A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives

Abstract

A new in principle method for the synthesis of 6 aryl(hetaryl) 3,5 diamino 1,2,4 triazines by decomposition of pre synthesized tetrazolo[1,5 b] [1,2,4]triazines was developed. The ad vantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.

New approach to the synthesis of azauracils and azaisocytosines

“…Earlier, we have described various procedures for partial destruction of azoloannelated pyrimidines and 1,2,4 triazines, 8-11 which were used as nontrivial syn thetic approaches for the synthesis of substituted nonfused 1,2,4 triazines, including the synthesis of the antiepileptic drug lamotrigine. 11 The efficiency and advantages of this procedure over conventional synthesis methods were demonstrated. 11 In the present study, we extended the scope of this synthetic approach and used it for introducing an alkyl substituent at the N(4) position of 3,5 dioxo and 3 ami no 5 oxo 1,2,4 triazines, which are aza analogs of uracil and isocytosine, respectively.…”

“…11 The efficiency and advantages of this procedure over conventional synthesis methods were demonstrated. 11 In the present study, we extended the scope of this synthetic approach and used it for introducing an alkyl substituent at the N(4) position of 3,5 dioxo and 3 ami no 5 oxo 1,2,4 triazines, which are aza analogs of uracil and isocytosine, respectively. This became possible due to the fact that N alkylation of tetrazolo[1,5 b] 1,2,4 triazin 7 one (1) and subsequent cleavage of the tetrazole ring occur selectively.…”

Drug Discovery in Epilepsy: A Synthetic Review

“…The acid or base promoted intramolecular cyclization of aminoguanidine intermediates (method A) consists of the most studied and effective route so far, providing desired LTG product in moderate yield (52%) (Dalmasses Barjoan & Bessa Bellmunt, 2004). Alternatively, the synthesis of LTG has been also accomplished by using tetrazolamine instead of aminoguanidine (method B) (Ulomskii et al, 2005) or by the direct Suzuki coupling of a preformed diamino triazine halide with the corresponding boronic acid (method C) (Titirmare, 2007). But despite the potential applicability of these two approaches, the preparation of required intermediates as well as the poor reaction yields obtained limits considerably their scope.…”

Spin-spin coupling constants 13C-15N and 1H-15N in the investigation of azido-tetrazole tautomerism in a series of 2-azidopyrimidines

“…One of the successful examples for the directed reduction of the tetrazole cycle is the synthe sis of the modern antiepileptic drug lamotrigine and its analogs. 16 It is also important to know parameters of the azido tetrazole equilibrium for the use of photoaffine labels in the field of molecular biology. This is related to the fact that the azide form is photochemically more active than the tetrazole form.…”

“…In this case, to introduce the 15 N atom into the azide group/tetrazole fragment, it is necessary to use labeled 5 aminotetrazole, which builds up the azine fragment. 16,18 The 15 N isotope can be included into posi tion 2 of 5 aminotetrazole by the treatment of aminoguani dine with nitrous acid or by the interaction of 15 20 However, in this case, a mixture of 15 N isotopo mers was formed at the  and  positions of the azido group. The use of compound 4** makes it possible to obtain samples of 15 N tetrazolo [1,5 a]pyrimidines with the homogeneous isotope composition.…”