- Immobilization of cholesterol esterase for use in multiple batch biotransformations to prepare (-)- FTC (emtricitabine)
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2′,3′-Dideoxy-5-fluoro-3′-thiacytidine [(-)-FTC], the active ingredient in the antiviral drug emtricitabine (Emtriva), was prepared by a bioresolution process using cholesterol esterase immobilized on Accurel PP to resolve optical isomers of racemic FTC butyrate. Cholesterol esterase was immobilized at 1.9-kg scale. Recycling studies were carried out with racemic FTC butyrate that indicated a high degree of immobilized cholesterol esterase stability resulting in 15 successive cycles of use (14 recycles). Racemic FTC butyrate (~8 kg, 200 g/L) was resolved with immobilized cholesterol esterase using a 1-pentanol/potassium dihydrogen phosphate buffer-solvent system to give (-)-FTC·HCl (98% ee, 2.17 kg, 31% molar yield based on racemic FTC butyrate).
- Osborne, Andrew P.,Brick, Dean,Ruecroft, Graham,Taylor, Ian N.
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Read Online
- Emtricitabine synthesis method
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The invention provides an emtricitabine synthesis method, which comprises: carrying out condensation on cheap and easily available dihaloacetic acid as a raw material and L-menthol, hydrolyzing to obtain menthyl glyoxylate hydrate, condensing with 2,5-dihydroxy-1,4-dithiane, carrying out halogenation, coupling with silylated 5-flucytosine, reducing, carrying out salt forming with salicylic acid toobtain emtricitabine salicylate, and finally re-crystallizing to obtain optically pure emtricitabine. According to the present invention, the whole synthesis process has characteristics of inexpensive and easily available raw materials, simple synthesis process and mild synthesis conditions, such that the synthesis cost of emtricitabine is substantially reduced; various raw materials have characteristics of good reaction selectivity and high utilization rate, such that the yield of the obtained emtricitabine is high; and the chiral substrate is easily removed during the synthesis, and the generated three-waste pollutants are less, such that the method is suitable for industrial large-scale production of emtricitabine.
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Paragraph 0028; 0035; 0036; 0038
(2019/11/29)
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- Asymmetric preparation method for Emtricitabine
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The invention provides an asymmetric preparation method for Emtricitabine. The preparation method comprises the steps of subjecting L-menthyl chloroformate, which serves as a raw material, to condensation with 2-halo ethanol, carrying out oxidation so as to obtain a stable intermediate, i.e., an aldehyde alcohol menthyl ester, subjecting the intermediate to condensation with 2,5-dihydroxyl-1,4-dithiane, carrying out halogenation, then, carrying out coupling with silanized 5-flucytosine, then, carrying out hydrolyzing, then, carrying out salt forming with salicylic acid, and finally, carrying out recrystallization, thereby obtaining purified Emtricitabine. According to the method, raw materials employed in a whole synthesis process are cheap and readily available, thus, the synthesis cost of the Emtricitabine disclosed by the invention is reduced greatly, the synthesis process is simple, the synthesis conditions are moderate, and the obtained Emtricitabine is relatively high in yield; and meanwhile, a chiral substrate is easy to remove during synthesis, produced pollutants, i.e., waste gases, waste water and waste residues are few, and thus, the method is applicable to industrial large-scale production of the Emtricitabine.
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Paragraph 0028; 0036; 0038
(2019/11/21)
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- Preparation method of emtricitabine (by machine translation)
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The synthesis cost of the emtricitabine is greatly reduced, the synthetic process is simple, 5 - the (S)- (+) - synthesis conditions are mild, the chiral substrate is easily removed in the synthesis process, 2,5 - the generated triwaste pollutants are few, and the entreabine is suitable for large-scale production of entreabine 5 . (by machine translation)
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Paragraph 0027; 0034; 0036
(2019/11/21)
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- Preparation method for emtricitabine isomer
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The invention discloses a preparation method for an embritabine isomer. The preparation method comprises the following steps: with Solketal as a starting material, allowing the Solketal to undergo a six-step reaction of esterification, hydrolysis, oxidation, condensation cyclization, acetylation and glycosylation condensation so as to synthesize four mixture intermediates of emtricitabine; and splitting the four isomer intermediates into a cis-isomer mixture and a trans-isomer mixture through a chiral reagent. According to the invention, by adoption of a simple starting material, a mixture forsplitting key intermediates of four optical isomers of the emtricitabine is synthesized through the six-step reaction, and chiral acid is utilized to split the four isomers into a mixture of cis andtrans isomers, so the preparation method provided by the invention has the advantages of simple and convenient operation, high yield and high isomer chiral purity.
