Patent ID: 9150498
Filing Date: 2015-10-06
Classification: C07C,C07D,C07F

Abstract:
1. A process for the preparation of oseltamivir with enantioselectivity 98% ee and methyl 3-epi-shikimate, wherein the said process comprises: (i) monosilylating of cis-1,4-butene diol (6) in a dry aprotic solvent and imidazole and a silylating agent at the temperature ranging between 0-25 deg C for a period ranging between 4-8 hours to obtain mono-silyl allylic alcohol (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol (7): (ii) asymmetric epoxidizing mono-silyl allylic alcohol (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol (7) with Ti(OiPr)4, (+) DET (diethyl tartarate), anhydrous TBHP (tert-butyl hydroperoxide) in a aprotic solvent at a temperature ranging between −10° C. C to −20° C. for a time period of 10 to 20 minutes to obtain epoxy alcohol ((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxiran-2-yl)methanol of formula (8) followed by oxidizing with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl)/BAIB[bis(acetoxy)iodo]benzene] mixture to obtain aldehyde2R,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxirane-2-carbaldehyde of formula (9); (iii) subjecting aldehyde (9) to diasteroselective Barbier allylation in the presence of ethyl 2-(bromomethyl)acrylate, Zn dust in an aprotic solvent and NH (iv) adding N,N-dipropylethylamine (hunig's base) to a solution of compound 10 as obtained in step (iii) in a dry aprotic solvent in the presence of a protecting agent at a temperature ranging between 0-25° C. for a period of 10-16 hours to obtain compound (R)-ethyl 4-((2S,3R)-3-((tert-butyldimethylsilyloxy)methyl)oxiran-2-yl)-4-(methoxymethoxy)-2-methylenebutanoate of formula 11 followed by desilylation using TBAF (tetrabutyl ammonium fluoride) to obtain compound 12: (v) oxidizing the compound 12 with an oxidizing agent IBX (2-iodoxy benzoic acid) and an aprotic solvent to obtain unstable aldehyde followed by subjecting to Seyferth-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 ranging between 8-12 h to obtain the terminal alkyne (R)-methyl 4-((2S,3R)-3-ethynyloxiran-2-yl)-4-(methoxymethoxy)-2 methylenebutanoate of formula 13: (vi) reducing the alkyne 13 with Lindlar's catalyst (Pd adsorbed on CaCO3) in an aprotic solvent at a temperature ranging between 25-30° C. for a time period ranging between 2-6 hours to obtain diene followed by ring closing metathesis using Grubb's IInd generation catalyst (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine) ruthenium in dry aprotic solvent at a temperature ranging between 25-50° C. for a time period ranging between 14-24 hours to obtain epoxide compound (1R,5R,6S)-methyl 5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylate of formula 14: (vii) regioselective opening of epoxide compound 14 with 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 compound (3S,4R,5R)-methyl 3-azido-4-hydroxy-5-(methoxymethoxy)cyclohex-1-enecarboxylate of formula 15: (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 obtain diol compound 19 followed by deprotecting MOM of 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-epi shikimate(2): (ix) aziridinizing the compound 15 as obtained in step (vii) with triphenyl phosphene (PPh3), toluene at 110° C. for a time period ranging between 3-12 hours to obtain a aziridine compound (1S,5R,6S)-methyl 7-acetyl-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate, of formula 16: (x) regioselective ring opening of aziridine (16) with pentan-3-ol in the presence of BF3.Et2O at a temperature ranging between 0-25° C. for a time period ranging between 2-12 hours to obtain compound 17 followed by MOM deprotection in an alcohol and HCL at a temperature ranging between 25-30° C. for a time period of 4-12 hours to give compound 17 (3R,4R,5R)-Ethyl 4-acetamido-5-hydroxy-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate; and (xi) converting compound 17 to Oseltamivir