A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
Loading...
Access rights
openAccess
URL
Journal Title
Journal ISSN
Volume Title
A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
This publication is imported from Aalto University research portal.
View publication in the Research portal (opens in new window)
View/Open full text file from the Research portal (opens in new window)
View publication in the Research portal (opens in new window)
View/Open full text file from the Research portal (opens in new window)
Date
2009
Department
Major/Subject
Mcode
Degree programme
Language
en
Pages
1340-1351
Series
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, issue 9
Abstract
This paper describes a new procedure for the enantioselective synthesis of the important anticonvulsant drug Pregabalin, which shows biological properties as the (S) enantiomer only. The key step of the synthetic sequence is the Michael addition reaction of Meldrum’s acid to a nitroalkene mediated by a quinidine derived thiourea. A variety of novel catalysts bearing different groups at the thiourea moiety were synthesized and tested. The most successful catalyst that incorporates a trityl substituent provided up to 75% ee of (S)-4. The conjugate addition reaction was carried out on a multigram scale with low loadings of catalyst (10 mol-%). Moreover, the catalyst can be recycled showing the same capability in chemical yield and asymmetric induction. Then, hydrogenation of nitroalkane 4 followed by decarboxylation of diacid 5 provides Pregabalin hydrochloride in 59% overall yield. Enantioenrichment by crystallization of the free amino acid 1 improves the (S)/(R) enantiomeric ratio to 9:1.Description
Keywords
Other note
Citation
Bassas , O , Huuskonen , J , Rissanen , K & Koskinen , A M P 2009 , ' A Simple Organocatalytic Enantioselective Synthesis of Pregabalin ' , European Journal of Organic Chemistry , no. 9 , pp. 1340-1351 . https://doi.org/10.1002/ejoc.200801220