(12) United States Patent (10) Patent No.: US 9,150,498 B2 Rawat Et Al

Home , Acrylic acid, Methanesulfonyl chloride

US009 150498B2

(12) United States Patent (10) Patent No.: US 9,150,498 B2 RaWat et al. (45) Date of Patent: Oct. 6, 2015

(54) PROCESS FOR THE PREPARATION OF (56) References Cited OSELTAMVR AND METHYL 3-EP-SHIKIMATE U.S. PATENT DOCUMENTS (71) Applicant: Council of Scientific & Industrial 7,531,687 B2 5/2009 Trussardi

(72) Inventors: Varun Rawat, Pune (IN); Soumen Dey, Abrecht, Stefan et al. The Synthetic Development of the Anti-Influ Pune (IN); Sudalai Arumugam, Pune enza Neuraminidase inhibitor Oseltamivir Phosphate (TatniflurR): A (IN) Challenge for Synthesis & Process Research, Chima, vol. 58, No. 9. (73) Assignee: Council of Scientific & Industrial 2004, p. 621-629. Research (IN) Mita, Tsuyoshi et al., Second Generation Catalytic Asymmetric Syn thesis of Tamiflu: Allylic Substitution Route, Organic Letters, vol. 9, (*) Notice: Subject to any disclaimer, the term of this No. 2, 2007, p. 259-262. patent is extended or adjusted under 35 Satoh, Nobuhiro et al., A Practical Syntheis of (-)-Oseltamivir, U.S.C. 154(b) by 0 days. Agnew. Chem. Int. Ed. 2007, vol. 46, p. 5734-5736. Trost, Barry, M. et al., A Concise Synthesis of (-)-Oseltamivir, (21) Appl. No.: 14/354,478 Angew. Chem. Int. Ed. 2008, vol. 47, p. 3759-3761. D. Grandjean et al.; “Base-Promoted Intramolecular Cyclization of Bromoacetylenic Alcohol Derivatives': Tetrahedron Letters; vol. 33; (22) PCT Filed: Oct. 25, 2012 No. 34; E. 1992. (86). PCT No.: PCT/IN2012/000703 REASENSEE, S371 (c)(1), Stereoselective Glycosylations of Deoxyfuranose Glycals and (2) Date: Apr. 25, 2014 3-Amidofuranose Glycals'; Journal of the American Chemical Soci ety 1996; 118(28); pp. 6648-6659. (87) PCT Pub. No.: WO2013/061340 Enyme,Jonathan and D. psiArt.NetMoseley et al., “Influenence on Lipase-Catalysed of Ester Chain tyrol, Length, of PCT Pub. Date: May 2, 2013 Meso-Oxiranedimethanol Esters. Part 2"; Tetrahedron: Asymmetry 11 (2000); pp. 3197-3209. (65) Prior Publication Data Patrick Pale et al., “Silver-Catalyzed Cyclization of Acetylenic Alcohols: Synthesis of Functionalized 2-Methylene-Oxolanes'; US 2014/O243537 A1 Aug. 28, 2014 European Journal of Organic Chemistry 2000; pp. 1019-1025. Jingwei Li et al.; "Tandem Enyne Metathesis-Metallotropic 1.3- (30) Foreign Application Priority Data Shift for a Concise Total Syntheses of (+)-Asperpentyn, (-)- Harveynone, and (-)-Tricholomenyn A; American Chemical Soci Oct. 25, 2011 (IN) ...... 3O39/DELA2011 ety 2009: pp. 571-574. Varun Rawat et al.: “Synthesis of the Anti-Influenza Agent (-)- (51) Int. Cl. Oseltamivir Free Base and (-)-Methyl 3-epi-Shikimate'; Organic & C07D 303/16 (2006.01) R. R. "R"'E.R.Ration control in th C T E. 3:08: RegioselectiveIuliana Kugni Opening et al., of 2,3-Bifunctionalizedy on Une Unelation Epoxides'; Uonuro Tetrahe in Une dron 57 (2001); pp. 5649-5656. C07F 7/08 (2006.01) Ying-Yeung Yeung et al.: “A Short Enantioselective Pathway for the C07C 227/16 (2006.01) Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir CD7C23L/2 (2006.01) from 1.3-Butadiene and Acrylic Acid”; Journal of the American CD7C23/8 (2006.01) Chemical Society 2006; pp. 6310-6311. CD7C 247/4 (2006.01) C07F 7/18 (2006.01) Primary Examiner — Michael Barker C07C 67/327 (2006.01) (74) Attorney, Agent, or Firm — Blank Rome LLP CO7D 303/248 (2006.01) (52) U.S. Cl. (57) ABSTRACT CPC ...... C07C227/16 (2013.01); C07C 67/327 The present invention discloses high yielding enantioselec (2013.01); C07C231/12 (2013.01); C07C tive process for synthesis of Oseltamivir from readily avail 231/18 (2013.01); C07C 247/14 (2013.01); able starting material, cis-1,4-butenediol. The process fea C07D 203/26 (2013.01); C07D 303/16 tures incorporation of chirality using sharpless asymmetric (2013.01); C07D 303/40 (2013.01); C07D epoxidation (AE) and diastereoselective Barbier allylation 303/48 (2013.01); C07F 7/0834 (2013.01); and construction of cyclohexene carboxylic acid ester core C07F 7/1856 (2013.01); C07C 2101/16 through a ring closing metathesis (RCM) reaction. Further (2013.01) also disclosed herein is synthesis of (-)-methyl 3-epi-shiki (58) Field of Classification Search mate. None See application file for complete search history. 9 Claims, No Drawings US 9,150,498 B2 1. 2 PROCESS FOR THE PREPARATION OF -continued OSELTAMVR AND METHYL Formula 2 3-EP-SHIKIMATE R

This application is a U.S. national phase application of 5 PCT/IN2012/000703, filed Oct. 25, 2012, which claims the priority of Indian Patent Application No. 3039/DEL/2011, MOMO CoMe filed Oct. 25, 2011, the disclosures of which are incorporated Wherein R = OH herein by reference. 10 R2 = N3 or R1 + R2 = O or NAc

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION 15 Influenza, commonly referred to as flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviri dae (the influenza viruses). Influenza spreads around the The present invention relates to a high yielding enantiose world in seasonal epidemics, resulting in the deaths of lective process for synthesis of Oseltamivir from readily between 200,000 and 500,000 to people every year, up to available starting material, cis-1,4-butenediol. The process millions in Some pandemic years. The development of effec features incorporation of chirality using sharpless asymmet tive antiviral medicines is hampered by the exceptionally high ric epoxidation (AE) and diastereoselective Barbierallylation mutation rates of influenza virus. Therefore, in order to be Successful, new drugs should target the molecular mecha and construction of cyclohexene carboxylic acid ester core nisms specific to the proliferation of the virus. through a ring closing metathesis (RCM) reaction. The 25 Antiviral drug Such as Oseltamivir is an orally active present invention also relate to synthesis of (-)-methyl 3-epi neuraminidase inhibitor, which has been widely used for the shikimate. More particularly, the present invention relates to treatment of H5N1 avian influenza as well as a recent out compounds of general formula 1 and 2. break of H1N1 Swine flu. The drug is sold under the trade name Tamiflu, and is taken orally in capsules or as a Suspen 30 sion. It has been used to treat and prevent influenza A virus and influenza B virus infection in over 50 million people since Formula 1 1999. The anti-influenza drug was initially discovered by Gilead Sciences and subsequently licensed to Roche for pro duction. CoEt The initial synthesis of Tamiflu, developed by Gilead Sci P ences, employs (-)-quinic acid as the starting material, alter Wherein R1 = CHO, CH2OH or natively, shikimic acid was used for the commercial produc R2 = TBSO or alkylnyle OMOM tion. Large quantities of (-)-shikimic acid are obtained by extraction from Star anise plant which is grown in China by a biocatalytic process which uses glucose as carbon Source. The process is described below in Scheme 1:

Scheme 1 HO, CO2H Ot,

1) EtOH; SOCl2, reflux, 3 h DX --3-pentanone (exc.) '' 2) MeC(OMe), cat. TfGH, EtOAc, HOW TsOH cat., EtOAc, O 40° C., 100 mbar 150-200 mbar,< 35° C., 4h OH 3) MsCl, EtN, EtOAc

O, COEt NaHCO TiCl, EtSiH EtOH/HO, 60° C., 1.5 h He Hoss CH2Cl2, -34°C. 2-6 h w extr. and cryst. hexane HO OMS 4 US 9,150,498 B2

-continued

NaNNHCI

COEt tootOH/H2-OHAHO O, A. COEt -- 60-650 C. N OH 6a (1:9) 5

O, COEt PhP, EtN, MSOH NaN3, HSO4 He O, CO2Et -- DMSO, 50° C., 1 h * DMSO, 35° C., 4h HOS N HN 6b 7

Ac2O, BuO BuP, cat. AcOH O COEt -> Her V, 0-259 C., O. COEt EtOH/HO, 5-20°C.

