- Preparation method of anti-HCV medicine
-
The invention relates to the technical field of medical intermediates, in particular to a preparation method of an anti-HCV drug, which comprises the following steps: 1) reacting a compound I with a compound II in the presence of Lewis acid and alkali to obtain a compound III; and 2) reacting the compound III with a compound IV to obtain a compound V. The method effectively solves the problems of tedious steps, difficulty in purification, high cost and the like in the prior art. Meanwhile, the whole route is mild in reaction condition, convenient to operate, high in yield and purity and suitable for industrial large-scale production.
- -
-
-
- Synthesis and evaluation of 2′-dihalo ribonucleotide prodrugs with activity against hepatitis C virus
-
[Figure presented] Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2′-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2′-deoxy-2′-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
- Chris Krueger,Chen, Hui-Ju,Randolph, John T.,Brown, Brian S.,Halvorsen, Geoff T.,Heyman, Howard R.,Li, Tongmei,Marvin, Christopher C.,Shanley, Jason P.,Voight, Eric A.,Bow, Daniel A.J.,Van Handel, Cecilia,Peterkin, Vincent,Carr, Robert A.,Stolarik, DeAnne,Dekhtyar, Tatyana,Irvin, Michelle L.,Krishnan, Preethi,Henry, Rodger F.,Wagner, Rolf,DeGoey, David A.
-
-
- Method for preparing sofosbuvir
-
The invention discloses a method for preparing sofosbuvir. The method comprises the following steps: reacting tetrahydrofuran with a tetrahydrofuran solution of a material A, a material B, DMAP and ananiline compound under the protection of nitrogen, and monitoring the reaction by TLC until the reaction of the material A is finished, wherein the aniline compound is N,N-dimethylaniline or N,N-diethylaniline; and carrying out post-treatment on the obtained reaction product. The method for preparing sofosbuvir has the advantages of high reaction efficiency, high product yield (up to 90% or above), high purity (up to 98% or above), easiness in industrial large-scale production and great application values.
- -
-
Paragraph 0029-0042; 0073-0077; 0079-0082
(2020/04/22)
-
- Preparation method of anti-hepatitis C medicine sofosbuvir
-
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.
- -
-
Paragraph 0052; 0073-0074
(2020/07/02)
-
- Method for synthesizing Sofosbuvir
-
The invention discloses a method for synthesizing Sofosbuvir. The method comprises the steps of adding a compound 1, a compound 2 and dichloromethane into a reaction bulb, cooling the temperature to 0DEG C, then, adding aluminum chloride, adding a proper amount of pyridine, and carrying out a reaction at a reaction temperature of 15 DEG C to 20 DEG C, thereby producing the Sofosbuvir. According to the method, the reaction is high in conversion ratio and good in regioselectivity and stereoselectivity, so that the synthesis cost of the Sofosbuvir is reduced, and the method has remarkable socialand economic benefits.
- -
-
Paragraph 0030-0067
(2020/04/17)
-
- Method for carrying 3,3- diarylpropenal combined Grignard reagent to catalyze preparation of Soxavir (by machine translation)
-
To the method, 3,3 - compound, is subjected to catalytic activation: and compound 2 to be subjected to catalytic activation, and the method, is used for catalyzing and activating compound 3 with 1 diarylpropenal and Grignard reagent; so that product yield and purity: can be reduced 3,3 - by two-substitution by-product generation process. 2. (by machine translation)
- -
-
Paragraph 0024-0032
(2020/05/30)
-
- Sofosbuvir synthesis process
-
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%.
- -
-
Paragraph 0022-0025
(2019/11/19)
-
- Preparation method of sofosbuvir products in crystal and amorphous forms
-
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.
