- Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′- C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection
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We report the synthesis and biological evaluation of a series of 4′-fluoro-2′-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
- Wang, Guangyi,Dyatkina, Natalia,Prhavc, Marija,Williams, Caroline,Serebryany, Vladimir,Hu, Yujian,Huang, Yongfei,Wan, Jinqiao,Wu, Xiangyang,Deval, Jerome,Fung, Amy,Jin, Zhinan,Tan, Hua,Shaw, Kenneth,Kang, Hyunsoon,Zhang, Qingling,Tam, Yuen,Stoycheva, Antitsa,Jekle, Andreas,Smith, David B.,Beigelman, Leonid
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p. 4555 - 4570
(2019/05/17)
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- Sofosbuvir synthesis process
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The invention relates to a sofosbuvir synthesis process. A traditional sofosbuvir synthesis process is optimized and improved, 1-((2R,3R,4R,5R)-3-fluro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione and isopropyl(S)-(perfluorophenoxyl)(phenoxy)phospho)-L-alanine are taken as raw materials, tert-butylmagnesium chloride is added in batches to obtain a reactant,the reactant is quenched through ethyl acetate hydrochloride and subjected to decompression concentration, then dissolving is conducted through ethyl acetate, washing is conducted through hydrochloricacid, the pH of a reaction system is adjusted through sodium bicarbonate, then decompression distillation and methyl tertiary ether are conducted, silica gel is used for adsorption, then dichloromethane is used for crystallization, then filtering, washing and drying are conducted, and thus white powder sofosbuvir is obtained. The sofosbuvir synthesis process has the advantages of cost lowering, energy saving and environmental protection, and the yield of the obtained sofosbuvir reaches up to 90%.
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Paragraph 0022-0025
(2019/11/19)
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- Preparation method of sofosbuvir products in crystal and amorphous forms
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The invention discloses a preparation method of sofosbuvir products in crystal and amorphous forms. The preparation method comprises the following steps: (1) preparation of sofebuvir: (2'R)-2'-deoxy-2'-fluorine-2'-methyluridine and N-[(S)-(2, 3, 4, 5, 6-pentafluorophenoxy) phenoxyphosphatidyl]-L-alanine isopropyl ester are used for preparing the crude product of sofebuvir under the action of a grignard reagent under anhydrous and anaerobic conditions; (2) preparation of sofosbuvir product in crystal form: the crude product of sofebuvir is placed in a ketones solvent, a decolorant is added, andthe sofosbuvir product in crystal form is obtained after dissolution, decolorization, crystallization and dryness; and (3) preparation of sofosbuvir product in amorphous form: the crude product of sofebuvir is placed in the ketones solvent, the decolorant is added, and the sofosbuvir product in amorphous form is obtained after dissolution, decolorization, crystallization, pulverization and dryness. The preparation method has the advantages of being simple and practicable, strong in operability, less in waste generation and lower in cost, and effectively solves deficiencies existing in the existing preparation method for the sofosbuvir product in crystal form.
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Paragraph 0023
(2019/03/29)
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- Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution
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The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl-2-{[chloro(phenoxy)phosphoryl]-amino}propanoate (8). A high stereoselectivity was obtained when the right protective group for 3′-OH was chosen. Ester and carbonate-based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P-stereogenic centre. Starting from the γ-lactone of 2-deoxy-2-fluoro-2-methylpentonic acid, the synthesis was accomplished in eight steps in 40 % overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.
- Cini, Elena,Barreca, Giuseppe,Carcone, Luca,Manetti, Fabrizio,Rasparini, Marcello,Taddei, Maurizio
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p. 2622 - 2628
(2018/04/30)
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- PROCESS FOR THE PREPARATION OF SOFOSBUVIR
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The present invention relates to a process for the synthesis of Sofosbuvir of formula (I) comprising the selective mono-deacetylation reaction of a compound of formula (V) to obtain a compound of formula (IV).
