- Research and Development of a Second-Generation Process for Oseltamivir Phosphate, Prodrug for a Neuraminidase Inhibitor
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A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride - amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35-38% for two previous processes, respectively, to 61%.
- Harrington, Peter J.,Brown, Jack D.,Foderaro, Tommaso,Hughes, Robert C.
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Read Online
- Preparation method and intermediate of oseltamivir
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The invention relates to a preparation method of oseltamivir (a compound shown as a formula I) and an intermediate of the oseltamivir. The method is implemented according to a route described in the specification. The method is convenient and safe to operate, high in yield, small in environmental pollution, suitable for industrial production and good in economic effect.
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- Novel synthesis method of oseltamivir
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The invention provides a novel synthesis method of oseltamivir. The synthesis method comprises the following steps: taking a compound (E)-2-(2-nitrovinyl) isoindoline-1,3-diketone and ethyl pyruvate as initial raw materials, and carrying out Michael addition reaction under the condition of catalysis of a thiourea catalyst to obtain a corresponding Michael addition product; then, subjecting the Michael addition product and (formyl methylene) triphenyl phosphine to a Wittig reaction and a Henry reaction in a pot so as to obtain a ring closing product; and forming an etherified product from the ring closing product and a trichloroacetonitrile intermediate, and performing reduction, acetylation and de-protection to obtain oseltamivir. The reaction route comprises six steps, raw materials used in each step of reaction are easy to obtain and not expensive, the operation is easy, the yield of each step of reaction is high, no heavy metal or azide is used in the whole synthesis process, and the method is green and safe and can be applied to industrial production.
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Paragraph 0130; 0165-0170
(2021/05/19)
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- FLOW SYNTHESIS PROCESS FOR THE PRODUCTION OF OSELTAMIVIR
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This invention provides for a flow synthesis process for producing Oseltamivir and pharmaceutically acceptable salts thereof from shikimic acid in particular but not exclusively to a flow synthesis process for producing Oseltamivir phosphate from shikimic acid in a nine-step flow synthesis that provides for superior reaction times and product yields compared to known methods.
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Page/Page column 7; 32-33
(2020/09/27)
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- Preparation method of oseltamivir
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The invention discloses a preparation method of oseltamivir. The preparation method comprises the steps: taking (1S,5R,6S)-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester as a raw material; carrying out a ring-opening reaction with benzylamine, carrying out catalytic hydrogenation debenzylation protection, carrying out Boc-protected N-acylation, carrying out an O-sulfonylation reaction with substituted sulfonyl chloride or trifluoromethanesulfonic anhydride, and carrying out a substitution reaction with benzylamine; carrying out catalytic hydrogenation debenzylation protection and O-acetylation reaction again; and finally removing Boc protection under an acidic condition to prepare oseltamivir. The preparation process is simple, low in cost and suitable for process amplification preparation to meet industrial production of oseltamivir raw drugs.
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Paragraph 0075; 0090; 0091
(2020/08/22)
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- Synthesis method of oseltamivir (by machine translation)
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The invention relates to a synthetic method of oseltamivir, and belongs to the technical field of compound synthesis. The technical problem to be solved by the invention is to provide a synthetic method of oseltamivir. The synthesis method comprises the steps of opening an oxygen ring, synthesizing a nitrogen ring, opening a nitrogen ring, acylation, salt formation, and refining; wherein when the tert-butyl group is taken off, the tert-butyl reaction is carried out by adding concentrated sulfuric acid. H2 SO4 : OSTSTW-SM ＝ 0.5 - 1.5: 1. Compared with the existing route adopting trifluoroacetic acid to take off tert-butyl, the feeding ratio is greatly reduced, the influence on equipment, personnel and environment is small, and the method has obvious advantages in industrial production. (by machine translation)
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Paragraph 0047; 0050-0052
(2020/12/08)
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- Method for preparing oseltamivir phosphate by azide process
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The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing oseltamivir phosphate by an azide process. The method comprises the following steps:reacting a compound shown in a formula (III) with sodium azide and ammonium chloride, opening a nitrogen heterocyclic ring, performing acetylation, reducing an azide group, removing tert-butyl, salifying with phosphoric acid, and purifying to obtain pure oseltamivir phosphate shown in a formula (I). According to the method, diallylamine with strong corrosivity and expensive palladium acetate do not need to be used so that the enterprise cost is reduced.