- -
-
Paragraph 0023
(2019/03/29)
-
- Preparation of rope non-cloth wei (by machine translation)
-
The invention relates to a preparation method of rope non-cloth wei, in particular under the conditions of a magnesium chloride/TEA passing through type I and side chain reaction preparation of rope non-cloth wei. Through this method can completely prevent the rope non-cloth wei degradation impurities. (by machine translation)
- -
-
Paragraph 0010; 0018; 0019
(2019/04/11)
-
- Novel process for preparing sofosbuvir
-
The invention provides a preparation process for sofosbuvir. According to the invention, in a butting process of two key fragments, tert-butylmagnesium chloride/lithium chloride is used as base, so selectivity of the base is improved; the conversion rate
- -
-
Paragraph 0010-0012
(2019/03/28)
-
- 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
-
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
-
p. 4555 - 4570
(2019/05/17)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR
-
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Sofosbuvir. The present invention involves use of reagents that are less expensive, easier to handle and eco-friendly process.
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-
-
- PROCESS FOR THE PREPARATION OF (Sp)-SOFOSBUVIR AND INTERMEDIATES THEREOF
-
The present invention is directed towards process for preparation of an optically pure (Sp)-Sofosbuvir of Formula-(I) and its intermediate namely (Sp)-isomer of isopropyl alanyl phosphoramidate of Formula (III) thereof.
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-
Page/Page column 13; 14
(2018/03/28)
-
- Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution
-
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
-
p. 2622 - 2628
(2018/04/30)
-
- The protecting-group free selective 3′-functionalization of nucleosides
-
The direct and chemoselective 3′-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3′-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 3′-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach.
- McCabe Dunn, Jamie M.,Reibarkh, Mikhail,Sherer, Edward C.,Orr, Robert K.,Ruck, Rebecca T.,Simmons, Bryon,Bellomo, Ana
-
p. 2804 - 2810
(2017/04/06)
-
- Nucleoside phosphoramidate compound as well as pharmaceutical composition and application thereof
-
The invention discloses a nucleoside phosphoramidate compound as well as a pharmaceutical composition and application thereof. Novel nucleoside phosphoramidate disclosed by the invention is characterized in that amino acid in the phosphoramidate part is D-amino acid, while amino-acid ester or carboxylic ester is introduced into the 3' position of a nucleoside sugar ring. With the creative design, the solubility and pharmacokinetic characteristics of a drug are improved, the concentration ratio of drugs in tissues cells and plasma is increased, and further the creative effect, the safety and the tolerability of the drugs are improved; the nucleoside phosphoramidate compound has a good clinical application aspect.
- -
-
-
- Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189
-
A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.
- Simmons, Bryon,Liu, Zhuqing,Klapars, Artis,Bellomo, Ana,Silverman, Steven M.
-
supporting information
p. 2218 - 2221
(2017/05/12)
-
- A high-purity rope fluorine cloth Wei compound and the preparation method of the substance
-
The invention belongs to the technical field of medicine, and provides a method for preparing high-purity sofosbuvir, which comprises the following steps: carrying out deprotection on the accessible raw material SF-2 by using MeONa to generate a key intermediate SF-1, connecting with the side chain of phosphate, and treating to obtain the high-purity target product sofosbuvir, in which the impurity SF-P content is extremely low. The MeONa is creatively used as the deprotection reaction reagent, and the strongly-acidic resin is used for removing alkali in the after treatment, thereby simplifying the production technique and obtaining the intermediate key intermediate SF-1 with higher purity and yield. In the sofosbuvir preparation technique, the new after-treatment method is adopted to obtain the high-purity sofosbuvir API.
- -
-
-
- A method for preparing rope fluorine cloth Wei (by machine translation)
-
The invention relates to the field of medical technology, in particular to a method for preparing rope fluorine cloth Wei, the method to D - ribose as the starting material, through the esterification reaction, hydroxy protecting reaction, hydroxy oxidation reaction, the methylation reaction, the fluorination reaction, butt reaction, hydrolysis, connected with the phosphoric acid ester side chain such as a series of reaction, the product finally obtained rope fluorine cloth Wei. The preparation of the invention rope fluorine cloth Wei method to D - ribose as the raw material, the raw materials and the cost is low, the reaction in step hydrolysis of few reaction steps, easy industrialization. (by machine translation)
- -
-
-
- PROCESS FOR THE PREPARATION OF PURE SOFOSBUVIR
-
The present invention provides pure sofosbuvir and a process for the preparation of pure sofosbuvir and its intermediates.
