Lopinavir, synthesis

There are many other examples of drugs based on an amino acid backbone. Stoner et al. recently reported a synthesis of the HIV protease inhibitor ABT-378 (Lopinavir) (84) (133). In a similar synthesis to that of the related compound. Ritonavir, key intermediate (85)is prepared by stepwise diastereoselective reduction of enaminone (86).This means that the existing chiral center, derived from natural L-phenylalanine (protected to 87), controls the formation of the two new stereocenters as... 

Gomes, C. R. B., Moreth, M., Cardinot, D., Kopke, V., et cd. (2011). Synthesis and antimyco-bacterial activity of novel amino alcohols containing central core of the anti-HIV drugs lopinavir and ritonavir. Chem. Biol. Drug Des., 78,1031-1034. 

Synthesis of Lopinavir and Ritonavir Core In 2007, Menche and co-workers published an asymmetric reductive amination methodology for p-hydroxy ketones 132 for synthesizing a range of l,3-sy -ammo alcohols 135.The reaction was optimized using Ti(Oi-Pr)4 for the coordination of the intermediate imino alcohol 133 and polymethylhydrosiloxane (PMHS) as the hydride source. The reaction was believed to proceed via the initial formation of an imino alcohol that would coordinate to the Lewis acid to undergo reduction through a Zimmerman-Traxler-type transition state 134 to furnish the corresponding iy -l,3-amino alcohol (Scheme 39.40). 

This new methodology paved the way for an easy and straightforward route to the synthesis of core of HIV-protease inhibitors Ritonavir 141 and Lopinavir 142 containing the hydroxyl-amine scaffold. The first step included a diastereoselective aldol coupling of phenyla-cetone 136 with phenylalanine-derived aldehyde 137 to afford the intermediate hydroxy-ketone 138. This was then reacted with -anisidine under the optimized... 

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