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Paragraph 0087; 0088; 0090; 0091
(2019/04/26)
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- Asymmetric synthesis method of emtricitabine
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The present invention provides an asymmetric synthesis method of emtricitabine. L-menthyl chloroformate is used as raw material to condense with 2-chloro-1-ethanol, then hydrolyze under the conditionof catalyst to obtain acetaldehyde alcohol optically active ester which is then induced by chiral promoter to condense with 2, 5-dihydroxyl-1,4-dithiane to give trans 5-hydroxyl-1,3-oxythiacyclopentane-2-methyl-L-menthol carbonate, the trans 5-hydroxyl-1,3-oxythiacyclopentane-2-methyl-L-menthol carbonate is halogenated and coupled with silanized 5-fluorocytosine, emtricitabine is obtained by removing the chiral auxiliary agent under the condition of weak alkalinity. As that raw materials used in the whole synthesis process are cheap and easy to obtain, the raw material utilization ratio is high, so that the synthesis cost of the emtricitabine is greatly reduced, and the synthesis process is simple, the synthesis condition is mild, the yield of the obtained emtricitabine is high, meanwhile,the chiral assistant is easy to remove in the synthesis process, the three waste pollutants generated are less, and the preparation method is suitable for the large-scale industrial production of theemtricitabine.
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Paragraph 0027; 0028; 0034-0036
(2019/10/29)
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- A Suitqable to preparation method
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The invention discloses a Suitqable to preparation method. Refined pure 5 S - (5 '- fluorocytosine yl - 1') - 1, 3 - oxathiolane - 2 - ethoxy carbonyl - (1 'R, 2'S, 3' R) - menthyl ester; in the weak base and the solvent removed under the condition of chiral L - menthol get products Suitqable to. The invention required the starting raw material is cheap, mild reaction conditions, the atom utilization rate is high, the operation technique is simple, the reagents used in the environmental protection, the resulting high purity, reach the medical standard, is suitable for the industrial production of kindness or gemcitabine.
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Paragraph 0042; 0064-0066
(2019/04/02)
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- Benzoic acid Suitqable to salt, its preparation method and uses the benzoic acid Suitqable to salt preparation Suitqable to method
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The invention discloses emtricitabine benzoate, a preparation method thereof, and a method of preparing emtricitabine from emtricitabine benzoate, and belongs to the biochemistry field. Emtricitabine benzoate is a novel compound, has not been reported before, and is not recorded in any product catalogue. The emtricitabine benzoate is prepared by combining benzoic acid and emtricitabine in a water phase or an organic phase. When benzoic acid and emtricitabine are combined in a water phase or an organic phase, emtricitabine benzoate can be easily separated from the reaction system. By adding organic base or inorganic base into the water phase/organic phase reaction system, emtricitabine benzoate can be decomposed to obtain emtricitabine. By preparing emtricitabine from emtricitabine benzoate, after the reactions, emtricitabine can be easily separated from the reaction system, the purity of the obtained emtricitabine is more than 99%, and the yield is usually more than 80%.
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Paragraph 0026-0027
(2018/11/03)
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- PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE
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This invention provides for flow and batch synthesis processes for the production of Lamivudine and Emtricitabine, including flow and batch synthesis processes wherein at least of the synthesis steps are conducted in a solvent free environment.
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Page/Page column 22; 23; 24
(2018/01/20)
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- Suitqable to salicylate and its crystalline form, preparation method and use thereof
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Emtricitabine sylicylate crystalline, preparing methods and uses thereof are disclosed. The chemical structure of emtricitabine sylicylate is shown in formula 2, wherein, when n=0, formula 2 represents anhydrous emtricitabine sylicylate, and when n=1, it represents emtricitabine sylicylate monohydrate.
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Paragraph 0155-00157
(2017/08/26)
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- Preparation method for emtricitabine hydrohalide
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The invention discloses a preparation method for emtricitabine hydrohalide. The preparation method for the emtricitabine hydrohalide provided by the invention comprises the following steps: subjecting crude emtricitabine and hydrogen halide to a salt-forming reaction in an alcohol solvent so as to obtain emtricitabine hydrohalide, wherein the HPLC purity of the crude emtricitabine is larger than 85%; the hydrogen halide is selected from the group consisting of hydrogen chloride, hydrogen bromide or hydrogen iodide; and X is selected from the group consisting of chlorine, bromine or iodine. The preparation method provided by the invention has the advantages of simple operation, simple and convenient postprocessing and high yield; and the prepared emtricitabine product has high purity, can reach standards of raw medicines, has an HPLC purity larger than 99.60% and a largest single impurity less than 0.10%, is low in production cost, and is applicable to industrial production.
