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The Synthetic-Technical Development of Oseltamivir Phosphate Tamiflu<Sup>

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The Synthetic-Technical Development of Oseltamivir Phosphate Tamiflu<Sup> HOT TOPICS: SANDMEIER PRIZE 2006 93 doi:10.2533/chimia.2007.93 CHIMIA 2007, 61, No. 3 Chimia 61 (2007) 93–99 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 The Synthetic-Technical Development of Oseltamivir Phosphate TamifluTM: A Race against Time Stefan Abrechta , Muriel Cordon Federspielb , Heinrich Estermannb , Rolf Fischerb , Martin Karpf*a , Hans-Jürgen Mairb , Thomas Oberhauserc , Gösta Rimmlerb , René Trussardia , and Ulrich Zuttera Recipients of the Sandmeyer Prize 2006 of the Swiss Chemical Society Abstract: The clinical development of the first orally available neuraminidase inhibitor prodrug oseltamivir phos- phate (TamifluTM) proceeded very fast. In order to support this program an unprecedented team effort in chemical process research, development, piloting, production and analytics took place, which allowed the successful launch of TamifluTM in 1999, only two and a half years after it was licensed from Gilead Sciences. This article describes selected aspects of the commercially used synthesis route and a brief summary of alternative syntheses devised by Roche chemists. Keywords: Analytics · Influenza neuraminidase inhibitor · Oseltamivir phosphate · Production · Synthesis · Technical development 1. Introduction H O H O CO H In September 1996 a license agreement be- H O 2 O CO Et tween Gilead Sciences, Foster City, Califor- 2 H O nia and F. Hoffmann-La Roche Ltd, Basel AcHN H N NH was signed for the co-development of the AcHN 2 NH2 •H3 PO4 novel orally available neuraminidase inhibi- NH tor prodrug molecule 1 (Fig. 1) patented by Gilead Sciences in February 1995,[1] today 1 2 known as oseltamivir phosphate, trade name TamifluTM. In April 1999, after only two and Oseltamivir phosphate Zanamivir a half years of development time, a new drug TamifluTM RelenzaTM GS-4104-02 GG-167 application (NDA) for 1 was filed with the RO0640796-002 US Food and Drug Administration (FDA) for the use of 1 for the treatment of influenza Fig. 1. Marketed neuraminidase inhibitors virus infections. This ambitious development and technical development activities lead- program was in part triggered by the parallel ing to commercial route selection followed development of zanamivir ( 2), trade name Re- by piloting and including all related analyti- lenzaTM by GlaxoSmithKline. This neuramin- cal activities had to be challenged in order idase inhibitor emerging from the research ef- to finally allow for a successful and timely forts of Prof. von Itzstein, Monash University, launch production of several metric tonnes. Australia[2] was already patented in 1990 and An unprecedented and overlapping team is equipotent in vitro to 1 but shows low oral effort regarding decisions on critical mile- *Correspondence: Dr. M. Karpfa bioavailability and was filed with the NDA for stones was required throughout the func- Tel.: + 41 61 688 5299 Fax.: + 41 61 688 1670 the topical treatment of influenza using disc tions involved. E-Mail: [email protected] inhaler technology in October 1998. F. Hoffmann-La Roche Ltd Due to the exceptionally fast clinical Pharmaceuticals Division a Synthesis & Process Research development program for 1 , the standard 2. A Swift Start b Chemical Process Development chemical-technical development plans in- c Technical Project Management cluding trouble-shooting of the discovery In September 1996, chemists from Grenzacherstrasse 124 synthesis, synthesis & process research the Synthesis & Process Research depart- CH-4070 Basel HOT TOPICS: SANDMEIER PRIZE 2006 94 CHIMIA 2007, 61, No. 3 ment of F. Hoffmann-La Roche Ltd were 1) SO2 Cl2 first confronted with the synthetic pathway 2) pyrrolidine H O shown in Schemes 1 and 2 (taken from H O Pd(PPh3 ) 4 cat. CO Et H O CO H O CO Et O 2 2 2 3) H SO extr. refs[3,4]) created and used by Rohloff et 2 4 O H O O al., Gilead Sciences for the scale-up of the 43% transformation of quinic acid ( 3 ) to oselta- OH ~70% OMs cryst. OMs mivir phosphate ( 1 ), published in 1998.[3] 3 4 5 Due to the limited information available (-)-Quinic acid yield and safety ? O on the majority of issues circled in the two selectivity ? HClO cat. Schemes 1 and 2 ( e.g. the availability of world supply ? 4 the starting material 2 on a large scale, the feasibility, safety and scalability of several BH . Me S NaHCO3 /H2 O 3 2 synthetic steps) the immediately required CO Et CO Et O 2 EtOH CO Et O 2 assessment was largely based on the confi- O 2 TMSOTf dence in the skills of the chemists who were 67% O O availability H O oil OMs to be involved. OMs price ? 