cas 204255-11-8, Oseltamivir phosphate | Articles data

Articles about 204255-11-8Total 49 be found

Article title
Article abstract
Author
Journal number and time
Download

Synthesis method of oseltamivir phosphate
The invention belongs to the technical field of oseltamivir phosphate, and particularly relates to a synthesis method of oseltamivir phosphate. The synthesis method of oseltamivir phosphate comprises the following steps: step 1, carrying out acetylation reaction on a compound as shown in a formula IV to obtain a compound as shown in a formula V; step 2, removing tertiary butyl from the compound as shown in the formula V to obtain a compound as shown in a formula VI; and step 3, removing a phthaloyl protecting group from the compound as shown in the formula VI, and then carrying out salt-forming reaction on the obtained product and phosphoric acid to obtain oseltamivir phosphate as shown in the formula I. The invention provides the synthesis method of oseltamivir phosphate, and provides the industrial synthesis method of oseltamivir phosphate, wherein the method does not need an expensive metal catalyst, has high yield, is convenient to operate and does not have heavy metal residues.
-
Paragraph 0041; 0053-0054

(2022/03/18)

Method for preparing oseltamivir phosphate
The invention discloses a method for preparing oseltamivir phosphate. The method comprises the following steps: reacting OSTW-5, an organic solvent and 1, 3-dimethyl barbituric acid in the presence of a palladium catalyst and heteropoly acid to obtain oseltamivir phosphate after the reaction is finished. In the method, the heteropoly acid is silicotungstic acid or silicomolybdic acid. The method is simple and convenient in process, the yield of oseltamivir phosphate obtained by the method is higher than that of oseltamivir phosphate obtained by an existing method and can reach 95%, the purity of oseltamivir phosphate can reach 98%, and the method has important application value.
-
Paragraph 0018; 0020; 0032-0036

(2022/04/03)

Preparation method and intermediate of oseltamivir
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.
-
(2021/06/26)

Preparation method of oseltamivir phosphate
The invention relates to the technical field of drug synthesis, and particularly discloses a preparation method of oseltamivir phosphate, which comprises the following steps: heating trifluoroacetic acid and hydrochloride to react, diluting and concentrating, adjusting pH, layering, extracting, washing, dehydrating, concentrating, crystallizing and drying to obtain an intermediate product; preparing an intermediate product/ethanol solution, stirring and mixing 1, 3-dimethyl barbituric acid, triphenylphosphine, palladium acetate and absolute ethyl alcohol to obtain a mixture, dropwise adding the mixture into the intermediate product/ethanol solution, decolorizing, carrying out suction filtration, dropwise adding the filtrate into a phosphoric acid/ethanol solution, stirring, adding absolute ethyl alcohol, standing, carrying out suction filtration, washing and drying to obtain an oseltamivir phosphate crude product; and heating and stirring the oseltamivir phosphate crude product, absolute ethyl alcohol and distilled water, decolorizing, carrying out suction filtration, adding absolute ethyl alcohol into the filtrate, cooling and crystallizing, carrying out suction filtration, washing, and drying to obtain the oseltamivir phosphate refined product. The oseltamivir phosphate prepared by the preparation method disclosed by the invention is relatively high in purity and relatively good in yield.
-
Paragraph 0025-0026; 0028-0056

(2021/08/28)

FLOW SYNTHESIS PROCESS FOR THE PRODUCTION OF OSELTAMIVIR
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.
-
(2020/09/27)

Method for preparing oseltamivir phosphate by azide process
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.
-
(2020/10/20)

Preparation method of oseltamivir phosphate
The invention belongs to the field of pharmaceutical chemicals, and specifically relates to a preparation method of oseltamivir phosphate. According to a reaction path of the preparation method, a compound I is used as an initial raw material; the tert-butyl group of the compound I is removed under the action of trifluoroacetic acid to obtain a compound II; the compound II is subjected to acetylation at low temperature to obtain a compound III; then an allyl group is removed under the action of palladium acetate, triphenylphosphine and 1,3-dimethylbarbituric acid; and finally, salification with phosphoric acid is conducted so as to realize high-yield preparation of a high-purity compound as shown in a formula IV.
-
(2020/06/30)

Continuous synthesis for oseltamivir phosphate
The invention discloses a preparation method for an oseltamivir phosphate compound, and belongs to the field of organic chemistry. The method is a continuous and automated method for producing compounds. The preparation method includes the following processes: preparing a solution, performing a reaction, performing mixing, performing centrifuging, performing stirring, performing heating, performing decoloring, performing cooling, and performing centrifuging and drying. Reactants are conveyed by using a metering diaphragm pump, the output of a product is adjusted by adjusting the conveying speed, and the target product is finally obtained by centrifugal drying. The preparation method greatly shortens the production cycle, reduces the manual use, improves the safety in the production process, and reduces the use of materials.
-
Paragraph 0058-0169