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- Preparation method of oseltamivir phosphate
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The invention discloses a preparation method of oseltamivir phosphate. The method comprises the steps that firstly an intermediate represented in a formula (IV) reacts with palladium acetate, triphenylphosphine, N,N-dimethylbarbituricacid in a solvent, and allyl is removed to obtain an intermediate represented in a formula (III); then the intermediate represented in the formula (III) is acidized,and tertiary butyl is removed to obtain oseltamivir free alkali represented in a formula (II); finally the oseltamivir free alkali reacts with phosphoric acid in a solvent, and crystallization and purification are carried out. The preparation method of the oseltamivir phosphate has the advantages that the residual quantities of main heavy metals such as palladium, arsenic, cadmium, cobalt, copper,mercury, lithium, nickel, lead, antimony, titanium and vanadium in the oseltamivir phosphate are all within a limit range, and the ICH standard is met.
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Paragraph 0020; 0024
(2019/05/04)
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- Synthesis method of oseltamivir
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The invention belongs to the technical field of organic synthesis, aims at solving the problems that an existing synthesis method of oseltamivir is multiple in reaction steps, low in overall yield and high in cost. The invention provides a synthesis method of oseltamivir. The method comprises the following steps of (1) adopting 3-pentyloxy acetaldehyde and nitroolefin as substrates and reacting under catalysis of a catalyst in the presence of lewis acid to obtain an aldehyde intermediate A; (2) reacting the obtained aldehyde intermediate A with 2-diethoxy oxygen-phosphorus acrylic acid ethyl ester under the action of an alkali catalyst to obtain a cyclohexenyl intermediate B; (3) reacting the cyclohexenyl intermediate B with thiocresol to obtain a cyclohexane intermediate C; (4) preparing a compound D from the cyclohexane intermediate C under the action of zinc powder and trimethylchlorosilane; and (5) obtaining a final product oseltamivir from the intermediate D obtained in the step (4) under the action of an ammonia gas and potassium carbonate. The method has the characteristics that the route is short and the catalyst is easy to recover.
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- Stereoisomers of oseltamivir-synthesis, in silico prediction and biological evaluation
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Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.
- Hajzer, Viktória,Fi?era, Roman,Latika, Attila,Durmis, Július,Kollár, Jakub,Frecer, Vladimír,Tu?eková, Zuzana,Miertu?, Stanislav,Kostolansky, Franti?ek,Vare?ková, Eva,?ebesta, Radovan
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p. 1828 - 1841
(2017/03/09)
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- Multistep Continuous-Flow Synthesis of (-)-Oseltamivir
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A continuous-flow synthesis of (-)-oseltamivir composed of five flow units was accomplished. In each unit, the following reactions proceed efficiently: (1) a diphenylprolinol silyl ether mediated Michael reaction, (2) a domino reaction of Michael and intermolecular Horner-Wadsworth-Emmons reactions, (3) protonation, (4) epimerization, and (5) reduction of a nitro group to an amine. (-)-Oseltamivir was obtained in 13% total yield through a single flow with a residence time of 310 minutes.
- Ogasawara, Shin,Hayashi, Yujiro
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supporting information
p. 424 - 428
(2016/12/24)
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- Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza
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Influenza virus causes severe respiratory infections that are responsible for up to half a million deaths worldwide each year. Two inhibitors targeting viral neuraminidase have been approved to date (oseltamivir, zanamivir). However, the rapid development of antiviral drug resistance and the efficient transmission of resistant viruses among humans represent serious threats to public health. The approved influenza neuraminidase inhibitors have (oxa)cyclohexene scaffolds designed to mimic the oxonium transition state during enzymatic cleavage of sialic acid. Their active forms contain a carboxylate that interacts with three arginine residues in the enzyme active site. Recently, the phosphonate group was successfully used as an isostere of the carboxylate in oseltamivir, and the resulting compound, tamiphosphor, was identified as a highly active neuraminidase inhibitor. However, the structure of the complex of this promising inhibitor with neuraminidase has not yet been reported. Here, we analyzed the interaction of a set of oseltamivir and tamiphosphor derivatives with neuraminidase from the A/California/07/2009 (H1N1) influenza virus. We thermodynamically characterized the binding of oseltamivir carboxylate or tamiphosphor to the neuraminidase catalytic domain by protein microcalorimetry, and we determined crystal structure of the catalytic domain in complex with tamiphosphor at 1.8 ? resolution. This structural information should aid rational design of the next generation of neuraminidase inhibitors.
