FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
ONE POT SYNTHESIS FOR PREPARATION OF OXCARBAZEPINE
M/S AMOLI ORGANICS PVT. LTD, 407 DALAMAL HOUSE, J.B.ROAD, NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under
the companies Act, 1956
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

Field of the invention
The present invention relates to "ONE POT SYNTHESIS FOR PREPARATION OF OXCARBAZEPINE"
Oxcarbazepine is structurally a derivative of Carbamazepine, adding an extra oxygen atom to the benzylcarboxamide group. This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia occasionally associated with Carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as Carbamazepine - sodium channel inhibition -and is generally used to treat partial seizures in epileptic children and adults.
Background of the invention
Oxcarbazepine is commercially developed by NOVARTIS, and marketed as TRILEPTAL®. It is chemically designated as 10,11-Dihydro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide. Its empirical formula is C15H12N2O2, its molecular weight is 252.26, and its structural formula is;

The process for preparation of Oxcarbazepine has been described in various patents and to cite a few references, US Patent No. 3,462,775 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 temperature at around 95°C. and the hydrochloric acid produced leads to the formation of undesirable impurities. The associated disadvantage of this process is use of phosgene gas and high temperature making this process commercially unattractive.


US Patent No. 5,808,058 discloses the preparation of Oxcarbazepine as describe in Scheme B, which consist of starting group 10-methoxy-5H-dibenz[b, f]azepine and subjecting it to direct carbomoylation with isocyanic acid generated insitu from cyanates and acids and subjecting the product to acid hydrolysis of enol ether. An alternative process to obtain Oxcarbazepine start with hydrolysis reaction before the carbomoylation in that case carbomoylation agent is chlorosulfonyl isocyanate. There are few disadvantages associated with this method is use of halogenated hydrocarbons as a solvent and higher temperature of about 40°-50°C.

US Patent No. 7,982,032 describes the process for preparation of Oxcarbazepine by different route which comprises reacting compound of formula (Ivb) with alkali metal methoxide to yield compound of formula (II); and then compound of formula (I) as describe in reaction scheme C.


US Pat. No. 6,670,472 describes the process for preparation of Oxcarbazepine which includes reacting 10-methoxyiminostilbene with cyanic acid (HOCN) in the presence of mild acidic reagent in a solvent and also discloses the improved method for hydrolysis in biphasic system. This process suffered from higher reaction temperature conditions of about 75°-90°C and thus not suitable for large scale manufacturing practices, process may be illustrated as in Scheme D;

In view of the increasing demand for Oxcarbazepine production in pharmaceutical industries and by looking at the earlier industrially unattractive processes which requires drastic condition there is an urgent emergence of the need to develop an industrially applicable and environment friendly method for production of Oxcarbazepine. Surprisingly we are come up with the method for the preparation of Oxcarbazepine which is efficient and more economical and successfully avoid the use of halogenated solvent and higher reaction temperature condition. Said method for the preparation of Oxcarbazepine also eliminate the use of catalyst in the process as required in the prior art. Thus, adding one more economical benefit to the process.

Object and Summary of the Invention
The principal object of the present invention is to provide an industrial green process for preparation of Oxcarbazepine.
Yet another object of the present invention is to overcome the use of drastic reaction condition and environmentally hazardous solvent like halogenated solvent. One more object of the present invention is to provide the cost effective, direct, one pot synthesis and industrially feasible process for preparation of Oxcarbazepine. Further object of the present invention is to provide the process for preparation of Oxcarbazepine in its substantially pure form with high yield.
The present invention provides a process for preparation of 10,11-Dihydro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide, compound of formula (1). Preferred embodiment of the process comprises

(a) reacting compound of formula (2) with alkaline earth or alkali metal isocynate in presence of weak acid to yield compound of formula (3); and

(b) converting compound of formula (3) to formula (1) by acid hydrolysis and;
(c) Further purify the resulting compound using suitable purification method.