(2020/02/14)

Method for preparing antiviral drug oseltamivir phosphate intermediate tert-butylamine derivative I
The invention discloses a method for preparing a tert-butylamine derivative, and relates to the field of drug synthesis. The method comprises the following steps: 1, preparing a magnesium-amine compound, namely, adding magnesium halide and tert-butylamine A into an aprotic solvent, and carrying out a mixing stirring reaction for 0.5-1.5 h at a temperature of 0-15 DEG C to prepare a mixed solutionA; 2, adding a compound B into the mixed solution A prepared in the step 1, and carrying out a stirring reaction for more than 8 hours to prepare a mixed solution B; and 3, supplementing tert-butylamine D into the mixed solution B prepared in the step 2, and carrying out a stirring reaction for 24-48h at a temperature of 50-70 DEG C to prepare a tert-butylamine derivative I. By controlling the preparation temperature of the compound, the addition mode of tert-butylamine and the time of the ring-opening reaction, the curing phenomenon in the reaction and the increase of by-products can be effectively controlled.
-
Paragraph 0034-0035

(2020/06/05)

Preparation method of oseltamivir phosphate
The invention provides a novel preparation method of ethyl (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate, and belongs to the technical field of chemical drug synthesis. An acetamido group is introduced into the construction process of oseltamivir phosphate molecules by using a Ritter reaction. The preparation way of the initial raw material in the invention is close to the shikimic acid end of a natural product, so the novel preparation method has the advantages of mild conditions, simplicity in operation, high total yield, and suitableness for commercial production of oseltamivir phosphate bulk drugs. The method successfully avoids an original research route to overcome protection period limitation of an original research and preparation methodpatent, and can accelerate the solving of the problem of medication accessibility of the medicine in China.
-
(2019/12/25)

Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction
Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.
-
(2019/09/02)

Method for preparing oseltamivir phosphate
The invention discloses a method for preparing oseltamivir phosphate. The method includes steps of carrying out reaction on intermediates shown as a formula (IV) with palladium acetate, triphenylphosphine and N,N-dimethylbarbituricacid in solvents, and removing allyl to obtain intermediates shown as a formula (III); carrying out acid treatment on the intermediates shown as the formula (III), and removing tertiary butyl to obtain oseltamivir free alkali shown as a formula (II); carrying out reaction on the oseltamivir free alkali with phosphoric acid in solvents, and carrying out crystallization purification. An equivalence ratio of the intermediates shown as the formula (IV) to the palladium acetate to the triphenylphosphineto the N,N-dimethylbarbituricacid is 1:0.01:0.04:1.2. The method has the advantages that the residual quantities of main heavy metal such as palladium, arsenic, cadmium, cobalt, copper, mercury, lithium, nickel, lead, antimony, titanium and vanadium in the oseltamivir phosphate prepared by the aid of the method are within the limit ranges, and accordingly the ICH standards can be met.
-
Page/Page column 6-11

(2019/04/17)

Oseltamivir phosphate preparation method
The invention discloses an oseltamivir phosphate preparation method which includes the steps: taking (3R, 4R, 5s)-4-n-acetyl (1, 1-dimethyl ethyl) amino-5-N, N-diallyl amino-3-(1-ethyl propoxy)-1-cyclohexene-1-ethyl carboxylate hydrochloride acquired by non-azide reaction as a starting raw material; removing tertiary butyl and diallyl; enabling the raw material and phosphoric acid to form salt toobtain crude oseltamivir phosphate; refining the crude oseltamivir phosphate by an ethanol water solvent to obtain high-purity oseltamivir phosphate with a crystal form A. The method does not adopt sodium azide, azide and sodium hydride and is safe and environmentally friendly. The purity of the starting raw material is 99.9% or more, the purity of an intermediate and a crude product is 99.5% or more, the purity of the oseltamivir phosphate is 99.9%, the quality and the yield of the oseltamivir phosphate are improved, cost is reduced, and the preparation method is simple, good in repeatabilityand suitable for mass production.
-
Paragraph 0023; 0025; 0026-0029

(2019/04/02)

Preparation method of oseltamivir phosphate
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.
-
(2019/05/04)

Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via the Iron-Catalyzed Stereoselective Olefin Diazidation
We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been previously problematic. Preliminary catalyst structure-reactivity-stereoselectivity relationship studies revealed that both the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment using both differential scanning calorimetry (DSC) and the drop weight test (DWT) has also demonstrated the feasibility of carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.
Li, Hongze,Shen, Shou-Jie,Zhu, Cheng-Liang,Xu, Hao
p. 10619 - 10626
(2018/08/03)