- Albina?a, Carlos Berenguer,MacHara, Ale?,Rezacov, Pavlína,Pachl, Petr,Konvalinka, Jan,Kozísek, Milan
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p. 100 - 109
(2016/06/09)
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- Pathogen detection
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Pathogens are detected through the use of mutation-resistant ligands.
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Page/Page column 84; 85; 86
(2016/02/29)
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- Oseltamivir preparation method
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The present invention relates to the field of pharmaceutical synthesis, in particular a novel oseltamivir preparation method. By using an organic solvent agent, a reaction is performed for 2-4 hours by the Lindlar catalyst, the palladium content of which is 5%, under a certain pressure to obtain oseltamivir, wherein the reaction temperature is room temperature. According to the preparation method provided by the present invention, a column chromatography method is not necessarily used for purification, the experiment operation is simplified, the reaction time is shortened, the cost is lowered, and the obtained yield is high.
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Paragraph 0037; 0038
(2016/10/17)
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- Novel compound, its synthetic method and therapeutic use (by machine translation)
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Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidase activity are also described.
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Paragraph 2414-2426
(2016/10/07)
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- Time Economical Total Synthesis of (-)-Oseltamivir
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A time economical 60 min total synthesis of (-)-oseltamivir was accomplished in a single reaction vessel over five steps. One of the key issues is reduction in the number of steps by eliminating lengthy reaction steps with substitution of a rapid epimerization step. A catalytic system consisting of three reagents, namely, diphenylprolinol silyl ether, thiourea, and acid, was developed for a rapid asymmetric Michael reaction with excellent diastereo- and enantioselectivities. All reactions were optimized in terms of not only yield and selectivity but also reaction time.
- Hayashi, Yujiro,Ogasawara, Shin
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p. 3426 - 3429
(2016/07/26)
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- A new and efficient asymmetric synthesis of oseltamivir phosphate (Tamiflu) from D-glucose
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Abstract The anti-influenza drug, oseltamivir phosphate (Tamiflu) was synthesized from d-glucose via a novel and efficient synthetic route. A unique feature of the synthesis is that the key intermediate aziridine cyclohexene was synthesized as a mixture of diastereomers, via a metal-mediated domino reaction and ring closing metathesis (RCM). The iodoxylose compound was prepared in 9 steps from d-glucose. Both isomers of aziridine cyclohexene intermediate could be converted into Tamiflu via two pathways. First, both isomers of aziridine cyclohexene underwent aziridine-ring opening yielded diastereomeric of 1,2-amino mesylate cyclohexene esters. The trans-1,2-amino mesylate isomer could be transformed to tamiflu by formation of aziridine then regio- and stereoselective nucleophilic substitution of the azide to afford 1,2-amino azido compound whereas the cis-isomer could be transformed directly by SN2 substitution of azide to give the same azido product, which then converted into oseltamivir phosphate.