Detailed description of the invention
We have now developed industrial green process for the preparation of 10,11-Dihydro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide, compound of formula (1), starting from compound of formula (2) to give compound of formula (3) and converting further in to compound of formula (1) by the process as disclosed herein and said process can be schematically illustrated as below;

One embodiment of the invention comprises reacting compound of the formula (2) with alkaline earth or alkali metal isocyanate and weak acid to get the compound of formula (3) and subsequent acid hydrolysis would lead to formation of title compound. The present invention describes the preparation of Oxcarbazepine, comprises;
reacting compound of formula (2) with alkali or alkaline earth metal isocyanates which include but not limited to the compounds like Potassium isocyanate, Sodium isocyanate and the like, preferably sodium isocyanate, in presence of weak acid include but not limited to glacial acetic acid, monochloro acetic acid, monobromo acetic acid, propionic acid, formic acid, dichloro acetic acid, trichloro acetic acid, 2-chloropropionic acid preferably the said acid is glacial acetic acid to get the compound of formula (3).
Further embodiment of the present invention comprises performing the said reaction between compound of formula (2) and said isocyanate in presence of weak acid at room temperature.
According to one more embodiment of the present invention compound of formula (3) is converted to compound of formula (1) through hydrolysis by acid includes but not limited to Sulfuric acid, Hydrochloric acid, Nitric acid, Perchloric acid, Boric acid and the like, preferably the acid used in hydrolysis is 45-50% Sulfuric acid.

Already described the invention with reference to certain preferred embodiments, other embodiment will be come apparent to person skilled in the art from consideration of the specification. The invention is further described by reference to the following examples disclosing in detail the preparation of Oxcarbazepine of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The details of the invention are further illustrated in the following examples.
Example 1: Preparation of 10.1 l-Dihvdro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide
In a 5 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, Glacial Acetic acid (400 g, 6.66moles) was charged and cooled to 18°-24°C. Now add 10-methoxy-5H-dibenzo[b, f]azepine (100 g, 0.44moles) and Sodium isocyanate (65 g, 0.6moles) stir the reaction mixture for 3 hours at the same temperature, make slurry and add slowly sulfuric acid (98 g, 2.91moles) and water (135 ml) again stir for 2 hours at the same temperature add water (4 liter) filter and wash with water and optionally purified by reflux in Methanol. Resulted solid obtained was filtered and dried under vacuum of about 500mmHg and finally purified by known method in the art. Product was weighed lOOg. (HPLC purity-97.5% and Yield 0.88%).
Example 2: Purification of 10,11-Dihydro-10-oxo-5H-dibenzr[b, f]azepine-5-carboxamide
In a 3 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, 10,1 l-Dihydro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide (50g) as obtained in Example 1 with Acetone (1200 ml) and water (300 ml) reflux and maintain for 1 hour at 55°-60°C. add activated charcoal (2.5g) to the resultant mixture and filter the solution to get the wet cake subsequently wash with water and add Conc.HCl (0.18 ml) stir for 15 minutes and filter the resultant solution to get the wet cake and dry under vaccum of about 600-650mmHg. (HPLC purity-99.8% and Yield 0.80%)

We claim:
1. A process for preparation of 10,11-Dihydro-10-oxo-5H-dibenz[b, f]azepine-5-carboxamide, compound of formula (1),

a) Reacting compound of formula (2) with alkali or alkaline-earth metal
isocyanate in presence of weak acid to obtain the compound of formula
(3);
b) Hydrolyzing the said compound of formula (3) by using mineral acid to obtain the compound of formula (1);
c) Purifying the compound of formula (1) by refluxing it in to the suitable solvent or mixture thereof.
2. The process as claimed in claim 1 is one-pot process.
3. The process as claimed in claim 1(a), wherein said alkali or alkaline-earth metal
isocyanate is selected from Sodium isocyanate and potassium isocyanate.
4. The process as claimed in claim 1(a), wherein the said weak acid is selected from glacial acetic acid, carbonic acid, Oxalic acid, and formic acid preferably glacial acetic acid.
5. The process as claimed in claim 1, wherein said process to obtain compound of formula (1) is performed at 15°-25°C and optionally purified the said compound in suitable solvent or mixture thereof.

6. The process as claimed in claim 1 (b), wherein a mineral acid is 45-50% Sulfuric acid.
7. The process as claimed in claim 1(c), wherein suitable solvent is selected from Acetone, Ethyl acetate, acetonitrile, Dimethylformamide, Dimethylsulfoxide and water or mixture thereof, preferably acetone and water mixture.