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Page/Page column 11
(2017/09/09)
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- A ribofuranose method for the preparation of phosphoric acid ester derivative
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Disclosed in the present invention is a method for preparing ribofuranose phosphate derivatives, and the preparation steps thereof comprises: coupling starting materials of isopropyl L-alanine hydrochloride, phenol dichlorophosphate and substituted phenol under the action of alkali; reducing carbonyl into alcoholic hydroxyl by means of treating (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro pentonic acid GAMMA-lactone 3,5-dibenzoate with a strong reducing agent in the solvent of dichloromethane or ethers; reacting the intermediate of formula 2-1 with p-toluene sulfonyl chloride under the action of alkali to obtain p-toluene sulfonate; coupling the intermediate of formula 2-2 with a benzoyl cytosine derivative under the action of a condensation agent; converting cytosine of the intermediate of formula 2-3 into uracil under the action of an organic acid; removing benzoyl acting as protecting group from the intermediate of formula 2-4 under the action of an alkaline reagent; and coupling the intermediate of formula 2-5 with formula 1 under the action of a Grignard reagent to obtain Sofosbuvir.
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Paragraph 0080; 0081
(2016/11/07)
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- A nucleoside phosphoramide prodrug and its preparation method and its application
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The invention relates to a nucleoside phosphamide prodrug as well as a preparation method and application of the nucleoside phosphamide prodrug. The nucleoside phosphamide prodrug is selected from any one of a compound I and a compound II, wherein in the formulas of the compound I and the compound II, X is selected from any one of F, Cl, Br and I. Compared with GS7977andGS7851, The compound I or II disclosed by the invention has more excellent resistance to hepatitis C virus, wherein the formulas I and II are respectively as shown in specifications.
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- IMPROVED PROCESSES FOR THE PREPARATION OF SOFOSBUVIR AND INTERMEDIATES THEREOF
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The present disclosure provides new procedures and intermediates for the preparation of Sofosbuvir.
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- SELECTIVE PROCESS FOR SYNTHESIS OF NUCLEOSIDE PHOSPHORAMIDATES
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A process for preparing a nucleoside phosphoramidate, in particular to a process for preparing sofosbuvir, wherein a phosphoramidate derivative is used as starting material.
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Page/Page column 133
(2016/12/22)
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- Sofosbuvir intermediate and method for preparing Sofosbuvir from Sofosbuvir intermediate
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The invention relates to the technical field of pharmaceutical synthesis and specifically discloses a compound which is used for preparing Sofosbuvir and is as shown in the formula VI and a preparation method of the compound. Meanwhile, the invention also discloses a method for preparing Sofosbuvir from the above compound. According to the method for preparing Sofosbuvir, only one protective group is used. Thus, selectivity of primary alconol and secondary alcohol is raised, lots of chemical materials will not be wasted, and the fundamental philosophy of green chemistry is realized. In addition, generation of unnecessary impurities is avoided by the method for preparing Sofosbuvir. Reaction selectivity is high, by-products are few, and economy of atom is further increased.
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Paragraph 0084
(2016/12/12)
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- Preparation method and intermediate of sofosbuvir
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The invention relates to a preparation method and an intermediate of sofosbuvir, and especially relates to a new method for preparing sofosbuvir which is a mammal hepatitis c treatment drug, an intermediate for synthesizing the medicine, and a preparation method of the intermediate. The preparation method of sofosbuvir has the advantages of simplicity, easy control, suitableness for industrial application, effective increase of the yield of the above target product, production cost reduction, and mitigation of patients' drug use burden.
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Paragraph 0117; 0118; 0119; 0120
(2016/11/24)
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- A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE
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The present invention pertains to process for preparing nucleoside phosphoramidate and its intermediate. The present invention provides novel intermediate, its process for preparation and its use for the preparation of Sofosbuvir.
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- SOLID STATE FORMS OF SOFOSBUVIR
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The present disclosure encompasses solid state forms of Sofosbuvir and pharmaceutical compositions thereof.
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Paragraph 0060-0062
(2015/09/23)
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- METHODS OF STEREOSELECTIVE SYNTHESIS OF SUBSTITUTED NUCLEOSIDE ANALOGS
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The present invention relates to the novel diastereoselective syntheses for generating phosphorothioate compounds. Examples include nucleoside phosphorothioate analogs that are useful in treating diseases and/or conditions such as viral infections.
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Paragraph 0411; 0412
(2014/10/18)
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- METHODS FOR TREATING HCV
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This invention relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.
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- NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
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Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.
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Page/Page column 40
(2010/02/17)
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- N- [ (2 ' R) -2 ' -DEOXY-2 ' -FLUORO-2 ' -METHYL-P-PHENYL-5 ' -URIDYLYL] -L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR ITS PRODUCTION
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Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.
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Page/Page column 53
(2010/12/18)
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