HN i AcHN

8 9

Or, COEt HPO, EtOH Or, COEt -- 50-20°C., cryst. AcHN ACHN NH, NHH,PO, 10 11

However, the supply of (-)-shikimic acid of consistent 50 purity is problematic due to seasonal and geographical con straints. U.S. Pat. No. 7,531,687 (Applicant Roche) relates to a process for the conversion of Shikimic acid to oseltamivir (I), and optionally to an acid addition salt, via the intermediate 55 phosphoramide VII. The process is described in Scheme 2 below:

Scheme 2 60 HO, CO2H HO, COEt MsO. COEt

-e- -e- -e- X * Step 1 w Step 2 HO w HO w MsO w OH OH 65 OMS II III IV US 9,150,498 B2

-continued ~~ N3, COEt COEt O, COEt 1. O -e- R-P-N -e- | s Step 3 Step 4 N MsOS R R1TYN R H OMS OMS OMS V VI VII

O, COEt O, COEt

-e- Step 6a HN AcHN

OMS OMS VIII-1 VIII-2

VII stepN 5b Step 7b

O O, COEt O, COEt l -e-Step 6b 1N R1 | SN HN R H 2 N N X XI

O, COEt O, COEt

His Step 8 R3RN R3RN N, NH, HPO,

IX I

The process comprises the steps of (step 1) converting an Article titled “The Synthetic Development of the Anti alkyl shikimate ester (III) to the corresponding tris-mesylate Influenza Neuraminidase Inhibitor Oseltamivir Phosphate IV by reacting III with methanesulfonyl chloride the presence 50 (TamifluR): A Challenge for Synthesis & Process Research” of an aprotic organic Solvent and an organic base; (step 2) by Karf. Trussadiet. al in CHIMIA International Journal for Stereoselectively displacing the mesyloxy Substituent on C-3 Chemistry (2004), Volume: 58, Issue: 9. Pages: 621-629 dis with azide in an organic solvent optionally in the presence of closes synthesis of Oseltamivir Phosphate from naturally water and a phase transfer catalyst to afford V: (step 3) con available (-)-shikimic acid as a chiral pool starting material. tacting V with a trialkylphosphite in an inert organic Solvent 55 to induce a Staudinger reaction and provide the aziridine (VI); The process is depicted in Scheme 3 below: (step 4) opening the aziridine by contacting VI with a Lewis acid in the presence of a first alcohol to form VII; (step 5a) contacting VII with a strong acid in a second alcoholic solvent Scheme 3 to hydrolyze of the phosphoramidate and afford the amine 60 HO CO2H VIII-1, (step 6a) contacting VIII-1 with an acylating agent EtOH, SOCI -as and a base to afford VIII-2; (step 7a) contacting VIII-2 with a esterification azide in a second organic solvent and in the presence of a third HO alcohol to displace the remaining mesyloxy group to afford IX and (step 8) contacting IX with a reducing agent to afford 65 OH oseltamivir (I) which is optionally converted to a pharmaceu (-)-Shikimic Acid tically acceptable salt. US 9,150,498 B2

-continued -continued HO COEt --> --- 5

w '' TSOH ~~ HO ketalization O., COEt OH PhCHO Hs t-BuOMe, - HO w unselective imine 10 HO formation NH2 Ot COEt ti. MsCl, EtN He Ow" meSylation 15 OH ~~ O?, COEt MsCl, EtN -EtNHCI 2O Hip meSylation Ot COEt HO TMSOTf BH-Me2S N- Ph Ow' 63-75.9% 25 ketal reduction, Hunter conditions 80% over three steps 30 ~~ RO. COEt Or, COEt 4n-N'- KHCO 4.0 equiv.y 15r. 4 tb '' -e- MsO' . s ROS aq. EtOH 35 HCI/HO 96% OM 0. N- Ph tranSimination S epoxidation thenaziridination 10:1:1 inseparable mixture of: R = H, R = H, R = 3-pentyl, R = H. R = H, R = 3-pentyl 40

O., COEt 21 N-1 NH2 -- 21N1 Nsir Ph He 45 COEt 0.2 equiv. MgBrOEt HN 9:1 t-BOMe, MeCN 559 C., 16 h; aziridine then opened by (NH4)2SO4/H2O allylamine 97% 50 epoxide opening

H2N-N-1-1. Pd/C, EtOH 55 ~~ ~~ reflux, 3 h OH O, 2. COEt O, COEt -e- w 2. H2SO4/HO -- 60 HO - N-deallylation770, . HNi Ph n-1S "Nu-1sN Second transmination 65 followed by acidic hydrolysis US 9,150,498 B2 10 -continued -continued

5 O, COEt Ac2O, AcOH 2. MSOH He t-BuOMe, 15 h 20° C., 83% N-acetylation 10 HN NH2-HPO. N-1s Oseltamivir phosphate 80% over four steps (Tamiflu) 1.10% Pol/C, EtOH 15 HN

~~ N1reflux, 3 Noh O, COEt . 2. HPO, EtOH An article titled “Short Enantioselective Pathway for the He 70% 20 Synthesis of the Anti-Influenza Neuramidase Inhibitor Osel AcHN N-deallylation, tamivir from 1,3-Butadiene and Acrylic Acid' by E. J. Corey Salt formation HN published in J. Am. Chem. Soc., 2006, 128 (19), pp 63.10 nu-1S 6311 discloses synthesis of Oseltamivir from 1,3-Butadiene and acrylic Acid as shown in Scheme 4.

Scheme 4

O O

Et “ NHBoc Boc

9 8

HN1 Br h Ac 10

AcHN OEt i -> AcHN OEt ~~ He- O, OEt Bry AcNH NHBoc N HBOc E NHBoc 11 12 13 US 9,150,498 B2 11 12 -continued ~~ O O, O

Et AcNH SHHPO, 15

Article titled “Second Generation Catalytic Asymmetric -continued Synthesis of Tamiflu: Allylic Substitution Route' by 15 gH Masakatsu Shibasaki et. al in Org. Lett., 2007, 9 (2), pp NHA 259-262 discloses Catalytic asymmetric synthesis of Tamiflu. NHAe After the catalytic enantioselective desymmetrization of - -, meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol%) derived from ligand 2, an allylic oxygen function and C1 unit 20 NC NHBOc on the CC double bond are introduced through cyanophos phorylation of enone and allylic Substitution with an oxygen nucleophile (Scheme 5). O

25 NHAc Scheme 5 w N3 w EtOC NH2-HPO. - 30 Tamiflu NHCOAir Article titled “A Practical Synthesis of (-)-Oseltamivir” by

NHA Fukuyama et. al (Part I) in Angew. Chem. Int. Ed. 2007, 46. O C 35 5734-5736 discloses preparation of Oseltamivir from pyri (EtO) lO -- dine and acrolein. The asymmetric Diels-Alder reaction with 2 NHB acrolein 3 is carried out with the McMillan catalyst to the OC aldehyde 4 as the endo isomer which is oxidized to the car boxylic acid 5 with sodium chlorite. The process is given below in Scheme 6

Scheme 6 N N

2 - || N

Cbz 1 2 )- H 3

N1 Cbz N1 Cbz N1 Cbz Br a- a N N O O O O HO H 6 5 4 US 9,150,498 B2 13 14 -continued O boc boc N -boc N1 N1 NH Br Br 3 Br He NH2 O O O OH O 8 9

In the article “A Concise Synthesis of (-)-Oseltamivir by Barry M. Trost, Ting Zhang in Angew. Chem. Int. Ed. 2008, 15 47, 1-4, synthesis of Oseltamivir is disclosed which is given --- below in Scheme 7: O, .. COE DMAPAc2O Her pyridine SES Scheme 7 NN NPhth 6 (R,R)-L THF O -e- 25 2. TsOH.H2O O, COEt Qe EtOH w BuNF O -e- 1 SES.N. THF

30 Ac NPhth yCOEt 7 w PhSSOPh KN(SiMe3) He THF 35 O va, COEt" N.H., NPhth -e- EtOH 2 ACHN 40 NPhth SPh 1. mCPBA 8 COEt NaHCO 2. DBU He O, COEt toluene 45

NPhth AcHN 3 NH, SESNH 50 Phi(OCtBu)2 9 COEt Rh2(esp)2 MgO Her Since control of stereochemistry is important, as the mol PhC1 ecule has three Stereo centers, the prior art processes use 55 costly chiral reagents or catalysts to obtain the desired enan tioselectivity. Furthermore, the commercial production of NPhth Oseltamivir from the biomolecule shikimic acid or from its 4 enantiomer is restricted by limited supply of the plant world OH wide. 60 Due to the limited supply of shikimic acid, searches for SES-N COEt N-N- alternative synthetic routes preferably skipping shikimic acid -- are underway. Further, though Oseltamivir is not a complex BFEt2O moleculeyetits practical synthesis on a large scale, enough to NPhth guard against an influenza pandemic, presents a formidable 65 challenge. 5 In view of the above, there remains a need to provide a high-yielding enantioselective approach towards the synthe US 9,150,498 B2 15 16 sis of Anti-Influenza Agent Oseltamivir from readily avail able and less expensive starting materials. OH OBJECTIVE OF THE INVENTION 5 TBSO The main objective of the invention is to provide a high yielding enantioselective process for the synthesis of Anti influenza Oseltamivir from readily available and less expen sive starting material cis-1,4-diol. Another object of the invention is to provide synthesis of 10 OH (-)-methyl 3-epi-shikimate, a key intermediate in the process O of Oseltamivir. -as Another object of the invention is to provide compound of TBSO general formula 1 and 2 8 15

