- Preparation method of intermediate
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The invention relates to the field of pharmacy, in particular to a preparation method of an intermediate of a solovir intermediate (2 ’ R) -2 ’ - deoxidized -2 ’ -fluoro -2 ’ -methyl urea, and a compound represented by the formula II is reacted with triethylamine/methanol to generate a dehydroxylation protection reaction. By adopting the technical scheme disclosed by the invention, the total yield is high, the purity of the target product is high, the product stability is good, and the method is suitable for large-scale production. , Due to the fact that the adopted raw material cost is low, the process conditions are mild and non-rigorous, the method is easy to operate and easy to popularize.
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Paragraph 0030-0035; 0040-0043
(2021/09/08)
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- Preparation method of sofosbuvir key intermediate
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The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a sofosbuvir key intermediate. The preparation method of the sofosbuvir intermediate hasthe advantages of short reaction steps, mild reaction conditions and higher yield than that of an existing preparation method, is economical and effective, and is suitable for large-scale industrial production.
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Paragraph 0013
(2020/05/01)
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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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Paragraph 0052; 0071-0072
(2020/07/02)
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- Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase
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To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2′- and/or 4′-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2′-OH with 2′-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2′-fluorination, the introduction of fluorine at the ribose 4′-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2′-C-ethynyl-4′-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.
- Wang, Gang,Lim, Siew Pheng,Chen, Yen-Liang,Hunziker, Jürg,Rao, Ranga,Gu, Feng,Seh, Cheah Chen,Ghafar, Nahdiyah Abdul,Xu, Haoying,Chan, Katherine,Lin, Xiaodong,Saunders, Oliver L.,Fenaux, Martijn,Zhong, Weidong,Shi, Pei-Yong,Yokokawa, Fumiaki
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p. 2324 - 2327
(2018/05/28)
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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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- Nucleoside phosphoramidate compound optical isomer and its application
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The invention belongs to the field of medicinal chemistry, and in particular relates to a nucleoside phosphoramidate compound optical isomer or its hydrate, solvate, crystal or a pharmaceutically acceptable salt, process for their preparation and pharmaceutical compositions containing these compounds and these compounds or compositions used as virus infectious disease treating drug use, in particular as viral hepatitis treatment drug use. The experimental result shows, the compounds of this invention to hepatitis c virus 1 b subtype and 1 a subtype exhibit good inhibitory activity, while at the same time to the host cell has very low toxicity, high effectiveness, the safety is good, suitable for the treatment and/or prevention of diseases associated with HCV infection.
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- Biphenyl nucleoside phosphoramidate application of compound
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The invention belongs to the field of medicinal chemistry, provided the present invention of the formula 1 compound or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or crystallization in preparation for the treatment of flavivirus, especially hepatitis c virus infection after the drug resistance of the patient, and/or prevention of drug-resistant patient disease onset or recurrence of the application of the medicament. The invention of the formula 1 compound has good medicine chest activity of HCV.
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Paragraph 0033; 0036; 0037
(2018/07/07)
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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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- 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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- Method for preparing (2'R)-2'-deoxy-2-fluoro-2-methyluridine
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The invention provides a method for preparing sofosbuvir intermediate (2'R)-2'-deoxy-2-fluoro-2-methyluridine (compound VII), which comprises the following steps: (1) enabling a compound I to react with lithium diisopropylamide in aprotic solvent serving as a reaction solvent, controlling the reaction temperature to 0-5 DEG C, and treating after the reaction is completed to obtain a compound X; and (2) enabling the compound X to react with an NaClO solution having a concentration of 6-10 percent in the existence of a phase transfer catalyst, keeping the reaction temperature to 20-30 DEG C, and treating after the reaction is completed, wherein the reaction solvent is the aprotic solvent. The method does not require column chromatography in post-treatment, has a yield reaching 8 percent, and is applicable to industrial production.
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Paragraph 0010; 0021; 0022
(2018/01/17)
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- PSI - 7977 intermediate compound preparation method (by machine translation)
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The invention belongs to the field of medical technology, in particular to a process for the synthesis of PSI - 7977 intermediate compound preparation method. The method has simple operation, mild reaction conditions, easy after treatment, the reaction cycle is short, high yield, the advantages of the safety-controllable, the resulting intermediate compound I with high optical purity, the advantage of stable nature, more suitable for large scale industrial production. (by machine translation)
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Paragraph 0053; 0054
(2017/07/01)
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- Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
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The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. According to the method, (2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid GAMMA-lactone is taken as a raw material and is subjected to reduction and protection, a fluoro ribose fragment with three identical protection groups is obtained and directly reacts with uracil, deprotection is performed, and a target compound is obtained. Compared with an existing technical route adopting an eight-step reaction, the route of the preparation method is shortened to adopt four steps, and the problems that the existing technical route adopts complicated steps, the atom economy is low, the cost is high and the like are effectively solved; besides, an obtained intermediate can be recrystallized and refined, the whole route is simple, and the method is convenient to operate, high in yield and suitable for large-scale industrial production.
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- A (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside preparation method (by machine translation)
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The invention discloses a (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside (type I) synthetic method. Cheap and easily available starting material, through the hydroxyl protection, cyclization, the links such as fluoride, obtains the type I compound. (by machine translation)
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- Intermediate compound for synthesis of sofosbuvir and synthetic method thereof
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The invention discloses an intermediate compound for synthesis of sofosbuvir and a synthetic method thereof; the intermediate compound comprises 4 intermediate products and 1 target compound, wherein the 4 intermediate products include methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl) benzoate, methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) benzoate, (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate, and ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methyltetrahydrofuran-2-yl) methyl benzoic acid, and the target compound is (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine. Compared with existing synthetic methods, the synthetic method has high content of target compound and has little impurities generated in the synthetic process; the results of the synthetic method are stable, the synthetic method is simple to perform and is applicable to large-scale industrial production and technical popularization.
