/jazepme-5-carboxamide (oxcarbazepine), a compound of formula I, is used in therapy as an anticonvulsant. It has a depressant effect on the central nervous system. Also it has been used for the treatment of psychosomatic disturbances, epilepsy and trigeminal neuralgia and for the treatment of Parkinson's disease and/or Parkinsonian syndromes.

Various methods for preparing oxcarbazepine have been described in the prior art.

U.S. Pat. No. 3,642,775 describes the synthesis of oxcarbazepine [I] from a compound of formula II by reaction with phosgene in toluene followed by amidation (ethanol and ammonia) to give 10-methoxyiminostilbene (MISB) [III]. Hydrolysis of MISB [III] with dilute mineral acid gives the desired product oxcarbazepine [I].

The main disadvantage of this process is the use of phosgene, a toxic and hazardous substance and is therefore impractical in commercial scale.

Canadian Pat. No. 1,112,241 describes the synthesis of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbazepine [V] ₅ which itself can be prepared from carbamezapine [IV] by reaction with m-chloroperbenzoic acid.

IV

The main drawback of this process is the use of carbamazepine as a reagent, which is an expensive raw material. Furthermore, the epoxidation reaction is substrate sensitive and thus gives low yields when using conventional epoxidants such as peracetic acid, or it requires remarkable excesses of expensive reagents such as m-chloroperbenzoic acid. Moreover, the rearrangement reaction requires large amounts of costly catalysts and is difficult to control, thus requiring thorough purifications and hence low yields.

European Pat. No. 028028 describes the synthesis of oxcarbazepine from 5- cyanoiminostilbene [VII] (by reaction of iminostilbene [VI] with cyanogen chloride) through nitration, reduction and hydrolysis.

The main drawback of this process is the use of cyanogen chloride, a difficult to handle toxic gas; nitration using nitrating agents such as N ₂ O ₃ and N ₂ O ₄ , which are difficult to use and hydrolysis of cyano group using BF ₃ complexes, which are expensive and difficult to handle.

Swiss Pat. No. 642,950 describes the synthesis of oxcarbazepine starting from a compound of formula X followed by halogenation, treatment with alkali metal alkoxide and acid hydrolysis.

The main drawback of this invention is the use of bromine/chlorine gas for the bromination/chlorination step, which are hazardous and are difficult to handle at commercial scale. Moreover, the conversion of XIII to XIV requires deadly toxic phosgene gas.

According to U.S. Pat. No. 5,808,058, oxcarbazepine [I] can be prepared by the carbamoylation of MISB [II] using an alkali metal cyanate like sodium cyanate and a relatively strong organic or inorganic acid, followed by the hydrolysis of the enol-ether group under mild acidic conditions.

The major drawback of this process is that during carbamoylation reaction, hydrolysis of the enol-ether group of the compound of formula II also occurs, to give the corresponding ketone of the formula XVI. The ketone of formula XVI will not undergo any further reaction with metal cyanate and strong mineral acid such as 98% sulfuric acid, 98% anhydrous hydrochloric acid or hydrobromic acids in acetic acid, formic acid etc. to give the corresponding oxcarbazepine [I], thus, producing a mixture of products and related impurities, which requires tedious and uneconomical purification methods and thus low yield of oxcarbazepine.

US Pat. No. 6,670,472 assigned to Jubilant Organosys describes the synthesis of oxcarbazepine [I], by reacting 10-methoxyiminostilbene of formula [II] with an alkali metal cyanate and a mild acidic reagent, followed by the hydrolysis with a dilute mineral acid.

US Pat. Application No. US20050282797 describes the synthesis of oxcarbazepine by reacting oximinostilbene [XVI] with chlorosulfonyl isocyanate in an inert organic solvent to give the intermediate of formula [XVII], which on hydrolysis gives oxcarbazepine [I].