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Paragraph 0051; 0053
(2017/08/27)
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- Purifying method of emtricitabine
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The invention relates to the field of medicine chemistry and particularly relates to a purifying method of emtricitabine. The purifying method of emtricitabine includes the steps of separating the emtricitabine, in the form of emtricitabine benzoate, from a water solution, and freeing benzoate to obtain the emtricitabine at high yield and purity. The method is simple and high-effective and is very suitable for industrial production.
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Paragraph 0037; 0038; 0039; 0040; 0041
(2016/10/31)
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- Highly stereoselective synthesis of lamivudine (3TC) and emtricitabine (FTC) by a novel N -glycosidation procedure
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The combined use of silanes (Et3SiH or PMHS) and I2 as novel N-glycosidation reagents for the synthesis of bioactive oxathiolane nucleosides 3TC and FTC is reported. Both systems (working as anhydrous HI sources) were devised to act as substrate activators and N-glycosidation promoters. Excellent results in terms of chemical efficiency and stereoselectivity of the reactions were obtained; surprisingly, the nature of the protective group at the N4 position of (fluoro)cytosine additionally influenced the stereochemical reaction outcome.
- Caso, Maria Federica,Dalonzo, Daniele,Derrico, Stefano,Palumbo, Giovanni,Guaragna, Annalisa
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supporting information
p. 2626 - 2629
(2015/06/16)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF EMTRICITABINE
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The present invention provides an improved process for the preparation of emtricitabine with high yield and purity.
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Page/Page column 9; 15; 16
(2014/11/13)
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- A STEREOSELECTIVE PROCESS FOR PREPARATION OF 1,3-OXATHIOLANE NUCLEOSIDES
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The present invention relates to a stereoselective glycosylation for the preparation of 1,3-oxathiolane nucleoside in high yield and high optical purity. The invention specifically relates to a process of the preparation of Lamivudine and Emtricitabine using zirconium (IV) chloride (ZrCl4) as a catalyst in glycosylation.
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Page/Page column 27; 28
(2013/03/26)
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- A PROCESS FOR THE ISOLATION OF EMTRICITABINE
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The present invention provides a process for the isolation of 4-amino-5-fluoro-1- [(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (emtricitabine) of formula I from the reaction mixture obtained by reacting (1R,2S,5R)-menthyl- (2S,5R)-5-(4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl)-1,3-oxathiolane-2- carboxylate (FCME) of the formula II with a solution of sodium borohydride in aqueous sodium hydroxide in the presence of dipotassium hydrogen phosphate and 9 volumes of a polar solvent at a temperature of 15°C-20°C, avoiding isolation of salt of emtricitabine, such as oxalate, monosalicylate, hydrochloride, hydrobromide, methane sulfonate etc. and subsequent convention of salt of emtricitabine to emtricitabine free base; using simple, cost-effective and industrially applicable process.
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Page/Page column 25-26
(2012/10/18)
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- PROCESS FOR OBTAINING EMTRICITABINE
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The invention refers to a process for obtaining or isolating emtricitabine which comprises the azeotropic distillation of methanol-B(OMe)3. The invention is also directed to emtricitabine having a content of boron species of not more than 0.1 % by weight.
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Page/Page column 12-13
(2011/10/13)
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- Process for obtaining emtricitabine
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The invention refers to a process for obtaining or isolating emtricitabine which comprises the azeotropic distillation of methanol-B(OMe)3. The invention is also directed to emtricitabine having a content of boron species of not more than 0.1 % by weight.
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Page/Page column 7
(2011/11/01)
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- NOVEL PROCESS FOR THE PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to an improved process for the preparation of cis-nucleoside derivative of formula-1 involving chlorination of the compound of formula-2 followed by reaction with compound of formula-3 in presence of a base to get compound of formula-4, reacting the compound of formula-4 with an alkyl halide (RiX) to get a quaternary ammonium salt then with cytosine derivative of formula-5 to provide the compound of formula-6, optionally de-protecting the compound of formula-6 to the compound of formula-7, reducing compound of formula-7 with metal catalyst in presence of a buffer solution, then adding an organic acid to get the compound of formula-8, and converting the compound of formula-8 to cis-nucleoside derivative of formula-1. The present invention further relates to novel cis-nucleoside derivative of formula-8. The present invention also relates to a pharmaceutical composition comprising cis-nucleoside derivative of formula-1 with excipients.