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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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Paragraph 0041; 0042
(2017/08/25)
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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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- 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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- Preparation method of (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside
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The invention discloses a preparation method of (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside. According to the method, the (2'R)-2'-deoxidation-2'-fluorine-2'-methylurea glucoside is prepared by using 2-C-methyl-D ribotide-1,4-lactone as a starting material through the steps of silanization, fluorination, reduction, etherification, butt joint and hydrolysis reaction. The preparation method has the advantages that the route is simple and short; the use of highly toxic and harmful substances of barium chloride is avoided; the generation of a large number of solid wastes such as triphenylphosphine oxide is avoided; the acid of the catalytic amount is subjected to deprotection reaction; the use of a large amount of ammonia gas methyl alcohol for protecting group degreasing is avoided; the usage amount of dissolvent and the generation quantity of industrial wastes are reduced; the target product of alpha isomers can be recovered and used; the generation of solid wastes is reduced to the greatest degree. The total yield of the route is high; the intermediate is easily refined and purified; the preparation method is suitable for large-scale industrial production.
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Paragraph 0010
(2017/05/27)
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- Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates
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The invention relates to a preparation method for sofosbuvir intermediates 9, 11. The preparation method comprises the following steps: by taking a compound I as an initial material, carrying out an additive reaction with electrophilic reagents acrylonitrile, cyanoacetylene, propargyl ester and acrylate and carrying out ring-closing reaction to prepare corresponding intermediates (VII, V, IV and II); carrying out a ring-opening reaction on the intermediates (VII, V, IV and II) and a fluorination reagent to obtain corresponding intermediates (VIII, VI, II and III), carrying out a reaction on the intermediate VIII and benzoyl chloride in an alkaline condition to prepare an intermediate IX, and further carrying out dehydrogenation reaction on the intermediate IX in the presence of an oxidizing agent to prepare an intermediate 9; carrying out a reaction on the intermediate VI and benzoyl chloride in the alkaline reaction to prepare the intermediate 9; and further carrying out dehydrogenation reaction on the intermediate III in the presence of an oxidizing agent to prepare the intermediate 11.
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Paragraph 0005; 0010
(2017/01/31)
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- IMPROVED FLUORINATION PROCESS
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A process comprising (i) providing a mixture comprising a compound of formula (I) or isomers, stereoisomers, diastereomers, enantiomers or salts thereof; (ii)subjecting the mixture provided in (i) to fluorinating conditions in the presence of a fluorination agent selected from the group consisting of diethylamino (difluoro) sulfonium tetrafluoroborate and difluoro(morpholino) sulfonium tetrafluoroborate obtaining a mixture comprising a compound of formula (II) or isomers, stereoisomers diastereomers, enantiomers or salts thereof; (iii) optionally subjecting the mixture obtained in (ii) to deprotection conditions, obtaining a mixture comprising the compound of formula (III) or isomers, stereoisomers, diastereomers, enantiomers or salts thereof.
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Page/Page column 96
(2016/05/19)
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- Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication
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In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2′-C-methyl containing nucleosides, 2′-C-Me-cytidine, 2′-C-Me-uridine and 2′-C-Me-2′-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5′-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ～550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.
- Maiti, Munmun,Maiti, Mohitosh,Rozenski, Jef,De Jonghe, Steven,Herdewijn, Piet
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p. 5158 - 5174
(2015/05/13)
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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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- Discovery of a luoro-2′-β- C -methyluridine Nucleotide Prodrug (PSI-7977) for the treatment of hepatitis C virus
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Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5′-phosphate derivative of the β-d-2′-deoxy-2′-α- fluoro-2′-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.
- Sofia, Michael J.,Bao, Donghui,Chang, Wonsuk,Du, Jinfa,Nagarathnam, Dhanapalan,Rachakonda, Suguna,Reddy, P. Ganapati,Ross, Bruce S.,Wang, Peiyuan,Zhang, Hai-Ren,Bansal, Shalini,Espiritu, Christine,Keilman, Meg,Lam, Angela M.,Steuer, Holly M. Micolochick,Niu, Congrong,Otto, Michael J.,Furman, Phillip A.
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experimental part
p. 7202 - 7218
(2010/12/25)
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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 39-40
(2010/12/18)
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- Design, synthesis, and antiviral activity of 2′-deoxy-2′- fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
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The pyrimidine nucleoside beta-D-2′-deoxy-2′-fluoro-2′-C- methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-D- arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2- methyl-3,5-di-O-benzoyl-β-D-ribofuranosyl]cytosine (7a). The protected 2′-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2′-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2′-C-methylcytidine and low cellular toxicity.
- Clark, Jeremy L.,Hollecker, Laurent,Mason, J. Christian,Stuyver, Lieven J.,Tharnish, Phillip M.,Lostia, Stefania,McBrayer, Tamara R.,Schinazi, Raymond F.,Watanabe, Kyoichi A.,Otto, Michael J.,Furman, Phillip A.,Stec, Wojciech J.,Patterson, Steven E.,Pankiewicz, Krzysztof W.
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p. 5504 - 5508
(2007/10/03)
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