EFFICIENT METHOD FOR PRODUCING LAMOTRIGINE
Field of the Invention
The present invention relates to an improved and economical method for producing 3?5-diamino-6-(2,3-dichlorophenyl)-l?2,4-triazine (Lamotrigine) of formula (I) which is suitable for treating disorders of the central nervous system, in particular epilepsy, and since 1990 has been used in spasmolytic medications in numerous countries.

Imporpved process for the production of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (Lamotrigine) of formula I involves Cyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried out with a metal cyanide by refluxing in a mixture of solvents comprising of alkylnitrile and a cosolvent selected from cycloalkanes or alkanes. 2,3-Dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonate in an organic solvent under acidic conditions, followed by cyclisation of the Schiff s base by refluxing in an aliphatic alkanol or water or their mixtures. The lamotrigine thus produced is optionally purified. Background of the Invention
Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine) of formula I was first disclosed in British Patent No. 759,014 (1956). Lamotrigine and its analogues were described in Canadian Patent Nos. 1,112,643 and 1,133,938, and in U.S. Pat. No. 4,602,017. To date a variety of methods for producing Lamotrigine have been disclosed. Processes for the preparation of Lamotrigine are also disclosed in international publications and patents WO 96/20934, WO 96/20935, WO 00/35888 and European Patent No. 963,980.

The compound of formula I may be obtained in a variety of ways. The following reaction model illustrates the reaction sequence disclosed in the prior-art patents or patent applications
3
U.S. Pat. No. 4,602,017 describes a process to produce lamotrigine by reacting 2,3 dichlorobenzoyl chloride (II) with cuprous cyanide and potassium iodide in dry xylene medium and reacting the resultant 2,3-dichlorobenzoyl cyanide (III) with aminoguanidine bicarbonate and cyclizing the reaction product in presence of 10% methanolic KOH and recrystallised in isopropanol.
In the reaction of acid chloride to acyl cyanide, the voluminous quantity of solvent dry xylene was used, which demands the larger reactor size. The usage of potassium iodide increases the cost of the process. In the final step of cyclization, an alcoholic solvent i.e. alcoholic KOH further adds up to the cost.
U.S. Pat. No. 6,111,101 claims similar invention as mentioned above with mixture of solvents viz., Acetonitrile and Xylene/toluene. Though it is economical as per the patent specification, its noteworthy that it employs drastic

conditions like refluxing at 140 and 110°C respectively for longer reaction hours, which is not desirable for scaling up.
Another U.S. Pat. No. 6,639,072 claims the process for the preparation of 2,3-dichlorobenzoyl cyanide, reacting 2,3 dichlorobenzoyl chloride with copper (I) cyanide (CuCN) in presence of potassium iodide using monochlorobenzene as solvent at reflux temperature. This particular reaction employs rigorous conditions like refluxing and distilling out the solvent at approximately 132 -135°C.
The process (as disclosed in Canadian Patent Nos. 1,112,643 and 1,133,938, U.S. Pat. No. 4,602,017 and in British Patent No. 759,014) for the preparation of Lamotrigine involves reaction of 2,3-dichlorobenzoyl cyanide and aminoguanidine bicarbonate in dimethylsulfoxide and 8N aqueous nitric acid. This process uses drastic conditions (20 eq. 8N HNO3), excess reagents and requires 7 days for completion of the reaction. The overall yield of the process from 2,3-dichlorobenzoyl cyanide is 15.6%. The process reported in WO 00/35888 for this reaction uses H2S04 instead of 8N HNO3. However, it also suffers from lower yield (40%) and longer reaction time like 2.5 days.
Cyclization of 2-(2,3-dichlorophenyl)-2-(guanidinylimino) acetronitrile (Formula IV) may be obtained in a variety of ways.
EP-A-0 963 980 cites as an additional undesirable impurity a compound of formula V
which is produced by hydiuiysis ui mmuuigmc unucr uasic conditions. For this reason, several of the methods of synthesis disclosed in the above cited patent applications are further disadvantageous because the cyclization reaction of the