- -
-
-
- Synthesis method of sofosbuvir
-
The invention provides a synthesis method of sofosbuvir. The synthesis method of the sofosbuvir comprises the following steps: performing mitsunobu reaction on ((2R,3R,4R)-3-benzoyloxy)-4-fluorine-5-hydroxyl-4-methyltetrahydrofuran-2-yl)methyl benzoate to produce sulfonate to obtain a compound 1; abutting the compound 1 and N-benzoylcytosine to produce a compound 2. The method adopts mitsunobu reaction to avoid production of an isomer, and the isomer is reduced to 5 percent or below; according to the method, sulfonate and N-benzoylcytosine are abutted, so the use ofa stannic chloride raw material is avoided; furthermore, the yield is high and few solid waste is generated during aftertreatment, so that the method is suitable for large-scale industrialized production.
- -
-
-
- An improved sofosbuvir preparation method
-
An improved sofosbuvir preparation method is provided. The method adopts (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine, and other raw materials and prepares the sofosbuvir through reacting in an organic solvent under existence of a Lewis acid and an alkali. The method has advantages of mild reaction conditions, safe agent using, simple and convenient operation, convenient after-treatment, and the like, and is prone to large-scale production in a factory.
- -
-
Paragraph 0044; 0091-0098
(2017/08/27)
-
- PROCESS FOR THE PREPARATION OF SOFOSBUVIR
-
A process for the preparation of intermediates 9, useful in the synthesis of sofosbuvir, as well as intermediates of formula [12] are disclosed herein.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR
-
The present invention relates to an improved process for the preparation Sofosbuvir Formula (I). The present further relates to Sofosbuvir having a purity of greater than 99.5%.
- -
-
-
- Method for preparing sofosbuvir
-
The invention discloses a method for preparing sofosbuvir and belongs to the technical field of medicine synthesis. The method comprises the following steps: putting tertiary butyl magnesium halide into a tetrahydrofuran solution of a compound 2 with certain amount of water, further putting a compound 3, and performing reaction, thereby obtaining sofosbuvir. As a certain amount of water is added in a reaction system, the conversion rate of reaction is remarkably increased, the content of main byproducts is reduced, then the preparation cost of the sofosbuvir is lowered, and remarkable social and economic benefits are achieved.
- -
-
Paragraph 0017; 0036-0039; 0044
(2017/10/25)
-
- PROCESS FOR THE PREPARATION OF SOFOSBUVIR
-
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).
- -
-
Page/Page column 11
(2017/09/09)
-
- A multifunctional catalyst that stereoselectively assembles prodrugs
-
The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorusstereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.
- DiRocco, Daniel A.,Ji, Yining,Sherer, Edward C.,Klapars, Artis,Reibarkh, Mikhail,Dropinski, James,Mathew, Rose,Maligres, Peter,Hyde, Alan M.,Limanto, John,Brunskill, Andrew,Ruck, Rebecca T.,Campeau, Louis-Charles,Davies, Ian W.
-
p. 426 - 430
(2017/05/04)
-
- Sofosbuvir intermediate and method for preparing Sofosbuvir from Sofosbuvir intermediate
-
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.
- -
-
Paragraph 0084
(2016/12/12)
-
- IMPROVED PROCESSES FOR THE PREPARATION OF SOFOSBUVIR AND INTERMEDIATES THEREOF
-
The present disclosure provides new procedures and intermediates for the preparation of Sofosbuvir.
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-
-
- A nucleoside phosphoramide prodrug and its preparation method and its application
-
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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-
-
- A ribofuranose method for the preparation of phosphoric acid ester derivative
-
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.