Formula 1 O O R CoEt R2 TBSO Wherein R1 = CHO, CH2OH or 9 R2 = TBSO or alkylnyle OMOM Formula 2 R2 25 (iii) subjecting aldehyde (9) to diasteroselective Barbier ally R lation in the presence of ethyl 2-(bromomethyl)acrylate, Zndust in an aprotic solvent and NHCl at the temperature ranging between 25-30°C. for a period of 8-12 hours to obtain the compound 10 ((R)-Ethyl 4-((2S,3R)-3-((tert MOMO CoMe 30 butyldimethylsilyloxy)methyl)oxiran-2-yl)-4-hydroxy-2- Wherein R = OH methylenebutanoate) R2 = N3 or R1 + R2 = O or NAc O 35 CHO -as SUMMARY OF THE INVENTION TBSO Accordingly, the present invention provides a process for 9 the preparation of Oseltamivir with enantioselectivity 98% COEt ee, and methyl 3-epi-shikimate wherein the said process com 40 prises: (i) monosilylating of cis-1,4-butenediol (6) in a dry aprotic Solvent and imidazole and a silyalting agent at the tempera OH ture ranging between 0-25 deg C. for a period ranging TBSO 45 between 4-8 hours to obtain mono silyl allylic alcohol 10 (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol (7). (iv) adding N,N-dipropylethylamine (hunig's base) to a solu OH 21 tion of compound 10 as obtained in step (iii) in a dry aprotic to / \-on -e- 50 Solvent in the presence of a protecting agent at a tempera ture ranging between 0-25°C. for a period of 10-16 hours 6 TBSO to obtain compound (R)-ethyl 4-((2S,3R)-3-((tert-bu tyldimethylsilyloxy)methyl)oxiran-2-yl)-4-(meth 55 oxymethoxy)-2-methylenebutanoate of formula 1 1 fol (ii) asymmetric epoxidizing mono silyl allylic alcohol (Z)-4- lowed by desilylation using TBAF (tetrabutyl ammonium (tert-butyldimethylsilyloxy)but-2-en-1-ol (7) with fluoride) to obtain compound 12. Ti(OiPr)4, (+) DET (diethyl tartarate), anhydrous TBHP (tert-butyl hydroperoxide) in a aprotic solventata tempera ture ranging between -10°C. C to -20°C. for a time period 60 COEt of 10 to 20 minutes to obtain epoxy alcohol ((2S,3R)-3- ((tert-butyldimethylsilyloxy)methyl)oxiran-2-yl)metha nol of formula (8) followed by oxidizing with TEMPO (2.2.6,6-tetramethyl-1-piperidinyloxyl)/BAIB bis(ac OH TBSO etoxy)iodobenzene mixture to obtain aldehyde 2R,3R)- 65 3-((tert-butyldimethylsilyloxy)methyl)oxirane-2-carbal 10 dehyde of formula (9); US 9,150,498 B2 18

-continued -continued COEt

O Ho OMOM COEt TBSO 14 11 COEt 10 (vii) regioselective opening of epoxide compound 14 with O NaN3 and mixture of solvent DMF:ethanol: water in the ratio of 1:1:0.5 to 2:2:1 at a temperature ranging between OMOM 25-30°C. for a time period of 10-12 hours to obtain com HO pound (3S,4R,5R)-methyl 3-azido-4-hydroxy-5-(meth 12 15 oxymethoxy)cyclohex-1-enecarboxylate of formula 15,

(V) oxidizing the compound 12 with a oxidizing agent IBX (2-iodoxy benzoic acid) and an aprotic solvent to obtain unstable aldehyde followed by subjecting to Seyferth-gil COMe bert homologation in the presence of diethyl 2-oxopropy lphosphonate, a base and a polar solvent at a temperature 14 ranging between 0-25° C. for a time period ranging between 8-12 h to obtain the terminal alkyne (R)-methyl HO, 4-((2S,3R)-3-ethynyloxiran-2-yl)-4-(methoxymethoxy)-2 25 methylenebutanoate of formula 13 MOMO COMe

COEt 15 30 (viii) Optionally treating cyclohexene epoxide (14) as obtained in step (vi) with sulphuric acid in THF:H2O in the OMOM ratio of 3:1 to 4:1 as solvent at a temperature ranging HO between 25 to 30° C. for a time period of 2 to 4hrs to obtain 12 35 diol compound 19 followed by de-protecting MOM of COEt compound 19 with HCL in an alcohol at a temperature ranging between 25°C. to 30°C. for a time period of 6 to 8 hrs to obtain Methyl 3-epishikimate (2)

40 OMOM

-e-

13 COMe 45 14 (vi) reducing the alkyne 13 with Lindlar's catalyst (Pd OH adsorbed on CaCO3) in an aprotic solvent at a temperature HO ranging between 25-30° C. for a time period ranging between 2-6 hours to obtain diene followed by ring closing He metathesis using Grubb's IInd generation catalyst (1,3-Bis 50 (2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro MOMO COMe (phenylmethylene) (tricyclohexylphosphine)ruthenium in 19 dry aprotic solvent at a temperature ranging between OH 25-50° C. for a time period ranging between 14-24 hours to obtain epoxide compound (1R,5R,6S)-methyl 5-(meth 55 HO oxymethoxy)-7-Oxabicyclo[4.1.0 hept-2-ene-3-carboxy late of formula 14, COEt HO COMe 2 60 (ix) aziridinizing the compound 15 as obtained in step (vii) OMOM with triphenyl phosphene (PPh3), toluene at 110°C. for a time period ranging between 3-12 hours to obtain a aziri 65 dine compound (1S,5R,6S)-methyl 7-acetyl-5-(meth 13 oxymethoxy)-7-azabicyclo4.1.0 hept-2-ene-3-carboxy late, of formula 16, US 9,150,498 B2 19 20 In one embodiment of the present invention the solvent selected from polar or non-polar solvents; protic or aprotic Solvents used is selected from the group comprising of tolu HO,a. ene, acetone, ethyl acetate, methanol, THF, DCM, DMSO. In another embodiment of the present invention the sily MOMO COMe lating agent used in step 1 (i) is selected from the group comprising of dimethylsilyl (TMS), tert-butyldiphenylsilyl 15 (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triso AcN propylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), 10 tert-butyl dimethylsilyl chloride (TBSCI). Still in another embodiment of the present invention the MOMO COMe base used in step (V) is selected from the group comprising of KCO, Et N. 16 15 Still in another embodiment of the present invention pro (X) regio-Selective ring opening of aziridine (16) with pentan tecting agent used in step (iv) is MOMC1 (methyl chlorom 3-ol in the presence of BF3.Et2O at a temperature ranging ethyl ether) between 0-25°C. for a time period ranging between 2-12 hours to obtain compound 17 followed by MOM de-pro Still in another embodiment of the present invention com tection in an alcohol and HCL at a -10 temperature ranging pounds of general formula 1 and 2 between 25-30°C. for a time period of 4-12 hours to give compound 17 (3R,4R,5R)-Ethyl 4-acetamido-5-hydroxy Formula 1 3-(pentan-3-yloxy)cyclohex-1-enecarboxylate O AcN 25 P- R R Wherein R1 = CHO, CH2OH or MOMO COMe 30 16 -(SCoEtOMOM R2 = TBSO or alkylnyle Formula 2 35 R AcHN

HO COEt 40 OMOMRId, CoMe 17 Wherein R1 = OH R2 = N3 or (xi) Conversion of 17 to oseltamivir by method known in the R1 + R2 = O or NAc art. 45 Still in another embodiment of the present invention com pounds of general formula 1 and 2 are represented by the group of the following compounds:

50 O AcHN Y

TBSO > . HO COEt 55 17 ((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxiran-2- yl)methanol (Compound 8)

60 O AcHN

TBSO

HN' COEt 65 (2R,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxirane-2- carbaldehyde. (Compound 9) US 9,150,498 B2 21 22

COEt

OMOM AcHN Y TBSO

(R)-ethyl 4-((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl) 10 CO2H oxiran-2-yl)-4-(methoxymethoxy)-2-methylenebutanoate (Compound 11) OH HO/ COMe 15 HO COMe

OMOM A. Oseltamivir molecule (Fig 1) has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers. Hence control of Stereochemistry is important during the synthesis (R)-methyl 4-((2S,3R)-3-ethynyloxiran-2-yl)-4-(meth of said molecule. The process of the current invention over Oxymethoxy)-2-methylenebutanoate. (Compound 13) comes the shortcomings of processes known in the art by incorporation of chirality using sharpless asymmetric epoxi dation (AE) and diastereoselective Barbier allylation, Fur ther, cyclohexene carboxylic acid ester core is constructed 30 through a ring closing metathesis (RCM) reaction. Oseltama vir free base with 98% ee is achieved by the present invention. The process for preparation of Oseltamivir with enantiose COMe lectivity 98% ee, comprises the steps of 1. Monosilylation of cis-1,4-butene diol (6) to obtain (1R,5R,6S)-methyl 5-(methoxymethoxy)-7-Oxabicyclo 35 mono-silyl allylic alcohol (7); 4.1.0 hept-2-ene-3-carboxylate. (Compound 14) 2. Asymmetric epoxidation of allylic alcohol (7) with Ti(O- iPr). (-)-DET, anhydrous TBHP to give epoxy alcohol (8) followed by oxidation with TEMPO/BAIB mixture N to aldehyde (9); 40 3. Zinc mediated diasteroselective Barbier allylation of HO aldehyde (9), to syn-epoxy alcohol (10); 4. Selective protection of syn epoxy alcohol (10) with methyl chloromethyl ether (MOMCI) in presence of MOMO COMe Hunig's base to give corresponding MOM-ether (11) 45 followed by desilylation of (11) to obtain alcohol (12); 5. Oxidation of (12) with IBX/DMSO mixture to unstable (3S,4R,5R)-methyl 3-azido-4-hydroxy-5-(meth aldehyde, extracting in diethyl ether and Subjecting to Oxymethoxy)cyclohex-1-ene-carboxylate. Compound 15; Seyferth-Gilbert homologation in presence of a base and methanol to afford the terminal alkyne (13) with a com 50 pletely transesterified methyl ester; AcN 6. Reduction of alkyne (13) with Lindlar's catalyst to cor responding diene followed by ring closing metathesis using Grubb's II" generation catalyst under high dilu tion (large excess of solvent, (100 mL) to afford the MOMO COMe 55 carbocyclic core in epoxide (14); 7. Regioselective opening of cyclohexene epoxide (14) with NaNs and NHCl to obtain azido alcohol (15); (1S,5R,6S)-methyl 7-acetyl-5-(methoxymethoxy)-7-azabi 8. Aziridination of alcohol (15) with EtN and MsCH cyclo[4.1.0 hept-2-ene-3-carboxylate (Compound 16) followed by acylation to obtain aziridine (16); 60 9. Regioselective ring opening of aziridine (16) followed by MOM deprotection to give compound 17; and DETAILED DESCRIPTION OF THE INVENTION 10. converting 17 to Oseltamivir by method known in the art procedure known in literature X. Lu, F.-F. Wang, N. The present invention relates to enantioselective synthesis Quan, X. X. Shi and L.-D.Nie, Tetrahedron: Asymmetry, of Anti-Influenza Agent Oseltamivir (1) and (-)-methyl 65 2011, 22, 1692) 3-epi-shikimate (2) from readily available raw material, cis The chirality in the molecule is achieved by subjecting 1,4-butenediol. mono silyl protected allylic alcohol (7) to sharpless asymmet US 9,150,498 B2 23 24 ric epoxidation with Ti(OiPr)4, (+)-DET (diethyl tartarate), 3-ol in presence of 1.5 equiv. of BFOEt, followed by MOM TBHP (tert-butyl hydroperoxide), 4 Angstrom Molecular deprotection with 2N HCl in MeOH to give 17 which is Seives (AM.S.) at -20°C. to yield epoxy alcohol (8). Alcohol converted to the Oseltamivir by known literature methods. (8) is further oxidized with a oxidizing mixture consisting of The above described process for the preparation of Osel TEMPO (2.2.6,6-tetramethyl-1-piperidinyloxyl) and BAIB 5 bis(acetoxy)iodobenzene to aldehyde (9). Zinc-mediated tamivir is schematically given below in Scheme 8. aqueous Barbierallylation of (9) with ethyl 2-(bromomethyl) acrylate in polar aprotic solvent in aq. sat. NH4C1 forms corresponding homoallylic alcohols (10) in good yields Scheme 8 (84%, for both diastereomers) and with good diastereoselec 10 o i tivity (10:1).). The syn-epoxy alcohol (10) was confirmed by HO / \ OH - - its correlation data (NOESY and COSY). In the process of the present invention, ring closing met 6 OH athesis has been used for the facile construction of cyclohex 21 ii ene carboxylic acid ester core. This is realized by Subjecting 15 the diene obtained by reduction of alkyne (13) to Grubb’s II' -e- generation catalyst (under high dilution condition) large TBSO excess of solvent) to cyclohexene epoxide (14). 7 In the process, the solvents include polar or non-polar OH

