WO2009069073A1

WO2009069073A1 - An improved process for the preparation of lamotrigine

Info

Publication number: WO2009069073A1
Application number: PCT/IB2008/054937
Authority: WO
Inventors: Keshav Deo; Sanjay Desai; Rajesh Sahu; Pradipkumar Sharma
Original assignee: Alembic Ltd
Current assignee: Alembic Ltd
Priority date: 2007-11-28
Filing date: 2008-11-25
Publication date: 2009-06-04
Anticipated expiration: 2010-05-28

Abstract

The present invention relates to an improved process for the preparation of Lamotrigine (I) comprising a step of cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.

Description

Description AN IMPROVED PROCESS FOR THE PREPARATION OF LAM-

OTRIGINE

Field of invention

[1]

[2] The present invention relates to an improved process for the preparation of Lam- otrigine [3] [4] The structural formula of Lamotrigine is represented by formula (I)

(I)

[5]

Background of the invention

[6]

[7] The chemical name of Lamotrigine is

6-(2,3-Dichlorophenyl)-l,2,4-triazine-3,5-diamine, molecular formula is C₉H₇Cl₂N₅ and molecular weight is 256.09. The current pharmaceutical product containing this drug is being sold by Glaxo Wellcome using tradename Lamictal, in the form of tablets.

[8]

[9] Lamotrigine of formula (I) is from the phenyltriazine class and useful as anticonvulsant. The precise mechanism by which Lamotrigine exerts its anticonvulsant action are unknown but In Vitro pharmacological studies suggest that Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids such as glutamate and aspartate.

[10]

[11] US4602017A first time discloses process for preparation of Lamotrigine according to the scheme shown below.

[12] *^"

2,3-dι chloro benzoyl cyanide

Lamotrigine 2-(2,3-dιchloro phenyl) -2- (guanidinoimino) acetonitrile

[13] The cyclization step is conducted in basic medium in alcohol. [14] [15] US6333198 discloses a process for the preparation of Lamotrigine as shown below in the scheme.

(II) (III) Lamotrigine (I)

[16] In this process, the cyclization is carried out by refluxing the compound in 1-propanol in neutral condition. In this process total impurities and individual impurity level is high in final step. The process needs recrystallization and charcoalization to purify the crude final product. This makes the process laborious and increases the overall cost.

[17] [18] Therefore, there is a need to develop a process for the preparation of Lamotrigine which minimize the generation of impurities and overcomes the drawbacks of the state of art.

[19] [20] Surprisingly, the present inventors have observed that the cyclization of 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile in acidic medium reduces the level of impurities generated during the process and also increases the overall yield of the Lamotrigine. The cyclization reaction is performed in acidic media using a mineral acid such as sulfuric acid in alcoholic solvent such as methanol.The total impurities and individual impurity level is very low than existing procedures in final step. The individual impurity i.e. (z)-2-(2,3-Dichlorophenyl)-(guanidine imino) acetonitrile is well controlled below the limit about 0.05% by using the process of the present invention. This isomeric impurity tends to cyclize in next step and is isolated with Lamotrigine which is effectively controlled.

[21]

Object of the invention [22] An object of the present invention is to provide an improved process for the preparation of Lamotrigine.

[23] [24] Another object of the present invention is to provide an improved process for the preparation of Lamotrigine with high yield and high purity.

[25] [26] Yet another object of the present invention is to provide a process which is simple, easy to handle at industrial scale and which is cost effective.

[27]

Summary of the invention [28] Accordingly the present invention provides an improved process for preparation of Lamotrigine comprising steps of: [29] (i) reacting 2,3-dichlorobenzoyl nitrile (II) with aminoguanidine bicarbonate in the presence of sulfuric acid to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III);

[30] (ii) cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile in the presence of alcohol and acid to give Lamotrigine (I). [31]

Detailed description of the invention [32] The process of the present invention is as shown below in the scheme.

(II) (III) Lamotrigine (I)

[33] A mino guanidine bicarbonate is slowly added in a solution of sulphuric acid in water at ambient temperature about 28⁰C to about 30° C . Acetonitrile and 2,3-dichloro benzoyl nitrile (II) is added to the reaction mixture. The mixture is stirred 30 to 35 hrs at about 25⁰C to about 35 ⁰C and heat to about 45⁰C to about 50⁰C. The reaction mixture is cooled, filtered and washed with water. The wet cake is slurred in water and basified with ammonia solution to pH from about 6 to about 7, and filtered. Again the wet cake is slurried in water and basified with sodium hydroxide solution to pH from about 9.5 to about 10 at 15° to 25 ⁰C and filtered, washed with water. The solid is d ried at about 6O⁰C to about 70 ° C to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III)

[34]