The major drawback of this reaction is that preparation of oximinostilbene [XVI] requires harsh conditions and involves a tedious work-up procedure. Moreover, chlorosulfonyl isocyanate is an expensive, highly moisture sensitive and toxic reagent and also the reaction with chlorosulfonyl isocyanate and subsequent hydrolysis requires a relatively complicated isolation procedure and thus gives a low overall yield.

PCT International Application no. WO/2005/066133 to Parkenky et al. discloses the process for preparation of Oxcarbazepine via novel intermediate. The process comprising preparing an intermediate 10-methoxy-5H-dibez[b,fjazeρine-5 carbonylchloride from 10-methoxyiminostilbene (II) using bis(trichloromethyl) carbonate (BTC) or triphosgene and an appropriate organic base and further converting said intermediate to the 10-methoxy-5H-dibenz [b,fj azepine-5-carboxamide using ammonia in organic solvent and resultant 10-methoxy-5H-dibenz [b,fj azepine-5- carboxamide is converted into Oxcarbazepine in the presence of lewis acids in appropriate organic solvent. The drawback of this invention is the use of toxic phosgene gas and the multi step reactions to get final product.

BTC/triphosgene

anic solvent

Lewis acid

III

The present invention provides an industrially feasible process for the preparation of oxcarbazepine via a novel intermediate which involves minimum time consumption, is economical by use of inexpensive reagents and gives overall good yield.

Summary of the Invention In accordance with principal embodiment of the present invention, there is provided an economically viable and cost effective process for preparation of oxcarbazepine of formula [I], the process comprising preparing a novel intermediate of formula [XVIII], which is further converted to oxcarbazepine of formula [I].

In accordance with one preferred embodiment of the present invention, there is provided a process for producing oxcarbazepine of formula [I] via a novel intermediate, wherein said intermediate is prepared by protecting iminostilbene of formula [VI] employing an appropriate protecting reagent to prepare N-substituted iminostilbene [X], alkoxyhalogenating the resultant N-substituted iminostilbene [X] with halogenating agent in presence of lower alcohol to obtain said intermediate of formula [XVIII].

In accordance with another embodiment of the present invention, there is provided a process for producing oxcarbazepine of formula [I] via a novel intermediate, wherein halogenating agent is selected from 1,3-dihalo-dimethylhydantoin, N-halosuccinimide, N-haloacetamide or 1,3-haloisocyanuric acid, more preferably dihalodimethyl hydantoin, and wherein said halogenating agent is recoverable and reusable in the process.

In accordance with another embodiment of the present invention, there is provided a process for producing oxcarbazepine of formula [I] via a novel intermediate, wherein the process further comprises dehydrohalogenating the obtained intermediate of formula [XVIII] to prepare the compound of formula [XIX], deprotecting the compound of formula [XIX] under basic condition to provide 10-alkoxyiminostilbene of formula [XX] ₅ further reacting the resultant 10-alkoxyiminostilbene of formula [XX] with cyanate in presence of organic solvent to provide 10-alkoxycarbamazepine of

formula [XXI] and hydrolysing the resultant compound [XXI] in presence of dilute acid to obtain the product Oxcarbazepine of formula [I].

In accordance with another embodiment of the present invention, there is provided a process for producing oxcarbazepine of formula [I] via a novel intermediate, wherein the dehydrohalogenation is carried out in the presence of organic base selected from the group comprising of trialkylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo

[2.2.2] octane, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene,

N-methylmorpholine, N-methylpiperidine, N- methylguanidine or a mixture thereof, and wherein said organic base is recoverable and reusable in the process.

In accordance with another embodiment of the present invention, there is provided a process for producing oxcarbazepine of formula [I] via a novel intermediate, wherein the process avoids production of side products and related impurities during the carboxamidation of 10-alkoxyiminostilbene, further the reaction is carried out in presence of organic solvent selected from an aromatic hydrocarbon or an aliphatic chlorinated solvent, preferably under reflux condition.