Solvents; protic or aprotic solvents and are selected from III toluene, dichloromethane (DCM), acetone, ethyl acetate, He methanol, THF, DCM, DMSO etc. Cis-1,4-butenediol (6) is mono protected with silyl group TBSO selected from trimethylsilyl (TMS), tert-butyldiphenylsilyl 8 (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triso 25 O propylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), He tert-butyl dimethylsilyl chloride (TBSCI) in a solvent to obtain corresponding mono silyl protected allylic alcohol (7). TBSO P- iv The mono silyl protected allylic alcohol (7) is subjected to 9 Sharpless asymmetric epoxidation with Ti(OiPr), (+)-DET 30 COEt (diethyl tartrate), TBHP (tert-butyl hydroperoxide), 4 AM.S. at -20° C. to yield epoxy alcohol (8). O w Compound (8) is oxidized with a oxidizing mixture con He sisting of TEMPO (2.2.6,6-tetramethyl-1-piperidinyloxyl) OH and BAIB bis(acetoxy)iodobenzene in dry CHCl to alde 35 TBSO hyde (9). Zinc mediated Barbier allylation of aldehyde (9) is effected with ethyl 2-(bromomethyl) acrylate in polar aprotic 10 Solventinaq. Sat. NHCl to obtain corresponding homoallylic COEt alcohols (10). Preferably, syn-epoxy alcohol (10) is obtained O vi and its formation is confirmed by its correlation data 40 Her (NOESY and COSY). Compound (10) is further treated with Methyl chloromethyl ether (MOMC1) in presence of Hunigs OMOM base (N.N. diisopropylethylamine) to give corresponding TBSO ether (11) followed by desilylation with TBAF (tetrabutyl 11 COEt ammonium fluoride) in presence of THF to give alcohol (12). 45 The free hydroxy group in (12) is oxidized with IBX (2-io doxy benzoic acid) in dry DMSO at 25 deg C. giving the O vii. corresponding aldehyde, which is found to be unstable during -- OMOM silica gel purification. The aldehyde is extracted in a solvent HO and immediately (without purification) is subjected to Sey 50 ferth-Gilbert homologation using dimethyl-(1-diazo-2-oxo 12 propyl)phosphonate (Bestman-Ohira reagent) in presence of COMe an inorganic base such as KCO in MeCH to obtain terminal alkyne (13). Subsequent reduction of alkyne (13) with Lind O viii -e- lar's catalyst (Pd adsorbed on CaCO3) in presence of MeOH, 55 gave the corresponding diene, which is further Subjected to OMOM ring closing metathesis using Grubb's II"generation catalyst (1,3-Bis(2,4,6-trimethylphenyl)-2 imidazolidinylidene) dichloro(phenylmethylene)(tricyclohexylphosphine)ruthe 13 nium (under high dilution condition) to carbocyclic core (14). 60 The regioselective opening of epoxide (14) with NaN, and 9., NHCl in a mixture of DMF:EtOH:H2O (2:2:1) gives azido ix alcohol (15). Aziridine formation from azido alcohol (15) is -e- facilitated by treating compound (15) with PPhs in MsCH and MOMO COMe in presence of a base such as Et Nanda solvent THF followed 65 by acylation with acylating agent in presence of a base EtsN 14 to give aziridine (16). Aziridine (16) is reacted with pentan US 9,150,498 B2 25 26 -continued N O HO X TBSO Her MOMO COMe The intermediate (11) (R)-ethyl 4-((2S,3R)-3-((tert-bu 1 5 tyldimethylsilyloxy)methyl)oxiran-2-yl)-4-(meth oxymethoxy)-2-methylenebutanoate is disclosed. AcN 10 Xi COEt MOMO COMe O 1 6 15 OMOM TBSO 1 Intermediate 13, (R)-methyl 4-((2S,3R)-3-ethynyloxiran Lit. -e- 2-yl)-4-(methoxymethoxy)-2-methylenebutanoate. AcHN

COMe YCOMe 25 17

O 30 AcHN The novel intermediate, (14) (1R,5R,6S)-methyl 5-(meth oxymethoxy)-7-Oxabicyclo4.1.0 hept-2-ene-3-carboxylate.

HN CO2H 35

Reagents and conditions: (i) TBSC1, imid., dry CHCl, 0-25°C., 8 h, 73%; (ii) Ti(OiPr), (+)-DET, TBHP, 49 AM.S., 40 COMe -10°C., 12 h, 93%; (iii) Tempo, BAIB, dry CHC1, 25°C. 1 h, 95%; (iv) Zn dust, ethyl 2-(bromomethyl)acrylate, THF, A novel intermediate (15), (3S,4R,5R)-methyl 3-azido-4- aq sat. NHCl, 25°C., 10h, 64%; (v) MOMC1, Hunigs base, hydroxy-5-(methoxymethoxy)cyclohex-1-ene-carboxylate. dry CHC1, 0-25° C., 10 h, 90%; (vi) TBAF, THF, 0-25°C., 2 h, 88%; (vii) (a) IBX, dry DMSO, 25°C., 2 h; (b) diethyl 45 2-oxopropylphosphonate, KCO, MeOH 82% (for two N steps); (viii) (a) Lindlars cat., ETHYL/PYIRIDINE/1- OCTENE, MeOH, 25°C., 6 h; (b) Grubbs II, dry CHC1,50° HO C., 12 h, 85% (for two steps); (ix) NaN, DMF:EtOH:H2O 50 (2:2:1), 25°C., 10 h, 83%; (x) PPhs, toluene, reflux, 3 h; (c) MOMO COMe Ac2O, EtN, EtOAc, 25°C., 2h, 81% (for two steps); (xi)(a) 3-pentanol, BFOEt, 0°C., 2 h; (xii) (b) HCl, EtOH, 25°C., In another embodiment, an intermediate (16) (1S,5R,6S)- 4h, 64% (for two steps). methyl 7-acetyl-5-(methoxymethoxy)-7-azabicyclo4.1.0 The present invention disclose a novel intermediate of for 55 hept-2-ene-3-carboxylate, is provided. mula (8); (2S,3R)-3-((tert-butyldimethylsilyloxy)methy poxiran-2-yl)methanol. AcN

O 60

MOMO COMe TBSO > y

65 The present invention discloses synthesis of Methyl 3-epi The intermediate (9); (2R,3R)-3-((tert-butyldimethylsily shikimate (2) from the cyclohexene epoxide precursor (14). loxy)methyl)oxirane-2-carbaldehyde. Compound (14) is derived from cis-1,4-butenediol (6) by the US 9,150,498 B2 27 28 aforementioned process steps. Accordingly, conversion of Based on retrosynthesis analysis, the present inventors epoxide (14) to triol of formula (2) comprises ring opening of concluded that cyclohexene epoxide (14) can be considered as key precursor in the synthesis of oseltamavir (1) and (-)- epoxide (14) with sulphuric acid in THF:H2O (5:1) as solvent methyl 3-epi-shikimate (2). mixture, to obtain the corresponding diol-19; followed by The stereochemistry of the cyclohexene epoxide derivative MOM deprotection in compound 19 with 2N HCl in metha 5 (14) is confirmed by its conversion to a literature known nol. compound (2) given above. Correlation with literature values, The synthesis of 3-epimer of (-)-methyl shikimate (2) is confirms the relative as well as absolute stereochemistry of given below in Scheme 9. the functionalized carbocyclic core. The present invention discloses synthesis of oseltamavir 10 with high enantioselectivity from the novel intermediate cyclohexene epoxide (14), which process comprises the fol Scheme 9 lowing steps; 1. Regioselective opening of cyclohexene epoxide (14) with NaN, and NHCl to obtain azido alcohol (15); 15 2. Aziridination of alcohol (15) with Ph3P in refluxing toluene followed by acylation to obtain aziridine (16); 3. Regioselective ring opening of aziridine (16) with pen COMe tan-3-ol followed by MOM deprotection to give com 14 pound 17; and 4. Conversion of 17 to Oseltamivir by method known in the art.