[35] 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile is dissolved in alcohol. The examples of alcohol includes but not limited to C_M0 alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, 2-propanol, hexanol, pentanol. The preferred alcohol is methanol. The catalytic quantity of acid is added to it. The acid is selected from the group of organic acid and inorganic acid. The examples of organic acid includes but not limited to formic acid, oxalic acid, mandalic acid, adipic acid, succinic acid, p- toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid and the like or mixture thereof. The examples of inorganic acid includes but not limited to HCl, HBr, HI, HF, nitric acid (HNO₃), sulfuric acid (H₂SO₄), H₃PO₃, polyphosphoric acid, perchloric acid (HClO₄), chloric acid (HClO₃), chlorous acid (HClO₂), hypochlorous acid (HClO) and the like or mixture thereof. The preferred acid used here is sulfuric acid. The reaction mixture is heated to reflux for about 3 to 4 hr. The reaction mixture is filtered and distilled out 75% of original volume of methanol under reduced pressure. Reaction mixture is cooled to about 25⁰C to about 35 ⁰ C and stirred for 30 to 60 minutes. The reaction mixture is filtered and washed with methanol. The wet cake is dissolved in methanol and heated to about 7O⁰C to about 75 ° C. The mixture was filtered to get clear solution. The methanol from filtrate is distilled out 75% of original volume of methanol under reduced pressure. The reaction mixture is cooled to about 25⁰C to about 35 ⁰ C and stirred for 30 to 60 minutes. The reaction mixture was filtered and dried at about 4O⁰C to about 6O ⁰ C under vacuum to give Lamotrigine.

[36]

[37] The advantage of the above process is that a separate purification step is not required.

The purification of the crude takes place in situ which is very convenient at industrial scale. The yield and purity is increased in comparison with the prior art processes.

[38]

[39] The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

[40] [41] Example-1

[42] Preparation of 2-(2,3-dichlorophenyl)-2-(guanidinoimino)acetonitrile

[43] A mino guanidine bicarbonate (102.2g) was slowly added in sulfuric acid (1030g) in water (545ml) at 28° to 30° C . Acetonitrile (2ml) and 2,3-dichloro benzyl chloride (100 ml) was added to the reaction mixture. The reaction mixture was stirred for 30 hr at 25⁰C to 35 ⁰C and then heated at 45⁰C to 50⁰C. The reaction mixture was cooled, filtered and washed with water (100ml). The wet cake slurry in water (1300ml) was prepared and basified with ammonia solution to pH 6-7. The mixture was filtered. Again the wet cake slurry in water (900ml) was prepared and basified with sodium hydroxide solution to pH 9.5-10 at 15⁰C to 25 ⁰C. The mixture was filtered and washed with water (300ml). The solid was d ried at 60-70 ° C to give the title product (9Og)

[44] Yield: 70.30%

[45]

[46] Example-2

[47] Preparation of Lamotrigine

[48] 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (25g) was dissolved in methanol (750ml). Catalytic quantity of cone, sulfuric acid was added to it. The reaction mixture was heated to reflux for 3-4 hr. The reaction mixture was filtered and the filtrate was distilled out 75% of original volume of methanol under vacuum. Reaction mixture was cooled to 25⁰C to 35 ⁰C and stirred for 30 to 60 minutes. The reaction mixture was washed with methanol (50ml). Above wet cake was dissolved in methanol (750ml) and heated at 7O⁰C to 75 ⁰C to make clear solution. The reaction mixture was filtered and distilled out 75% of original volume of methanol under vacuum. The reaction mixture was cooled to 25⁰C to 35 ⁰C and stirred for 30 to 60 minutes. The reaction mixture was filtered and dried at 4O⁰C to 60 ⁰C under vacuum to give the title product (20.5g).

[49] Yield: 82%

Claims

[1] 1. A process for preparation of Lamotrigine (I)

(I) comprising a step of cyclizing

2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.

[2] [3] 2. A process for preparation of Lamotrigine (I)

(I) comprising steps of:

(i) reacting 2,3-dichlorobenzoyl nitrile (II)

(II) with aminoguanidine bicarbonate in the presence of sulfuric acid to give 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile (III) ;

(III)

(ii) cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid to give Lamotrigine (I). [4] [5] 3. The process as claimed in claim 1 or 2, wherein said acid is selected from the group consisting of organic and inorganic acids or mixture thereof. [6] [7] 4. The process as claimed in claim 3, wherein the organic acid is selected from the group comprising formic acid, oxalic acid, mandalic acid, adipic acid, succinic acid, p-toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid. [8] [9] 5. The process as claimed in claim 3, wherein the inorganic acid is selected from the group comprising HCl, HBr, HI, HF, nitric acid (HNO₃), sulfuric acid (H₂SO₄

), H₃PO₃, polyphosphoric acid, perchloric acid (HClO₄), chloric acid (HClO₃), chlorous acid (HClO₂), hypochlorous acid (HClO) [10] [11] 6. The process as claimed in claim 1 or 2, wherein said alcohol is selected from the group consisting of Cn₀ alcohol such as methanol, ethanol, n-propanol, iso- propanol, butanol, 2-propanol, hexanol, pentanol or mixture thereof.