Facile, alternative route to lubeluzole, its enantiomer, and the racemate.
Lubeluzole [(S)-9] has been synthesized by a convergent synthesis, alkylation of N-methyl-N-piperidin-4-yl-1,3-benzothiazol-2-amine (4) with (+)-(R)-1-chloro-3-(3,4-difluorophenoxy)propan-2-ol [(+)-(R)-8] being the key step. Alcohol (+)-(R)-8 was obtained from commercially available (R)-epichlorohydrin [(R)-6], while the thiazole derivative 4 was easily obtained starting from N-protected piperidin-4-one (1) in a three-step procedure. The same method was used in order to obtain both the (R)-stereoisomer of lubeluzole [(R)-9] and its racemate [(RS)-9]. Overall yields ranged from 20% to 35%. The enantiomeric excess values for (S)-9 and (R)-9 were 97% and 94% respectively, as analyzed by chiral HPLC.
Bruno
Claudio
C
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Bari, Italy.
Carocci
Alessia
A
Catalano
Alessia
A
Cavalluzzi
Maria M
MM
Corbo
Filomena
F
Franchini
Carlo
C
Lentini
Giovanni
G
Tortorella
Vincenzo
V
D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
D002317:Cardiovascular Agents; D010880:Piperidines; D013844:Thiazoles; C097722:lubeluzole