The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors
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
p. 105 - 115
(2017/10/06)

A new and efficient asymmetric synthesis of oseltamivir phosphate (Tamiflu) from D-glucose
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
p. 2393 - 2399
(2015/03/30)

A PROCESS FOR THE PREPARATION OF INTERMEDIATE FOR THE PREPARATION OF OSELTAMIVIR PHOSPHATE
The present invention discloses an economic, simple, azide and azindine complexity free process for the synthesis of osletamivir phosphate (Tamiflu) by stereospecific amidoalkylation of imidazothiazolone from easily available L-cysteine via Ramberg- Backlund reaction and Sharpless-Reich protocol.
-
(2015/04/22)

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
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,
-
(2014/03/24)

A novel azide-free asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from Roche's epoxide
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
p. 638 - 642
(2013/07/05)

Facile method for the synthesis of oseltamivir phosphate
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
p. 163 - 170
(2013/11/19)

Synthesis of (-)-oseltamivir phosphate (tamiflu) starting from cis-2,3-bis(hydroxymethyl)aziridine
Oseltamivir phosphate (Tamiflu) has been synthesized from cis-2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis(hydroxymethyl)aziridine with a Boc group, desymmetrization provided a chiral aziridine, which was a key intermediate to install the required stereogenic center containing a nitrogen atom. Allylation and ring closing metathesis are the key reactions to obtain the cyclic product that was successfully converted to the desired oseltamivir phosphate.
Oh, Hong-Se,Kang, Han-Young
p. 8792 - 8796,5
(2020/09/15)

A new and efficient asymmetric synthesis of oseltamivir phosphate(Tamiflu) from D-mannose
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
p. 6209 - 6211,3
(2012/12/11)

A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from d-mannose
A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive and abundant starting material, d-mannose. This synthetic route featured an intramolecular Horner-Wadsworth-Emmons reaction as the key step to furnish the cyclohexene ring product. The hydroxyl group was converted stereo specifically into an amino group by oxidation to the ketone and reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.
Chuanopparat, Nutthawat,Kongkathip, Ngampong,Kongkathip, Boonsong
p. 6803 - 6809
(2012/08/28)

A new efficient synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid
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
p. 1561 - 1563
(2012/05/05)

Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid via cyclic sulfite intermediates
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
p. 1692 - 1699
(2012/01/02)

Enantioselective synthesis of oseltamivir phosphate
The key steps in the enantioselective synthesis of Tamiflu include an asymmetric Diels-Alder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Epoxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxybenzoic acid (IBX) following Nicolaou's protocol failed. The unsaturated ester was prepared by phenylselenylation followed by selenoxide elimination.
Raghavan, Sadagopan,Babu, Vaddela Sudheer
p. 2044 - 2050
(2011/04/17)

Sugar-based synthesis of tamiflu and its inhibitory effects on cell secretion
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
supporting information; experimental part
p. 4533 - 4540
(2010/08/19)

An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis
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
supporting information; experimental part
p. 3208 - 3210
(2010/08/07)

A practical synthesis of (-)-oseltamivir
Oseltamivir phosphate (Tamiflu) is a potent inhibitor of neuraminidase, and is used worldwide as a drug for type A or B influenza. The industrial synthesis of oseltamivir uses shikimic acid as a starting material, but the price fluctuates, depending on the supply of star anise. We have developed a practical synthesis of oseltamivir from pyridine, which features an asymmetric Diels-Alder reaction of dihydropyridine using MacMillan's catalyst, a bromolactonization, Hofmann rearrangement with PhI(OAc)2, and a domino transformation of the bicyclo[2.2.2] system into an aziridine compound.
Satoh, Nobuhiro,Akiba, Takahiro,Yokoshima, Satoshi,Fukuyama, Tohru
experimental part
p. 3239 - 3245
(2009/08/15)

PROCESS FOR OBTAINING PURE OSELTAMIVIR
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.
-
(2009/06/27)

Polymorphic Forms of Oseltamivir Phosphate
The present invention relates to polymorphic forms of (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester phosphate, which is a potent inhibitor of viral neuraminidase.
-
Page/Page column 4

(2009/07/18)

Preparation of oseltamivir phosphate
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.
-
Page/Page column 9

(2009/04/24)

SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
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.
-
Page/Page column 80

(2009/04/25)

METHOD OF FORMING OSELTAMIVIR AND DERIVATIVES THEREOF
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).
-
Page/Page column 43

(2009/07/18)

ISOQUINUCLIDINE DERIVATIVE AND METHOD FOR PRODUCING 1-CYCLOHEXENE-1-CARBOXYLIC ACID DERIVATIVE BY USING THE SAME
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.
-
Page/Page column 18-19

