- BI- AND MONOCYCLIC NUCLEOSIDE ANALOGS FOR TREATMENT OF HEPATITIS E
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The present disclosure is directed toward bi- and monocyclic nucleoside analogs, and compositions comprising these compounds for use in the treatment of hepatitis E infections.
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- Preparation method of anti-hepatitis C medicine sofosbuvir
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The invention discloses a preparation method of an anti-hepatitis C medicine sofosbuvir. The method comprises the following steps: taking r-ethyl glycerate acetonide as an initial raw material, enabling the r-ethyl glycerate acetonide to react with ethyl alpha-fluoropropionate under the action of potassium tert-butoxide, performing carbonyl reduction, hydroxyl acylation, hydrolytic cyclization under an acidic condition, hydroxyl acylation, red aluminum reduction and chiral column separation so as to obtain a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-hydroxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate, performing 2-hydroxyl acetylation, enabling acetylized material to react with 2-trimethylsiloxy-4-benzamidopyrimidine, removing benzamido under an acidic condition, performing dehydroxylation protection, and finally enabling obtained material to react with N-[(S)-(2,3,4,5,6-Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester to obtain the sofosbuvir. The method has the advantages of short synthesis route, high yield, avoidance of a fluorination reaction step in the synthesis process, and mild synthesis reaction conditions.
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- Preparation method of sofosbuvir key intermediate
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The invention discloses a preparation method of a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation method comprises the following steps: by using (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a starting material, performing acylating chlorination, performing a reaction with alpha-fluoropropionic acid, performing carbonyl reduction, performing hydroxyl protection, performing hydrolytic cyclization, performing hydroxymethyl protection, performing reduction, and performing chlorination to prepare the sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation scheme has a short synthetic route and a high yield, and avoids a fluorination reaction step in the synthetic process.
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- Method for preparing sofosbuvir intermediate
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The invention provides a method for preparing a sofosbuvir intermediate. The method includes following steps: allowing 2-C-methyl-4, S-O-(1-methylethylene)-D-arabonic acid ethyl cyclosulfate and 4-phenyl-2-oxazolidone to be in condensation reaction to obtain a first compound; allowing the first compound and a fluorinating agent for fluorinating reaction, and adding acid for deprotection reaction to obtain a second compound; allowing the second compound to react with sodium ethoxide to obtain a third compound; allowing the third compound to be in rearrangement reaction, and allowing a rearrangement product to react with benzoyl chloride to obtain the sofosbuvir intermediate. The method provides a new idea for synthesizing the sofosbuvir intermediate.
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Paragraph 0040; 0047; 0048; 0049; 0053; 0054; 0058
(2019/04/17)
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- PROCESS FOR PREPARATION OF LACTONE DERIVATIVES AND INTERMEDIATES THEREOF
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A novel process for the preparation of lactone derivatives, and intermediates thereof is described. The lactone derivatives are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir.
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- Preparation method of sofosbuvir intermediate
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The invention discloses a preparation method of a sofosbuvir intermediate of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid-g-lactone 3,5-dibenzoate. The intermediate structure corresponds toa formula I shown as the description. The method comprises the step that the sofosbuvir intermediate shown as the formula I is finally obtained by using (D2) (S)-(+)-4-phenyl-2-oxazolidinone of a compound shown as a formula II as a raw material through six-step reaction of condensation, fluorination, Adol addition, oxidation cyclization, isomerization and benzoylation. The preparation method hasthe advantages that the raw materials are cheap and can be easily obtained; the reaction conditions are mild; the route is short; the yield is high; three wastes are few; the pollution is little; thepreparation method is suitable for industrial production.
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- Synthetic method of sofosbuvir intermediate
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The invention provides a synthetic method of a sofosbuvir intermediate, wherein the method, with a compound (II) as an initial raw material, includes the steps of: 1) performing a de-protective reaction and a cyclization reaction to the compound (II) to obtain an inter-product (VIII); 2) performing esterification to the inter-product (VIII) with benzoyl chloride to obtain an inter-product (IX); and 3) dissolving the inter-product (IX) in a solvent, and slowly adding dropwise a sulfonyl chloride solution in the presence of organic alkali and triethylamine trihydrofluoride, wherein in the reaction process, the compound (X) serves as an intermediate and is unnecessary to separate, so that a fluoronation reaction thereof can be completed directly in the reaction system, thereby producing the sofosbuvir intermediate.
