FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR THE PREPARATION OF RUFINAMIDE"
Applicant
Name: Torrent Pharmaceuticals Lim ited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF RUFINAMIDE
FIELD OF THE INVENTION:
The present invention relates to novel intermediate l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-1,2,3-triazole of formula (V) and its process for preparation. The present invention further comprises a novel intermediate of formula (VI) and its process of preparation. The invention also relates to use of these novel intermediates of formula (V) & (VI) for the preparation of Rufinamide and its pharmaceutically acceptable salts and solvates.
BACKGROUND OF THE INVENTION:
Rufinamide is an anticonvulsant medication. It has been used in combination with other medication and therapy to treat Lennox-Gastaut spasms and various other seizure disorders. Rufinamide, a triazole derivative, first time disclosed in 1984, was developed by Novartis Pharma and is manufactured by Eisai. The chemical name for Rufinamide is 1- (2,6-difluorobenzyl)-l H-1 ,2,3-triazole-4-carboxamide (formula I), which has the structural formula (I):

Rufinamide is marketed as Banzel® in the USA and as Inovelon ® in Europe. It is available as 100, 200 and 400 mg tablets of Rufinamide.
Rufinamide was first time disclosed in EP 199262. The synthetic method for the preparation of Rufinamide as disclosed in EP 199262 is depicted in the following reaction Scheme-1.

Scheme-1

A 2,6-difluorobenzylchloride of formula II and sodium azide are reacted in the presence of dimethyl sulfoxide to obtain 2-(azidomethyI)-l ,3-difluorobenzene of formula III, which is then treated with 2-propiolic acid and further reacted with methanol in the presence of sulfuric acid to yield methyl l-(2,6- difluorobenzyl)-l H-l,2,3-triazo!e-4-carboxylate intermediate of formula IV. This intermediate is then isolated and further converted into Rufinamide by animation using methanolic ammonia.
EP 199262 also discloses the preparation of Rufinamide by reacting 2,6- difluorobenzyl azide of formula (III) with propio'lic acid to give the corresponding carboxylic acid intermediate which is then treated with thionyl chloride and subsequently aminated with ammonia to obtain Rufinamide.
The process as disclosed in EP 199262 suggests the direct use of carboxylic acids with azides, which under goes cycloaddition reaction during the synthesis of 1,2,3-triazoles, is not recommended as organic azides are explosive in nature and its contact with acids liberates hydrazoic acid. Further, the suggested reaction is slow and resulting very less yield.
International patent application WO 98002423 discloses a process for preparation of Rufinamide by novel intermediate by reacting 2,6-difluorobenzylazide with 2-chloroacry lonitrile.

International patent application WO 010043849 discloses a process for preparation of Rufinamide by following scheme-2.
Scheme-2

A 2,6-difluorobenzylhalide of formula (II), wherein X is halogen, is reacted with an azide to obtain 2-(azidomethyl)-l,3- difluorobenzene of formula (III), which is then treated with methyl propiolate to obtain methyl l-(2,6-difluorobenzyi)-l H-1,2,3-triazole-4-carboxylic acid of formula (IV), This intermediate is then subjected to amination with methanolic ammonia to yield Rufinamide of formula (I).
Tetrahedron Letters 2010, 51(24), 3229-3231 discloses that compound of formula (I) can be prepared from 2,6-Difluorobenzylazide of formula(III) by reacting it with methyl-3-methoxyacrylate followed by methanolic ammonia to afford Rufinamide, which is illustrated in Scheme 3a.


and also discloses that compound of formula (I) also can be prepared from 2,6-Difluorobenzylazide by reacting it with 3-methoxyacrylonitrile followed by hydrolysis with aqueous alkali to afford Rufinamide, which is illustrated in Scheme 3b.
Scheme-3b

Prog in natural science 2006, 16(9), 925-929 discloses that compound of formula (I) can be prepared from 2,6-Difluorobenzylazide of formula(III) by reacting it with Ethyl propiolate followed by methanolic ammonia to afford Rufinamide, which is illustrated in Scheme-4.
Scheme-4

However, the use of alkyl propiolate as per Prog in natural science 2006, 16(9), 925-929 is highly lachrymator substance and has handling problem during commercial manufacturing.
J .Chem. Soc. (C), 1969 discloses the compound of formula (VI) can be prepared from N-(2-chloro-l,l-dimethylethyl) propiolamide ) by dissolving it in a solution of potassium hydroxide in t-butylalcohol, which was heated under reflux, is illustrated in scheme-5.