compound of formula IV is performed in a highly basic environment, such that the undesirable impurity V is able to form through hydrolysis even during lamotrigine synthesis.
European Patent No. 21121 described cyclisation of adduct with methanolic potassium hydroxide solution to the final product in 15 % yield calculated on the starting material. The disadvantage of this is the extremely aggressive reaction medium, the long reaction time as well as the very low yield.
WO 96/20934 teaches that the cyclization of compound of Formula II must be initiated photochemically, however, and this is invariably coupled with technical difficulties in view of industrial production.
The European Patent No. 247842 describes a process in which 8 M solution of sulfuric acid is used instead of 8 N nitric acid in the condensation reaction, and the reaction time is 48 h. The cyclization reaction is carried out in n-propanol at reflux temperature. The disadvantages of this process are the low yield and the aggressive reaction medium.
Basically similar process is described in the U. S. Patent No. 6111101, in which the condensation is carried out in a mixture of diluted sulfuric acid and acetonitrile for 60 hours, and then the cyclization is carried out with 1 % aqueous potassium hydroxide solution. The crude product is purified by recrystallization from methanol. The disadvantages of the process are the aggressive medium, the low yield and the very long reaction time.
The modification of the above process is described in the European Patent No. 963980, in which the cyclization reaction is carried out in n- propanol at reflux temperature. The product is purified by recrystallization from n-propanol. The disadvantages of this process are also the long reaction time and the aggressive reaction medium.
Hence, there exists a continuing need to develop methods to obtain lamotrigine industrially, as economically as possible and in purest possible form.

Thus, an object of the present invention was to provide a method for producing lamotrigine that eliminates the aforementioned drawbacks.
Objective of the Invention
The main objective of the present invention is to provide an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2?4-triazine formula (I) or its pharmaceutical^ acceptable salts which is safe and convenient.
Yet another object of the invention is to provide a process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of the formula I, more particularly lamotrigine, which is less time consuming.
Yet another object of the invention is to provide a process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of the formula I commonly known as lamotrigine, which is efficient, economical and eco-friendly.
Still another object of the invention is to provide a process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of the formula I, commonly known as lamotrigine, which is suitable for industrial scale manufacture.
Summary of the Invention
Accordingly, the present invention relates to an improved and economical process for the preparation of the compound of Formula I

which comprises the following steps :

i) Cyanode-halogenation of formula II with copper (I) cyanide in the presence of C 1.3 alkylnitriles and a co-solvent selected from the group C6.8 cycloalkanes, straight or branched chain Ce-^ alkanes or a mixture there of, preferably mixture of acetonitrile and cyclohexane to produce compound of formula III

ii) reacting compound of formula (III) obtained in step (i) with aminoguanidine or a salt there of, preferably with aminoguanidine bicarbonate to produce a compound of formula IV

iii) cyclizing the compound of formula IV in presence of CM alcohol or water or mixture thereof to produce a compound of formula I


Detailed Description of the Invention
The present invention provides an efficient and industrially feasible process for preparing Formula (I) more particularly 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine, which is also known as Lamotrigine, in good yield and relatively high purity and pharmaceutically acceptable salt thereof.
In the present invention 2,3-dichlorobenzoylchloride (II) is transformed into 2,3-dichlorobenzoyl cyanide (III), as shown in step (i). The reaction is carried out under mild conditions in the presence of C1.3 alkylnitriles preferably acetonitrile and a cosolvent selected from the group Ce-scycloalkanes, C6.8 n-alkanes or a mixture there of preferably cyclohexane. Alkylnitriles are used for complexation with copper cyanide. Copper cyanide complexed with alkylnitriles preferably acetonitrile as solvent gives good yields. Further the co-solvents used are economical and eco-friendly.
2,3-dichlorobenzoyl cyanide (III) obtained is coupled with aminoguanidine or its salts preferably aminoguanidine bicarbonate to produce a compound of formula IV.
The compound of formula IV is cyclised to form 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine, which is also known as Lamotrigine Formula (I) in presence of CM alcohol or water or mixture thereof. With the help of this route, cyclisation becomes very much cost effective and eco-friendly.
The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention.