Scheme 10

AcN HO.

COMe MOMO COMe MOMO COMe 14 15 16 |

Y Lit. AcHN a

HN CO2H HO COMe 1 17

-continued (i) NaN, DMF:EtOH:H2O (2:2:1), 25°C., 12 h, 83%; (ii) OH PPhs, toluene, reflux, 3 h; (iii) Ac2O, EtN, EtOAc, 25°C., 2 h, 81% (for two steps); (iv) 3-pentanol, BFOEt, 0°C., 2 h; HO, 50 (v) HCl, EtOH, 25°C., 4 h, 64% (for two steps). The present invention relates to the use of the compound Oseltamivir prepared by the instant process for the treatment MOMO COMe or prevention of influenza. 19 The invention relates to the use of the compound for the 55 preparation of a medicament for the treatment or prevention of influenza. OH The compound of the present invention is suitably formu HO. lated into pharmaceutical compositions for administration to 60 human Subjects in a biologically compatible form Suitable for administration in vivo. The present invention provides a phar maceutical composition comprising the compound of the HO COMe instant invention either alone or as its salts along with Suitable pharmaceutically acceptable excipients such as carrier, dilu 65 ent, binder, lubricant etc. Reagents and conditions: (i) H2SO4, THF:H2O, 25°C., 2 In conclusion, the present invention provides a novel enan h, 96%; (ii) HC1, MeOH, 25°C., 4 h, 74%. tioselective synthetic route towards (-)-Methyl 3-epi-shiki US 9,150,498 B2 29 30 mate and Anti-Influenza Agent Oseltamivir incorporating a (5.6 g. 20 mol%) was added under nitrogen atmosphere. The Successful application of Sharpless asymmetric epoxidation reaction mixture was cooled to -10°C. and (+)diethyl tartrate (AE) and diastereoselective Barbier allylation. Ring closing (4.4g, 30 mol%) added and stirred for 10 min. To the above metathesis (RCM) has been used for the facile construction of solution, tert-butyl hydroperoxide 5-6 molar solution in cyclohexene carboxylic acid ester core. Throughout the Syn 5 decane (35.2 mL, 2 equiv.) was added and stirred at -10°C. thesis, operationally simple reactions with high overall yields for further 30 min, after which allylic alcohol 7 (20g, 98.83 requiring a relatively low amount of inexpensive and non mmol) dissolved in dry CHCl (150 mL) was added and toxic reagents are used which make the present approach an stirred at -10°C. for 12 h. After completion of the reaction attractive and useful process. (monitored by TLC), the reaction mixture was quenched with 10 1MNaOH (25 mL) with further stirring for 1 hat-1.0°C. The GENERAL INFORMATION organic layer was then separated, washed with brine solution, dried over anhyd. NaSO and concentrated under reduced Solvents were purified and dried by standard procedures pressure. The crude compound was purified by column chro before use. Optical rotations were measured using Sodium D matography using petroleum ether?ethyl acetate (8:2 V/v) to line on a JASCO-181 digital polarimeter. "H NMR and 'C 15 NMR spectra were recorded on Brucker AC-200 spectrom afford the epoxy alcohol (-)-8 as a colorless liquid. eter unless mentioned otherwise. Elemental analysis was car Yield: 93%; colorless liquid; C-11.1 (c 2.0, CHC13) ried out on a Carlo Erba CHNS-O analyzer. IR spectra were IR(CHC13): 777,837, 1047, 1257, 1472,2858,2955,3441 recorded on a Perkin-Elmer model 683 B and absorption is cm': "H NMR (200 MHz, CDC1): 8 0.04 (s, 6H), 0.86 (s, expressed in cm. Purification was done using column chro 9H), 2.9 (brs, 1H), 3.13-3.20 (m, 2H), 3.65-3.73 (m, 4H); 'C matography (230-400 mesh). NMR (50 MHz, CDC1): 8 -5.3, -5.4, 18.6, 25.8, 56.2, 56.5, The present invention is illustrated herein below with 60.6, 61.6: Anal. Calcd for C10H22O3Si requires C, 55.00: examples, which are illustrative only and should not be con H, 10.15. Found: C, 55.07; H, 10.18%. Strued to limit the scope of the present invention in any man Example 3 . 25 Example 1 (2R,3R)-3-((tert-butyldimethylsilyloxy)methyl)ox irane-2-carbaldehyde, (+)-9 (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol, (7) O 30 OH

TBSO

TBSO 35 To a solution of epoxy alcohol (+)-8 (15.0 g) in dry CHCl was added in one portion bis-acetoxy iodobenzene (24.34. 75.6 mmol) and TEMPO (1.07 g. 6.9 mmol). The reaction To a solution of cis-1,4-butenediol (6) (20.0 g, 227.27 mixture was then allowed to stir at 25° C. for 1 h. After mmol) in dry CHCl (700 mL) at 0°C. was added imidazole completion of reaction (monitored by TLC), the reaction (23.21 g, 340.91 mmol) and tert-butyldimethylsilyl chloride 40 mixture was quenched by addition of saturated Solution of aq. (37.68 g. 250.0 mmol). The reaction mixture was stirred at 0° ammonium thiosulphate (log in 100 mL water). The organic C. for 6 h. After completion of reaction (monitored by TLC), layer was separated, washed with brine and Subjected to col it was diluted with CHCl (500 mL) washed with water, umn chromatographic purification with petroleum ether/ brine and dried over anhydrous NaSO Removal of solvent ethyl acetate (9:1 V/v) to afford the epoxy aldehyde (+)-9. under reduced pressure gave the crude product which was 45 Yield: 95%; yellow liquid; C.D25+43.0 (c 3.0, CHC13). then purified by column chromatography with petroleum IR(CHC13): 778,838, 1099, 1256, 1472, 1720, 2858,2930 ether/EtOAc (9:1 V/v) to give (7) as a colorless liquid. cm': "H NMR (200 MHz, CDC1): 8 0.08 (s, 6H), 0.89 (s. Yield: 73%; colorless liquid; IR (CHC1): 777, 837, 1033, 9H), 3.34-3.44 (m, 2H), 3.90-4.09 (m, 2H), 9.47 (d. J–4.2 Hz, 1088, 1255, 1471, 2857, 2929, 3354 cm; H NMR (200 1H); 'C NMR (50 MHz, CDC13): 8 -5.5, 18.2, 25.7, 57.4, MHz, CDC1): 8 0.04 (s, 6H), 0.86 (s, 9H), 2.2 (brs, 1H), 50 59.8, 60.1, 1974; Anal. Calcd. for C10H20O3Si requires C, 4.17-4.26 (m, 4H), 5.57-5.61 (m, 2H); 'C NMR (50 MHz, 55.52; H, 9.32. Found: C, 55.60; H, 9.43%. CDC1): 6-5.3, 18.3, 25.9, 58.6, 59.5, 130. 1, 131.1; Anal. Calcd for CHO Si requires C, 59.35; H, 10.96. Found: C, Example 4 59.38: H, 10.99%. (R)-ethyl 4-((2S,3R)-3-((tert-butyldimethylsilyloxy) Example 2 55 methyl)oxiran-2-yl)-4-hydroxy-2-methylenebu tanoate, (10) ((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxi ran-2-yl)methanol, (-)-8 COEt 60 O

