Field of the Invention
This invention relates to an industrial scale process for producing 6-(2,3-dichlorophenyl)- 1,2,4-triazine-3,5-diamine (Lamotrigine).
Background of the Invention
Lamotrigine, chemically known as 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine having chemical structure as depicted in formula I, is useful in the treatment of central nervous system (CNS) disorders, and particularly useful as an anticonvulsant, especially in treatment of epilepsy.
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European patent EP 21121 discloses a process for preparing Lamotrigine by cyclisation of 2-(2,3-dichlorophenyl)-2-(aminoguanidine)acetonitrile of formula(II), in an aliphatic alcohol under reflux in presence of a strong base to obtain lamotrigine.
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US 6111101, further discloses a process for producing lamotrigine, wherein the cyclisation reaction is carried out by using 1% aqueous potassium hydroxide solution, at 80°C to reflux temperature.
EP 963980 discloses that the cyclisation reaction is carried out in n-propanol at reflux temperature. All the above processes require long reaction times to complete the reaction and in addition low yield of the final product.
W009620934 provides an alternate process for producing lamotrigine employing an intermediate, which is further converted to Lamotrigine by cyclizing in a photochemical reactor resulting in 80% yield of the final product. The intermediate is difficult to produce and hence it is not a feasible process for industrial scale production of lamotrigine.
Product patent US 4602017 discloses a process for preparing Lamotrigine by cyclisation of compound of formula (II) under reflux in an alkanol, preferably, C1.4 alkanol such as methanol and ethanol, in presence of a strong base such as potassium hydroxide.
US 4847249, discloses an alternate process for preparing Lamotrigine, wherein the cyclisation reaction is carried out in n-propanol at reflux temperature to yield 41% of lamotrigine. These prior art processes for preparing lamotrigine require aggressive medium and long reaction times to complete the reaction. Moreover, a low yield of the final product is obtained.
According to US 6586593, the process for preparing lamotrigine involves preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine monohydrate, wherein the cyclisation of 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile is carried out in presence of a base and isopropyl alcohol/water or NMP/water mixture. The process requires removal of monohydrate and drying of the product for long hours at high temperature thereby making the process not feasible for large scale production.
Existing processes in addition require multiple recrystallization steps to obtain lamotrigine of high purity thereby resulting in loss of yield. Moreover, the above processes require large amount of expensive organic/inorganic bases and solvents such as alkanol to obtain the final product.
Therefore, there exists a need to develop an improved process for producing lamotrigine that reduces the manufacturing cost, involves less consumption of expensive solvents and is less time consuming. Moreover the process should produce lamotrigine in high yield with minimal impurities and should be amenable for large scale production of lamotrigine.
Summary of the Invention
It is a principal object of the present invention to provide an improved process for producing 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine, wherein the process is industrially feasible and cost effective.
It is another object of the present invention to provide a high yielding process for producing 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine with minimal impurities.
It is yet another object of the present invention to provide a process for large scale production of 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine in lesser time, wherein the process requires lesser quantity of solvent.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with a preferred embodiment of the present invention, there is provided an industrial scale process for producing the 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5- diamine comprising stirring a suspension of 2(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile in Ci- C4 alkanol under reflux till equilibrium is attained followed by treatment with activated charcoal to obtain pure 6-(2,3-dichlorophenyl)-l,2,4-triazine- 3,5-diamine.
In accordance with another embodiment of the present invention there is provided an industrial scale process for producing the 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5- diamine wherein the process further comprising filtering the resultant reaction mass and refluxing the filtrate to obtain the 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine.
In accordance with still another embodiment of the present invention there is provided a process for producing the 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine, wherein the Ci- C4 alkanol is selected from methanol, ethanol and isopropyl alcohol, preferably methanol.
In accordance with yet another embodiment of the present invention there is provided a process for producing the 6-(2,3-dichlorophenyl)-I,2,4-triazine-3,5-diamine wherein at equilibrium stage a clear solution of said suspension is obtained.
In accordance with still another embodiment of the present invention there is provided a process for producing the 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine, wherein the 6-(2,3-dichlorophenyl)-I,2,4-triazine-3,5-diamine obtained is characterized by having impurity less than 0.1% and low moisture content.
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 present invention discloses an industrial scale process for producing 6-(2,3- dichlorophenyl)-l,2,4-triazine-3,5-diamine with high yield and minimal impurities.
Further, the present invention discloses an economical process for preparation of the 6- (2,3-dichlorophenyl)-I,2,4-triazine-3,5-diamine (lamotrigine) from the compound 2(2,3- dichlorophenyl)-2-(aminoguanidine) acetonitrile, wherein the process involves use of lesser volume of aliphatic alcohols.
The lamotrigine so obtained according to the process provided in the present invention is characterized by having high purity greater than 99.9% and low moisture content. Impurity content of the lamotrigine is less than 0.1%
According to the present invention, the industrial scale process for producing the lamotrigine comprises of stirring a suspension of 2(2,3-dichlorophenyl)-2- (aminoguanidine) acetonitrile in Ci- C4 alkanol under reflux till equilibrium is attained followed by treatment with activated charcoal to obtain lamotrigine.
According to the process for producing 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5- diamine which comprises of stirring a suspension of 2(2,3-dichlorophenyl)-2- (aminoguanidine) acetonitrile in the presence of Ci- C4 alkanol under reflux, wherein the process results in cyclization of the 2(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile to produce 6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine.
According to the process disclosed in the present invention, the reflux is performed in the absence of an inorganic/organic base and puriflcation by treatment with activated carbon.
According to the present invention the Ci- C4 alkanol used in the process is alone or as Ci- C4 alkanol /water solution preferably aliphatic alcohol and water solution.
