Description:FIELD OF INVENTION
The present invention relates to a one pot process for the preparation of highly pure oxcarbazepine. The present invention further relates to a one pot process for the preparation of highly pure oxcarbazepine substantially free of impurities in high yield. The present invention still further relates to an environmental friendly, commercially viable one pot process for the preparation of highly pure oxcarbazepine substantially free of impurities in high yield.
BACKGROUND OF THE INVENTION
Oxcarbazepine is commercially available as TRILEPTAL®, which has been approved by the United States Food and Drug Administration for use in the treatment of epilepsy and use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children.

Formula (I)

Oxcarbazepine was first claimed and disclosed in US 3,642,775 assigned to Ciba-Giegy Corporation. The preparation of Oxcarbazepine included, reaction of 10-methoxy- 5H-dibenzo[b,f]azepine with phosgene gas to give 10-methoxy-5H- dibenzo[b,f]azepine-5-carbonyl chloride and ammonolysis of the resultant compound to give the amide followed by hydrolysis to give Oxcarbazepine.

US 5,808,058 assigned to Trifarma S.R.L., claims a process for the preparation of Oxcarbazepine by carbomylating 10-methoxyiminostilbene with sodium or potassium cyanate in the presence of strong non-aqueous acid, followed by mild aqueous acid hydrolysis of the methoxy group. It results in formation of impurities and results in lower yield.

US 6,670,472 B2 assigned to Max India Limited, claims a process for the preparation of Oxcarbazepine, which comprises reacting 10-methoxyiminostilbene with cyanic acid generated in situ by reaction of an alkali metal cyanate and a mild aromatic acidic reagent such as benzoic acid, the obtained 10-methoxycarbamazepine is hydrolyzed to form Oxcarbazepine. The major disadvantage of this process is the reported yields are very low of about 28-49%.

US 2005/0203297 Al assigned to Glenmark Pharmaceuticals, claims a process for the preparation of 5H-dibenzo[b,f]azepine-5-carboxamide by reacting 5H- dibenzo[b,f]azepine with one or more alkali or alkaline-earth cyanates in the presence of one or more unsaturated dicarboxylic acid. But, this process involves multiple purifications.

US 7112673B2 assigned to Novartis provides a process for the production of a compound of formula III by carbamoylation of a compound of formula II with a metal cyanate, whereby the reaction is effected using acetic acid, in the presence of of metal cyanate and in the absence of a further solvent. It is further subjected to acidic hydrolysis to provide Oxcarbazepine of formula (I). The yields obtained by this process are on lower side and needs purifications to remove compounds of formula (III) and (V).

Wherein R1 is C1-4 alkyl.
Scheme-1
However, the oximinostilbene of formula (V) is formed as an impurity in significant amounts.

formula (V)
Likewise, 10-Methoxycarbamazepine of formula (III), iminostilbene of formula (IV) and 10-methoxyiminostilbene of formula (II) are also formed as an impurity in significant amounts. (Formula II is the unreacted starting material and formula III is the unreacted intermediate).

formula (II) formula (III) formula (IV)

Accordingly, there is a need to provide a process for production of highly pure oxcarbazepine substantially free of impurities.

OBJECT OF THE INVENTION
A first aspect of the present invention provides a one pot process for the preparation of Oxcarbazepine of Formula (I),

Formula (I)
comprising the steps of:
a) contacting a compound of formula (II)

Formula (II)
with metal cyanate in the presence of a C1-C4 aliphatic acids in a non-polar organic solvent to obtain a compound of formula (III);

Formula (III)
b) contacting a compound of formula (2) with acid in an organic solvent to produce pure oxcarbazepine of formula (I);
c) contacting crude oxcarbazepine with a mixture of two acids to provide a highly pure oxcarbazepine.
A second aspect of the present invention provides a one pot process for the preparation of Oxcarbazepine of Formula (I),

Formula (I)
comprising the steps of:
a) contacting a compound of formula (II)

Formula (II)
with sodium cyanate in the presence of a C1-C4 aliphatic acids in a non-polar organic solvent to obtain a compound of formula (III);

Formula (III)
b) contacting a compound of formula (III) with acid in an organic solvent to produce pure oxcarbazepine of formula (I).

A third aspect of the present invention provides a one pot process for the preparation of Oxcarbazepine of Formula (I),

Formula (I)
comprising the steps of:
a) contacting a compound of formula (II)

Formula (II)
with sodium cyanate in the presence of a C1-C4 aliphatic acids in a non-polar organic solvent to obtain a compound of formula (III);

Formula (III)
b) contacting a compound of formula (2) with acid in an organic solvent to produce oxcarbazepine of formula (I);
c) contacting crude oxcarbazepine with a mixture of two acids to provide a highly pure oxcarbazepine with substantially less than 0.5% of oximinostilbene impurity of formula (V) and less than 0.1% of 10-Methoxycarbamazepine impurity of formula (III).

