Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1997-06-25
1999-07-20
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C07D253075
Patent
active
059257555
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of lamotrigine and its pharmaceutically acceptable acid addition salts.
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, of formula (I) ##STR2##
It is a known compound, useful in the treatment of disorders of the central nervous system (CNS), in particular epilepsy, described for example in EP-A-0021121. Lamotrigine isethionate, disclosed in EP-A-0247892, is a preferred salt for parenteral administration.
The present invention provides a process for the preparation of lamotrigine which comprises treating 6-(2,3-dichlorophenyl)-5-chloro-3-thiomethyl-1,2,4-triazine of formula (II) ##STR3## with ammonia.
The reaction of the compound of formula (II) with ammonia may be carried out in an organic solvent. Suitable solvents include C.sub.1-6 alkanols, such as methanol, ethanol, propan-1-ol or propan-2-ol, preferably ethanol. The temperature of the reaction may range from ambient temperature to the boiling point of the solvent. Alternatively, the reaction may be conducted under pressure at a temperature above the boiling point of the solvent, for instance in an autoclave. In that case a suitable temperature is about 180.degree. C. and a suitable pressure about 1930 kPa (280 psi).
Instead of using ammonia in an organic solvent, aqueous ammonia can be employed. Alternatively, the compound of formula (II) may be treated directly with liquid ammonia under pressure, for instance in an autoclave.
The compound of formula (II) is novel. The invention therefore further provides 6- (2,3-dichlorophenyl) -5-chloro-3-thiomethyl-1,2,4-triazine.
The compound of formula (II) may be prepared by treating 6-(2,3-dichlorophenyl)-5-oxo-3-thiomethyl-1,2,4-triazine, which has the formula (III), ##STR4## with a chlorinating agent.
Suitable chlorinating agents include phosphorus oxychloride, thionyl chloride, phosphorus trichloride and phosphorus pentachloride. Phosphorus oxychloride is particularly preferred. The chlorination is of a conventional type and is performed under routine synthetic conditions.
Owing to keto-enol tautomerism, the compound of formula (III) may also exist with the following structure: ##STR5## It is to be understood that all references herein to the compound of formula (III) relate to either or both of the keto and enol tautomers.
The compound of formula (III) is novel. The invention therefore further provides 6-(2,3-dichlorophenyl)-5-oxo-3-thiomethyl-1,2,4-triazine.
The compound of formula (III) may be prepared by treating 6-(2,3-dichlorophenyl)-5-oxo-3-thio-1,2,4-triazine of formula (IV) ##STR6## with a methylating agent.
Suitable methylating agents include methyl halides, for instance MeCl, MeBr and MeI, methyl sulphonate and methyl p-toluenesulphonate. Methyl iodide is especially preferred. Methylation is conducted under conventional conditions. For instance, the reaction of the compound of formula (IV) with methyl iodide is preferably carried out in alkaline aqueous solution, e.g. in an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, at ambient temperature.
As with compound (III), compound (IV) exhibits keto-enol tautomerism and may consequently exist with the following structure: ##STR7## It is to be understood that all references herein to the compound of formula (IV) relate to either or both of the keto and enol tautomers.
The compound of formula (IV) is novel. The invention therefore further provides 6-(2,3-dichlorophenyl)-5-oxo-3-thio-1,2,4-triazine. The compound of formula (IV) may be prepared by treating 2,3-dichlorophenylglyoxylic acid of formula (V) ##STR8## with thiosemicarbazide.
The reaction of the compound of formula (V) with thiosemicarbazide is preferably carried out in alkaline aqueous solution, e.g. in an aqueous solution of sodium hydroxide or potassium hydroxide. It is preferably carried out at a temperature ranging from ambient temperature to the boiling point of the solvent, more preferably at reflux.
The compound of formula (V) ray be prepared by oxidising 2,3-di
Ford John M.
Glaxo Wellcome Inc.
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