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Paragraph 0041; 0042; 0043
(2017/07/04)
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- A method for the synthesis of pharmaceutical intermediates (by machine translation)
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The invention relates to medical and chemical field, in particular to a method for synthesis of pharmaceutical intermediates. The method in order to compound I as the raw material, under the action of the oxidizing agent in the oxidizing reaction to produce compound II. The invention is directed to the present synthetic route in industrial production, the production cost of products is relatively high, the problem of low yield, innovative use of oxidizing agent of the high yield for preparing compound II, synthesize the low cost, simple process, and is suitable for industrial mass production. (by machine translation)
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Paragraph 0021; 0031-0048
(2017/04/28)
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- Method for preparing sofosbuvir intermediate and recovering byproduct
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The invention relates to a method for preparing a sofosbuvir intermediate [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methylbenzoate represented by formula (II) and recovering a byproduct (2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]dibenzoate represented by formula (III). The method comprises the following steps: (1) reacting a compound (I) 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribosinic acid-gamma-lactone in a first solvent under the action of a reducing agent at a temperature of from 0 DEG C to the reflux temperature of the first solvent for 1-20 hours to produce the sofosbuvir intermediate (II) and the byproduct (III); and (2) filtering the above product to obtain a filter cake which is the byproduct (III), dissolving the filter cake in a second solvent, and reacting the obtained solution in an acidic environment with the pH value of 1-6 under the action of an oxidant and a catalyst at a temperature from 0 DEG C to the reflux temperature of the second solvent for 0.5-5 hours in order to generate the compound (I).
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Paragraph 0045
(2017/10/28)
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- Preparation method for 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone
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The invention discloses a preparation method for 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone. The preparation method comprises the following steps: subjecting a starting raw material D-mannitol to acetone protection and sodium periodate oxidation; then subjecting the treated D-mannitol and a self-made ylide reagent to the Witting reaction; then carrying out selective oxidation by using an aqueous sodium permanganate solution; then successively carrying out sulfonylation, fluorination with potassium fluoride, and ring closing with a concentrated protective group protective group; protecting the hydroxyl group by using benzoyl chloride; and then carrying out purification so as to obtain the final product 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone. The preparation method provided by the invention uses easily available and cheap raw materials, so production cost is greatly reduced; and the operation of the preparation method is coherent and simple, and the quantity of waste gas, waste water and industrial residues is lower than the quantity of waste gas, waste water and industrial residues reported in the prior art.
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- rope non-cloth Wei the preparation of intermediates
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The invention discloses a preparation method of a Sofosbuvir intermediate, and particularly provides a preparation method of a Sofosbuvir key intermediate, namely, 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribotide-gamma-lactone. According to the method, a needless alpha-configuration by-product obtained in the Sofosbuvir preparation process is transformed into the useful intermediate, so that the total yield of an overall project is increased.
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Paragraph 0022; 0023; 0024
(2016/11/09)
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- Preparation for sofosbuvir key intermediate
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The invention relates to preparation for a sofosbuvir key intermediate. With (E)-(S)-3-(2,2-dimethyl-1,3-dioxolane-4-base)-2-ethyl methacrylate being an initial raw material, preparation of 3,5-bis-O-benzoyl-2-deoxidation-2-fluorine-2-C-methyl-D-riboic acid-gamma-lactone is achieved through an epoxidation reaction, fluoridation, a de-acetonylidene cyclization reaction and a benzoyl reaction. According to the method, a synthesis route is short, and in the reaction process, a reagent that oxidability is high, and in the aftertreatment process, potassium permanganate or sodium permanganate and high-corrosivity SOCl2 deep in waste water color will generate a lot of waste water will not be involved.
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- Preparation method and intermediate body of (2S, 3R, 4R)-3,5-bis-sustituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-gamma-lactone
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The invention relates to a preparation method and an intermediate body of (2S, 3R, 4R)-3,5-bis-sustituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-gamma-lactone. The intermediate body has the structure as shown in formula II. A compound in the formula II serves as the intermediate body for preparing (2S, 3R, 4R)-3,5-bis-sustituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-gamma-lactone, stereoselectivity is good, the yield is high, reaction conditions are mild, raw materials 2-C-methyl-D-ribonic acid-1,4 lactone for preparing the intermediate body are wide in source, preparation is easy, and cost is low.