Formula (V) Formula (III)
A fourth aspect of the present invention provides a one pot process for the preparation of Oxcarbazepine of Formula (I),

Formula (I)
comprising the steps of:
a) contacting a compound of formula (II)

Formula (II)
with sodium cyanate in the presence of a C1-C4 aliphatic acids in a non-polar organic solvent to obtain a compound of formula (III);

Formula (III)
b) contacting a compound of formula (2) with acid in an organic solvent to produce oxcarbazepine of formula (I);
c) contacting crude oxcarbazepine with a mixture of two acids to provide highly pure oxcarbazepine in high yield.
A fifth aspect of the present invention provides a one pot process for the preparation of highly pure Oxcarbazepine of Formula (I), which is about 99.95% pure as measured by HPLC.
A sixth aspect of the present invention provides a one pot process for the preparation of highly pure Oxcarbazepine of Formula (I), with a high yield of at least 98%.
A seventh aspect of the present invention provides a one pot process for the preparation of high yielding and highly pure Oxcarbazepine of Formula (I), which has a high yield of at least 98% and is about 99.95% pure as measured by HPLC.
An eight aspect of the present invention provides a one pot process for the preparation of highly pure Oxcarbazepine of Formula (I), having a non-detectable limit of impurities of formula (III), formula (IV) and Formula (V) as measured by HPLC.

formula (III) formula (IV) formula (V)