In accordance with another embodiment of the present invention, there is provided a novel intermediate, N-substituted- 10-halo- 11 -alkoxy- 10, 11 -dihydro-5H-dibenzo[ό _j /] azepine of formula [XVIII] for preparing 10-alkoxyiminostilbene, wherein said intermediate of formula [XVIII] is dehydrohalogenated to prepare the compound of formula [XIX], which is deprotected under basic condition to provide 10- alkoxyiminostilbene of formula [XX], a useful intermediate to prepare Oxcarbazepine of formula [I], wherein said intermediate 10-alkoxyiminostilbene of formula [XX] is further reacted with cyanate in presence of organic solvent to provide 10- alkoxycarbamazepine of formula [XXI] which is followed by hydrolysis in presence of dilute acid to obtain the product Oxcarbazepine of formula [I].

In accordance with further embodiment of the present invention, there is provided a novel process for the preparation of 10-alkoxyiminostilbene [XX] a useful intermediate to prepare Oxcarbazepine of formula [I] ₅ via the novel intermediate [XVIII], wherein

'-"J- UU §

the process comprises protecting iminostilbene of formula [VI] employing an appropriate protecting reagent to prepare N-substituted iminostilbene [X], alkoxyhalogenating the resultant N-substituted iminostilbene [X] with halogenating agent in presence of lower alcohol to obtain said intermediate of formula [XVIII], dehydrohalogenating the said intermediate of formula [XVIII] to prepare the compound of formula [XIX], deprotecting the compound of formula [XIX] under basic condition to provide 10-alkoxyiminostilbene of formula [XX], which is further converted to the product Oxcarbazepine of formula [I] according to the present invention.

Detailed Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The disclosed embodiment of the present invention deals with a process for the preparation of novel intermediate [XVIII], useful in preparing anti-convulsant oxcarbazepine [1], which is economically viable and cost effective and thus obviates the disadvantages mentioned in prior art.

Reaction Scheme

Vl XVIII

wherein R is C ₁ -C ₃ alkyl chain; P is -(CO)alkyl, -CHO ₅ -(CO)Oalkyl, -Fmoc, -(SO ₂ )R ₁ alkyl is C ₁ -C ₄ alkyl chain

R ₁ is C ₁ -C ₄ alkyl, substituted or unsubstituted aromatic ring and X is Cl ₅ Br or I

Thus, the subject of the present invention is a process of preparing oxcarbazepine of formula [I], the process comprising:

(i) protecting iminostilbene [VI] with an appropriate protecting reagent to give N-substituted iminostilbene [X];

(ii) alkoxyhalogenating with a halogenating agent in lower alcohol to give

[XVIII];

(iii) dehydrohalogenating the compound of formula [XVIII] obtained above, to give the compound of formula [XIX]; (iv) deprotecting to give 10-alkoxyiminostilbene [XX];

(v) carboxamidating 10-alkoxyiminostilbene [XX] with cyanic acid generated in situ by reaction of an alkali metal cyanate with a mild acidic reagent in a solvent to give a compound of formula [XXI];

(vi) hydrolysis of 10-alkoxycarbamazepine [XXI] with a dilute acid.

The process may be performed via the isolation and the optional purification of the individual intermediates of the formula X and XIX ₅ or, preferably by minimizing this procedure i.e. working directly on the crude reaction product from the partial worked up preceding steps as illustrated in the experimental section.

Protecting the nitrogen of said iminostilbene of formula [VI] is carried out by acylation, wherein acylation is performed employing an acylating agent, preferably formaldehyde, acetic anhydride, acetyl chloride, acetic acid or sodium acetate, most preferably formaldehyde. The molar ratio of acylating agent relative to the compound of formula [VI] used in the process is preferably in the range of 0.4:1 and 0.6:1 and more preferably in the range of about 0.5:1. The reaction is preferably performed in the temperature range of 80-140°C and more preferably in the temperature range of 90-

100 ⁰ C. Further the resultant reaction mixture is subjected to minimum workup by removing the volatiles by distillation and is used directly for alkoxyhalogenation reaction without further purification. The nitrogen atom of compound of formula VI can also be protected using 9-fluorenylmethyl chloroformate or aryl sulphonylchlorides.