The Ci- C4 alkanol employed in the process herein according to the present invention is selected from methanol, ethanol and isopropyl alcohol, preferably methanol. The Cp C4 alkanol employed in the process is approximately 15-25 volumes of the suspension.
According to the process disclosed herein, the suspension is stirred under reflux for 1 to 4 h to attain the equilibrium stage. The equilibrium stage is attained when a clear solution of said suspension is obtained. Further, the clear solution is treated with activated carbon at a temperature preferably between 60-65 °C. The equilibrium is attained between the 2 (2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile and the lamotrigine.
The term 'activated carbon' and the 'activated charcoal' have been used in synonymous in the present invention.
According to the present invention, the process for producing the lamotrigine further comprises filtering the resultant reaction mass and refluxing the filtrate to obtain the lamotrigine. The resultant reaction mass is further refiuxed for 14 to 16 hrs for completion of the reaction. In accordance with a preferred embodiment of the present invention, the step of filtration is performed under hot condition.
The above described embodiments involve producing lamotrigine of high grade purity in a lesser time, employing reduced volume of the expensive solvent such as methanol. Further, the process disclosed herein produces the lamotrigine with low moisture content and minimal impurities.
The invention is further explained in detail in the following examples which are provided by way of illustrations only and should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of 6-(2.3-dichlorophenvn-1.2,4-triazine-3.5-diamine: A suspension of 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile (50.0 gm, 0.195 mol) in methanol 900 ml is stirred at reflux for about 2 hrs to get a clear solution. Activated carbon (1.0 gm) is then added to the solution and stirred at 63-65°C for 15 min. The hot solution is filtered through celite at 60-65°C. The filtrate is heated to reflux and maintained for 15 hrs. After completion of the reaction the reaction mass is cooled to 10°C and stirred for 1 hr at same temperature. The solid material is filtered and product washed with chilled methanol. The product is dried under vacuum at 70-75°C to yield 47.0 gm (94%) of product of the title.
EXAMPLE 2
Preparation of 6-(2.3-dichloroDhenvn-1.2.4-triazine-3.5-diamine: A suspension of 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile (10.0 gm, 0.039 mol) in methanol 180 ml is stirred at reflux for about 2 hrs to get clear solution. Activated carbon (0.2 gm) is added to the solution and stirred at 63-65°C for 15 min. The hot solution is filtered through celite at 60-65°C. The filtrate is heated to reflux and maintained for 15-16 hrs. After completion of the reaction the reaction mass is cooled to room temperature and stirred for 1 hr at the same temperature. The solid material is filtered and washed with methanol. The product is dried under vacuum at 70-75°C to yield 8.4 gm (84%) of product of the title.
EXAMPLE 3
Preparation of 6-(2,3-dichlorophenyl)-l ,2,4-triazine-3.5-diamine:
A suspension of 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile (50.0 gm, 0.195 mol) in methanol 900 ml is stirred at reflux for 1.30 hrs to get clear solution. The reaction is continued for 1.30 hrs at 62-65°C and the reaction solution is treated with activated carbon (1.0 gm) at 63-65°C for 15 min. The hot solution is filtered through celite at 60- 65 °C. The filtrate is heated to reflux and maintained for 14-16 hrs. After completion of the reaction the reacfion mass is cooled to 10-15 °C and stirred for 1 hr at same temperature. The solid material is filtered and washed with chilled methanol. The product is then dried under vacuum at 70-75°C to yield 45.0 gm (90%) of product of the title.
EXAMPLE 4
Preparation of 6-(2, 3-dichlorophenvl)-l, 2, 4-triazine-3, 5-diamine: A suspension of 2-(2,3-dichlorophenyl)-2-(aminoguanidine) acetonitrile (500.0 gm, 1.95 mol) in methanol 9.0 lit is stirred at reflux for about 2 hrs to get clear solution. Activated carbon (10.0 gm) is added to the solution and stirred at 63-65°C for 15 min. The hot solution is filtered through celite at 60-65°C. The filtrate is heated to reflux and maintained for 15-16 hrs. After completion of the reaction the reaction mass is cooled to 10°C and stirred for 1 hr at same temperature. The solid material is filtered and washed with chilled methanol. The product is then dried under vacuum at 70-75°C to yield 470.0 gm (94%) of product of the title.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:
1. An industrial scale process for producing 6-(2,3-dichlorophenyl)-1,2,4- triazine-3,5-diamine comprising stirring a suspension of 2(2,3-dichlorophenyl)-2- (aminoguanidine) acetonitrile in Ci- C4 alkanol under reflux till equilibrium is attained followed by treatment with activated charcoal to obtain pure 6-(2,3-dichlorophenyl)- 1,2,4-triazine-3,5-diamine.
2. The process according to claim 1, wherein the process further comprising filtering the resultant reaction mass and refluxing the filtrate to obtain the 6-(2,3- dichlorophenyl)-1,2,4-triazine-3,5-diamine.
3. The process according to claim 1, wherein the Ci- C4 alkanol is selected from methanol, ethanol and isopropyl alcohol.
4. The process according to claim 1, wherein the Cj- C4 alkanol is methanol.
5. The process according to claim 1, wherein volume of the Ci- C4 alkanol employed is approximately 15-25 volumes of the suspension.
6. The process according to claim 1, wherein the suspension is stirred under reflux for 1 to 4 h to attain the equilibrium stage.
7. The process according to claim 6, wherein at the equilibrium stage a clear solution of said suspension is obtained.
8. The process according to claim 1, wherein the treatment with activated charcoal is performed at a temperature of 60-65 °C.
9. The process according to claim 1, wherein the 6-(2,3-dichlorophenyl)- l,2,4-triazine-3,5-diamine obtained is characterized by having impurity less than 0.1% and low moisture content.