Target Duloxetine

06 May 2012 - Applied orgo

duloxetine synthesis Suzuki 2012  What: enantioselective synthesis
Target: Duloxetine
Who: Yuta Suzuki et al.
Publication: Journal of Organic Chemistry 2012 (DOI)
Key feature: enantioselective Aldol reaction. Current commercial product is enantiopure and based on kinetic resolution and recycling with mandelic acid.
How: step 1: Aldol reaction of 2-thiophencarboxaldehyde with N,N-diallyl thioacetamide using duphos, tetrakis(acetonitrile)copper(I) hexafluorophosphate and the lithium salt of 4-methoxyphenol followed by organic reduction of the thioketone by Lithium aluminium hydride, step 2 : removal of the allyl protective groups by Tetrakis(triphenylphosphine)palladium(0) and dimethyl barbituric acid to the free amine, then acylation using methyl chloroformate, step 3: reduction of the carbamate group using Lithium aluminium hydride and finally nucleophilic aromatic substitution with 1-fluoronaphthalene using sodium hydride.
The upside: clever duphos recovery (expensive), usually the presence of copper salts are in the way but postponing the recovery untill after reductive step loses copper salt as copper(0).
The downside: in step one 20% yield is lost in Aldol condensation