Industrial Synthesis of the Key Precursor in the Synthesis of the Anti-Influenza Drug Oseltamivir Phosphate (Ro 64-0796/002, GS-4104-02):  Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate

Abstract

Starting from (−)-quinic acid, the title compound was synthesized in seven chemical steps and an overall yield of 35−38%. The route of the improved Gilead synthesis was not changed. However, significant improvements in each step led to a doubled overall yield, a 30% reduction in the number of unit operations, and an excellent quality (≥99%) of the resulting epoxide. A highly regioselective method for the dehydration of a quinic acid to a shikimic acid derivative and for the reduction of a cyclic ketal was found. Alternatively, the title compound was synthesized in six chemical steps and 63−65% yield from commercially available (−)-shikimic acid. Compared to the optimized quinic acid route, the production time was reduced by about 50%. The quality of epoxide produced from either natural product was equivalent. Therefore (−)-shikimic acid is the preferred raw material. The absolute configuration of the epoxide was determined by X-ray single crystal structure analysis and it was demonstrated that the epoxide was stereoisomerically pure.

A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (−)-shikimic acid

“…The other miscellaneous routes started from prochiral cyclohexene derivatives [23][24][25] or substituted benzenes, [26][27][28] and used chiral organometallic catalysts or enzymes to provide an access to the required chirality. Among all the above synthetic routes, only the route developed by Roche [11][12][13] can be used in the current industrial synthesis. The starting material for Roche's synthesis is (À)-shikimic acid, which can be obtained either by extraction from the Chinese star anise (1 kg of shikimic acid from 30 kg of the dried plant) or by fermentation using genetically modified Escherichia coli.…”

Application of Heterogeneous Catalysts in the First Steps of the Oseltamivir Synthesis

“…The first step described in the Gilead [18] and Hoffmann-La Roche [9,19] routes is the acetalization of quinic acid with 2,2-dimethoxypropane in acetone catalyzed by p-toluenesulfonic acid (PTSA) (Scheme 3). Many sulfonic solids have been described as catalysts for acid-catalyzed procedures [21][22][23], and several of them were chosen ( Figure 1) as potentially interesting alternatives for PTSA:…”

“…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). Hence, its availability and price generate a bottleneck for this synthesis, and in fact, the shortage of Tamiflu in 2005 during the avian flu pandemic is attributed to this problem.…”

Effizienter Zugang zu Oseltamivirphosphat (Tamiflu) über das O‐Trimesylat von Shikimisäureethylester

“…Eine gemeinsame Entwicklungsanstrengung [3,4] führte zur derzeit verwendeten technischen Synthese von 1 ausgehend von Shikimisäure (3), die, in Zusammenarbeit mit Partnern auf der ganzen Welt, die über eine langjährige Erfahrung in der großtechnischen Durchführung von Reaktionen mit Aziden verfügen, eine jährliche Produktion von mehreren hundert Tonnen Tamiflu erlaubt, um bei einer auftretenden Pandemie gerüstet zu sein.…”

“…September 2007) basiert. Nachdem nun große Mengen an Shikimisäure (3) verfügbar sind und wir auf gute Erfahrungen mit Partnern für die Reaktionen mit Aziden im technischen Maßstab aufbauen können, untersuchten wir die in Schema 2 gezeigte Umwandlung von 3 in 1 über das O-Trimesylat 5 von Shikimisäureethylester (4), das in hoher Ausbeute aus 3 über 4 [4] und anschließende Mesylierung erhalten wurde. Die Behandlung von 5 mit Natriumazid bei Raumtemperatur unter nichtsauren Bedingungen bewirkte die regio-und stereoselektive Substitution des allylischen O-Mesylates in Position 3 unter Bildung von 6.…”