- Kongkathip, Boonsong,Akkarasamiyo, Sunisa,Kongkathip, Ngampong
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p. 2393 - 2399
(2015/03/30)
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- METHOD FOR PREVENTING OR TREATING ARRHYTHMIA, METHOD FOR PREVENTING OR TREATING ATRIAL FIBRILLATION, MODEL OF SUSTAINED ATRIAL FIBRILLATION, METHOD FOR PRODUCING THE MODEL, AND METHOD FOR SCREENING FOR ATRIAL FIBRILLATION INHIBITOR
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A method for preventing or treating atrial fibrillation, including: administering, to an individual, an atrial fibrillation inhibitor containing a compound expressed by one of the following Structural Formulas (I) to (VI) or a pharmacologically acceptable salt thereof: where in the Structural Formula (III), Gluc refers to glucuronic acid,
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Paragraph 0101
(2014/03/24)
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- Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors
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A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza the two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display enhanced inhibition with IC50 values in the low nanomolar range against neuraminidases from wild-type and oseltamivir-resistant strains. Potential advantages of including the N-hydroxyguanidine moiety in neuraminidase inhibitors are also discussed.
- Mooney, Caitlin A.,Johnson, Stuart A.,'T Hart, Peter,Quarles Van Ufford, Linda,De Haan, Cornelis A. M.,Moret, Ed E.,Martin, Nathaniel I.
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supporting information
p. 3154 - 3160
(2014/05/06)
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- PROCESS FOR THE PREPARATION OF OSELTAMIVIR AND METHYL 3-EPI-SHIKIMATE
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The present invention discloses high yielding enantioselective process for synthesis of Oseltamivir from readily available starting material, cis-1,4-butene diol. The process features incorporation of chirality using sharpless asymmetric epoxidation (AE) and diastereoselective Barbier allylation and construction of cyclohexene carboxylic acid ester core through a ring closing metathesis (RCM) reaction. Further also disclosed herein is synthesis of (?)-methyl 3-epi-shikimate.
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Paragraph 0124-0126
(2014/09/03)
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- INTERMEDIATE COMPOUNDS OF TAMIFLU, METHODS OF PREPARATION AND USES THEREOF
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Chiral amino compounds, methods of preparation and uses thereof. Tamiflu can be obtained from the said compounds. Multi-substituted chiral tetrahydropyrrolyl amine which can be used as intermediate compounds of medicament can also be produced by the said compounds.
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- PROCESS FOR THE PREPARATION OF OSELTAMIVIR AND METHYL 3-EPI-SHIKIMATE
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The present invention discloses high yielding enantioselective process for synthesis of Oseltamivir from readily available starting material, cis-1,4-butene diol.The process features incorporation of chirality using sharpless asymmetric epoxidation(AE) and diastereoselective Barbier allylation and construction of cyclohexene carboxylic acid ester core through a ring closing metathesis (RCM) reaction. Further also disclosed herein is synthesis of (-)-methyl 3-epi-shikimate.
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Page/Page column 29
(2013/05/21)
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- Facile method for the synthesis of oseltamivir phosphate
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A ten-step scheme for the preparation of an antiviral agent, ethyl (3R,4R,5S)-4-acetylamino-5-amino-3-(pent-3-yloxy)cyclohex-1-enecarboxylate phosphate, from (-)-shikimic acid was studied. The main parameters of the synthesis were determined and the optimal conditions for the preparation of the intermediate compounds were selected. The total yield of oseltamivir phosphate calculated based on (-)-shikimic acid was 27%.
- Kalashnikov,Sysolyatin,Sakovich,Sonina,Shchurova
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p. 163 - 170
(2013/11/19)
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- One-pot synthesis of (-)-oseltamivir and mechanistic insights into the organocatalyzed Michael reaction
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The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2- nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone. (-)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E-Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine. Copyright
- Mukaiyama, Takasuke,Ishikawa, Hayato,Koshino, Hiroyuki,Hayashi, Yujiro
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p. 17789 - 17800
(2014/01/17)
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- A novel azide-free asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from Roche's epoxide
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A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu) starting from Roche's epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF3· OEt2-catalyzed epoxide-opening with acetonitrile as a nucleophile. Compound 3 was then transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in 91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield. In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucleophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82% yield.