A ninth aspect of the present invention provides a one pot process for the preparation of highly pure pharmacopeial grade Oxcarbazepine.
A tenth aspect of the present invention provides a simple and environment friendly one pot process for the preparation of highly pure Oxcarbazepine avoiding the use of hazardous reagents.
A eleventh aspect of the present invention provides a commercially viable one pot process for the preparation of highly pure Oxcarbazepine.
DETAILED DESCRIPTION OF INVENTION
For the purpose of promoting an understanding of the application of principles of the invention, reference will now be made to the embodiments in the specific language to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated process, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skilled in the art to which this invention belongs. The composition, methods, and examples provided herein are illustrative only and not intended to be limiting.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods and materials are now described.
The terminology and structure employed herein is for describing, teaching, and illuminating some embodiments and their specific features and elements and does not limit, restrict, or reduce the spirit and scope of the invention.
The term contacting refers to carbamoylation or hydrolysis reaction and has been used interchangeably throughout the specification.
The term highly pure refers to pharmaceutical grade Oxcarbazepine and has been used interchangeably throughout the specification.
The term substantially free of impurities refers to impurities either not detected or less than or equal to 0.05%.
The term V refers to Volume of solvent or reagent. The volume of the solvent or reagent is calculated with reference to weight of the crude oxcarbazepine.
The term IP refers to Indian Pharmacopoeia, EP to European Pharmacopoeia and USP to United States Pharmacopeia.
The reaction scheme of the one pot process for the preparation of Oxcarbazepine is depicted below in Scheme-2.
Scheme-2
The carbamoylation reaction of compound of formula (II) with a metal cyanate to provide a compound of formula (III) is effected with an acid in a non polar organic solvent.
The metal cyanate is preferably sodium or potassium cyanate.
The acid carbamoylation reaction of compound of formula (II) is selected from the group comprising of C1-C4 aliphatic acids such as acetic acid, formic acid, propionic acid, n-butyric acid, iso-butyric acid and mixtures thereof.
The temperature employed for the carbamoylation reaction is in the range of -5 to 250C, preferably from 0 to 200C, most preferably from 0 to 150C.
The hydrolysis reaction of compound of formula (III) to provide a oxcarbazepine of formula (I) is efffected with an acid in an organic solvent.
The non polar organic solvent is selected from toluene, hexane, cyclohexane, petroleum ether, chloroform, diethyl ether, carbon tetrachloride, benzene, xylene, methylene dichloride, heptane, decane, chlorobenzene, methyl tertiary butyl ether or esters of aliphatic acids such as ethyl acetate, methylacetate, isopropyl acetate, buyl acetate and mixtures thereof.
The product of carbomylation is used as such without its isolation.
The hydrolysis reaction of compound of formula (III) to provide oxcarbazepine of formula (I) is efffected with an acid in an organic solvent.
The acid for the hydrolysis reaction of compound of formula (III) is selected from the group comprising of inorganic acids such as but not limited to hydrohalides (e.g.hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like.
The organic solvent for the hydrolysis reaction of compound of formula (III) is selected from acetone, ethyl acetate, butyl acetate, propylene glycol, diethyl ether, ethylene glycol, methyl isobutyl ketone, 2-methyltetrahydrofuran, dichloroethane, chlorobenzene or mixtures and the like.
The temperature for the hydrolysis reaction employed is in the range of 20 to 700C, preferably from 25 to 600C, most preferably from 35 to 550C.
The hydrolysis reaction completion is followed by the pH adjustment using a base. Suitable base is selected from the group comprising of metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide, metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; and metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate.
The purification of oxcarbazepine is carried out in the presence of an acid in a solvent.
The acid for the purification of oxcarbazepine is selected from the group comprising of C1-C4 aliphatic acids such as acetic acid, formic acid, propionic acid, n-butyric acid, iso-butyric acid and mixtures thereof.
The acid used for the purification of oxcarbazepine is a mixture of more than two acids. More preferably it is a mixture of more than one acid. Most preferably it is a mixture of two acids. The most preferable mixture of two acids is formic and acetic acid.
The ratio of mixture of acetic acid to formic acid is selected from 1.5:4.5, 2:4, 2.5:3.5, 1:1, 3.5:2.5, 4:2 and 4.5:1.5. Most preferable ratio of acetic acid to formic acid is 1:1 in the mixture.
The solvent used for purification of oxcarbazepine is selected from the group comprising of organic solvents. The organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such asethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, toluene or mixtures thereof.
Detailed experimental parameters suitable for this one pot process of making oxcarbazepine are provided by the following examples, which are intended to be illustrative and not limiting of all possible embodiments of the invention.
Example-1: Process for preparation of highly pure Oxcarbazepine
In a 4-necked RBF equipped with cooling and stirring, 300 ml toluene was charged followed by 46 g of sodium cyanate and 100 g of compound of formula (II) at 25 to 350C under stirring. Reaction mass was cooled and then charged 300 ml of glacial acetic acid under stirring. Reaction mass was stirred at 0 to 150Cfor 3-5hrs. Reaction progress was monitored by HPLC. After completion of reaction (compound III) charged acetone (0.6 Volume) followed by con. HCl (1.0 Volume). The reaction mass was heated to 35-45oC for 2-4hrs. Reaction progress was monitored by HPLC (98% conversion). After completion of reaction, adjust the pH of the mass to neutral with NaOH solution, filtered the solids, washed with water to obtain Oxcarbazepine crude. The HPLC purity of the crude Oxcarbazepine was 99.9%. The crude material was dissolved in mixture of Glacial acetic acid (1V) and Formic acid (1V) under stirring. To the solution was charged water (V) under stirring. Filtered the solid, washed with hot water. The material obtained was dried under vacuum to obtain Oxcarabzepine in the pure form as white crystalline solid. Yield:98%.
HPLC purity of Oxcarbazepine: 99.95%
HPLC profile of Impurities:
Impurity of formula (II): Not Detected; Impurity of formula (III): Not Detected; Impurity of formula (IV): <0.05; Impurity of formula (V): Not Detected.
The other purification methods attempted are summarized below.
Example-2: Purification of Oxcarbazepine crude (Method-II)
In a 4-necked RBF equipped with cooling and stirring, Glacial acetic acid (10V) was charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was heated and filtered. To the solution was charged water (5V) under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine. Yield:95%.
Example-3: Purification of Oxcarbazepine crude (Method-III)
In a 4-necked RBF equipped with cooling and stirring, anhydrous formic acid (3V) was charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was filtered. To the solution was charged water (10V) under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine.Yield:94-95%.
Example-4: Purification of Oxcarbazepine crude (Method-IV)
In a 4-necked RBF equipped with cooling and stirring, glacial acetic acid (4V) and Toluene (5V) were charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was heated and filtered. To the solution was charged water (5V) under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine. Yield:93-94%.
Example-5: Purification of Oxcarbazepine crude (Method-V)
In a 4-necked RBF equipped with cooling and stirring, Glacial acetic acid (4V) and MDC (4V) were charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was heated and filtered. To the solution was charged water under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine. Yield:93%.
Example-6: Purification of Oxcarbazepine crude (Method-VI)
In a 4-necked RBF equipped with cooling and stirring, Glacial acetic acid (2V) and Formic acid (4V) were charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was heated and filtered. To the solution was charged water under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine. Yield:94%.
Example-7: Purification of Oxcarbazepine crude (Method-VII)
In a 4-necked RBF equipped with cooling and stirring, Glacial acetic acid (4V) and Formic acid (2V) were charged followed by Oxcarbazepine crude obtained from Example 1 at 25 to 350C under stirring. Reaction mass was heated and filtered. To the solution was charged water under stirring and obtained solids were filtered, washed with water, and then dried to yield Oxcarbazepine. Yield:94.5%.
Comparison with prior art process
The preparation of Oxcarbazepine was performed as per procedure prescribed in the journal organic process Research & Development 2009, 13, 870–874 (prior art 1) and CA 2639210A1 (prior art 2). The advantage of the one pot process of Oxcarbazepine over the prior art processes is provided below.

