- Synthesis and biological evaluation of deuterated sofosbuvir analogs as HCV NS5B inhibitors with enhanced pharmacokinetic properties
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A series of deuterated sofosbuvir analogs were designed and prepared with the aim of improving their pharmacokinetic properties. The devised synthetic routes allow for site-selective deuterium incorporation with high levels of isotopic purity. As expected, the deuterated analogs (37-44) are as efficacious as sofosbuvir when tested in vitro inhibition of viral replication (replicon) assays. Compared with sofosbuvir, deuterated analog 40 displays improved in vivo pharmacokinetics profiles in rats and dogs in terms of the metabolite and the prodrug. The Cmax and area under the curve (AUC) of 40 in dogs were increased by 3.4- and 2.7-fold, respectively. Due to the enhanced pharmacokinetic properties and the great synthetic advantage of an inexpensive deuterium source (D2O) for 40, it was chosen for further investigation.
- Ao, Wangwei,Ma, Xueqin,Lin, Youping,Wang, Xiaojing,Song, Wei,Wang, Qinglin,Zhang, Xiquan,Xu, Hongjiang,Zhang, Yinsheng
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p. 215 - 229
(2019/05/07)
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- A key intermediate for the preparation of rope non-cloth wei (by machine translation)
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The invention relates to a kind of the formula (I): As shown by a rope non-cloth wei key intermediate of the preparation method, the present invention in order to compound 3, 5 - dibenzoyl - 2 - deoxy - 2 - fluoro - 2 methyl - D - ribose - γ - lactone as
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Paragraph 0028; 0035; 0042
(2019/04/02)
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- Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution
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The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl-2-{[chloro(phenoxy)phosphoryl]-amino}propanoate (8). A high stereoselectivity was obtained when the right protective group for 3′-OH was chosen. Ester and carbonate-based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P-stereogenic centre. Starting from the γ-lactone of 2-deoxy-2-fluoro-2-methylpentonic acid, the synthesis was accomplished in eight steps in 40 % overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.
- Cini, Elena,Barreca, Giuseppe,Carcone, Luca,Manetti, Fabrizio,Rasparini, Marcello,Taddei, Maurizio
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p. 2622 - 2628
(2018/04/30)
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- Β-selective D-psicofuranosylation of pyrimidine bases and thiols
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N-Glycosidation of D-psicofuranosyl donor 1 with pyrimidine bases took place β-selectively in a β/α-ratio of 8:1 ~ 7:1. For S-glycosidation, 3,4-O-(3-pentylidene)-protected D-psicofuranosyl donor 15 was effective to increase β-selectivity up to 7:1.
- Ueda, Atsushi,Nishimura, Yuri,Makura, Yui,Tanaka, Masakazu,Uenishi, Junichi
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p. 729 - 743
(2019/04/26)
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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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Paragraph 0050; 0052-0053
(2017/08/30)
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- Bridged ring fluoroester, and preparation method and application thereof
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The invention discloses fire-new bridged ring fluoroester (1R,4R,5R,6R)-6-fluoro-6-methyl-2,7-dioxygen bicyclo [2.2.1] heptyl-5-formic ether (the structural formula is shown as a formula V), a preparation method of the bridged ring fluoroester, and application of the bridged ring fluoroester to synthesis of PSI-6130 by using the compound V for further synthesis of sofosbuvir. The structure is in the specification. The fire-new bridged ring fluoroester has the advantages that the synthesis path is simple and short; the three-dimensional configuration selectivity is excellent and controllable; heavy metal and virulent raw materials are not used in the reaction process; few three wastes are generated; the environment-friendly effect is achieved; the obvious economic benefits are realized; the fire-new bridged ring fluoroester is suitable for industrial mass production.
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Paragraph 0094
(2017/10/13)
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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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Page/Page column 26
(2017/06/09)
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- Deuterated nucleoside derivative
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The present invention relates to deuterated nucleoside derivative, particularly to a compound having a structure represented by a formula I or a pharmaceutically acceptable salt thereof. According to the present invention, the compound represented by the formula I has excellent pharmacokinetic properties and is expected to reduce the clinical dose so as to reduce the treatment and benefit more patients. The formula I is defined in the specification.
