- 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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- Method for preparing 3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-one
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The invention discloses a method for preparing 3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-one, comprising the following steps that: ((2R, 3R, 4R)-3-(benzyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate is dispersed in an organic solvent, excessive strong acid is added for heating reflux, the organic solvent is removed, and pulping, filtering and drying are performed, wherein the strong acid is methanesulfonic acid, sulfuric acid, trifluoromethanesulfonic acid or concentrated hydrochloric acid. ((2R, 3R, 4R)-3-(benzyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate is adopted as a raw material to be subjected to a reflux reaction with excessive specific strong acid, a high-purity and high-yield product can be obtained only through a one-step reaction, the process steps are simple, and mass production of the product is facilitated.
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Paragraph 0020-0044
(2020/11/05)
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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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Page/Page column 36; 37
(2018/03/09)
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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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Paragraph 0108; 0109; 0112; 0113; 0116; 0117
(2018/03/01)
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- Synthesizing method for drug intermediate
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The invention discloses a synthesizing method for a drug intermediate, and relates to the field of drug synthesis, in particular to the field of organic synthesis. In the synthesizing method, compound V(4S,5R)-ethyl-5-((R)-2,2-dimethyl-1,3-dioxolame-4-base)-4-methyl-1,3,2-dioxathiolane-4- carboxylic acid-2,2'dioxide serves as a raw material, a compound II is prepared through three synthesizing methods, and an intermediate compound I is prepared through the compound II. The provided synthesizing technology has the beneficial effects that cost is low, few byproducts are generated, the yield is high, and pollution to the environment is weak.
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Paragraph 0103-0106; 0111-0113; 0117-0119
(2017/06/02)
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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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Paragraph 0030; 0054
(2017/06/02)
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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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Paragraph 0017; 0018
(2016/10/20)
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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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- 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 0116; 0117; 0118
(2016/11/07)
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- The synthesis of hydroxyaminopurine nucleosied (by machine translation)
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A compound or salt thereof having the following structure useful for the treatment of hepatitis C virus (HCV): wherein R 7 is C 1-6 alkyl or C 3-6 cycloalkyl and R 8 is -O(C 1-6 alkyl) or -O(C 3-6 cycloalkyl).
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Paragraph 0213
(2016/10/10)
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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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Paragraph 0064; 0065; 0066
(2015/11/02)
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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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Paragraph 0510
(2014/07/08)
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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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Page/Page column 17
(2014/07/23)
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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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Paragraph 0086
(2013/03/28)
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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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- 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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body text
p. 305 - 312
(2009/08/15)
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- NOVEL PROCESS FOR THE PREPARATION OF (2R)-2-DEOXY-2-FLUORO-2-METHYL-D-ERYTHRO-PENTONO-GAMMA-LACTONE AND (2S)-2-DEOXY-2-FLUORO-2-METHYL-D-ERYTHRO-PENTONO-GAMMA-LACTONE
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The present invention provides novel methods for preparing compounds (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentono-γ-lactone (11) and (2S)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentono-γ-lactone (12), which are intermediates for preparing a key intermediate 3,5-di-O-acyl-2-fluoro-2-C-methyl-D-ribono-γ-lactone (B), for the preparation of 1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)cytosine (A), which is a potent and selective anti-hepatitis C virus agent.
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Page/Page column 4-5; 9
(2008/12/07)
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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
(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; 24-25
(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 30
(2008/06/13)
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