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- Preparation method of fluorodesoxyribofuranose
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The invention provides a preparation method of fluorodesoxyribofuranose. The structure of the fluorodesoxyribofuranose is represented by general formula 1 shown in the description; and the general formula 1, 1a:R = F, and R' = Me; and 1b:R = Me, and R' = F. The fluorodesoxyribofuranose prepared through the brand new preparation method can be used in researching of new medicines, or can be used in researches as a research model. The method adopts glyceraldehyde acetonide as a raw material and allows enantiomers in all intermediates to be effectively separated through a four-step reaction by adopting a rectification or distillation and re-crystallization technology, and a 2-posiion single optical isomer in the target product is directly constructed through an enol addition reaction, so the preparation of the target compound is smooth completed, and the method has the advantages of high yield, simple operation, and suitableness for promotion and application.
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Page/Page column 0132; 0133
(2016/10/09)
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- A method for the manufacture of lactones fluoro ribose
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The invention relates to a preparation method for fluoro ribose lactone, and concretely relates to a preparation method for 3,5-dibenzoyl-2-deoxidized-2-fluoro-2-methyl-D-ribose-gamma-lactone. A compound B is subjected to benzoylation to obtain 3,5-dibenzoyl-2-deoxidized-2-hydroxy-2-methyl-D-ribose-gamma-lactone, and then the above product reacts with fluorinated reagent sulfuryl fluoride to form the fluoro ribose lactone. The preparation method is advantaged by low cost, high safety, simple operation, high product yield and good quality, and is suitable for industrialized production.
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Paragraph 0033-0034; 0037; 0040
(2018/02/04)
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- Method for preparing intermediate of Sofosbuvir
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The invention provides a method for preparing 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribose-gamma-lactone of D-ribofuranose lactone (structural formula 1). The compound is an important intermediate of a hepatitis C virus (HCV) NS5B polymerase inhibitor Sofosbuvir. The formula 1 is shown in the specification.
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- (2R)-2-DEOXY-2,2-DISUBSTITUTED-RIBONO-1,4-LACTONE AND PREPARATION METHOD AND USE THEREOF
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This invention disclose (2R)-2-deoxy-2,2-disubstituted-ribono-1,4-lactone in a single configuration and preparation method and use thereof. The (2R)-2-deoxy-2,2-disubstituted-ribono-1,4-lactone, or a pharmaceutically acceptable salt, an ester, a prodrug or a solvate thereof according to the invention are important intermediates of a variety of anti-viral and anti-tumor active ingredients. A compound obtained from (2R)-2-deoxy-2,2-disubstituted-ribono-1,4-lactone via an acylation reaction can be directly used for preparing various anti-viral and anti-tumor drugs. The Chiral synthesis method and the spontaneous resolution method of the compound of (2R)-2-deoxy-2,2-disubstituted-ribono-1,4-lactone according to the invention have the following advantages: the reaction routes are short and simple with high yield and low cost, which are suitable for industrial application.
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- A neighboring group participation strategy: Facile synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone
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A simple and efficient approach for the synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone through a neighboring group participation mechanism is reported. This compound could be a useful precursor for the synthesis of nucleoside antiviral agents.
- Xie, Yuanchao,Zhang, Jian,Tian, Guanghui,Xu, Mingshuo,Hu, Tianwen,Jiang, Xiangrui,Shen, Jingshan
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p. 4345 - 4348
(2015/06/22)
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- PRODUCTION METHOD OF (2R)-2-FLUORO-2-C-METHYL-D-RIBONO-γ-LACTONE
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PROBLEM TO BE SOLVED: To provide a production method of (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone. SOLUTION: A (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone precursor containing various diastereomers can be produced by performing Reformatsky reaction using activated metal to a 2-fluoro-2-halopropionate derivative and a D-glyceraldehyde derivative. The obtained mixture containing the (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone precursor is subjected to deprotection and lactonizing under an acidic condition, is converted to a diastereomer mixture containing 2-fluoro-2-C-methyl-D-ribono-γ-lactone and is recrystallized, thereby inducing the mixture to (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone. COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0113; 0114; 0115
(2016/11/07)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.