- Nie, Liang-Deng,Wang, Fei-Feng,Ding, Wei,Shi, Xiao-Xin,Lu, Xia
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p. 638 - 642
(2013/07/05)
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- A new and efficient asymmetric synthesis of oseltamivir phosphate(Tamiflu) from D-mannose
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Oseltamivir phosphate (Tamiflu) was synthesized from D-mannose through a short and practical synthetic route. A unique feature of the route is that the bulky 3-pentyloxy group and adjacent acetamide of Tamiflu were introduced at an early stage of the synthesis by copper-catalyzed regioselective ringopening of the 2,3-pentylidene ketal of D-lyxofuranoside. The D-lyxofuranoside ethylphosphonate precursor was then cyclized via an intramolecular Horner-Wadsworth-Emmons reaction to furnish the Tamiflu skeleton.
- Chuanopparat, Nutthawat,Kongkathip, Ngampong,Kongkathip, Boonsong
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supporting information
p. 6209 - 6211,3
(2012/12/11)
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- Synthesis and in vitro study of novel neuraminidase inhibitors against avian influenza virus
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Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31-PMC-36, synthesised according to the outcomes of a rational design analysis aimed to investigate the effects of substitution at the 5-amino and 4-amido groups of oseltamivir on its antiviral activity, were screened for their inhibition against neuraminidase N1 and N3. The enzymes used as models were from the avian influenza A H7N1 and H7N3 viruses. The neuraminidase inhibition assay was carried out by using recombinant species obtained from a baculovirus expression system and the fluorogenic substrate MUNANA. The assay was validated by using oseltamivir carboxylate as a reference inhibitor. Among the tested compounds, PMC-36 showed the highest inhibition on N1 with an IC50 of 14.6 ± 3.0 nM (oseltamivir 25 ± 4 nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC50 of 0.1 ± 0.03 nM (oseltamivir 0.2 ± 0.02 nM). The analysis of the inhibitory properties of this panel of compounds allowed a preliminary assessment of a structure-activity relationship for the modification of the 4-amido and 5-amino groups of oseltamivir carboxylate. The substitution of the acetamido group in the oseltamivir structure with a 2-butenylamido moiety reduced the observed activity, while the introduction of a propenylamido group was well tolerated. Substitution of the free 5-amino group of oseltamivir carboxylate with an azide, decreased the activity against both N1 and N3. When these structural changes were both introduced, a dramatic reduction of activity was observed for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an isopropyl group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1.
- Kongkamnerd, Jarinrat,Cappelletti, Luca,Prandi, Adolfo,Seneci, Pierfausto,Rungrotmongkol, Thanyada,Jongaroonngamsang, Nutthapon,Rojsitthisak, Pornchai,Frecer, Vladimir,Milani, Adelaide,Cattoli, Giovanni,Terregino, Calogero,Capua, Ilaria,Beneduce, Luca,Gallotta, Andrea,Pengo, Paolo,Fassina, Giorgio,Miertus, Stanislav,De-Eknamkul, Wanchai
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p. 2152 - 2157
(2012/05/05)
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- Synthesis of the anti-influenza agent (-)-oseltamivir free base and (-)-methyl 3-epi-shikimate
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A new enantioselective synthesis of the anti-influenza agent (-)-oseltamivir free base (7.1% overall yield; 98% ee) and (-)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has been described from readily available raw materials. Sharpless asymmetric epoxidation and diastereoselective Barbier allylation of an aldehyde are the key reactions employed in the incorporation of chirality, while the cyclohexene carboxylic ester core was constructed through a ring closing metathesis reaction.
- Rawat, Varun,Dey, Soumen,Sudalai, Arumugam
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supporting information; experimental part
p. 3988 - 3990
(2012/06/15)
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- Thiol-free synthesis of oseltamivir and its analogues via organocatalytic michael additions of oxyacetaldehydes to 2-acylaminonitroalkenes
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The organocatalytic addition of substituted oxyacetaldehydes to 2-acylaminonitroethenes proceeded with good to high diastereoselectivities and enantioselectivities. The resulting adducts reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly functionalized cyclohexenes. A thiol-free protocol for cyclization has been developed that leads to a separable mixture of two diastereoisomers. The unwanted diastereoisomer can be efficiently epimerized. The resulting cyclohexenes are precursors to oseltamivir and its analogues. The synthesis of the key reagent, 3-pentyloxyaldehyde, was also improved. Georg Thieme Verlag Stuttgart · New York.