- -
-
-
- 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 126
(2016/12/22)
-
- NUCLEOSIDE PHOSPHORAMIDATES USEFUL FOR THE TREATMENT OF VIRAL INFECTIONS AND PREPARATION THEREOF
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The present invention relates to an industrially applicable process for the preparation of phosphoramidates useful for the treatment of viral infections, such as sofosbuvir, and to intermediates useful for the preparation thereof. Formula (I):
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Page/Page column 34
(2016/10/11)
-
- Preparation method of sofosbuvir
-
The invention provides a preparation method of sofosbuvir. The preparation method takes 4-trifluoromethoxyphenol as a leaving group to react with (S)-2-phenoxy-chloro-phosphoryl amino isopropyl propionate to obtain racemized (S)-2-[(4-trifluoromethoxy-phenoxy)-phenoxy-phosphorylamino] isopropyl propionate; after the resolution, the racemized (S)-2-[(4-trifluoromethoxy-phenoxy)-phenoxy-phosphorylamino] isopropyl propionate reacts with (2minuteR)-2minute-deoxy-2minute-fluoro-2minute-methyluridine to obtain the sofosbuvir. The method provided by the invention takes the 4-trifluoromethoxyphenol as the leaving group and the resolution effect is good, so that the reaction yield is improved and the method is suitable for industrial production.
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-
Paragraph 0020
(2017/03/14)
-
- Medicine sofosbuvir midbody capable of resisting hepatitis C virus and preparation method thereof
-
The invention relates to a sofosbuvir midbody III and a preparation method thereof. The method comprises the following steps that a compound I is used as a starting material under the protection of inert gas, the starting material is subjected to a reaction with a compound II in a solvent after being activated by dehydrogenating agent to obtain the midbody compound III, and the compound III is further oxidized and dehydrogenated to obtain sofosbuvir, wherein R is a leaving group.
- -
-
Paragraph 0004; 0011
(2016/10/17)
-
- Preparation method of sofosbuvir
-
The invention discloses a preparation method of sofosbuvir. The preparation method includes following steps: in the absence of water and oxygen, enabling (2'R)-2'-deoxidized-2'-fluorine-2'-methyluridine, N-[(S)-(2, 3, 4, 5, 6-pentafluorophenoxy) phenoxy phosphoryl]-L-alanine isopropyl ester and Grignard reagent to react in the presence of a reaction solvent; dissolving mother liquid of sofosbuvir in a solvent, adding an adsorbent, depressurizing for concentration to be dry, adding solvent, pulping at room temperature, suction filtering, collecting filtrate, depressurizing for evaporation to dryness to obtain a oily product, adding solvent into the oily product, heating for dissolving to clearness, and cooling to 0-5 DEG C for crystallization to obtain recycled pentafluorophenyl; enabling D-alanine isopropyl ester and phenyl dichlorophosphate to be in reaction at minus 70-minus 80 DEG C, and adding a solvent solution of pentafluorophenyl and alkali for reaction to obtain a compound shown in a formula II. In the synthesis process of sofosbuvir, molecular pentafluorophenyl is removed, and pentafluorophenyl is recycled and used for preparation of an intermediate of sofosbuvir synthesis materials, so that pentafluorophenyl is recycled and influence on environment is reduced.
- -
-
Paragraph 0022
(2016/10/10)
-
- Preparation method of sofosbuvir
-
The invention relates to a preparation method of sofosbuvir, and especially relates to a synthetic method of sofosbuvir for treating mammal hepatitis c. The method comprises the following steps: reacting a raw material A with a reaction B under the action of an appropriate Lewis acid and an appropriate base to obtain a target product C mixed solution, carrying out chromatography on the product C mixed solution, extracting, crystallizing, and pumping to prepare a purified product C. The key factor substantially influencing the preparation effect of the above compound C is amazedly found in the invention, and effect maximization of the preparation method is promoted, so efficient and practical realization of industrial production of the compound C is guaranteed, and the method adapts to market demands of the product, reduces the production cost, and benefits general patients.
- -
-
Paragraph 0057; 0061; 0062
(2016/10/10)
-
- PHOSPHORIC ACID/PHOSPHONIC ACID DERIVATIVES AND MEDICINAL USES THEREOF
-
The present invention relates to phosphoric acid/phosphonic acid derivatives shown by formula (I), wherein, R1 or R2 represents the following structures: (Q1), or (Q2), or (Q3). Q1 represents ester derivatives of L-amino acid, wherein R3 is alkyl with 1-6 carbon atoms or cycloalkyl, R4 is H or alkyl with 1-6 carbon atoms; Q2 represents hydroxyl substituted benzodioxane derivatives; Q3 represents hydroxyl substituted benzodioxolane derivatives; R1 or R2 is the same or different, but at least one of them is Q2 or Q3; D represents residues of pharmacologically active molecules containing a phosphate/phosphonate group, i.e. formula (II) represents pharmacologically active molecules containing a phosphate/phosphonate group; and when R1 and R2 are different, the configuration of the P atom connected to R1 and R2 is of R or S type.