OH TBSO > . TBSO 65 To a stirred suspension of powdered 4 A molecular sieves To a pre-cooled (0°C.), well stirred mixture of (+)-9 (4.g. (10.0 g) in dry CHCl (700 mL), titanium tetraisopropoxide 18.51 mmol), Zn dust (3 g, 45 mmol) and ethyl 2-(bro US 9,150,498 B2 31 32 moester)acrylate (8g, 41 mmol) in 80 mL of THF was added purified by chromatography (petroleum ether?ethyl a saturated solution of NHCl (8 mL). The mixture was stirred acetate=9/1) to give MOM protected compound 11 as a col for 10h at ambient temperature 25°C. until the aldehyde was orless oil. totally consumed (monitored by TLC). The mixture was fil Yield: 90%; colorless liquid; C.’ +2.9 (c 1.0, CHCl); tered and the precipitate was thoroughly washed with THF IR (CHC13): 778,838, 1150, 1257, 1716, 2857, 2955 cm; (3x10 mL). THF was then removed under vacuum and the "H NMR (200 MHz, CDC13): 8 0.08 (d. J–2.9 Hz, 6H), 0.90 remaining solution extracted with EtOAc (100 mL). The (s, 9H), 1.31 (t, J=7.1 Hz, 3H), 2.53-2.57 (m, 2H), 2.96-3.09 organic layer was washed with brine and dried over anhy (m. 2H), 3.32 (s.3H), 3.62-3.87(m,3H), 4.16 (q, J=7.2, 14.4 drous NaSO. Removal of solvent under reduced pressure Hz, 2H), 4.56 (dd, J=6.7 Hz, 1H), 4.84 (dd, J=6.8 Hz, 1H), gave crude product which on chromatographic separation 10 5.68 (s, 1H), 6.25 (s, 1H); 'C NMR (50 MHz, CDC13): 8 with petroleum ether?ethyl acetate (8:2 V/v) gave title com -5.4, -5.2, 14.2, 18.3, 25.9, 35.4, 55.5, 55.6, 59.1, 60.7, 61.8, pound Syn-epoxy alcohol 10 along with minor amount of its 73.3, 95.3, 127.7, 136.2, 1664; Anal. Calcd for corresponding diastereomeras a yellow colored liquid in 4:1 C18H34O6Si: C, 57.72; H, 9.15. Found: C, 57.78; H, 9.12%. ratio. Yield: 64%; yellow liquid; C.I -19.2 (c 2.0, CHCl); 15 Example 6 98% ee HPLC analysis: Column: Chiracel OJ-H (4.6x250 (R)-ethyl 4-((2S,3R)-3-(hydroxymethyl)oxiran-2-yl)- nm), mobile phase: hexanefisopropyl alcohol (90/10), flow 4-(methoxymethoxy)-2-methylenebutanoate, (12) rate: 0.5 mL/min, retention time: 15.747 min (+)-isomer, 17.517 min (-)-isomer; IR (CHC1): 778,838, 1097, 1256, 1472, 1715, 2857, 2956, 3471 cm; H NMR (200 MHz, COEt CDC1): 8 0.10 (d. J=3.3 Hz, 6H), 0.91 (s.9H), 1.32 (t, J=7.0 Hz, 3H), 2.58 (dd, J=7.8, 14.1 Hz, 1H), 2.74 (dd, J=3.8, 14.1 HZ, 1H), 2.91 (m, 1H), 3.12 (m. 1H), 3.18 (brs, 1H), 3.61 (m, OMOM 1H), 3.78 (dd, J=5.8, 11.8 Hz, 1H), 3.90 (dd, J=5.8, 11.5 Hz, 25 HO 1H), 4.24 (q, J=7.3, 14.3 Hz, 2H), 5.76 (s, 1H), 6.29 (s, 1H): 'C NMR (50 MHz, CDC1): 8-5.4, -5.3, 14.1, 18.2, 25.8, To a well stirred solution of silyl ether 11 (1.1 g, 2.94 37.8, 56.1, 58.2, 60.9, 61.9, 69.0, 127.9, 136.5, 167.6: Anal. mmol) was added 1 M solution of tetrabutylammonium fluo Calcd for CHO, Si: C, 58.15; H, 9.15. Found: C, 58.20; H, ride (6.2 mL, 5.87 mmol) at 0°C. The reaction mixture was 9.12%. 30 stirred at this temperature for 2 h after which the solvent was removed under reduced pressure and the residue was sub jected to column chromatography with petroleum ether/ethyl acetate (5:5 V/v) to afford free alcohol 12 oily liquid. Yield: 88%; colorless liquid; (O) +4.1 (c 0.6, CHCl); 35 IR (CHC1 cm): 919, 1048, 1305, 1410, 1632, 1716, TBSO 2983.3,3453; "H NMR (200MHz, CDC1): 1.22 (t, J=7.1 Hz, 3H), 2.44 (dd, J=9.0, 14.0 Hz, 1H), 2.68 (dd, J-3.4, 13.6 Hz, Yield: 16%:yellow liquid; H NMR (200 MHz, CDC1): 8 1H), 2.83 (m. 1H), 3.09 (m, 1H), 3.24 (brs, 1H), 3.30 (s.3H), 0.08 (d, J-3.0 Hz, 6H), 0.90 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 40 3.55 (m, 2H), 3.79 (m. 1H), 4.11 (q, J–7.1, 13.3 Hz, 2H), 4.52 2.54-2.60 (m, 2H), 2.99 (dd, J–4.2, 7.3 Hz, 1H), 3.14 (dd. (d. J–7.2 Hz, 1H), 4.66 (d. J–7.2 Hz, 1H), 5.59 (s, 1H), 6.16 J=4.7, 10.5 Hz, 1H), 3.68-3.81 (m, 2H), 4.20 (q, J=7.1, 14.3 (s, 1H); CNMR (50 MHz, CDC1): & 14.2,36.5, 55.4, 56.1, Hz, 2H), 5.72 (s, 1H), 6.27 (s, 1H); 'C NMR (50 MHz, 57.8, 59.9, 60.7, 72.6, 96.0, 127.7, 136.4, 166.7: Anal. Calcd CDC1): 8 -5.3, -5.2, 14.2, 18.3, 25.9, 37.1, 57.7, 59.8, 60.9, for CHO requires C, 55.37; H, 7.74. Found: C, 55.43; H, 7.90%. 61.7, 68.7, 128.1, 136.2, 166.9. 45 Example 5 Example 7 (R)-ethyl 4-((2S,3R)-3-((tert-butyldimethylsilyloxy) (R)-methyl 4-((2S,3R)-3-ethynyloxiran-2-yl)-4- (methoxymethoxy)-2-methylenebutanoate, (13) methyl)oxiran-2-yl)-4-(methoxymethoxy)-2-methyl 50 enebutanoate, (11) COMe COEt

55 OMOM OMOM TBSO A

To a solution of compound 10 (3 g, 9.9 mmol) in dry 60 To a solution of epoxy alcohol 12 (1.4g, 4 mmol) in DMSO CHCl (50 mL) was added DIPEA (Hunig's base) 1.3.g. 29.7 (5 mL) in a round-bottomed flask was added IBX (1.68 g. 6 mmol), followed by addition of MOMC1 (1 mL, 19.8 mmol) mmol) in one portion and the reaction mixture was stirred for at 0°C. The mixture was stirred for 10 hand HO (10 mL) was 1 hat ambient temperature (25°C.). The reaction mixture was added to quench the reaction. The aqueous layer was quenched with diethylether (5 mL), H2O (0.5 mL) and filtered extracted with CHCl (30 mLX3). The combined organic 65 through a pad of celite. The residue was repeatedly washed layers were washed with brine (20 mL) and dried over with diethyl ether (50 mL). The filtrate was washed with H2O, NaSO. After evaporation of the solvent, the residue was brine, dried (NaSO) and concentrated to give the crude US 9,150,498 B2 33 34 aldehyde, which was pure enough and used in the next step To a solution of cyclic epoxy ester 14 (107 mg, 0.5 mmol) without further purification. To a solution of crude aldehyde in DMF/EtOH/H2O (1:1:0.5 mL) were added NH4C1 (160.5 and KCO (900 mg, 8 mmol) in 20 mL dry MeCH and g, 3 mmol) and NaN3 (197.4g, 3 mmol) at 0°C. The mixture diethyl-1-diazo-2-oxopropylphosphonate (1.26 g. 6 mmol) was then stirred at 25° C. for 10 h. After completion of were added under continuous stirring till completion of the reaction (monitored by TLC), EtOH was removed by rotary reaction was indicated by TLC (2 h) (25°C.). The reaction evaporation. The remaining solution was extracted with mixture was diluted with diethylether (100 mL), washed with EtOAc (100 mLX3). The combined organic layers were aq. solution of NaHCO, and dried over NaSO. Evaporation washed with, brine (20 mLx6) and dried (Na2SO4). After of solvent yielded analytically pure terminal alkyne 13 evaporation of the solvent, the residue was purified by chro Yield: 82%; colorless liquid; C. -9.4 (c 0.5, CHCl); 10 matography (petroleum ether/ethyl acetate (7/3 V/v) to obtain IR (CHC1 cm): 818, 1149, 1304, 1441, 1514, 1632, 1721, compound 15. 2116, 2924; H NMR (200 MHz, CDC1): 2.45 (d. J=1.6 Hz, Yield: 83%; yellow liquid; C.D25+17.3 (c. 0.7, CHC13): 1H), 2.61 (dd, J–7.4, 14.3 Hz, 1H), 2.79 (dd, J=5.4, 15.3 Hz, IR (CHC13, cm): 1073, 1176, 1235, 1365, 1448, 1489, 1H), 2.98 (dd, J=3.7, 8.1 Hz, 1H), 3.34 (s.3H), 3.48-3.51 (m, 15 1561, 1714, 2106,2994,3345; H NMR (200 MHz, CDC1): 1H), (3.77 (s.3H), 3.80 (m, 1H), 4.63 (d. J=6.7 Hz, 1H), 4.71 2.17-2.34 (m. 1H), 2.89-3.00 (m. 1H), 3.45 (s.3H), 3.63-3.67 (d. J=6.8 Hz, 1H), 5.72 (d. J=1.0 Hz, 1H), 6.27 (d. J=1.3 Hz, (m,2H), 3.77 (s.3H), 4.10 (m, 1H), 4.77 (s. 2H), 6.59 (t, J–2.5 1H); C NMR (50 MHz, CDC1): 8 35.4, 45.2, 51.8, 55.7, Hz, 1H); 13C NMR (50 MHz, CDC13): & 30.5, 52.1, 55.8, 58.5, 73.6, 75.1, 78.2, 95.7, 127.7, 136.2, 167.4; Anal. Calcd 63.3, 74.5, 77.8, 96.7, 129.8, 134.3, 165.7; Anal. Calcd for for CHOs requires C, 59.99; H, 6.71: O, 33.30. Found: C, C10H15N3O5 requires C, 46.69; H, 5.88: N, 16.33. Found: 60.02; H, 6.78%. C, 46.61; H, 5.85; N, 16.38%. Example 8 Example 10 (1R,5R,6S)-methyl 5-(methoxymethoxy)-7-Oxabicy 25 cloak. 1.0 hept-2-ene-3-carboxylate, (14) (1S,5R,6S)-methyl 7-acetyl-5-(methoxymethoxy)-7- O. azabicyclo4.1.0 hept-2-ene-3-carboxylate, (16)