- Rehak, Juraj,Huka, Martin,Latika, Attila,Brath, Henrich,Almassy, Ambroz,Hajzer, Viktoria,Durmis, Julius,Toma, Stefan,Sebesta, Radovan
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experimental part
p. 2424 - 2430
(2012/09/07)
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- Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid via cyclic sulfite intermediates
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A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (-)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively. Copyright
- Nie, Liang-Deng,Shi, Xiao-Xin,Quan, Na,Wang, Fei-Feng,Lu, Xia
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experimental part
p. 1692 - 1699
(2012/01/02)
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- PROCESS FOR PRODUCING OSELTAMIVIR PHOSPHATE AND INTERMEDIATE COMPOUND
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Disclosed are a process suited to large scale synthesis with high yield for producing oseltamivir phosphate, in which a preparation of oseltamivir phosphate which is highly safe as a pharmaceutical product can be produced, and an intermediate compound for producing oseltamivir phosphate. In this production process, an intermediate compound represented by general formula (V) is synthesized by employing Michael reaction/Michael reaction/Horner-Wadsworth-Emmons reaction, and oseltamivir phosphate is produced by converting the substituent groups in this intermediate compound.
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Page/Page column 41
(2011/04/24)
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- One-pot reactions accelerate the synthesis of active pharmaceutical ingredients
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All in one: A one-pot synthesis of the dipeptidylpeptidase IV selective inhibitor ABT-341 (see structure) by using an "uninterrupted sequence of reactions" has been developed. This strategy broadens the spectrum of one-pot reactions and is poised to speed up the synthesis of medicinally relevant drug compounds. (Figure Presented)
- Vaxelaire, Carine,Winter, Philipp,Christmann, Mathias
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scheme or table
p. 3605 - 3607
(2011/06/20)
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- Development of a concise synthesis of (-)-oseltamivir (Tamiflu)
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We report a full account of our work towards the development of an eight-step synthesis of anti-influenza drug (-)-oseltamivir (Tamiflu) from commercially available starting materials. The final synthetic route proceeds with an overall yield of 30 %. Key transformations include a novel palladium-catalyzed asymmetric allylic alkylation reaction (Pd-AAA) as well as a rhodium-catalyzed chemo-, regio-, and stereoselective aziridination reaction.
- Trost, Barry M.,Zhang, Ting
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supporting information; experimental part
p. 3630 - 3643
(2011/05/12)
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- Synthesis of (-)-oseltamivir by using a microreactor in the curtius rearrangement
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A microflow reaction of the Curtius rearrangement by using trimethylsilyl azide as an azide source, followed by trapping of the generated isocyanate with a nucleophile was established, which is safe, inexpensive, and suitable for large-scale synthesis. By this flow reaction in the Curtius rearrangement and recrystallization of the late-stage acetamide intermediate the third-generation synthesis of (-)-Oseltamivir has been established, which is efficient, practical, and safe. A safe and efficient total synthesis of (-)-Oseltamivir has been developed by using the Curtius rearrangement with a microflow system, which avoids the isolation of a hazardous and potentially explosive intermediate. In addition, the product, possessing an acetamide group, was easily purified by recrystallization. Thus, this procedure can be scaled up as an industrial process.
- Ishikawa, Hayato,Bondzic, Bojan P.,Hayashi, Yujiro
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p. 6020 - 6031
(2011/12/15)
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- Sugar-based synthesis of tamiflu and its inhibitory effects on cell secretion
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Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side-effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D-glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late-stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we inves-tigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC 12 cells, and suggests a mechanism underlying the Tamiflu side-effects, in particular its possible adverse influences on neurotransmitter release in the central nervous system.
- Ma, Jimei,Zhao, Yanying,Ng, Simon,Zhang, Jing,Zeng, Jing,Than, Aung,Chen, Peng,Liu, Xue-Wei
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supporting information; experimental part
p. 4533 - 4540
(2010/08/19)
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- A practical and azide-free synthetic approach to oseltamivir from diethyl d -tartrate
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A short and practical synthesis of oseltamivir was accomplished in 11 steps from inexpensive and abundant diethyl d-tartrate starting material. This azide-free route featured an asymmetric aza-Henry reaction and a domino nitro-Michael/Horner-Wadsworth-Emmons (HWE) reaction as the key steps to construct the relevant cyclohexene ring of the product, which provided an economical and practical alternative for the synthesis of oseltamivir.
