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Oseltamivir Phosphate): Cis -Aziridine As the Key Synthon and RCM Shubhash P

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Oseltamivir Phosphate): Cis -Aziridine As the Key Synthon and RCM Shubhash P RSC Advances This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 4 RSC Advances A concise synthetic approach towards Tamiflu (Oseltamivir phosphate): Cis -aziridine as the key synthon and RCM Shubhash P. Chavan,* Prakash N. Chavan and Lalit B. Khairnar The key synthon cis -aziridine has been efficiently utilised for the synthesis of Tamiflu (Oseltamivir phosphate), using Wittig olefination, Barbier addition, Mitsunobu reaction and ring closing metathesis (RCM) as key essentials. Manuscript Accepted Advances RSC RSC Advances Page 2 of 4 Organic & Biomolecular Chemistry RSC Publishing COMMUNICATION A concise synthetic approach toward Tamiflu (Oseltamivir phosphate): Cis -aziridine as the key Cite this: DOI: 10.1039/x0xx00000x synthon and RCM† Subhash P. Chavan,* Prakash N. Chavan and Lalit B. Khairnar Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/ Manuscript The key synthon cis -aziridine has been efficiently utilised (tamiflu) is given in the form of an oral prodrug and it has high for the synthesis of the oseltamivir phosphate, using Wittig bioavailability. olefination, Barbier addition, Mitsunobu reaction and ring Tamiflu is effective against both H5N1 and H1N1 viral strains but closing metathesis (RCM) as key essentials. its dose should be administered within 36-48 h after influenza The constant and continuous world-wide threat of the seasonal symptoms detection. 2 The first report for tamiflu synthesis by Gilead influenza to human and animal health is the cause for concern due to science 3 and Roche’s 4 processes from the (–)-shikimic acid is utilized the mortality and mobility of viral strain. 1 Neuraminidase inhibition for industrial scale synthesis of tamiflu. is necessary for stopping the spreading the viral infection from the One of the major factors which restrict the large scale production Accepted infected host cell. These surface glycoproteins cleave the sialic acid of neuraminidase inhibitor drugs is the shortage of the synthetic complex, which invade the lead of the viron in new cells. The precursor (–)-shikimic acid, whose natural source is limited. The 30 molecules which were investigated for blocking the neuraminidase kg of dried star anise plant provides 1 kg (–)-shikimic acid through active site, help the inhibition of the viral infection and avoid the extraction method. Whereas 30% of its total requirement supplied by viron aggregation. Two of these molecules such as Zanamivir fermentation process.5 Recently many synthetic groups focused on (Relenza ®) and Oseltamivir phosphate (Tamiflu ®) are the drugs the alternative synthetic strategies from the cheap and more readily available in the market for the treatment and prevention of the available starting materials which resulted in the different synthetic seasonal influenza caused by mutant viral strains (Fig. 1). routes for the synthesis of the tamiflu. 6 OH HO Shibasaki and co-workers reported different approaches based on OH asymmetric aziridine opening, Diels-Alder reaction and ring closing Advances 7 H metathesis. whereas Corey et al reported the synthesis of tamiflu O 8 O NHAc involving a Diels-Alder reaction while Hayashi’s report on three NHAc HOOC “one-pot” operational stratergy for tamiflu synthesis is the highest 9 NH yielding protocol so far fro the tamiflu. There are also other . synthetic routes reported for the tamiflu synthesis which involve L- RSC EtOOC NH 2 H3PO 4 HN serine, D-xylose, D-ribose, D-mannitol, L-methionine and D-tartarate NH 2 chiral starting materials as alternatives to the (-)-shikimic acid.10 Tamiflu Relenza However these synthetic strategies suffer from several limitations, Fig. 1 Neuraminidase inhibitors which include the utilization of expensive starting materials, hazardous chemicals, tedious reaction conditions, azide The Zanamivir has low bioavailability and is administrated by intermediates and low yielding reaction steps. Due to this there is inhalation which could be problematic in case of patients suffering still a need to design and develop new synthetic routes which from the respiratory disease. Whereas the Oseltamivir phosphate overcome the drawbacks of the reported strategies. The main task is to substitute the raw material of current manufacturing process. The This journal is © The Royal Society of Chemistry 2012 J. Name ., 2012, 00 , 1-3 | 1 Page 3 of 4 RSC Advances COMMUNICATION Journal Name increasing demand of the tamiflu on worldwide seasonal pandemics O O O O of influenza puts increasing pressure to fulfill this need. O O PPh MeBr Since its discovery by Gabriel in 1888, aziridines are synthetically O DIBAL-H, DCM H 3 N N t attractive intermediates and the building blocks for the synthesis of -78 oC KO Bu, toluene 11 rt, 65% natural products. They have been extensively explored for the over 2 steps construction of stereogenic centers containing nitrogen compounds. 