Advantage of one pot process for the preparation of Oxcarbazepine of the present invention with the prior art process 1 and 2
1. The present invention is a one pot reaction with reaction conversion >99% and major impurity formed as per prior art processes is Oximinostilbene. As per the present invention Oximinostilbene impurity of formula (V) content is not detectable level.
2. The usage of toluene as solvent in combination of Acetic acid and carrying out reaction at 0 – 15oC in the process has got more advantages with respect commercialization of Oxcarbazepine as the impurity formation is drastically controlled in the process. The traces of impurities formed are washed out during isolation of product along with toluene mother liquor.
3. The yield obtained by the process of the present invention is 98%, the quality of Oxcarbazepine produced meets IP, USP and EP Pharmacopeial specifications.
4. The process involved is easily scalable, operational friendly and robust, does not involve usage of any hazardous reagents and hence it is environmentally friendly.
5. The crystallization of product is done by dissolving the material in acetic acid and formic acid mixture followed by precipitation by adding water to get pharmaceutical grade Oxcarbazepine API.
It has now surprisingly been found that highly pure pharmaceutical grade oxcarbazepine in high yield can be obtained in a one pot process in presence of a mild acid and an additional solvent (toluene) when compared with prior art process where only acid has been used avoiding any solvent. It results in substantially reducing the impurities obtained in prior art process 1 and 2. As a consequence the purity and yield is significantly improved. , Claims:WE CLAIM:
1. A one pot process for preparing highly pure oxcarbazepine of formula (I) substantially free from impurities,

(I)
the process comprising the steps of:
a. contacting a compound of formula (II)

(II)
with metal cyanate in the presence of a C1-C4 aliphatic acids in a non polar organic solvent to obtain a compound of formula (III);

(III)
b. contacting a compound of formula (III) with acid in an organic solvent to produce pure oxcarbazepine of formula (I);
c. contacting pure oxcarbazepine with a mixture of two acids to provide a highly pure oxcarbazepine.
2. A one pot process for preparing highly pure oxcarbazepine substantially free from impurities as claimed in claim 1, wherein C1-C4 aliphatic acid of step (a) is selected from acetic acid, formic acid, propionic acid, n-butyric acid, iso-butyric acid and mixtures thereof.
3. A one pot process for preparing highly pure oxcarbazepine substantially free from impurities as claimed in claim 1, wherein non polar organic solvent of step (a) is selected from toluene, hexane, cyclohexane, petroleum ether, chloroform, diethyl ether, carbon tetrachloride, benzene, xylene, methylene dichloride, heptane, chlorobenzene, methyl tertiary butyl ether and esters of aliphatic acids or decane and mixtures thereof.
4. A one pot process for preparing highly pure oxcarbazepine substantially free of impurities as claimed in claim 1, wherein the contacting of step (a) is carried out between a temperature of -5 to 250C.
5. A one pot process for preparing highly pure oxcarbazepine substantially free from impurities as claimed in claim 1, wherein organic solvent of step (b) is selected from ethyl acetate, butyl acetate, propylene glycol, acetone, diethyl ether, ethylene glycol, methyl isobutyl ketone, 2-methyltetrahydrofuran, dichloroethane, chlorobenzene or mixtures thereof.
6. A one pot process for preparing highly pure oxcarbazepine substantially free from impurities as claimed in claim 1, wherein mixture of two acids of step (c) is selected from acetic acid, formic acid, propionic acid, n-butyric acid and iso-butyric acid.
7. A one pot process for preparing highly pure oxcarbazepine substantially free from impurities as claimed in claim 1, wherein the yield of oxcarbazepine is greater than 98%.
8. Highly pure oxcarbazepine as claimed in claim 7, which is 99.95% pure as measured by HPLC.
9. Highly pure oxcarbazepine as claimed in claim 7, having a non-detectable limit of impurities of formula (III), formula (II) and formula (V) as measured by HPLC.