- Weng, Jiang,Li, Yong-Bo,Wang, Rui-Bin,Li, Feng-Quan,Liu, Can,Chan, Albert S. C.,Lu, Gui
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supporting information; experimental part
p. 3125 - 3128
(2010/08/20)
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- High-yielding synthesis of the anti-influenza neuraminidase inhibitor (-)-oseltamivir by two one-pot sequences
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The efficient asymmetric total synthesis of (-)-oseltamivir, an antiviral reagent, has been accomplished by using two one-pot reaction sequences, with excellent overall yield (60%) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wadsworth-Emmons reaction combined with retro-aldol/Horner-Wadsworth-Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (-)-oseltamivir has also been established. Fighting the flu: Two one-pot and column-free asymmetric sequences are used to accomplish the synthesis of (-)-oseltamivir, known as the anti-influenza drug Tamiflu (see scheme; TMS: trimethylsilyl). This high-yielding synthesis takes advantage of a diphenylprolinol silyl ether as an organocatalyst and single-pot domino operations.
- Ishikawa, Hayato,Suzuki, Takaki,Orita, Hideo,Uchimaru, Tadafumi,Hayashi, Yujiro
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supporting information; experimental part
p. 12616 - 12626
(2011/01/12)
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- An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis
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An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.
- Wichienukul, Pawinee,Akkarasamiyo, Sunisa,Kongkathip, Ngampong,Kongkathip, Boonsong
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supporting information; experimental part
p. 3208 - 3210
(2010/08/07)
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- Organocatalytic michael addition of aldehydes to protected 2-amino-1-nitroethenes: The practical syntheses of oseltamivir (tamiflu) and substituted 3-aminopyrrolidines
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Figure Presented Hey Mickey, you're so fine! Organocatalytic Michael additions of aldehydes with protected 2-amino-1-nitroethene could go through three different transition-states to afford adducts with usual and unusual stereochemistry, thereby providing a facile entry to Tamiflu (see scheme) and substituted 3-aminopyrrolidines. TMS = trimethylsilyl, Ac = acetyl.
- Zhu, Shaolin,Yu, Shouyun,Wang, You,Ma, Dawei
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supporting information; experimental part
p. 4656 - 4660
(2010/08/20)
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- Preparation of oseltamivir phosphate
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The invention provides a new process for the conversion of shikimic acid to oseltamivir (I), and optionally to an acid addition salt, via the intermediate phosphoramide VII.
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Page/Page column 9
(2009/04/24)
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- METHOD OF FORMING OSELTAMIVIR AND DERIVATIVES THEREOF
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A process is provided for the synthesis of 4,5-diamino cyclohexene carboxylate ester (1): or a pharmaceutically acceptable salt thereof. R1 - R3 are a silyl-, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. R4, R11 and R12 are H, a silyl-group, an aliphatic, alicyclic, aromatic, arylaliphatic, or an arylalicyclic group. 3,4-Dihydropyran compound (9): with R5 and R6 being suitable protecting groups, is reacted to form aldehyde (4): which is oxidized and converted to N-substituted carbamate (3): with R7 being a suitable protecting group. (3) is, via oxazolinidone (13): converted to azido carboxylate ester (2): and then to 4,5-diamino cyclohexene carboxylate ester (1).
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Page/Page column 42-43
(2009/07/18)
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- SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
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Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.