4 Tamiflu contains ether, vicinal trans diamine as three contiguous 5 chiral centers in the cyclohexene structure. Hence, the well- O OH organized and accurate placement of these groups is essential for its O OH TMSOTf, DCM synthesis. The aziridine ring can be used to access the trans diamine. NaIO 4, DCM N N We herewith report the synthetic approach towards oseltamivir 0 oC, 2 h, 85% rt, 1.5 h phosphate from the D-mannitol as an inexpensive and abundant chiral starting material involving aziridine as key precursor. 6 7 Retrosynthetic analysis is shown in scheme 1. Aziridine 2 was considered a key precursor, which could be obtained by OH intramolecular RCM of bis -olefin 3. Bis olefin 3 in turn could be COOEt N obtained from the aziridine 4 by consecutive DIBALH reduction, O one carbon Wittig olefination, acetonide deprotection, oxidative COOEt H Br i) p-NO 2PhCOOH cleavage of diol and Barbier addition. The aziridine 4 is the key N DEAD,PPh 3 3a toluene, rt, 2.5 h synthon which could be easily prepared from D-mannitol. 12 THF, NH 4Cl Zn, 10 min, 94% ii) NaOEt, EtOH OH -20 oC, 0.5 h, 69% Manuscript 8 COOEt N 3b EtOOC EtOOC OH OMs Grubbs II, DCM MsCl, TEA, DMAP 3b Ti(OiPr) , reflux N N 4 DCM, 0 oC- rt, 2 h, 12 h, 74% 79% Accepted 9 10 EtOOC ref 14 EtOOC BF 3.Et 2O, DCM 4.4% formic acid Scheme 1 Retrosynthetic analysis for Tamiflu 1 3-pentanol, 3 h Pd/C N NH then Et 3N, 1 h O O According to retrosynthetic plan, the synthesis began with cis - rt, 80% 11 aziridine 4, which was easily prepared from the D-mannitol and 12 ref 4b benzhydril amine in good yield using the reported protocol. The 2 aziridine ester 4 was reduced to the corresponding aldehyde 5 using DIBAL-H at -78 oC (Scheme 2). The resultant aldehyde 5 without Tamiflu 1 purification was directly subjected to one carbon Wittig Scheme 2 Synthesis of Aziridine 2 Advances homologation using KO tBu in toluene to furnish olefin 6 in 65% yield over two steps. Our next task was to obtain the RCM precursor The relative stereochemistry of distereomer 3a and 3b was 3a from the olefin 6 by appropriate chemical transformation. confirmed by transforming the compound 3b to 10 by ring closing Accordingly, acetonide deprotection of olefin 6 was carried out metathesis using Grubbs’ II generation catalyst in refluxing DCM to with TMSOTf in DCM to afford diol 7 in 85% yield. Diol 7 was furnish cyclohexene aziridine 9, which on mesylation furnished the RSC subjected to oxidative cleavage using NaIO 4 in DCM to afford corresponding mesylate 10 . The data of mesylate 10 was found to be aldehyde 8. The crude aldehyde 8 was directly subjected to the in good agreement with the documented data for 10 synthesized by Barbier addition of ethyl 2-(bromomethyl)-acrylate/Zn in THF/aq different route.14 From this the stereochemistry of compound 3b as NH 4Cl to furnish the diastereomeric mixture of 3a:3b in 3:2 ratio in well as 3a as assigned. According to our retrosynthetic plan, 94% yield. The diastereomers 3a and 3b were separated by careful remaining job was to convert the aziridine 10 to intermediate 2, flash chromatography using pet.ether:ethyl acetate (90:10) as eluent. which was carried out by the treatment with 3-pentanol in the The undesired stereoisomer 3a was readily converted to the desired presence of BF 3.Et 2O, which resulted into the regio and 3b by Mitsunobu inversion followed by ester hydrolysis with stereospecific ring opening of aziridine 10 and in situ re- NaOEt/EtOH to afford 3b in 69% yield. 13 aziridination to afford intermediate 2 in 80% yield (Scheme 2). Since 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 2012 RSC Advances Page 4 of 4 Journal Name COMMUNICATION the conversion of intermediate 2 to aziridine 11 and from aziridine 4 (a) M.
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