Preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (lamotrigene), useful for treating epilepsy, starting from 2,3-dichloronitrobenzene

摘要

A new process for the preparation of 6-(2,3-dichlorophenyl-1,2,4-triazine-3,5-diamine (lamotrigene) starting from 2,3-dichloronitrobenzene is disclosed. A novel process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (lamotrigine) of formula (I), comprises: (a) reduction of the 2,3-dichloronitrobenzene in 1-6C aliphatic alkanol with H2 gas at a pressure of 55-90 psi in the presence of a metal catalyst at 27-35[deg]C; (b) diazotization of the resulting 2,3-dichloroaniline with sodium nitrite and a mineral acid at -5[deg]C to 5[deg]C followed by cyano-de-diazonation with a metal cyanide at 65-80[deg]C; (c) hydrolysis of the resulting 2,3-dichlorobenzonitrile under acidic or alkaline conditions; (d) chlorination of the resulting 2,3-dichlorobenzoic acid with a chlorinating agent at 55-130[deg]C; (e) cyano-de-halogenation of the resulting 2,3-dichloro-benzoyl with a metal cyanide in the presence of an alkali metal iodide by refluxing in an aprotic solvent under an inert atmosphere; (f) condensation of the resulting 2,3-dichlorobenzoyl cyanide with aminoguanidine bicarbonate in an organic solvent in acidic conditions in the presence of a catalyst at 90-125[deg]C followed by in situ cyclization of the resulting Schiff's base of formula (IV): by refluxing in an aliphatic alkanol in the presence of a base; and (g) purification of the resulting crude lamotrigine of formula (I) by a known method such as recrystallization from an aliphatic alkanol or chromatographic separation. [Image] ACTIVITY : Anticonvulsant; Neuroprotective. MECHANISM OF ACTION : Inhibitor of the release of excitatory neurotransmitter.