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Page/Page column 56; 57; 59
(2009/04/25)
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- PROCESS FOR OSELTAMIVIR PHOSPHATE
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The present invention provides an improved and commercially viable process for the preparation of oseltamivir phosphate. Thus, for example, ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is acetylated with acetic anhydride in methylene chloride in the presence of triethyl amine in the absence of water to give ethyl (3R,4R,5S)-4-(acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
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Page/Page column 3
(2009/07/02)
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- High-yielding synthesis of the anti-influenza neuramidase inhibitor (-)-oseltamivir by three "One-Pot" operations
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Taking shortcuts: A remarkably short and high-yielding asymmetric total synthesis of (-)-oseltamivir takes advantage of organocatalysis and single-pot domino operations. The target, known as the drug Tamiflu, is prepared efficiently in a short time, and a
- Ishikawa, Hayato,Suzuki, Takaki,Hayashi, Yujiro
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supporting information; experimental part
p. 1304 - 1307
(2009/06/30)
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- Efficient asymmetric synthesis of oseltamivir from D-mannitol
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A highly practical asymmetric synthesis of oseltamivir has been accomplished in 18 steps from D-mannitol without any chromatographic purification, which features intramolecular aldol condensation of dialdehyde with a 3-pentyl ether moiety in constructing
- Mandai, Tadakatsu,Oshitari, Tetsuta
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scheme or table
p. 783 - 786
(2009/08/07)
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- PROCESS FOR OBTAINING PURE OSELTAMIVIR
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The present invention provides a process for obtaining highly pure crystalline form of oseltamivir free base, thus, for example, suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in well defined crystalline form. The present invention also provides a process for preparation of oseltamivir phosphate in high purity.
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- The first synthesis of [11C]oseltamivir: A tool for elucidating the relationship between Tamiflu and its adverse effects on the central nervous system
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Oseltamivir phosphate (Tamiflu) is an anti-influenza drug approved in many countries. Recently, in Japan, adverse effects on the central nervous system have been reported in younger patients administrated with Tamiflu. As a tool for elucidating the relationship between Tamiflu and its adverse effects, 11C-labeled oseltamivir was synthesized through a two-step reaction involving [11C]acetylation with [1-11C]acetyl chloride. Starting from approximately 37.0 GBq of [11C]CO2, 1.2-1.8 GBq (n=5) of [11C]oseltamivir was obtained at the end of synthesis (EOS) 36-39 min after the end of bombardment. Radiochemical purity and specific activity were greater than 98% and 2.7-6.3 GBq/μmol at EOS, respectively. Copyright
- Arai, Takuya,Konno, Fujiko,Ogawa, Masanao,Zhang, Ming-Rong,Suzuki, Kazutoshi
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experimental part
p. 350 - 354
(2011/06/25)
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- A synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reaction
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(Chemical Equation Presented) In pursuit of a better route: A new catalytic asymmetric synthesis of Tamiflu was developed. The key transformation was an asymmetric Diels-Alder-type reaction of 1 and 2 catalyzed by a barium/F 2-FujiCAPO complex in the presence of a CsF co-catalyst to construct the core of Tamiflu (see scheme; TMS=trimethylsilyl). The product was converted into Tamiflu in 11 steps on a gram scale.
- Yamatsugu, Kenzo,Yin, Liang,Kamijo, Shin,Kimura, Yasuaki,Kanai, Motomu,Shibasaki, Masakatsu
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supporting information; experimental part
p. 1070 - 1076
(2009/06/20)
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- ISOQUINUCLIDINE DERIVATIVE AND METHOD FOR PRODUCING 1-CYCLOHEXENE-1-CARBOXYLIC ACID DERIVATIVE BY USING THE SAME
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The present invention provides an isoquinuclidine derivative which can be used to easily synthesize oseltamivir or an analog thereof. In particular, the present invention provides an isoquinuclidine derivative represented by the following formula (1) or an enantiomer thereof: wherein in the formula (1), A represents a protective group for the nitrogen atom; R1 to R1 each independently represent an alkyl group which may have a substituent, an aryl group which may have a substituent, or a hydrogen atom; and X represents a halogen atom.
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Page/Page column 18
(2009/05/29)
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- PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OSELTAMIVIR AND ANALOGS THEREOF
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The present application relates to processes for the preparation of oseltamivir and the H3PO4 salt of oseltamivir, Tamiflu. The application further relates to novel intermediate compounds and to pharmaceutical compositions containing said compounds. The application further relates to a method of using the novel intermediates to treat or prevent influenza.
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Page/Page column 60
(2009/12/23)
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