Alkoxyhalogenation reaction according to the present invention is performed at a temperature of about -20°C to 20°C, preferably about 2-10°C. The halogenating agent used in the process is selected from dihalodimethyl hydantoin, N-halosuccinimide, 1,3- dihaloisocyanuric acid or N-haloacetamide, preferably dihalodimethyl hydantoin in the molar ratio of 1:0.6 and 1:0.4, preferably in the range of about 1 :0.5. Further the lower alcohol used in the process is preferably methanol. Furthermore, during the alkoxyhalogenation reaction, hydantoin is formed, which can be recovered from the mother liquor and reused after recrystallization from water.

Dehydrohalogenating the intermediate of formula [XVII] according the present invention is carried out in presence of organic bases, wherein said base is selected from trialkylamine, pyridine, l,8-diazabicyclo[2.2.2]octane, l,5-diazabicyclo[4.3.0]non-5- ene, l,8-diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, N-methylpiperidine or tetramethylguanidine, preferably triethylamine. Further the reaction is performed in presence of aprotic solvents at the refluxing temperature, wherein said solvent is selected from toluene, xylene, benzene or ethyl benzene, preferably toluene. The base is taken in the molar ratio of 1:1.5 to 1:2.2, preferably in the range of 1:2. Furthermore, during the dehydrohalogenation reaction, the base used with the halogen forms the solid amine salt, which can be filtered and reused in the process.

Deprotecting the resultant compound of formula [XIX] according to the present invention is carried out by deacylation of said compound in presence of base in the molar ratio of about 1:2 to about 1:6, preferably in the ratio of about 1:1.4 and a solvent, wherein said base is selected from alkali metal alkoxide or inorganic base consisting of sodium methoxide, potassium or sodium tertiary butoxide, potassium or sodium hydroxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium

peroxide, sodium or potassium hydride, preferably sodium methoxide and wherein said solvent is selected from the group comprising N,N-dimethylformamide, dimethylsulphoxide, N,N-dimetylacetamide, N-methylpyrrolidone, dimethylimidazolidone, C ₁ -C ₅ alcoholic solvents, toluene, xylene or acetonitrile. Optionally, phase transfer catalyst is used in the reaction. Further, said reaction is performed at a temperature in the range of 20-60°C, preferably at 40-50°C.

Carboxamidation of 10-alkoxyiminostilbene according to the present invention comprises reacting 10-alkoxyiminostilbene with HOCN in presence of organic medium, wherein the disclosed cyanates include sodium or potassium cyanate, preferably sodium cyanate and said organic medium is selected from an aromatic hydrocarbon solvent or an aliphatic chlorinated solvent such as benzene, toluene, xylene or dichloromethane. The generation of cyanate is performed in situ by the reaction of alkali metal cyanate with a mild acidic reagent. The acidic reagent is preferably a weak acid, such as an aromatic acid. Preferred aromatic acids include weak non-aliphatic organic acids such as benzoic acid or halo substituted benzoic acids; suitable substituents being halo especially chloro e.g. para-chlorobenzoic acid. Excess molar quantity of the weak acid is preferably used in comparison to 10- alkoxyiminostilbene [XX], in the range of from 2 to 10 molar excess, preferably about 5 to 8 times. Further the reaction is carried out employing an organic medium, preferably under reflux conditions. The organic medium is selected from aromatic hydrocarbon solvent or aliphatic chlorinated solvent, preferably benzene, toluene, xylene or dichloromethane.

Hydrolysis of 10-alkoxyiminostilbene is carried out using acidic conditions.

