FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10 and Rule 13]
Title
PROCESS FOR THE PREPARATION OF LAMOTRIGINE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention

PROCESS FOR THE PREPARATION OF LAMOTRIGINE
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine, which is also known as a lamotrigine. More particularly, the present invention pertains to the preparation of lamotrigine by reaction of 2,3-dichloro-phenylboronic acid with 6-bromo-3,5-diamino triazine in the presence of palladium catalysts and appropriate base.
BACKGROUND OF THE INVENTION:
Lamotrigine is an anti-epileptic drug of the phenyltriazine class. Lamotrigine is a known compound, useful in the treatment of disorders of the central nervous system (CNS), in particular epilepsy
NH2

The preparation of substituted 3,5-diamino-l, 2,4-triazine derivatives is known from the literature. Synthesis of substituted derivatives of triazines is described in Agr. Res. Serv. 3 188 (1996) and J. Med. Chem. 8 859 (1972)- according to which benzoyl cyanide is reacted with aminoguanidine in acidic medium and so obtained intermediate is cyclized under basic conditions.
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Lamotrigine is described in US 4, 602,017. According to the process described in US 4,602,017 (Scheme; 1) reaction of 2,3-dichloroiodobenzene with magnesium, followed by reaction of the Grignard reagent with solid carbon dioxide to produce 2,3-dichlorobenzoicacid, which on reaction with thionyl chloride in an inert atmosphere gives 2,3-dichlorobenzoylchloride. Reaction of 2,3-dichlorobenzoylchloride with metal cyanide in the presence of alkali metal iodide and organic solvent gives 2,3-dichlorobenzoylcyanide. This 2,3-dichJorobenzoylcyanide is reacted with the hydrogencarbonate salt of aminoguanidine in dimethyl sulfoxide as solvent, in presence of 8N nitric acid for 7 days. The obtained adduct is cyclized with methanolic potassium hydroxide solution to the final product in 15.6% yield. The disadvantages of this process are it uses magnesium for Grignard preparation, which requires anhydrous condition and solid CO2, which restricts operating temperature limit. The other disadvantages of the above process are the extremely aggressive reaction medium, the long reaction time as well as the very low yield. Furthermore, handling of metal cyanide is very hazardous and relatively costly. Scheme: 1

2

The European patent No. EP 0247892 discloses the same process as above in which dilute sulphuric acid is used instead of 8N nitric acid in the condensation reaction and the reaction takes 48 hours to complete. The cyclisation reaction is carried out in n-propanol at reflux temperature. The drawbacks of this reaction are low yield (41%) and aggressive reaction media.
Alternative methods of preparation of lamotrigine have also been disclosed in the following Patent literature: EP 0963980; WO 9620934; WO 9620935; WO 03008393; EP 1170588; WO 01049669; EP 1127873; EP 1311492; EP 1401374; EP 1458692.
The methods of preparation of Lamotrigine disclosed in the above-cited patents have some or all of the following disadvantages:
(1) Handling of extremely hazardous reaction media.
(2) Lengthy and long reaction procedure.
(3) Using hazardous and corrosive reagent, which are poisonous at ppm level. Requires proper care for handling of them.
(4) Not industrially feasible.
(5) Low yield.
(6) Formation of unwanted byproducts.
Moreover, EP-A- 0 963 980 discloses that during the synthesis of the 2,3-dichlorobenzoyl chloride a contaminant in the form of 2,3-dichlorobenzoicacid anhydride is produced and this anhydride can undergo side reaction with uncyclized adduct formed during reaction of 2,3-dichlorobenzoyl cyanide with aminoguanidine bicarbonate, which also undergo cyclization during the formation of lamotrigine in
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the subsequent reaction sequence. Hence it can contaminate lamotrigine to form a
compound of formula II, described as compound B.
H

CI ii
WO 96/20934 and WO 96/20935 describes that during the synthesis of lamotrigine, cyclization reaction of formula in highly basic environment produces an undesirable impurity of Formula IV described as compound A..
CN H

It is perceptible from the above-mentioned prior art that according to the known processes for the preparation of lamotrigine can only be synthesized in relatively low yield, using hazardous and corrosive reagents with long reaction times and also produces undesirable impurities.
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Hence, there exists a continuing need for process for preparation of lamotrigine, which is devoid of above mentioned impurities. Moreover there exist demand for preparation of lamotrigine, which is simple, industrially applicable, economically viable, requiring short reaction time using eco-friendly reagents with a good yield and purity.
SUMMARY OF THE INVENTION:
The present invention is to provide an improved process for preparing lamotrigine that eliminates the aforementioned drawbacks.
We have found that lamotrigine can be obtained by using simple, cost-effective & industrially viable process, which gives good yield with high purity and may be free
from impurities like formula II and IV by means of the process as given in following scheme.
The object of the present invention is to provide a process for the preparation of lamotrigine that is to avoid the use of hazardous and corrosive reagents.
Another object of the present invention is to provide a process for the preparation of lamotrigine that is simpler and having lesser steps.
Another object of this invention is to provide process for the preparation of lamotrigine that is cost-effective and industrially viable.
Accordingly, the present invention provides a process for the preparation of lamotrigine of formula (I)
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Cl (I)
Comprising:
1. Cross coupling reaction of 6-bromo-3,5-diamino-1,2,4-triazine (Formula VI)
with i.e.2, 3-dichloro-phenylboronic acid (Formula V) in presence of palladium catalyst and appropriate base in an organic solvent and/or an aqueous solvent.