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Page/Page column 39
(2011/09/14)
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- IMPROVED PROCESS FOR NUCLEOSIDES
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The present invention relates to improved process for the preparation of lamivudine or emtricitabine. Thus, (1'R,2'S,5'R)-menthyl- 5(R,S)-acetoxy-[1,3]-oxathiolane-2(R)-carboxylate is reacted with N-propinoyl cytosine in hexamethyl disilazane and then added trityl perchlorate to obtain a solid containing (1'R,2'S,5'R)-menthyl-5S-(N-4''-propionylcytosin-1''-yl)-[1,3]-oxathiolane -2R-carboxylate. The solid obtained above is reacted with methane sulfonic acid to obtain (2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)- [1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester. The above compound is reduced with sodium borohydride to obtain lamivudine.
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Page/Page column 17
(2011/08/03)
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- A PROCESS FOR STEREOSELECTIVE SYNTHESIS OF 5-FLUORO-1-(2R,5S)-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL]CYTOSINE
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The present invention provides an improved process for stereoselective preparation of 5-fluoro-l-(2R,5S)-[2-(hydroxymethyl)-l,3-oxathiolan-5-yl]cytosine and pharmaceutically acceptable salts thereof.
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Page/Page column 13
(2011/10/03)
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- PROCESS FOR PRODUCING 5-FLUORO-1-(2R,5S)-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YI]CYTOSINE
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Disclosed herein an improved process for producing 5-Fluoro-1-(2R, 5S)-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and its pharmaceutical acceptable salts.
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Page/Page column 10
(2009/08/14)
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- CRYSTALLINE L-MENTHYL (2R, 5S)-5-(4-AMINO-5-FLUORO-2-OXO-2H-PYRIMIDIN-1-YL)[1, 3]OXATHIOLAN-2-CARBOXYLATE AND PROCESS FOR PREPARATION THEREOF
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Provided herein is crystalline L-menthyl (2R, 5S)-5-(4-amino-5-fluoro-2-oxo-2H- pyrimidin-l-yl)[l,3]oxathiolan-2-carboxylate and a process for preparation thereof.
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Page/Page column 9
(2008/06/13)
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- PROCESS AND INTERMEDIATES FOR PREPARING EMTRICITABINE
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A novel process for preparing emtricitabine, and more particularly a process for preparing emtricitabine characterized by the formation and isolation of intermediate compounds in salified form, is described.
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- Processes for the diastereoselective separation of nucleoside analogue synthetic intermediates
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The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity and intermediates useful in those processes.
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- Processes for the diastereoselective synthesis of nucleoside analogues
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The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity, and intermediates useful in those processes.
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- Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds
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The present invention relates to a method of preparing the antiviral compounds 2'-deoxy-5-fluoro-3'thiacytidine (FTC) and various prodrug analogues of FTC from inexpensive precursors with the option of introducing functionality as needed; methods of using these compounds, particularly in the prevention and treatment of AIDS; and the compounds themselves. This synthetic route allows the stereoselective preparation of the biologically active isomer of these compounds and related compounds.
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- Asymmetric Synthesis and Biological Evaluation of β-L-(2R,5S)- and α-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and -Purine Nucleosides as Potential Anti-HIV Agents
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In order to study the structure-acivity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl pyrimidine and purine nucleosides were synthesized and evaluated for anti-HIV-1 activity in human peripheral blood mononuclear (PBM) cells.The key intermediate 8 was synthesized starting from L-gulose via 1,6-thiaanhydro-L-gulopyranose.The acetate 8 was condensed with thymine, 5-substituted uracils and cytosines, 6-chloropurine, and 6-chloro-2-fluoropurine to give pyrimidine and purine nucleosides.Upon evaluation of these final nucleosides, the 5-fluorocytosine derivative 51 was found to be the most potent compound among those tested.In the case of 5-substituted cytosine analogues, the antiviral potency was found to be in the following decreasing order: cytosine (β-isomer) > 5-iodocytosine (β-isomer) > 5-fluorocytosine (α-isomer) > 5-methylcytosine (α-isomer) > 5-methylcytosine (β-isomer) > 5-bromocytosine (β-isomer) > 5-chlorocytosine (β-isomer).Among the thymine, uracil, and 5-substituted uracil derivatives, thymine (α-isomer) and uracil (β-isomer) derivatives exhibited moderate anti-HIV activity.In the purine series, the antiviral potency is found to be in the following decreasing order: adenine (β-isomer) > 6-chloropurine (β-isomer) > 6-chloropurine (α-isomer) > 2-NH2-6-Cl-purine (β-isomer) > guanine (β-isomer) > N6-methyladenine (α-isomer) > N6-methyladenine (β-isomer).The cytotoxicity was also determined in human PBM cells as well as Vero cells.None of the synthesized nucleosides was toxic up to 100 μ in PBM cells.
- Jeong, Lak S.,Shinazi, Raymond F.,Beach, J. Warren,Kim, Hea O.,Nampalli, Satyanarayana,et al.
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p. 181 - 195
(2007/10/02)
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