- Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189
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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.
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Read Online
- Preparation method of anti-HCV medicine
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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.
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- Method for synthesizing Sofosbuvir
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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.
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Paragraph 0030-0067
(2020/04/17)
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- Method for carrying 3,3- diarylpropenal combined Grignard reagent to catalyze preparation of Soxavir (by machine translation)
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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)
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Paragraph 0024-0032
(2020/05/30)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR
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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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Page/Page column 5; 9
(2018/02/20)
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- PROCESS FOR THE PREPARATION OF (Sp)-SOFOSBUVIR AND INTERMEDIATES THEREOF
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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)
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- PROCESS FOR THE PREPARATION OF PURE SOFOSBUVIR
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The present invention provides pure sofosbuvir and a process for the preparation of pure sofosbuvir and its intermediates.
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- Synthesis method of sofosbuvir
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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.
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- An improved sofosbuvir preparation method
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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.
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Paragraph 0044; 0091-0098
(2017/08/27)
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- PROCESS FOR THE PREPARATION OF SOFOSBUVIR
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A process for the preparation of intermediates 9, useful in the synthesis of sofosbuvir, as well as intermediates of formula [12] are disclosed herein.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR
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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%.
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- A high-purity rope fluorine cloth Wei compound and the preparation method of the substance
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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.
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- Method for preparing sofosbuvir
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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.
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Paragraph 0017; 0036-0039; 0044
(2017/10/25)
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- A method for preparing rope fluorine cloth Wei (by machine translation)
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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)
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Paragraph 0027; 0035; 0036; 0044
(2017/08/28)
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- Preparation method of sofosbuvir
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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)
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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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Paragraph 00126
(2016/12/22)
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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 126
(2016/12/22)
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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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- 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)
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- Medicine sofosbuvir midbody capable of resisting hepatitis C virus and preparation method thereof
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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.
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Paragraph 0004; 0011
(2016/10/17)
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- Preparation method of sofosbuvir
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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.
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Paragraph 0022
(2016/10/10)
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- Preparation method of sofosbuvir
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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.
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Paragraph 0057; 0061; 0062
(2016/10/10)
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- PHOSPHORIC ACID/PHOSPHONIC ACID DERIVATIVES AND MEDICINAL USES THEREOF
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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)
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- PROCESS FOR MAKING PHOSPHORAMIDATE PROTECTED NUCLEOSIDE COMPOUNDS
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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)
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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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- Synthesis of diastereomerically pure nucleotide phosphoramidates
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Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5′-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.
- Ross, Bruce S.,Ganapati Reddy,Zhang, Hai-Ren,Rachakonda, Suguna,Sofia, Michael J.
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p. 8311 - 8319
(2012/01/03)
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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 56; 59
(2010/12/18)
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