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- PROCESS FOR THE PREPARATION OF A FLUOROLACTON DERIVATIVE
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A novel process for the preparation of a fluorolactone derivative of the formula (I) and of its acylated derivative of formula (V) wherein R1 stands for a hydroxy protecting group is described. The acylated fluorolactones of formula (V), particularly the benzoyl derivative with R1 =benzyl are important precursors for the synthesis of prodrug compounds which have the potential to be potent inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase.
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- Method for Producing (2R)-2-Fluoro-2-C-Methyl-D-Ribono-y-Lactone Precursor
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In the presence invention, a (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone precursor is produced in the form of a ring-opened fluorinated compound by reaction of a 1,2-diol with sulfuryl fluoride (SO2F2) in the presence of an organic base and, optionally, a fluoride ion source. The production method of the present invention secures less number of process steps as compared to the conventional production method (shortening of three steps: cyclic sulfurous esterification, oxidation and ring-opening fluorination to one step) and satisfies the requirements for industrial production (high yield and high reproductivity). The thus-obtained (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone precursor is useful as an important intermediate for the synthesis of 2′-deoxy-2′-fluoro-2′-C-methylcytidine with antivirus activity.
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- A practical synthesis of (2R)-3,5-di-O-benzoyl-2-fluoro-2-C-methyl-d-ribono-γ-lactone
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The title compound was synthesized in 23% overall yield using only one purification in four chemical steps. The key features of this practical synthesis include an asymmetric aldol condensation and an enzymatic hydrolysis to remove the major undesired iso
- Zhang, Pingsheng,Iding, Hans,Cedilote, Miall,Brunner, Stephan,Williamson, Thomas,Cleary, Thomas P.
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experimental part
p. 305 - 312
(2009/08/15)
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- An efficient and diastereoselective synthesis of PSI-6130: A clinically efficacious inhibitor of HCV NS5B polymerase
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(Chemical Equation Presented) R7128 is the prodrug of 2′-deoxy- 2′-fluoro-2′-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected D-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.
- Wang, Peiyuan,Chun, Byoung-Kwon,Rachakonda, Suguna,Du, Jinfa,Khan, Noshena,Shi, Junxing,Stec, Wojciech,Cleary, Darryl,Ross, Bruce S.,Sofia, Michael J.
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experimental part
p. 6819 - 6824
(2009/12/30)
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- PREPARATION OF NUCLEOSIDES RIBOFURANOSYL PYRIMIDINES
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The present process provides an improved method for the preparation of 4- amino-l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)-lH-pyrimidin-2-one of the formula (IV) which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase.
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Page/Page column 14-15
(2008/06/13)
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- PROCESS FOR PREPARING A SYNTHETIC INTERMEDIATE FOR PREPARATION OF BRANCHED NUCLEOSIDES
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A process is provided for the preparation of a key intermediate in the preparation of 2'-branched nucleoside compounds. The process includes contacting a protected precursor 3,4-O-isopropylidene-2-C-substituted-D-arabinono-l,5-lactone with a fluorinating agent under anhydrous conditions and converting the precursor into a protected 2-deoxy-2-halo-2-C-disubstituted ribono-l,5-lactone and optionally into a 2- deoxy-2-halo-2-C-disubstituted ribono- 1 ,4-lactone.
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Page/Page column 17; 25-26
(2008/06/13)
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- PREPARATION OF 2'-FLUORO-2'- ALKYL- SUBSTITUTED OR OTHER OPTIONALLY SUBSTITUTED RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIR DERIVATIVES
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The present invention provides (i) processes for preparing a 2'-deoxy-2'-fluoro-2'-methyl-D-ribonolactone derivatives, (ii) conversion of intermediate lactones to nucleosides with potent anti-HCV activity, and their analogues, and (iii) methods to prepare the anti-HCV nucleosides containing the 2'-deoxy-2'-fluoro-2'-C--methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally--occurring, nucleoside.
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Page/Page column 12
(2008/06/13)
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