Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2003-05-15
2004-01-27
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06683182
ABSTRACT:
The present invention relates to a method for producing Lamotrigine as well as intermediate products used in the method.
Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) has the formula I
This compound, disclosed for example in European patent publication EP-A-0 021 121, 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.
To date a variety of methods for producing Lamotrigine have been disclosed. Common to the methods disclosed in EP-A-0 021 121, EP-A-0 247 892, EP-A-0 963 980 and WO 00/35888 is the fact that cyclization of 2-(2,3-dichlorophenyl)-2-(guanidinylimino)acetronitrile (formula II) represents the final synthesis step.
The compound of formula II required for the cyclization reaction may be obtained in a variety of ways. The following reaction model illustrates the reaction sequence disclosed in EP-A-0 963 980:
The methods disclosed in the aforementioned patent applications for producing lamotrigine by way of a cyclization reaction with a compound of formula II deviate in individual steps from the reaction sequence illustrated above. Common to all of them, however, is that the compound of formula (II) is obtained by reacting 2,3-dichlorobenzoyl cyanide (formula VI) with aminoguanidine. In accordance with the aforementioned patent applications 2,3-dichlorobenzoyl cyanide is produced by reaction with copper cyanide from 2,3-dichlorobenzoyl chloride (formula V).
A drawback of the above-described method of synthesis for producing lamotrigine is that the 2,3-dichlorobenzoyl cyanide (formula VI) required for synthesizing the compound of formula II can only be obtained in a form that is oily and difficult to purify, in addition to which the compound is unstable and prone to dimerization Further, the copper cyanide needed for synthesis of the 2,3-dichlorobenzoyl cyanide (formula VI) is relatively costly.
Moreover, during synthesis of the 2,3-dichlorobenzoyl cyanide (formula VI) a contaminant in the form of 2,3-dichlorobenzoe acid anhydride is produced. According to EP-A-0 963 980 this anhydride can be reacted with lamotrigine in the subsequent reaction sequence to form a compound of formula VII, which is an undesirable impurity.
EP-A-0 963 980 also cites as an additional undesirable impurity a compound of formula VIII
which is produced by hydrolysis of lamotrigine under basic 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 II is performed in a highly basic environment, such that the undesirable impurity VIII is able to form through hydrolysis even during lamotrigine synthesis.
An alternative method of lamotrigine synthesis is disclosed in WO 96/20934, in which the cyclization reaction is performed using a compound analogous to the compound of formula II, which analogous compound contains an acid amide group instead of the cyanide group. Such a cyclization reaction must be initiated photochemically, however, and this is invariably coupled with technical difficulties.
The WO 96/20935 patent publication discloses a method for producing lamotrigine from 6-(2,3-dichlorophenyl)-3-methylthio-5-chloro-1,2,4-triazine. In replicating this method HPLC was used to identify larger quantities of unknown by-products in addition to lamotrigine in the reaction mixture.
Hence, there exists a continuing need for methods by which 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.
It was found unexpectedly that lamotrigine may be obtained in highly pure form in a cyclization reaction from an intermediate compound not heretofore described.
The present invention thus relates to a method for producing lamotrigine or a pharmaceutically acceptable salt thereof, in which a cyclization reaction is performed using a compound of formula XII
or a salt thereof, and optionally from which salt of the compound of formula 1 the free base is released and, if desirable, said free base is converted to a pharmaceutically acceptable salt.
As a result of the cyclization reaction according to the present invention with compound XII to lamotrigine, the latter is obtained in high yields and in especially pure form under mild conditions. In addition, the compound of formula XII is easily accessed using a simple method of synthesis and is readily purified by crystallization. Given the high purity of the reactant in the cyclization reaction according to the present invention, as compared to known reactions, it is possible to achieve an especially high purity level of the desired lamotrigine, a purity level required for pharmaceutical preparations, without the need for complex purification steps. In particular, there were no impurities of formulas VII and VIII cited in EP-A-0 963 980 detected in the lamotrigine produced according to the method of the present invention.
The cyclization reaction may be performed by heating under mild conditions, for example, at a temperature in the range of 100°-170° C., preferably 130°-170° C. It is preferable to perform the cyclization reaction in solution. Solvents suitable for the compound of formula XII are all organic solvents that have no adverse affect on the reaction, preferably dimethylsulfoxide or dimethylformamide. Especially preferred are solvents having a boiling point in the desired temperature range, such that the reaction may occur at the boiling temperature of the solvent under reflux. To adjust a desired boiling temperature it is feasible to also use solvent mixtures of, for example, dimethylsulfoxide or dimethylformamide and benzol, toluol or xylol.
The cyclization reaction should be performed to the exclusion of water or substantially to the exclusion of water.
The cyclization reaction may be performed with the free base of the compound of formula XII or with an acid addition salt of said compound. A preferred acid addition salt is dihydrochloride. When the cyclization reaction is performed using an acid addition salt, the product obtained is the acid addition salt of lamotrigine. In such case, the free lamotrigine base may, if desired, be obtained in nearly quantitative yield in a manner known to one skilled in the art, e.g. using aqueous sodium hydroxide solution in dimethylformamide.
The time required for the cyclization reaction is a function of the process conditions and in particular the temperature at which the reaction is performed. The time can range, for example, from 1-24 hours. An optimal time period is easily determined by one skilled in the art.
In a preferred embodiment of the method according to the present invention, the compound of formula XII required for the cyclization reaction is obtained by reacting a compound of formula XI
in which R is a substituted or unsubstituted straight- or branched-chained, or cyclical alkyl-, aryl- or aralkyl-residue, or a salt thereof, with aminoguanidine or a salt thereof.
In the compound of formula XI, R may be a straight-chained, branched or cyclical alkyl residue, preferably C
1-20
—, in particular C
1-10
-alkyl residue, such as for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or cyclohexyl. Preferred alkyl residues for R are phenyl and naphthyl, in particular phenyl. Preferred aralkyl residues for R are aryl-C
1-5
-alkyl residues, wherein aryl is defined as above, and in particular benzyl.
The aforementioned alkyl-, aryl-, and aralkyl-residues may optionally bear one or more, in particular 1 or 2 substitutents such as for example halogen, hydroxy, C
1-8
-alkoxy or nitro. The aryl- and aralkyl-residues may be substituted in addition to, or alternatively, with C
1-6
-alkyl.
R is preferably phenyl.
The compound of formula XII is produced by reacting the compound of formula XI with aminoguanidine or a salt thereof, preferably wit
Garaczi Sándor
Gegö Csaba Lehel
Lukács Ferenc
Máté Attila Gergely
Nyerges Miklós
Ford John M.
Helm AG
Shanks & Herbert
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