N-(2-ch1oro-1,1-dimethylethyl)propiolarnide ), wherein R= Me, Et, Bul
However, there still exists a need to simplify the manufacturing process for preparation of Rufinamide.
The aim of the invention has been achieved by obtaining novel l-(2,6-dif!uorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-triazole of formula (V) and (VI) and process for the preparation thereof, which are the key intermediate for the preparation of Rufinamide.
SUMMARY OF THE INVENTION:
The first embodiment of the present invention is to provide a novel compound of the formula (V).

Another embodiment of the present invention is to provide novel compound of the formula (VI).

wherein;
X is O, S or N;
R is alkyl straight chain or branched C1-C6 alkyl, cycloalkyl, aralkyl, acyl (R'-C=0);

R' is Straight chain or branched chain C1-C7 Alkyl, cycloalkyl or aryl provided when X is O then R is not C1-C4 alkyl.
Yet another embodiment present invention is to provide a process for the preparation of compound of formula (V),

comprising cycloaddition of oxazole compound of formula (VJ) with Azide of compound of formula (III),

optionally suitable base in the presence or absences of an inert solvent.
Yet another embodiment present invention is to provide a process for the preparation of compound of formula (VI),

comprising the reaction of formula (VII) with 2-amino-2-methylpropan-l-ol of formula (VIII),


optionally suitable base in the presence or absences of an inert solvent.
In general embodiment present invention provides process for the preparation of compound of formula (I),

comprising the steps of,
(a) cycloaddition of a compound of formula (VI) with azide compound of formula
(III) to give compound of formula (V);

(b) deprotection of the compound obtained in step (a) with an acid in the presence of an inert solvent to provide the compound of formula (IV) and,


(c) ammination of the compound of formula (IV) as obtained in step (b) in the presence of alcoholic ammonia in suitable solvent to obtain the compound of formula (I).
According to another embodiment of the present invention, there is provide a pharmaceutical composition comprising Rufinamide prepared according to the process of the present invention together with one or more pharmaceutical acceptable excipients.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
As used herein, "Novel compound" means novel intermediate of Rufinamide of compound formula (V) and (VI), whether in solid state such as a crystalline substance or dissolved in a solvent. It also includes all polymorphic and pseudo- polymorphic forms, if any, including hydrates, etc

The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
The present invention relates, in general, to an improved process for preparing 1 -(2,6-
difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-triazole of
formula (V) and compound of formula (VI) which are the key intermediate for the
preparation of Rufinamide and its pharmaceutically acceptable salts, as well as the use
of l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-
triazole of formula (V) and compound of formula (VI) prepared according to the present invention for the preparation of Rufinamide and its pharmaceutically acceptable salts as illustrated in scheme-6.
Scheme-6

In general embodiment present invention provides process for the preparation of 1 -(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-triazole compound of formula (V) and converted in to Rufinamide

2-(azidomethyl)-l,3- difluorobenzene of formula (III) can be prepared from 2,6-difluorobenzylhalide of formula (II), with an azide by any means known to the skilled artisan, such as by method as disclosed in WO 2010043849 and EP 199262 .
In step(a), formula (VI) undergoes cycloaddition with 2-(azidomethyl)-l,3-difluorobenzene of formula (III) optionally in the presence of one or more suitable solvent. Further, the compound of formula (III) can be formed insitu and reacted directly with formula (VI) with or without isolation of compound of formula (III),
The reaction mass was stirred for 5-6 hrs at 116°-120° and then cooled to obtain l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2yl)-1H-1,2,3-triazole compound of formula (V). The obtained l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-triazole of formula (V) can be optionally re-crystallized by using one or more suitable solvent at ambient temperature.
The suitable solvent used in formation of solution, isolation and crystallization of 1-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-l,2,3-triazole compound of formula (V) selected from the group comprising lower aliphatic alcohols, aromatic hydrocarbons, chlorinated solvent, esters, ethers, dipolar aprotic solvents, ketones, and cyclic or acyclic alkanes or mixtures thereof, preferably Methanol, Acetone and Ethylacetate, more preferably Acetone.
The preferred reaction can be also carried out in neat condition.
In step (b), l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-1,2,3-triazole compound of formula (V), undergoes deprotection by using an acid like conc. HC1 in presence of suitable inert solvent. The compound of formula (V) may be taken in a lower alcohol, i.e., a C1-C4 aliphatic, straight chain or branched alcohol or any one or more suitable solvents in the presence of reagents that includes, but is not limited to, acetic acid, formic acid and Hydrochloric acid. The reaction is carried out over a period of about 3 to about 24 hours, in the range of temperature generally at -5°C to 80°C, to obtain methyl 1- (2,6-difluorobenzyl)-l H-1 ,2,3-triazole-4-carboxylate of