30 AcN MOMO COMe To a solution of 13 (240 mg, 1 mmol) in 5 mL of ethyl acetate/pyridine/1-octene (10:1:1) was added Lindlar's cata 35 lyst (12.0 mg). The reaction mixture was stirred for 6 hunder MOMO COMe a balloon of H at room temperature and filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography using petro To a solution of azido alcohol 15 (150 mg, 0.58 mmol) in leum ether?ethyl acetate (7:3 V/v) as eluent to give diene toluene (5 mL) was added triphenylphosphine (152 mg, 0.58 A mixture of diene (400 mg, 1.65 mmol) and Grubbs 40 mmol) and the reaction mixture was refluxed for 3 hat 110° second-generation catalyst (70 mg, 5 mol%) in dry CH2Cl2 C. After removal of the solvent under reduced pressure, dieth (50 mL) was stirred under reflux for 14 h. The reaction mix ylether (1 mL) was added, and the mixture cooled with ice ture was evaporated and then purified on silica gel chroma bath. The precipitated triphenylphosphine oxide was tography by eluting with petroleum ether?ethyl acetate (7:3 removed by filtration and the filtrate evaporated. This proce V/v) to afford 14 (0.16 g. 82%) as gum. 45 dure was repeated to remove any traces of triphenylphosphine Yield: 90%; thick liquid; C.D25–32.7 (c 0.5, CHCl); IR (CHC1 cm): 1091, 1139, 1235, 1387, 1497, 1579, 1719, oxide. The residue obtained was then dissolved in dry CHCl 2986; H NMR (200 MHz, CDC1): 2.13-2.28 (m. 1H), 2.83 (20 mL) cooled at 0°C. To this solution was added Et-N (m. 1H), 3.45 (s.3H), 3.47 (m. 1H), 3.66(m, 1H), 3.76 (s.3H), (175.74 mg, 1.74 mmol), DMAP (4-Dimethylamine pyri 4.03 (m, 1H), 4.79 (s. 2H), 6.99 (t, J=3.4 Hz, 1H); 13C NMR 50 dine) (5 mg) and acetic anhydride (118.32 mg, 1.16 mmol) (50 MHz, CDC1): 8 26.5, 46.5, 51.9, 55.0, 55.4, 69.3, 95.9, and the mixture stirred at 25°C. for further 45 minutes. After 128.3, 131.1, 167.5: Anal. Calcd for C10H14O5 requires C, completion of reaction (monitored by TLC), the reaction 56.07; H, 6.59. Found: C, 56.01; H, 6.53%. mixture was quenched by addition of H2O (10 mL). The organic layer was separated, washed with brine, dried Example 9 55 (Na2SO4) and Subjected to column chromatographic purifi cation with petroleum ether?ethyl acetate (7:3 V/v) to afford (3S,4R,5R)-methyl 3-azido-4-hydroxy-5-(meth the cyclic acetamide aziridine 16. oxymethoxy)cyclohex-1-enecarboxylate (15) Yield: 81%; colorless liquid; C.D25-57.8 (c 0.5, CHC13): IR (CHC13, cm): 1073, 1195, 1255, 1324, 1369, 1448, N 60 1708, 1732, 2987, 3115; H NMR (200 MHz, CDC13): 2.10 HO (s, 3H), 2.20-2.27 (m. 1H), 2.86-2.96 (m, 2H), 3.16 (m. 1H), 3.36 (s.3H), 3.76 (s, 3H), 4.41-4.46 (m. 1H), 5.61-5.73 (m, 2H), 7.11 (t, J=1.9 Hz, 1H): 13C NMR (50 MHz, CDC13): 8 MOMO COMe 65 14.1, 23.8, 46.4, 51.9, 55.0, 55.4, 69.3, 95.9, 133.2, 148.3, 166.2, 1849;Anal. Calcd for C12H17NO5 requires C, 56.46; H, 6.71: N, 5.49. Found: C, 56.51; H, 6.85: N, 5.48%. US 9,150,498 B2 35 36 Example 11 mg, 2 mmol) was added, and the resulting Solution was stirred at 0°C. for 1 h. After TLC indicated completion of reaction, (3R,4R,5R)-ethyl 4-acetamido-5-hydroxy-3-(pentan further CHCl (20 mL) was added. The organic phase was 3-yloxy)cyclohex-1-enecarboxylate, (17) washed with brine and then dried over anhydrous NaSO. After the solvent was removed by a rotavaporator, the crude product was dissolved in DMF and NaNs (390 mg, 6 mmol) was added. The reaction mixture was stirred at 80°C. for 3 h. After completion of reaction (monitored by TLC), the reac tion mixture was partitioned between EtOAc and brine. The 10 AcHN Y organic layer was further washed with brine, dried over anhy drous NaSO. Removal of solvent under reduced pressure gave crude product which on chromatographic purification HO COEt with petroleum ether?ethyl acetate (4:6 V/v) gave the corre 15 sponding cyclic azide (this reaction is already known in lit erature) and the next reaction was done without the purifica To a well stirred solution of cyclic acetamide 16 (160 mg. tion of cyclic azide. The cyclic azide was dissolved in EtOH 0.64 mmol) in 3-pentanol (10 mL), a solution of 1.5 equiv. and Lindlar's catalyst (20 mg) added. The reaction mixture BF3.Et2O (0.96 mmol) in 3-pentanol (2 mL) was added at was stirred for 6 hunder a balloon of H at room temperature -10°C., followed by stirring at this temperature for 30 min and filtered through a celitepad. The filtrate was concentrated utes. After the completion of reaction (monitored by TLC), it and the residue was purified by silica gel column chromatog was quenched with a saturated aq. Solution of KCO. The raphy using petroleum ether?ethyl acetate (7:3 V/v) as eluent organic layer was washed with HO, brine and dried over to give (-)-oseltamivir free base as gum. anhydrous NaSO. Removal of solvent under reduced pres Sure gave crudeamino alcohol product of Sufficient purity as 25 Yield: 64%; CD25-47.8 (c 0.5, CHC13) (lit.4a CD25 a gum, which could be used for further reaction. To a well -54.2 (c. 0.48, CHC13)}: IR (CHC13, cm-1): 1068, 1127, stirred solution of crudeamino alcohol in EtOH (10 mL), a 2 1255, 1374, 1456, 1568, 1644, 1714, 2977, 3289 cm-1; 1H N solution of HCl (2 mL) was added. The reaction was stirred NMR (200 MHz, CDC13): 0.90 (m, 6H), 1.31 (t, J=7.1 Hz, for an additional 12 h at 25° C. After the completion of 3H), 1.42 (m, 4H), 2.03 (s.3H), 2.23 (m. 1H), 2.76 (m. 1H), reaction (monitored by TLC), the reaction mixture was 30 3.30 (m. 1H), 3.46 (m, 1H), 4.15 (m, 3H), 5.78 (m. 1H), 6.79 quenched by adding aqueous KCO. The reaction mixture (s, 1H); 13C NMR (50 MHz, CDC13): & 10.1, 10.2, 14.8, 24.5, was then partitioned between EtOAc and brine. The organic 26.3, 26.7, 34.3, 49.8, 59.5, 61.3, 75.7, 82.3, 129.9, 1380, layer was further washed with brine, dried over anhydrous 167. 1, 171.8; Anal. Calcd for C16H28N2O4 requires C, NaSO. Removal of solvent under reduced pressure gave 61.51; H, 9.03; N, 8.97. Found: C, 61.47; H, 8.98: N, 8.88%. crude product which on chromatographic purification with petroleum ether?ethyl acetate (2:8 V/v) gave title compound 35 17 as white solid. Yield: 64%; white solid; m.p. 129-131° C. Example 13 {lit.4a m.p. 131.9-132.2° C.: CD25 -83.8 (c 1.0, EtOAc) {lit.4a CD25+104 (c 3, EtOAc); IR (CHC13, cm-1): 1085, (4S.5R)-methyl 3,4-dihydroxy-5-(methoxymethoxy) 1274, 1266, 1306, 1373, 1455, 1585, 1649, 1707,2963,3311, 40 cyclohex-1-enecarboxylate, (19) 3396 cm-1; 1H NMR (200 MHz, CDC13): 0.90 (t, J=6.7 Hz, 6H), 1.25 (t, J=7.9 Hz, 3H), 1.42 (m, 4H), 1.99 (s.3H), 2.59 OH (m. 2H), 3.40 (m, 1H), 3.46 (s, 1H), 3.86 (m. 1H), 3.91 (t, J=6.7 Hz, 1H), 4.15 (m,3H), 4.41 (m, 1H), 5.78 (m, 1H), 6.84 HO, (s, 1H); 13C NMR (50 MHz, CDC13): 89.7, 9.8, 14.2, 23.8, 45 26.1, 26.7, 31.9, 55.2, 61.1, 67.4, 72.9, 82.3, 129.4, 136.4. 166.8, 171.8; Anal. Calcd for C16H27NO5 requires C, 59.46 MOMO COMe requires C, 61.32; H, 8.68; N, 4.47. Found: C, 61.47; H, 8.71; N, 4.56%. 50 To a well stirred solution of compound 14 (107 mg 0.5 Example 12 mmol) in THF/H2O (3:1), concentrated HSO (5 drops) was added. The reaction was stirred for 2 h at 25° C. After the (-)-Oseltamivir Free Base (1) completion of reaction (monitored by TLC), the reaction mixture was diluted with excess of EtOAc20 mL. The organic 55 layer is further washed with HO, brine, dried over anhydrous NaSO. Removal of solvent under reduced pressure gave crude product which on chromatographic purification with petroleum ether/ethyl acetate (2:8 V/v) gave title compound AcHN Y 19 as gum. 60 Yield: 96%; thick liquid; C.D25-45.1 (c 0.5, EtOH); IR (CHC13, cm-1): 1088, 1300, 1373, 1717, 2878, 2967,3387, 3468; 1H NMR (200 MHz, CDC13): 2.57-2.68 (m, 2H), 3.42 HN COEt (s.3H), 3.59 (m, 1H), 3.63 (m, 1H), 3.66 (s.3H), 3.7 (m, 1H), 4.05 (m, 1H), 4.41 (m, 1H), 4.72 (s. 2H), 6.83 (s, 1H); 13C Compound 17 (312 mg, 1 mmol) and triethylamine (303 65 NMR (50 MHz, CDC13): 830.9, 51.9, 55.8, 70.2, 77.6, 971, mg, 3 mmol) were dissolved in dry CHCl (15 mL), and the 127.9, 137.8, 166.6: Anal. Calcd for C10H16O6 requires C, solution was cooled to 0°C. Methane sulfonyl chloride (229.2 51.72; H, 6.94. Found C, 51.82; H, 6.98. US 9,150,498 B2 37 38 Example 14 perature ranging between -10°C. C to -20°C. for a time period of 10 to 20 minutes to obtain epoxy alcohol Methyl 3-epishikimate, (2) ((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxi ran-2-yl)methanol of formula (8) followed by oxidizing OH with TEMPO (2.2.6,6-tetramethyl-1-piperidinyloxyl)/ BAIBIbis(acetoxy)iodobenzene mixture to obtain HO aldehyde2R,3R)-3-((tert-butyldimethylsilyloxy)ime thyl)oxirane-2-carbaldehyde of formula (9);