The oxcarbazepine can also be prepared from the said 10-alkoxyiminostilbene using any prior known processes.

The invention is further illustrated but not restricted by the description in the following examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein.

Example 1

Preparation of 5-acetyl-lO-bromo-l l-methoxy-10,1 l-dihvdro-5H-dibenzor&,/1azepine, compound of formula [XVIII], when R = Me Iminostilbene [VI] (100 g) was gradually added to acetic anhydride (110 g) and the reaction mixture was heated to 90-95°C for a period of 4-5 h. After completion of the reaction, volatiles were removed by distillation in vacuo at 80-95°C and cooled to give crude [X] (When P is COCH ₃ ).

Methanol (250 ml) was added to the crude [X] at 45-50°C and stirred. The reaction mixture was cooled. Dibromodimethylhydantoin (80 g) was added at 4-8°C and stirred for 6 h. The reaction mixture was cooled and stirred. The solid thus formed, was filtered and washed with chilled methanol and dried in vacuo to give the novel intermediate of formula [XVIII], (when P is COCH ₃ ) (yield = 164 g)

The intermediate [XVIII] was characterized by ¹ H NMR, ¹³ C NMR, IR and LC-MS spectroscopy.

IR (KBr, cm ^"1 ): 3066, 2948, 2932, 1671, 1598, 1438, 1372, 1332, 1125, 772, 602, 588

¹ H NMR (400 MHz, CDCl ₃ , δ ppm): 2.30 (S, 3H, -COCH ₃ ), 3.60 (S, 3H, -OCH ₃ ), 5.08 (d, IH, -CHOMe), 5.21 (d, IH, -CHBr), 7.26-7.59 (m, 8H)

¹³ C NMR (400 MHz, CDCl ₃ , ppm): 22.7, 54.8. 59.3, 83.8, 125.7, 126.0, 127.1, 127.4, 128.3, 128.6, 128.7, 128.9, 129.2, 129.5, 133.7, 133.8, 169.6 ES (m/e): 346 (M+l) and 348 (M+3)

Example 2

Preparation of 5-formyl-lO-bromo-l l-methoxy-10,1 l-dihydro-5H-dibenzof6,flazepine, compound of formula [XVIII]. when R = Me

Iminostilbene [VI] (100 g) was gradually added to formic acid (200 g) and acetic anhydride (110 g) and the reaction mixture was heated to 60-65 ⁰ C for a period of 30 minutes. After completion of the reaction, volatiles were removed by distillation in vacuo at 80-95 ⁰ C and cooled to give crude [X] (P is formyl).

Methanol (700 ml) was added to the crude [X] at 45-50°C and stirred. The reaction mixture was cooled. Dibromodimethylhydantoin (80 g) was added at 4-8 ⁰ C and stirred for 6 h. The reaction mixture was cooled and stirred. The solid thus formed, was filtered and washed with chilled methanol and dried in vacuo to give the novel intermediate of formula [XVIII] (yield = 120 g)

The intermediate [XVIII] was characterized by ¹ H NMR, IR and LC-MS spectroscopy. IR (KBr, cm ^'1 ): 3429, 3362, 2927, 2879, 1769, 1694, 1600, 1580, 1496,1484,1447, 1400, 1341, 1280, 1259, 1149, 1119, 1085, 983, 794,775,761, 747, 674, 664, 605, 533, 500, 449

¹ H NMR (400MHz, CDCl ₃ , δ ppm): 3.2, 3.4(S, 3H, -OCH ₃ ), 4.68, 5.0 (d, IH, - CHOMe), 5.3, 5.7 (d, IH, -CHBr), 7.1-7.6 (m, 8H), 8.4, 8.7 (S, IH, -COH) ES (m/e): 332 (M+l) and 334 (M+3)

Example 3

Preparation of lO-methoxyiminostilbene, compound of formula [XX] when R = Me 5-Acetyl-10-bromo-l l-methoxy-10 ₅ ll-dihydro-5H-dibenzo[ό^]azeρine of the formula [XVIII] (160 g) was added to toluene (800 mL). Triethylamine (95 g) was added and the reaction mixture was heated to reflux for 24-25 h. The reaction mixture was cooled to room temperature and filtered. The solid was washed with toluene and the combined filtrate was concentrated by distillation in vacuo to give crude [XIX].