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-
Paragraph 0043; 0045
(2016/05/19)
-
- PROCESS FOR MAKING PHOSPHORAMIDATE PROTECTED NUCLEOSIDE COMPOUNDS
-
The present invention is directed to processs for making Compounds of Formula (II): (II), and salts thereof, wherein B, X, R2, R3, R4 R7, R8 and R9 are defined herein.
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Page/Page column 32
(2017/04/04)
-
- Preparation method and intermediate of sofosbuvir
-
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.
- -
-
Paragraph 0117; 0118; 0119; 0120
(2016/11/24)
-
- A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE
-
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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-
-
- Application of nucleoside compounds in preparation of drugs for treatment of Hepatitis C Virus(HCV)infectious diseases
-
The present invention relates to application of nucleoside compounds I and II in preparation of drugs for treatment of Hepatitis C Virus(HCV)infectious diseases, also relates to various optical isomers, pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of drugs for treatment of Hepatitis C Virus(HCV)infectious diseases. The invention also relates to application of a pharmaceutical composition comprising the nucleoside compounds I and II in preparation of drugs for treatment of Hepatitis C Virus(HCV)infectious diseases. R1, R2, R3 and AA in the compounds I and II are as defined in the specification.
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-
- Sofosbuvir intermediate and preparation method thereof
-
The invention provides a sofosbuvir intermediate and a preparation method thereof. The intermediate adopts the structure shown in the specification. The intermediate is prepared from 4-(trifluoromethoxy)phenol and (S)-2-phenoxy-chloro-phosphoryl aminopropionic acid isopropyl ester through a reaction. In a sofosbuvir preparation process, the intermediate has the good splitting effect and is suitable for industrial production, and the overall reaction yield is high.
- -
-
-
- Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus
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2′-α-C-Methyl-2′-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure?activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2′-β-F by Arg158, 3′-OH by N291, and the Watson?Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.
- Zeng, Debin,Zhang, Rui,Nie, Quandeng,Cao, Lin,Shang, Luqing,Yin, Zheng
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p. 1197 - 1201
(2016/12/18)
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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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- USE OF A L,3J5-TRIAZIN-2-YL PHOSPHORAMIDATE COMPOUND IN THE SYNTHESIS OF SOFOSBUVIR
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The present invention relates to a new type of 1,3.5-triazin-2-yl phosphoramidates of general formula I with the absolute configuration (S) at the phosphorus atom, an Sp diastereoisomer, wherein R1 and R2 can independently be H, a C1-C6 (un)branched alkyl, a C1-C6 (un)branched alkoxy group, a C1-C6 (un)branched alkylsulfanyl group, C1-C6 (un)branched monoalkylamino or dialkylamino group, including cyclic amino groups, e.g. pyrrolidino, piperidino or morpholino group; and to their use for the production of biologically active phosphoramidate prodrugs, especially sofosbuvir of formula II. Sofosbuvir II is a nucleotide inhibitor of the RNA polymerase, used for the treatment of hepatitis C in the form of a prodrug, releasing the active antiviral agent 2'-deoxy-2'-a-fluoro- P-C-methyluridine-5'-triphosphate in the organism.
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- PROCESS FOR THE PREPARATION OF SOFOSBUVIR
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The present disclosure relates to processes for the preparation of sofosbuvir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of sofosbuvir.
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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 0408; 0409; 0410
(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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- METHODS FOR THE PREPARATION OF DIASTEROMERICALLY PURE PHOSPHORAMIDATE PRODRUGS
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Provided are methods and intermediates for preparing diastereomerically pure phosphoramidate prodrugs of nucleosides of Formulas (la) and (lb): The compounds of Formula la and lb are useful for the treatment Hepatitis C infections.
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