HO COMe 10

OH To a well stirred solution of compound 19 (95 mg. 0.5 21 mmol) in MeOH (5 mL) was added 2N solution of HCl (1 mL). The reaction was stirred for an additional 6 h at 25°C. After the completion of reaction (monitored by TLC), the 15 TBSO reaction mixture was diluted with excess of EtOAc (10 mL). OH The organic layer was further washed with HO (2 mL), brine, O O dried over anhydrous NaSO. Removal of solvent under CHO reduced pressure gave crude product which on chromato -e- graphic purification with petroleum ether?ethyl acetate (2:8 TBSO V/v) gave title compound 2 in 74% yield as colorless solid. TBSO Yield: 74%: white solid; m.p. 131-133° C. (lit.13 m.p. 8 9 132° C.: CD25-13.1 (c 0.5, MeOH) { lit. 13 CD25-13.4 (c 0.5, MeOH)}; IR (CHC13, cm-1): 1089, 1176, 1245, 1378, 1489, 1661, 1714, 2106, 2994, 3456; 1H NMR (200 MHz, 25 (iii) subjecting aldehyde (9) to diasteroselective Barbier D2O): 2.23 (m, 1H), 2.81 (m, 1H), 3.47 (dd, J=8.5, HZ, 1H), allylation in the presence of ethyl 2-(bromomethyl)acry 3.76 (s.3H), 3.77 (m. 1H), 4.24 (m, 1H), 6.68 (m. 1H); 13C late, Zn dust in an aprotic solvent and NHCl at the NMR (50 MHz, D2O): 168.6, 138.4, 127.2, 76.4, 71.9, 68.6, temperature ranging between 25-30°C. for a period of 52.8, 31.7: Anal. Calcd for C8H12O5 requires C, 51.06; H, 8-12 hours to obtain the compound 10 ((R)-Ethyl 4-((2S, 6.43; O, 42.51. Found C, 51.11; H, 6.54. 30 3R)-3-((tert-butyldimethylsilyloxy)methyl)oxiran-2- yl)-4-hydroxy-2-methylenebutanoate): Advantages of the Present Invention The present invention provides a new enantioselective O method for the synthesis of anti-influenza agent (-)-oselta 35 CHO mivir and (-)-methyl 3-epi-shikimate from readily available -e- starting materials using Sharpless asymmetric epoxidation, TBSO diastereoselective Barbier allylation and ring closing met 9 athesis as key reactions. The synthesis has been completed COEt with excellent enantiomeric excess (98% from HPLC) and 40 good overall yield 7.1% and 16% for (-)-oseltamivir and (-)-methyl 3-epi-shikimate respectively. In the present invention inexpensive and non-toxic OH reagents and viable reaction conditions have been used which TBSO makes our approach more feasible and attractive for commer 45 cial production. 10 We claim: 1. A process for the preparation of oseltamivir with enan (iv) adding N,N-dipropylethylamine (hunig's base) to a tioselectivity 98% ee and methyl 3-epi-shikimate, wherein 50 Solution of compound 10 as obtained in step (iii) in a dry the said process comprises: aprotic solvent in the presence of a protecting agent at a (i) monosilylating of cis-1,4-butenediol (6) in a dry aprotic temperature ranging between 0-25° C. for a period of Solvent and imidazole and a silylating agent at the tem 10-16 hours to obtain compound (R)-ethyl 4-((2S,3R)- perature ranging between 0-25 deg C for a period rang 3-((tert-butyldimethylsilyloxy)methyl)oxiran-2-yl)-4- ing between 4-8 hours to obtain mono-silyl allylic alco 55 (methoxymethoxy)-2-methylenebutanoate of formula hol (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol (7): 11 followed by desilylation using TBAF (tetrabutyl OH ammonium fluoride) to obtain compound 12: o 21 HO / \ OH, -- 6 TBSO 60 COEt

(ii) asymmetric epoxidizing mono-silyl allylic alcohol (Z)- OH 4-(tert-butyldimethylsilyloxy)but-2-en-1-ol (7) with 65 TBSO Ti(OiPr)4, (+) DET (diethyl tartarate), anhydrous TBHP 10 (tert-butyl hydroperoxide) in a aprotic solvent at a tem US 9,150,498 B2 40 -continued -continued COEt

O -es

OMOM COMe TBSO 14 11 COEt 10 (vii) regioselective opening of epoxide compound 14 with O NaN3 and mixture of solvent DMF:ethanol: water in the ratio of 1:1:0.5 to 2:2:1 at a temperature ranging between 25-30° C. for a time period of 10-12 hours to obtain OMOM compound (3S,4R,5R)-methyl 3-azido-4-hydroxy-5- HO 15 12 (methoxymethoxy)cyclohex-1-enecarboxylate of for mula 15: (V) oxidizing the compound 12 with an oxidizing agent IBX (2-iodoxybenzoic acid) and an aprotic solvent to obtain unstable aldehyde followed by subjecting to Sey ferth-gilbert homologation in the presence of diethyl 2-oxopropylphosphonate, a base and a polar solvent at a temperature ranging between 0-25°C. for a time period COMe ranging between 8-12 h to obtain the terminal alkyne 25 14 (R)-methyl 4-((2S,3R)-3-ethynyloxiran-2-yl)-4-(meth oxymethoxy)-2 methylenebutanoate of formula 13: COEt HO, 30 MOMO COMe OMOM 15 HO 12 35 COMe (viii) optionally treating cyclohexene epoxide (14) as obtained in step (vi) with sulphuric acid in THF:H2O in the ratio of 3:1 to 4:1 as solvent at a temperature ranging between 25 to 30° C. for a time period of 2 to 4 hrs to OMOM 40 obtain diol compound 19 followed by deprotecting MOM of compound 19 with HCL in an alcohol at a A. temperature ranging between 25°C. to 30°C. for a time 13 period of 6 to 8 hrs to obtain Methyl 3-epishikimate(2):

45 (vi) reducing the alkyne 13 with Lindlar's catalyst (Pd

9, adsorbed on CaCO3) in an aprotic solvent at a tempera ture ranging between 25-30°C. for a time period ranging -e- between 2-6 hours to obtain diene followed by ring closing metathesis using Grubb’s IInd generation cata COMe lyst (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidi 14 nylidene)dichloro(phenylmethylene)(tricyclohexy lphosphine) ruthenium in dry aprotic solvent at a OH OH temperature ranging between 25-50° C. for a time period HO HO, ranging between 14-24 hours to obtain epoxide com 55 s pound (1R,5R,6S)-methyl 5-(methoxymethoxy)-7-ox abicyclo4.1.0 hept-2-ene-3-carboxylate of formula 14: MOMO COMe HO COMe COMe 19 2 60 (ix) aziridinizing the compound 15 as obtained in step (vii) OMOM with triphenyl phosphene (PPh3), toluene at 110° C. for a time period ranging between 3-12 hours to obtain a 65 aziridine compound (1S,5R,6S)-methyl 7-acetyl-5- 13 (methoxymethoxy)-7-azabicyclo4.1.0 hept-2-ene-3- carboxylate, of formula 16: US 9,150,498 B2 41 42 4. The process as claimed in claim 1, wherein the base used in step (V) is selected from the group comprising consisting of KCO, and EtN. HO. 5. The process as claimed in claim 1, wherein protecting agent used in step (iv) is MOMC1 (methyl chloromethyl ether). MOMO COMe 6. A compound of Formula 1 15 Formula 1 AcN O 10 > R1 wherein R MOMO COMe COEt,

-(S. O wherein R1 = (X) regioselective ring opening of aziridine (16) with pen tan-3-ol in the presence of BF3.Et2O at a temperature ranging between 0-25° C. for a time period ranging OMOM and between 2-12 hours to obtain compound 17 followed by MOM deprotection in an alcohol and HCL at a tempera R= CH-OTBS, or -C=CH. ture ranging between 25-30°C. for a time period of 4-12 7. The compound of claim 6, wherein the compound is hours to give compound 17 (3R,4R,5R)-Ethyl 4-aceta selected from the group consisting of mido-5-hydroxy-3-(pentan-3-yloxy)cyclohex-1-en ecarboxylate; and 25 AcN COEt

30 MOMO COMe OMOM TBSO 16 (R)-ethyl 4-((2S,3R)-3-((tert-butyldimethylsilyloxy)me 35 thyl)oxiran-2-yl)-4-(methoxymethoxy)-2-methyl enebutanoate (Compound 11), and COMe AcHN C YCOEt 40 17

(xi) converting compound 17 to Oseltamivir 45 (R)-methyl 4-((2S,3R)-3-ethynyloxiran-2-yl)-4-(meth Oxymethoxy)-2-methylenebutanoate, (Compound 13). 8. A compound of Formula 2 D O O Formula 2 R 50 AcHN AcHN R e

YCOEt HNY COEt. MOMO COMe 17 1 55 wherein R-OH and R=N; or R1+R2=O or NAc. 2. The process as claimed in claim 1, wherein the aprotic 9. The compound of claim 8, wherein the compound is Solvent and the polar solvent are each selected from the group selected from the group consisting of O7, consisting of toluene, acetone, ethyl acetate, methanol, THF. 60 DCM, and DMSO. 3. The process as claimed in claim 1, wherein the silylating agent used in step (i) is selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert MOMO COMe butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl 65 (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), and tert (1R,5R,6S)-methyl 5-(methoxymethoxy)-7-Oxabicyclo butyl dimethylsilyl chloride (TBSCI). 4.1.0 hept-2-ene-3-carboxylate, (Compound 14),