Abstract
The first steps of oseltamivir synthesis from quinic acid involve acetalization and ester formation. These reactions are catalyzed by either acids or bases, which may be accomplished by heterogeneous catalysts. Sulfonic solids are efficient acid catalysts for acetalization and esterification reactions. Supported tetraalkylammonium hydroxide or 1,5,7-triazabicyclo[4.4.0]dec-5-ene are also efficient base catalysts for lactone alcoholysis and in this work, these catalysts have been applied in two alternative synthetic routes that lead to oseltamivir. The classical route consists of an acetalization, followed by a lactonization, and then a lactone alcoholysis. This achieves a 66% isolated yield. The alternative route consists of esterification followed by acetalization and is only efficient when an acetone acetal is used.
Highlights
Pharmaceutical molecules are quintessentially specialty chemicals with structural complexity that require multistep synthetic routes [1]
The acetal–esters derived from quinic acid (3aa, 3ab and 3bb) can be prepared using heterogeneous catalysis through two different synthetic routes
The desired pentanone acetal ethyl ester 3bb has been prepared on a gram scale with an isolated yield of 66% by a sequential procedure consisting of two reaction steps: the sulfonic acid-catalyzed acetalization and the base-catalyzed alcoholysis of the acetal lactone 2b
Summary
Pharmaceutical molecules are quintessentially specialty chemicals with structural complexity that require multistep synthetic routes [1]. In addition to atom economy, other parameters such as step [2,3] and pot [4] economy have to be considered in assessments of synthetic routes. The option to carry out multistep chemical transformations in one pot would be of great interest for the synthesis of pharmaceuticals [5]. Oseltamivir is one of the most important anti-influenza drugs, and has interesting synthetic approaches, with various routes having from four to 25 steps [8]. The highest overall yield and step economy is provided by a route beginning with (−)-shikimic acid [9] (Scheme 1), which is a natural product obtained from the Chinese star anise (Illicium verum). Its availability and price generate a bottleneck for this synthesis, and the shortage of Tamiflu in 2005 during the avian flu pandemic is attributed to this problem
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