2. Isolating lamotrigine and optionally purifying thereafter.
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DETAILED DESCRD7TION:
The present invention provide an improved process for the preparation of 3,5-diamino-6- (2,3-dicMorophenyl)-l,2,4-triazine (Lamotrigine) comprises cross coupling reaction of 6-bromo-3, 5-diamino-l,2,4-triazine (III) with 2,3-dichloro-phenylboronic acid (II) in the presence of Palladium catalyst and base in an organic solvent and/or an aqueous solvent. Scheme-2 illustrates an exemplary process for the preparation of lamotrigine in accordance with the present invention.
SCHEME: 2

Stage I:

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Stage III;

The starting raw material of the formula (VII) i.e. 3-amino-l,2,4-triazine and formula (V) i.e. 2,3-dichloro-phenylboronic acid may be obtained commercially or as known in art.
The method of producing 6-bromo-3,5-diamino-l,2,4-triazine (VI) has already been disclosed in Rvkowski; Synthesis (1985). 884-886.
We have found that by using cross coupling reaction of 6-bromo-3, 5-diamino-1,2,4-triazine with 2,3-dichloro-phenylboronic acid in the presence of Palladium catalyst and base yields in lamotrigine with good yield and high purity.
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In one aspect of the present invention there is provided a method for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine of formula (I), which comprises the reaction of 6-bromo-3,5-diarnino-l,2,4-triazine of formula (VI), with 2, 3-dichloro-phenylboronic acid of formula (V), in presence of palladium catalyst and base in organic solvent and/or an aqueous solvent. The reaction mixture is heated to reflux temperature and maintained for about 4-8 hours. The reaction mixture is then cooled to room temperature and filtered. The filtrate is concentrated and then extracted by using solvents such as esters. Washing this extracted solution with water and concentrating it obtain solid precipitates of lamotrigine and optionally purifying it thereafter.
The catalyst used in the method of the present invention is a palladium catalyst. The palladium catalyst may selected from Pd(0) complex or a Pd (II) salt.
Palladium (0) catalyst can be selected from tris (dibenzylideneacetone) dipalladium (0) (Pd2 (dba) 3), bis (tri-t-butylphosphine) palladium (0), bis [1, 2-bis (diphenylphosphino) ethane] palladium (0), bis (tricyclohexylphosphine) palladium (0), or tetrakis (triphenylphosphine) palladium (0).
Palladium (II) can be selected from diacetatobis (triphenylphosphine) palladium (II),
dichlorobis (benzonitrile) palladium (II) (Pd (BnCN) 2Cl2), dichlorobis(acetonitrile)
palladium (II) (Pd (MeCN)2Cl2), dichloro (1,2-bis (diphenylphosphino) ethane)
palladium (II), dichloro [1, l'bis (diphenylphosphino) ferrocene] palladium (II),trans-
dichlorobis(tricyclohexylphosphine)palladium (II), trans-dichlorobis
(triphenylphosphine) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), trans-dichlorodiammine palladium(II), palladium(H) acetate, palladium (II) acetylacetonate, palladium(II) bromide, palladium(II) chloride, palladium(II)
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cyanide, palladium(II) iodide, or tetrakis(acetonitrile) palladium (II)
tetrafluoroborate.
In a preferred embodiment, Pd(PPh3)4 (palladium tetrakistriphenyl phosphine) or Pd(OAc)2 is used to catalyze this reaction.
The base used in the reaction may be either an inorganic base or an organic base or mixture thereof.
Base may be selected from the group comprising of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkali metal and alkaline earth metal acetates, alkali metal and alkaline earth metal alkoxides, alkali metal and alkaline earth metal phosphates, primary, secondary and tertiary amines, alkali metal and alkaline earth fluorides, or ammonium fluorides.
Particularly preferred base are alkali metal and alkaline earth metal phosphates, alkali metal and alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkali metal and alkaline earth fluorides, or ammonium fluorides. Most particularly preferred are relatively weak base such as Na2CO3 or K2CO3
The solvent used in this reaction may be either an organic, aqueous or biphasic or mixture thereof.
Solvents are selected from the group comprising of ethers (e.g., diethyl ether, dimethoxymethane, diethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether), hydrocarbons (e.g., hexane, isohexane, heptane, cyclohexane, benzene, toluene, xylene), alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol, 1-butanol, 2-butanol, tert-butanol), ketones