(2009/05/29)

PROCESS FOR OSELTAMIVIR PHOSPHATE
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.
-
Page/Page column 3

(2009/07/02)

Efficient access to oseltamivir phosphate (Tamiflu) via the O-trimesylate of shikimic acid ethyl ester
-
Karpf, Martin,Trussardi, Rene
scheme or table
p. 5760 - 5762
(2009/12/06)

A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid
Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield. The synthesis described in this article is characterized by two particular steps: the highly regioselective and stereoselective facile nucleophilic replacement of an OMs by an N3 group at the C-3 position of ethyl (3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylate 8.
Nie, Liang-Deng,Shi, Xiao-Xin
experimental part
p. 124 - 129
(2009/05/30)

A short and practical synthesis of oseltamivir phosphate (tamiflu) from (-)-shikimic acid
(Chemical Equation Presented) Oseltamivir phosphate (1) was synthesized from (-)-shikimic acid through a short and practical synthetic route via eight steps in 47% overall yield. In addition, the highly regioselective and stereoselective nucleophilic replacement of OMs by the N3 group in the third and seventh steps has been studied in detail, and the reaction conditions were optimized.
Nie, Liang-Deng,Shi, Xiao-Xin,Kwang, Hyok Ko,Lu, Wei-Dong
body text
p. 3970 - 3973
(2009/10/01)

A concise and flexible synthesis of the potent anti-influenza agents tamiflu and tamiphosphor
(Chemical Equation Presented) Tamiflu and the highly potent neuraminidase inhibitor tamiphosphor have been synthesized in 11 steps and greater than 20% overall yields from an haloarene (1S,2S)-cis-diol. The key transformations include a regio- and stereoselective bromoamidation, and a palladium-catalyzed carbonylation or phosphonylation reaction (see scheme; tamiflu: A = CO 2Et, B = NH3+H2PO4 -, tamiphosphor: A = PO(ONH4)2, B = NH 2).
Shie, Jiun-Jie,Fang, Jim-Min,Wong, Chi-Huey
supporting information; experimental part
p. 5788 - 5791
(2009/03/11)

Preparation of oseltamivir phosphate (Tamiflu) and intermediates starting from D-glucose or D-xylose
Novel processes for the preparation of the anti-viral agent, Oseltamivir Phosphate and novel intermediates prepared in such processes. The novel processes use as starting materials D-glucose or D-xylose in the preparation of Oseltamivir Phosphate.
-
Page/Page column 10

(2010/11/29)

PROCESS FOR OBTAINING PURE OSELTAMIVIR
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.
-
Page/Page column 5

(2008/06/13)

A concise synthesis of Tamiflu: third generation route via the Diels-Alder reaction and the Curtius rearrangement
Our third generation synthesis of Tamiflu was achieved in 12 steps from commercially available starting materials, using the Diels-Alder reaction and Curtius rearrangement as key steps.
Yamatsugu, Kenzo,Kamijo, Shin,Suto, Yutaka,Kanai, Motomu,Shibasaki, Masakatsu
p. 1403 - 1406
(2007/10/03)

IMPROVED PROCESS FOR OSELTAMIVIR PHOSPHATE
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.
-
Page/Page column 7

(2008/06/13)

Research and Development of a Second-Generation Process for Oseltamivir Phosphate, Prodrug for a Neuraminidase Inhibitor
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.
p. 86 - 91
(2013/09/04)

Process for preparing 1,2-diamino compounds
The invention provides a multi-step process for preparing 1,2-diamino compounds of formula wherein R1, R1′, R2, R2′, R3 and R4 have the meaning given in the specification and pharmaceutically acceptable addition salts thereof, from 1,2-epoxides of formula wherein R1, R1′, R2 and R2′ have the meaning given in the specification.
-
Page/Page column 11

(2008/06/13)

Stereo-specific synthesis of shimikic acid derivatives with improved efficiency
The invention provides a multistep synthesis for the preparation of 4,5-diamino shikimic acid derivatives of formula 1starting from an isophthalic acid derivative of formula 24,5-Diamino shikimic acid derivatives are potent inhibitors of viral neuraminidase.
-
(2008/06/13)

Practical Total Synthesis of the Anti-Influenza Drug GS-4104
-
Rohloff, John C.,Kent, Kenneth M.,Postich, Michael J.,Becker, Mark W.,Chapman, Harlan H.,Kelly, Daphne E.,Lew, Willard,Louie, Michael S.,McGee, Lawrence R.,Prisbe, Ernest J.,Schultze, Lisa M.,Yu, Richard H.,Zhang, Lijun
p. 4545 - 4547
(2007/10/03)