8 yield from (-)-quinic acid ~20% 7 6 Epoxide RO0640792 3. The Access to the Key Epoxide 8: Where to Start from? Scheme 1. Synthesis of epoxide 8 according to Rohloff et al.[3] Initially quinic acid ( 3 ) was used as the raw material which is isolated from the availability bark of the cinchona tree as a side prod- stench ? uct during the extraction of cinchona alka- NaN3 ,NH 4 Cl PMe 3 CO Et loids. The cinchona tree is indigenous pre- O CO Et EtOH ,65°C O 2 MeCN ,RT O CO Et dominantly in Central Africa, Zaire. The 2 2 worldwide yearly capacity for quinic acid H O O N H N was estimated to be approx. 80 tonnes. 3 Potential suppliers at the time offered to 819 0 Epoxide provide us with max. 15 tonnes per year RO0640792 safety of translating into approx. 5 tonnes of drug NaN ,NH Cl substance 1 , which was clearly below the selectivity ? azide reagents 3 4 &intermediates ? DMF, 85 °C quantities forecasted. Therefore for large- scale production an alternative raw mate- 1) Lindlar /H 2 Ac2 O O CO Et 2) H 3 PO pyridine rial had to be found. 2 4 O CO2 Et O CO2 Et AcHN 80% AcHN 35% H N 3.1. Problems when Starting from 2 NH •H3 PO4 N N Quinic Acid 3 2 overall yield from 3 3 The key problematic step in the trans- 1 (-)-quinic acid ~ 6% 12 11 Oseltamivir formation of quinic acid ( 3 ) to the ethyl- phosphate mesylshikimate ( 5 )was the dehydration of [3] hydroxymesylate 4 (Scheme 3). The origi- Scheme 2. Synthesis of oseltamivir phosphate ( 1 )according to Rohloff et al. nal method using SO2 Cl2 /pyridine was not particularly regioselective resulting in a Cl H O 3–4:1 mixture of the regioisomers 5 and 13 O CO Et CO Et O CO Et CO2 Et O 2 O 2 2 together with smaller amounts of the chloro + + derivative 14. In order to separate the de- O O O O sired crystalline isomer 5 without chroma- OMs OMs OMs OMs tography the mixture had to be subjected to 4 5 13 14 a Pd(0)-catalyzed substitution with pyrro- lidine, whereby only the allylic mesylate in Gilead [3] 1) SO Cl ,Pyridine, the undesired isomer 13 reacted, followed 2 2 CH2 Cl -25 °C by extractive removal of the corresponding 2) Pyrrolidine pyrrolidine derivative. A much higher regi- cat. Pd(PPh3 ) 4 3) H SO extr. oselectivity of 35–50:1 was achieved using 2 4 3-4 1 1 [5] Regioselectivity: 3-4/1 Vilsmeier’s salt. The desired product 5 (Yield: 43%) was isolated in 60% yield after crystalliza- tion from MeOH. Roche [5] Vilsmeier's salt + Cl- N Cl 3.2. Starting from Shikimic Acid (15) (in situ preparation or purchased) Shikimic acid ( 15), the ideal raw ma- DMF or ethyl acetate, 60-80 °C terial for the synthesis of 1 , was com- Regioselectivity: 35-50/1 3.5-5 0.1 1 mercially only available in small research (Yield: 58-65%) quantities by mid 1997. However, the newly Scheme 3. Regioselective elimination: from quinic acid derivative 4 to the corresponding shikimic generated high demand for this compound acid derivative 5 HOT TOPICS: SANDMEIER PRIZE 2006 95 CHIMIA 2007, 61, No. 3 quickly changed the situation. The two 1) Me C(OMe) (2.0 eq.) sources were and still are production by 1) EtOH, SOCl2 2 2 H O COOH (0.5 eq.) H O COOEt TsOH (0.01 eq.) COOEt fermentation using a recombinant E. coli [6] EtOAc, max. 35 O reflux, 3h °C strain and extraction of 15 from star anise. 2) evaporation O H O 2) evaporation H O Therefore the supply of sufficient quantities OH OH 95% OH 97% of shikimic acid ( 15) is secured even in the 15 16 18 face of the dramatically increased demand 1) MsCl (1.3 eq.) 1) 3-pentanone (25 eq.) 2) Et3 N(2.0 eq.) for Tamiflu ( 1 ) caused by the threat of an CF SO H(0.05 eq.) EtOAc, 0-5 °C 97% 3 3 89% 2) extraction 3) filtration influenza pandemic. 3) evaporation 4) evaporation The conversion of shikimic acid ( 15)to 5) cryst.MeOH the ketal 6 is outlined in Scheme 4. For the O COOEt O COOEt efficient production of 6 the longer route via O O the crystalline acetonide 5 is preferred since OH OMs in the one step shorter route via the ketal 17 17 5 all intermediates are oils, which are difficult 1) MsCl (1.3 eq.) 1) 3-pentanone (15 eq.) 2) Et N(2.0 eq.) 93% 98% to purify efficiently on large scale. 3 CF3 SO3 H(0.045 eq.) CH2 Cl2 ,0-5 °C 2) extraction Clearly shikimic acid ( 15)is the starting 3) extraction 3) evaporation material of choice giving access to the eth- O COOE t ylmesylshikimate intermediate 6 in about 80% overall yield compared to about 40% O overall yield starting from quinic acid 3 . OMs 6 The original reductive opening[3] of the ketal 6 with BH3 -SMe2 /TMSOTf proceed- Scheme 4.
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