- From plant to drug: Ionic liquids for the reactive dissolution of biomass
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We present an ionic liquid (IL) strategy for the reactive dissolution of star anise seeds using different Bronsted-acidic ionic liquids as the solvent and reaction media towards the isolation of important pharmaceutical intermediates; this procedure provi
- Ressmann, Anna K.,Gaertner, Peter,Bica, Katharina
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Read Online
- New Method for the Rapid Extraction of Natural Products: Efficient Isolation of Shikimic Acid from Star Anise
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A new, practical, rapid, and high-yielding process for the pressurized hot water extraction (PHWE) of multigram quantities of shikimic acid from star anise (Illicium verum) using an unmodified household espresso machine has been developed. This operationa
- Just, Jeremy,Deans, Bianca J.,Olivier, Wesley J.,Paull, Brett,Bissember, Alex C.,Smith, Jason A.
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- Industrial synthesis of the key precursor in the synthesis of the anti-influenza drug oseltamivir phosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1 -ene-1 -carboxylate
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Starting from (-)-quinic acid, the title compound was synthesized in seven chemical steps and an overall yield of 35-38%. The route of the improved Gilead synthesis was not changed. However, significant improvements in each step led to a doubled overall yield, a 30% reduction in the number of unit operations, and an excellent quality (≥99%) of the resulting epoxide. A highly regioselective method for the dehydration of a quinic acid to a shikimic acid derivative and for the reduction of a cyclic ketal was found. Alternatively, the title compound was synthesized in six chemical steps and 63-65% yield from commercially available (-)-shikimic acid. Compared to the optimized quinic acid route, the production time was reduced by about 50%. The quality of epoxide produced from either natural product was equivalent. Therefore (-)-shikimic acid is the preferred raw material. The absolute configuration of the epoxide was determined by X-ray single crystal structure analysis and it was demonstrated that the epoxide was stereo-isomerically pure.
- Federspiel, Muriel,Fischer, Rolf,Hennig, Michael,Mair, Hans-Jürgen,Oberhauser, Thomas,Rimmler, G?sta,Albiez, Thomas,Bruhin, Jürg,Estermann, Heinrich,Gandert, Carsten,G?ckel, Volker,G?tz?, Stephan,Hoffmann, Ursula,Huber, Gabriel,Janatsch, Günter,Lauper, Stephan,R?ckel-St?bler, Odette,Trussardi, Rene,Zwahlen, Andreas G.
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Read Online
- Method for preparing oseltamivir intermediate
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The invention relates to a preparation method of an oseltamivir intermediate (as shown in a formula IV). The method is prepared through a route as described in the specification. The method is simple and safe to operate, short in synthetic route, high in yield, small in environmental pollution, good in economic effect and suitable for industrial production.
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Paragraph 0023-0026
(2021/06/26)
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- Preparation method for impurity of oseltamivir synthesis process
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The invention provides a preparation method for impurity of an oseltamivir synthesis process. The preparation method comprises the following steps: with shikimic acid as a starting material, successively carrying out an esterification reaction, a Mitsunob
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Paragraph 0025-0028
(2021/06/26)
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- Crystallization method of intermediate 5 of high-purity oseltamivir phosphate
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5 (Pentane 5 -yloxy) -3 - oxo -7 - bicyclo [-] hep 4.1.0-3 -3 - carboxylate ethyl carboxylate is concentrated to precipitate crystals, and then crystals are directly put into a mixed solvent composed of an alkane solvent and an alcohol solvent. Through the crystallization method, the purity of the intermediate 5 can reach above 99.7%, and the requirement for preparing oseltamivir phosphate is completely met.
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Paragraph 0008-0009; 0023
(2021/10/27)
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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; 12-17
(2020/09/27)
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- Synthesis method of daphenanthrene key intermediate
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The invention relates to a synthetic method of a Duffy key intermediate. The synthetic method comprises the following steps of by taking shikimic acid as a starting material and performing reactions including esterification reaction, selective oxidation a
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Paragraph 0029-0031
(2020/06/20)
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- The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors
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Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure–activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50?=?0.1?±?0.04?μm, H3N2 IC50?=?0.26?±?0.18?μm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.
- Lin, Xiong,Qin-Hua, Chen,Peng, Li,Chun-Lei, Li,Guang-De, Yang
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p. 105 - 115
(2017/10/06)
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- Antioxidant
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PROBLEM TO BE SOLVED: To provide an improved antioxidant.SOLUTION: An antioxidant comprises a cyclohexanetriol derivative represented by formula (1) as an active ingredient.
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Paragraph 0029
(2019/01/05)
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- Cyclohexenes derivative or its pharmaceutically acceptable salts and its use
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Belonging to the field of pharmaceutical chemistry, the invention discloses a cyclohexene derivative shown as formula I or its pharmaceutically acceptable salt. The cyclohexene derivative or its pharmaceutically acceptable salt has good inhibitory activit
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Page/Page column 13
(2016/10/09)
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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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- Chemo-enzymatic enantioconvergent approach toward ethyl shikimate from ethyl 5-hydroxy-3,4-isopropylidenedioxycyclohex-1-enecarboxylate
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An enantioconvergent route for natural form of ethyl shikimate was achieved from Diels-Alder adduct of furan and acryloyl chloride. The key step was a highly enantioselective (E >500) and efficient acetylation of ethyl (3R*,4S*,5S*)-5-hydroxy-3,4-isopropylidenedioxycyclohex-1- enecarboxylate, which had a diastereomeric relationship with ethyl shikimate, mediated by Burkholderia cepacia lipase (Amano PS-IM). Both of the resolved enantiomers were converted to natural form of ethyl shikimate by inversion at C-5 for the former and at C-3 and C-4 for the latter, respectively.
- Yamashita, Yasunobu,Hanaya, Kengo,Sugai, Takeshi,Mizushima, Tohru,Shoji, Mitsuru
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p. 6527 - 6532
(2013/07/26)
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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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- A new efficient synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid
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New synthesis of oseltamivir phosphate was accomplished in 9 steps with a 27% overall yield from a readily available (-)-shikimic acid. Selective ring opening reaction of ketal and azide Mitsunobu reaction for facile replacement of a hydroxyl group by the N3 group at the C-3 position of (3R,4R,5R)-ethyl 4-hydroxy-5-(methoxymethoxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 4 and at the C-4 position of (3R,4S,5R)-ethyl 4-acetamido-5-hydroxy-3-(pentan-3-yloxy) cyclohex-1-enecarboxylate 7 successfully served as the key steps.
- Kim, Hee-Kwon,Park, Kyoung-Joo Jenny
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scheme or table
p. 1561 - 1563
(2012/05/05)
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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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supporting information; experimental part
p. 2152 - 2157
(2012/05/05)
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- EPOXIDE INTERMEDIATE IN THE TAMIFLU SYNTHESIS
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The present invention relates to technology for preparing derivatives of unsaturated, cyclic, organic acids and salts, thereof. Shikimic acid is an example of such an acid. More particularly, the present invention relates to preparing derivatives of these acids or salts thereof that are esterified, ketalized, functionalized with a leaving group, and/or provided with epoxide functionality. Preferred aspects may be used in the synthesis of Oseltamivir Phosphate starting from shikimic acid.
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Page/Page column 18; 20-21
(2008/06/13)
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