Example: 1
Preparation of 2,3-dichlorobenzoyl cyanide
Copper (I) cyanide (113.3 g, 1.26 moles), Cyclohexane (350mL) and acetonitrile (100ml) were added to a four necked round bottom flask containing 2,3-dichlorobenzoyl chloride (250g, 1.93 moles). The reaction mixture was refluxed for 12hrs. The reaction mixture was cooled and filtered to remove the undissolved inorganics. Solvent was distilled off to obtain 2,3-dichlorobenzoyl cyanide. The crude compound was washed with cyclohexane to give .title compound. Yield 200gm (purity by GC: >99%). Example: 2
Preparation of 2,3-dichlorobenzoyl cyanide
Copper (I) cyanide (45.3 g, 0.5 moles), n-hexane (160mL) and acetonitrile (40ml) were added to a four necked round bottom flask containing 2,3-dichlorobenzoyl chloride (100g, 0.477 moles). The reaction mixture was refluxed for 24hrs. The reaction mixture was cooled and filtered to remove the undissolved inorganics. The solvent was distilled off to obtain 2,3-dichlorobenzoyl cyanide. The crude compound was washed with n-hexane to give title compound. Yield 60gm (purity by GC: >99%).
Example 3:
Preparation of 2-(2,3-dichlorophenyl)-2-(aminoguanidine)acetonitrile:
Aminoguanidine bicarbonate (120g, 0.88 moles), followed by a solution of 2,3-dichlorophenyl cyanide (lOOg, 0.5 moles) in acetonitrile (200mL), was added to a stirred solution of concentrate sulphuric acid (600g) in water (600mL). The mixture was stirred at 20-30°C. for forty-eight hours and then filtered. The solid was added to a cooled solution of sodium hydroxide (76g) in water (350mls) below 30°C. The suspension was filtered and the resulting solid was washed

thoroughly with water to attain neutral pH and dried at 80°C. to give title compound. Yield 80g (purity by HPLC >97%)? Example 4: Preparation of 3,5-Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazone:
2-(2,3-dichlorophenyl)-2-(aminoguanidine)acetonitrile (60g; 0.234 moles) was suspended in methanol (600mL) and refluxed to the reaction completion. After completion of reaction, excess methanol (1.2L) was added and treated with charcoal. After Alteration of charcoal, methanol from the reaction mass was distilled to 2/3 of the total volume and cooled to ambient temperature. Solid was filtered and dried to give title compound. Yield 49g (purity HPLC >99.8%)
Example 5:
Preparation of 3,5-Diamino-6-(2,3-dichlorophenyl)-l,2,4-triazone:
2-(2,3-dichlorophenyl)-2-(aminoguanidine)acetonitrile (lOg; 0.039 moles) was suspended in water (lOOmL) and refluxed to the reaction completion. After completion of reaction, reaction mass was cooled to ambient temperature and the solid obtained was filtered and dried to give title compound. Yield 9g (purity HPLC >99.8%)

we claim:
1. A process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine formula (I) or its pharmaceutical^ acceptable salts

which comprises the following step of:
i) Cyano-de-halogenation of formula II with Copper Cyanide in the presence of Ci_3 alkylnitriles and a co-solvent selected from the group Ce-s cycloalkanes, straight or branched chain C^g alkanes or a mixture there of to produce compound of formula III, and it can be optionally purified in presence of solvents selected from Cg-g cycloalkane, straight or branched chain Ce-s alkanes or a mixture there of.

ii) reacting compound of formula (III) obtained in step (i) with aminoguanidine or a salt there of, preferably with aminoguanidine bicarbonate to produce a compound of formula IV


iii) cyclizing the compound of formula IV in presence of C14 alcohol or water or mixture thereof to produce a substantially pure compound of formula I

2. A process as claimed in claim 1, wherein step (i) the cyano-de-halogenation
of 2,3-dichlorobenzoyl chloride is carried out with copper (I) cyanide in
mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and
cylcohexane or cycloheptane or n-hexane or n-heptane or their mixture
thereof, preferably in a mixture of acetonitrile and cyclohexane.
3. A process as claimed in claim 1, wherein step (i) is carried out at a
temperature 60-150°C, preferably at 80-110°C.
4. A process as claimed in claim 1, wherein step (iii) cyclisation is carried out
without using any base.
5. A process as claimed in claim 1, wherein step (iii) cyclisation is carried out
in presence of solvents selected from methanol, ethanol, isopropyl alcohol,
and water or their mixtures thereof, preferably in methanol or water.

6. A process as claimed in claim 1, wherein step (iii) is carried out at reflux
temperature of solvent used.
7. A process as claimed in claim 1, wherein the lamotrigine is substantially
pure, having a purity >99.8%.