cas 817204-32-3, PSI-6130 derivative | Articles data

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Preparation method of intermediate
The invention relates to the technical field of biological pharmacy. More specifically, the compound shown in Formula -3 - is prepared by reacting a compound represented by Formula -4 - with a modified 4R red aluminum, and then subjecting the compound of
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Paragraph 0043-0045; 0054-0056

(2021/09/08)

Method for preparing sofosbuvir intermediate by using continuous flow micro-channel reactor
The invention discloses a process method for preparing (2 'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidyl-3 ', 5 '-dibenzoate, and belongs to the technical field of organic synthesis application, the process method is a novel process method for preparing a target product within reaction time of dozens of seconds from (2R, 3R, 4R, 5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate as a raw material in a continuous flow micro-channel reactor and stannic chloride as a catalyst by introducing materials into the reactor through a counting pump, heating, mixing andreacting to obtain a product; the method has the characteristics of simplicity and safety in operation, high yield and short reaction time, and can realize continuous production; the yield of the product is 55% or above, and the purity reaches 99%.
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Paragraph 0033-0046

(2020/07/02)

A preparation process of rope non-cloth wei improved method
The invention provides a method for improving technique of rope non-cloth wei, for the oxidation of olefinic bond when [...], the oxidizing agent is potassium permanganate into sodium permanganate, product yield from 78% improved to 90% or more; in cytosine with halo ethylthio butt coupling reaction using tin tetrachloride to replace the zinc chloride catalytic, yield from 75% to a 88%; using five fluoro phenol instead of the nitro phenol to prepare phosphoric acid ester side chain, so that the phosphoric acid ester side chain of the yield from 80% up to 95%.
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Paragraph 0008

(2019/03/28)

Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
Liu, Tongchao,Tang, Jiadeng,Liang, Jianpeng,Chen, Yabin,Wang, Xiaowen,Shen, Jingkang,Zhao, Dongmei,Xiong, Bing,Cen, Jun-Da,Chen, Yue-Lei
p. 1203 - 1213
(2019/01/29)

Technology for preparing sofosbuvir intermediate
A technology for preparing a sofosbuvir intermediate represented by formula 1 comprises the following steps: (a) reducing a compound 2 by sodium borohydride to generate a compound 3; (b) reacting thecompound 3 with a methanol-hydrochloric acid solution to generate a compound 4; (c) carrying out a fluorination reaction on the compound 4 and a fluorination reagent in a reaction solvent at -10 to -65 DEG C under the protection of nitrogen, and post-treating a reaction solution after the reaction is fully carried out in order to obtain a compound 5; (d) cooling an n-hexane or petroleum ether or cyclohexane solution of the compound 5 to -5-5 DEG C under the protection of nitrogen, adding thionyl chloride, slowly dropwise adding methanol or ethanol at a controlled temperature of -5-5 DEG C, rising the temperature to 10-40 DEG C after the dropwise addition, continuously performing stirring until the reaction is completed , and removing the solvent to obtain a compound 6; and (e) condensing the compound 6 and a compound 7, and carrying out hydrolysis treatment to obtain the target product which is the compound 1. The preparation technology has the characteristics of high yield, convenience and safety in operation, less discharge of three wastes, low production cost, and suitableness for industrial production.
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(2018/04/02)

Intermediate compound for synthesis of sofosbuvir and synthetic method thereof
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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Paragraph 0050; 0052-0053

(2017/08/30)

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.
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Paragraph 0037; 0045

(2017/07/19)

Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates
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; 0017

(2017/01/31)

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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Paragraph 0096-0103

(2017/01/05)

Preparation method of sofosbuvir intermediate or derivative thereof
The invention discloses a preparation method of a sofosbuvir intermediate or a derivative thereof. Compounds represented by formula 3 and formula 6 react with an alkali catalyst DBU or DMAP at 20-70DEG C to prepare a compound represented by formula 1. The method is simple to operate, and is suitable for industrial production.
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Paragraph 0027; 0028

(2016/12/16)

Preparing method for sofosbuvir intermediate and derivatives thereof
The invention discloses a preparing method for a sofosbuvir intermediate and derivatives thereof. The compound in the formula (1) is prepared from a compound (3) and a compound (6) through a heating reaction under the alkaline condition, wherein R1 and R2 are benzoyl groups substituted or not substituted. The preparing method is easy to operate, stannic chloride is removed from the improved process, the cost advantage is obvious, and the preparing method is suitable for industrial mass production.
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Paragraph 0025; 0026

(2016/11/17)

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.
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Paragraph 0059; 0060

(2016/11/07)

IMPROVED FLUORINATION PROCESS
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 102

(2016/05/19)

Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication
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
supporting information
p. 5158 - 5174
(2015/05/13)

PROCESS FOR THE PREPARATION OF 2-DEOXY-2-FLUORO-2-METHYL-D-RIBOFURANOSYL NUCLEOSIDE COMPOUNDS
An improved process for the preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine derivatives of formula I, (I), wherein R1 is selected from C1-4-alkyl is described. The (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine derivatives of formula I have the potential to be useful as prodrugs for potent inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase.
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Page/Page column 11; 12

(2014/01/07)

PROCESS FOR THE PREPARATION OF 2-DEOXY-2-FLUORO-2-METHYL-D-RIBOFURANOSYL NUCLEOSIDE COMPOUNDS
An improved process for the preparation of (2′R)-2′-deoxy-2′-fluoro-2′-methylcytidine derivatives of formula I wherein R1 is selected from C1-4-alkyl is described. The (2′R)-2′-deoxy-2′-fluoro-2′-methylcytidine derivatives of formula I have the potential to be useful as prodrugs for potent inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase.
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Paragraph 0051; 0052

(2014/01/07)

METHODS FOR TREATING HCV
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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Paragraph 0360

(2013/10/22)

NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
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 35

(2010/02/17)

An efficient and diastereoselective synthesis of PSI-6130: A clinically efficacious inhibitor of HCV NS5B polymerase
(Chemical Equation Presented) R7128 is the prodrug of 2′-deoxy- 2′-fluoro-2′-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected D-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.
Wang, Peiyuan,Chun, Byoung-Kwon,Rachakonda, Suguna,Du, Jinfa,Khan, Noshena,Shi, Junxing,Stec, Wojciech,Cleary, Darryl,Ross, Bruce S.,Sofia, Michael J.
experimental part
p. 6819 - 6824
(2009/12/30)

PREPARATION OF NUCLEOSIDES RIBOFURANOSYL PYRIMIDINES
The present process provides an improved method for the preparation of 4- amino-l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)-lH-pyrimidin-2-one of the formula (IV) which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase.
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Page/Page column 9-11

(2008/06/13)

Synthesis of 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranoses
The synthesis of methyl 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl- β-D-ribofuranoside and the conversion to the corresponding 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose and 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-r
Clark, Jeremy L.,Mason, J. Christian,Hobbs, Ann J.,Hollecker, Laurent,Schinazi, Raymond F.
p. 461 - 470
(2007/10/03)

Design, synthesis, and antiviral activity of 2′-deoxy-2′- fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
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.
p. 5504 - 5508
(2007/10/03)