formula (IV) can be optionally re-crystallized by using one or more suitable solvent at ambient temperature.
In step (c), the compound obtained in step (b) is react with ammonia gas in presence of suitable organic solvent like lower alcohol, i.e., a C1-C4 aliphatic, straight chain or branched alcohol or any one or more suitable solvents.
In another embodiment of the present invention provides process for the preparation of formula (VI) comprising the cycloaddition of formula (VIII) with 2-amino-2-methylpropan-1-ol of formula (VII) with a suitable an inert solvent.
The reaction is carried out over a period of about 1 to about 30 hours, preferably about 5 to about 20 hours and more preferably 10 to 15 ours in the range of temperature generally at 25-150°C, more preferably 65-116°C to obtained compound of formula (VI). The obtained compound of formula (VI) can be optionally re-crystallized by using one or more suitable solvent at ambient temperature.
The suitable solvent used in formation of solution and isolation of compound of formula (VT) selected from the group comprising lower aliphatic alcohols, aromatic hydrocarbans, chlorinated solvent, esters, ethers, dipolar aprotic solvents, ketones, and cyclic or acyclic alkanes or mixtures thereof, preferably Toluene, DMSO and Acetone, more preferably Toluene.
In another embodiment of the present invention, the l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)-1H-l,2,3-triazole of formula (V) is solid or in an isolated form (e.g solid such as amorphous or crystalline form).
In another embodiment of the present invention, the l-(2,6-difluorobenzyl)-4-(4,4-
dimethyI-4,5-dihydro-l,3-oxazoie-2-yl)-IH-l,2,3-triazole of formula (V) is
substantially pure. Purity may be at least 50% chemically pure, preferably at least 70% chemically pure, more preferably at least 90% chemically pure and most preferably at least 95% chemically pure.

In another embodiment of the present invention, the compound of formula (VI) is solid or in an isolated form (e,g solid such as amorphous or, crystalline form ).
In another embodiment of the present invention, the compound of formula (VI) is substantially pure. Purity may be at least 60% chemically pure, preferably at least 75% chemically pure, more preferably at least 85% chemically pure and most preferably at least 95% chemically pure.
In an another embodiment, present invention provides process for the preparation of Methyl l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylate of formula (IV) and converted in to Rufinamide by ammoniation..
The ammonia used in step (c) may be in the form of gaseous ammonia, liquid ammonia or aqueous ammonia, preferably gaseous ammonia.
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.
Example-1:
Preparation of 2-[2-ethoxyvinyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole (VI)
To a 1 L round bottom flask, charge 3-ethoxyacrylic acid (VII) (100.0 g, 0.861mol) and 500 ml of toluene. Charge 2-amino-2-methyl-l-propanol (96.0 g, 1.08 mol) to reaction mass under stirring. Reaction mass was heated to 110°C to 120°C (reflux) for 12-14 hrs. After completion of reaction, the reaction mass was cooled to 28°C to 32°C to solid precipitated. Then the reaction mass was stirred for 1-2 hrs. at 28°C to 32°C. Filter the reaction mass and wash the solid material with toluene. Again solid materials wash with methylene chloride. Finally the product was dried in hot air oven at 50°C. Dry weight is 136.3 gm (Yield = 93.70%)
Example-2:
Preparation of l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-1H-l,2,3-triazo!e of formula (V)

