Synthesis of (+/−)-Pregabalin and its novel lipophilic β-alkyl-substituted analogues from fatty chains†
Abstract
In this work, were synthesized for the first time a series of new lipophilic β-alkyl substituted GABA derivatives from fatty alkyl chains. The synthesis of these GABA analogues was investigated by two different bicomponent approaches as a key step. The results showed low yields in the path from aliphatic nitroolefins and Meldrum's acid, whereas the Knoevenagel condensation between aliphatic aldehydes and Meldrum's acid afforded fatty alkylidenes in good yields (75–97%). These compounds were subsequently subjected to a conjugate addition reaction with nitromethane, resulting in the fatty Michael adducts (in 87–97% yields) which were in turn submitted to a one pot domino hydrolysis-decarboxylation, leading to the isolation of β-alkyl-substituted γ-nitro acids in good yields (78–92%). Finally, the reduction of the fatty γ-nitro acids allowed for the access to new lipophilic β-alkyl substituted GABA analogues, which were isolated in high yields (90–98%). The new methodology was also applied to the synthesis of antiepileptic drug (+/−)-Pregabalin, which was obtained after four steps in high overall yield.
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