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(e.g., acetone, ethyl methyl ketone, iso-butyl methyl ketone), amides (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), water or mixtures thereof.
Particularly preferred solvents are ethers (e.g., dimethoxyethane, tetrahydrofuran), hydrocarbons (e.g., cyclohexane, benzene, toluene, xylene), alcohols (e.g., ethanol, 1-propanol, 2-propanol), water or mixtures thereof.
Most particularly preferred solvents are toluene, ethanol, water or mixtures thereof.
The esters used for the extraction in this process may be selected from ethyl acetate, methylacetate, propylacetate, n-butyl acetate, n-propyl acetate or other known in the art. Most preferred ester is ethyl acetate or methyl acetate.
The process for producing lamotrigine of the present invention is further illustrated by the examples mentioned hereinafter. These examples are provided for illustrative purpose only and are not intended to limit in any way the scope of invention.
Example: 1
100 mg. of 6-bromo-3,5-diamino-l,2,4-triazine was added to the round bottom flask containing 15 ml. ethanol, 15 ml toluene and 0.5 ml. water. 109 mg. of 2,3-dichlrophenylboronic acid, 167 mg. of Na2CO3 and 60 mg. of Pd(PPh3)4 were added to the above mixture.
The mixture was heated and maintained at reflux temperature till reaction is completed (approx. 6 hours). Sample was drawn and analyzed by TLC, which showed the absence of the 6-bromo-3,5-diamino-l,2,4-triazine. Reaction mass was cooled to room temperature and concentrated under vacuum and then extracted with
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ethyl acetate. The ethyl acetate solution was washed with water and then dried over Na2SO4 and this dried ethyl acetate solution was concentrated under vacuum. ISO mg. of yellow solids were obtained.
Subsequent column chromatography (dichloromethane & methanol as eluent) gives 50 mg. (Yield: 37.13%) of pure compound.
1 H NMR (DMSO-dg), 8 (ppm)=6.54 (2H, s, NH), 6.92-6.65 (2H, br s, NH), 7.73-7.71 (1H, d, ArH), 7.47-7.43 (1H, m, ArH), 7.38-7.33 (1H, m, ArH).
Example: 2
200 mg. of 6-bromo-3,5-diamino-l,2,4-triazine, 219 mg. of 2,3-dichlrophenylboronic acid, 334 mg. of K2CO3 and 23.5 mg of Pd(OAC)2 were added to the round bottom flask containing 20 ml. ethanol, 20 ml toluene and 0.5 ml. water. This mixture was stirred for 10 minutes at room temperature to obtain clear solution. Then charged 110 mg. of triphenylphosphine and stirred at the room temperature for 5 minute. This mixture was refluxed for 4 hours and allowed to cool at room temperature.
50 ml. ethyl acetate and 30 ml. water was added to the mixture and stirred it. Then organic layer is separated and washed twice with water and subjected to charcoal treatment. The organic layer distilled off under vacuum and solid mass was obtained containing some semisolid residue. To this residue 30 ml. of diethyl ether was added and stirred for 15-20 minutes to get 150mg. of solid mass.
This solid is again subjected to ether treatment and filtered to get 87 mg. (Yield: 32.34%) of pure compound.
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Example; 3
200 mg. of 6-bromo-3,5-diamino-l,2,4-triazine, 219 mg. of 2,3-dichlrophenylboronic acid, and 334 mg. of K2CO3 were added to the round bottom flask containing 20 ml. ethanol, 20 ml toluene and 1.0 ml. water. This mixture was stirred for 5 minutes at room temperature to obtain clear solution. Then charged 23.63 mg of Pd(OAC)2 and l 10 mg. of triphenylphosphine, stirred at the room temperature for 5 minute. This mixture was refluxed for 5 hours and allowed to cool at room temperature.
100 ml. ethyl acetate and 50 ml. water was added to the mixture and stirred it. Then organic layer is separated and washed twice with water. The organic layer distilled off under vacuum and to this residue 30-40 ml. of ether was added and stirred for 15-20 minutes filtered to get 106 mg. (Yield: 39.40%) of pure compound.
Dated this on 19th September, 2005

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ABSTRACT:
The present invention relates to an improved process for the preparation lamotrigine. An improved process for the preparation of lamotrigine comprises cross coupling reaction of 2,3-dichloro-phenylboronic acid with 6-bromo-3,5-diamino triazine in the presence of palladium catalysts and appropriate base.