To a 250 ml round bottom flask, charge 105 ml of N,N-dimethylformamide and sodium azide (21.2 g , 0.325mol). charged 2, 6-difluorobenzyl chloride ( 52.9 g, 0.325mol) to reaction mass under stirring. Then extract the reaction mixture with methylene chloride and water. Then the organic layer was separated. Organic layer was charged with water twice. Then again separate the organic layer and charged with 2-[2-ethoxyvmyl]-4,4-dimethyl-4,5-dihydro-l,3-oxazole (VI). Heat the reaction mixture to 115°C to 120°C and stirred for 5 to 6 hrs. After completion of the reaction, the reaction mixture was cooled to solid formed. The reaction mass was filtered and wash the solid material with 25ml of chilled acetone. Finally the product was dried in hot air oven at 50°C. Dry weight is 44.9 gm (Yield is 45.00% )
Example-3
Preparation of Methyl-l-(2,6-diflurobenzyl}-1H-1,2,3-triazole-4-carboxylate of
formula (IV)
To a 50 ml round bottom flask, Charge l-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)-1H-1,2,3-triazole (V) ( 20 g, 0.0684 mol) and 100 ml of methanol. Charge 20 ml of conc.HCl to reaction mass under stirring at 28°C to 32°C . Heat the reaction mass near to 65°C. After completion the reaction the reaction mixture was stirred at reflux temperature for 5 to 6 hrs. Then the reaction mass was cooled to solid precipitate. Reaction mass was filtered and washed twice the solid material with 10 ml of methanol. Finally the product was dried in hot air oven. Dry weight is 33.1 gm (Yield is 75.6%); HPLC purity: >99.85%
Example-4:
Preparation of l-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4-carboxanlde
(Rufinamide) (I)
To a 250 ml round bottom flask, charge methyl-l-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate (IV) (7.0 g, 0.027 mol) and 140 ml of methanol under stirring for 5-10 min. Then 10 g of ammonia gas purged into reaction mixture at 27°C-33°C for 14 to 18 hrs. After completion of the reaction, the reaction mass was filtered and Wash with methanol and dry in hot air oven to obtain l-(2, 6-difluoro benzyl)-1H-1, 2. 3-triazole-4-carboxamide.Dry weight is 5.9 gm (Yield is 89.66%); HPLC purity: >99.6%

We Claim:
1. A process for the preparation of compound of formula (VI)

wherein X is O, S or N, and R is alkyl straight chain or branched C1-C6 alkyl, cycloalkyl, aralkyl, acyl (R'-C=O); R' is Straight chain or branched chain C1 -C7 alkyl, cycloalkyl or aryl provided when X is O then R is not C1-C4 alkyl.
with 2-amino-2-methylpropan-l-ol of formula (VIII)
comprises the reaction of compound of formula (VII)


by using inert solvent optionally in the presence of base.

comprises the cycloaddition of the compound of formula (III)
2. A process for the preparation of compound of formula (V)


with the compound of formula (VI)

by using inert solvent optionally in the presence of base. 3. A compound of formula (VI):

wherein X is O, S orN, and R is alkyl straight chain or branched C1-C6 alkyl, cycloalkyl, aralkyl, acyl (R'-C=0); R' is Straight chain or branched chain C1-C7 alkyl, cycloalkyl or aryl provided when X is O then R is not C1-C4 alkyl.
4. A compound of formula (V)

5. Use of compound of formula (V), as an intermediate in the preparation of
rufinamide.
6. Use of compound of formula (VI) as an intermediate in the preparation of


mfinamide
7. A process for the preparation of Rufinamide of formula (I)
Comprises following steps, (i) Reaction of 2,6-difluorobenzylhalide of formula (II), wherein X is chloride, bromide or iodide, with an azide to obtain 2-(azidomethyl)-1,3-difluorobenzene of formula (III);
(ii) cycloaddition of 2-(azidomethyl)-1 ,3-difluorobenzene of formula III with compound of formula VI without isolation of compound III to obtain 1-(2,6-difluorobenzyl)-4-(4,4-dimethyl-4,5-dihydro-l,3-oxazole-2-yl)-lH-1,2,3-triazole of formula (V);
(iii) reaction of l-(2,6-difluorobenzy])-4-(4,4-dimethyI-4,5-dihydro-l,3-oxazo1e-2~yl)-1H-l,2,3-triazole of formula (V) with an acid like Conc. HCI in presence of inert solvent to obtain of formula (IV)

(IV) (iv) amonolysis of compound obtained in step (iii) of formula (IV) with
ammonia to obtain Rufinamide of formula I and, (v) optionally recrystallization in suitable solvent.

8. The process according to any preceding claims, wherein the suitable solvent is selected from the group comprising lower aliphatic alcohols, aromatic hydrocarbans, chlorinated solvent, esters, ethers, dipolar aprotic solvents, ketones, and cyclic or acyclic alkanes or mixtures thereof.
9. A process for the preparation of Rufinamide substantially as herein described, particularly with reference to the foregoing examples.