The crude [XIX] was cooled and DMF (250 ml) was added. The resulting solution was cooled and solid sodium methoxide (35 g) was added. The reaction mixture was stirred at room temperature. Methanol was added and the reaction mixture was further stirred for 1 h. The reaction mixture was poured into ice-cold water and stirred. The suspension was filtered and washed with water. The solid thus formed was dried in hot air at 50-55°C for 24 h to give compound of formula [XX] (yield = 100 g)

Example 4

Preparation of 10-methoxyiminostilbene, compound of formula [XXl when R = Me 5-Formyl-10-bromo-l l-methoxy-10,1 l-dihydro-5i7-dibenzo[έ _j /]azepine of the formula [XVIII] (160 g) was added to toluene (800 ml). DBU (l,8-diazabicyclo[5.4.0]undec-7- ene) (95 g) was added and the reaction mixture was heated to reflux for 30 minutes. The reaction mixture was cooled. Water was added and the resulting mixture was stirred. The organic layer was separated and solid KOH (70 g) and PEG-200 (30 g) was added. The reaction mixture was heated to reflux and cooled. Water was added and the organic layer was separated and concentrated by distillation in vacuo to give compound of formula [XX] (yield = 80 g)

Example 5

Preparation of 10-oxo-lOJ l-dihydro-5H-dibenz[6,/]azepine-5-carboxamide (Oxcarbazepine), compound of formula [I] 10-Methoxyiminostilbene, compound of formula [XX], (100 g) was dissolved in toluene (1000 ml). Sodium cyanate (100 g) and benzoic acid (190 g) were added and the reaction mixture was vigorously stirred and heated at 85-90°C for 1O h. After the reaction completion, the reaction mixture was cooled, followed by the addition of aqueous NaOH solution (10%, 800 ml) to pH 11. The reaction mixture was stirred for 3 h at this temperature followed by cooling to 0-5 ⁰ C. The reaction mixture was filtered and washed with toluene and water and dried to give the compound of formula [XXI] (yield = 110 g).

The crude [XXI] was taken in a RB flask and methanol (600 ml) was added. The reaction mixture was heated to reflux. The reaction mixture was cooled, methanol was distilled off and toluene (50 ml) was added and further distilled. The residual [XXI] was cooled and toluene (500 ml) was added and stirred. Water was added followed by addition of cone. HCl. The reaction mixture was heated at 75-80°C. The reaction mixture was cooled and the crude oxcarbazepine [I] was filtered, washed with toluene, 5% NaHCO ₃ and DM water and vacuum dried to give crude oxcarbazepine of formula

[I] (yield = 82 g). The oxcarbazepine thus formed can be purified by dissolving in methanol (600 ml). The reaction mixture was stirred for 15-20 min. The pH of the

reaction mixture was maintained in the range of 7.5-8.5. The reaction mixture was stirred and heated to reflux at 65-70°C for 2 h, and cooled, filtered and washed with methanol and dried to give oxcarbazepine [I], which was further purified by heating in methanol (1400 ml) and dichlormethane (1400 mL). The reaction mixture was refluxed for 30 min and treated with activated carbon. The reaction mixture was filtered through Hyflo bed and washed with methanol and dichloromethane mixture (1:1). The solvent was distilled to residual volume of 1000 mL. The reaction mixture was cooled and maintained. The reaction mixture was filtered through buchner funnel and washed with methanol and dried under vacuum at 50-60°C to give pure oxcarbazepine (90 g).

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.