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Paragraph 0145; 0151-0153
(2016/10/07)
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- PROCESS FOR THE PREPARATION OF 2-DEOXY-2-FLUORO-2-METHYL-D-RIBOFURANOSYL NUCLEOSIDE COMPOUNDS
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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
(2014/01/07)
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- PROCESS FOR THE PREPARATION OF 2-DEOXY-2-FLUORO-2-METHYL-D-RIBOFURANOSYL NUCLEOSIDE COMPOUNDS
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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)
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- Highly diastereoselective synthesis of modified nucleosides via an asymmetric multicomponent reaction
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We have developed a practical synthesis of unique nucleoside derivatives via TiCl4 promoted multicomponent reaction of optically active dihydrofuran, ethyl pyruvate/glyoxylate, and a TMS protected nucleobase in a single-pot operation.
- Ghosh, Arun K.,Kass, Jorden
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supporting information; experimental part
p. 1218 - 1220
(2010/06/15)
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- An efficient and diastereoselective synthesis of PSI-6130: A clinically efficacious inhibitor of HCV NS5B polymerase
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(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.
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experimental part
p. 6819 - 6824
(2009/12/30)
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- Synthesis and antiviral evaluation of 4'-C-azidomethyl -β-D- ribofuranosyl purine and pyrimidine nucleosides
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In the search for inhibitors of the replication of RNA viruses, including hepatitis C virus (HCV), the hitherto unknown 4'-C-azidomethyl - D-ribofuranosyl nucleosides of the five naturally occurring nucleic acid bases have been synthesized and their antiviral properties examined. These 4'-C-branched nucleosides were stereospecifically prepared by glycosylation of purine and pyrimidine aglycons with a suitable peracylated 4-C-azidomethyl-D-pentofuranose sugar, followed by removal of the protecting groups. The prepared compounds were tested for their activity against several viruses, but they did not show an antiviral effect.
- Griffon, Jean-Francois,Dumas, Audrey,Storer, Richard,Sommadossi, Jean-Pierre,Gosselin, Gilles
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experimental part
p. 435 - 449
(2010/07/14)
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- PREPARATION OF NUCLEOSIDES RIBOFURANOSYL PYRIMIDINES
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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)
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- Synthesis of enantiomerically pure 4-substituted riboses
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An efficient and flexible synthesis of 4-substituted ribose analogues is described. The key step involves the simple addition of a Grignard reagent to a ketone derived from a commercially available ribose. The addition of a range of Grignard reagents proc
- Maddaford, Adrian,Guyot, Thierry,Leese, David,Glen, Rebecca,Hart, James,Zhang, Xiurong,Fisher, Ray,Middleton, Donald S.,Doherty, Cheryl L.,Smith, Nick N.,Pryde, David C.,Sutton, Scott C.
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p. 3149 - 3154
(2008/09/19)
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- Synthesis and biological evaluation of l- and d-configurations of 2′,3′-dideoxy-4′-c-methyl-3′-oxacytidine analogues
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Novel L- and D-configuration 2′,3′-dideoxy-4′-C-methyl-3′-oxacytidine and their 5-fluoro analogues have been synthesized from 1-benzyloxy-2-propanone and L-ascorbic acid in eight steps and evaluated for biological activity.
- Liu, Mao-Chin,Luo, Mei-Zhen,Mozdziesz, Diane E.,Lin, Tai-Shun,Dutschman, Ginger E.,Gullen, Elizabeth A.,Cheng, Yung-Chi,Sartorelli, Alan C.
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p. 2301 - 2304
(2007/10/03)
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- Synthesis of L-dioxolane nucleosides and related chemistry
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(+)-L- or (+)-(2R,4S)-1-[4-(hydroxymethyl)-1,3-dioxolan-2-yl]-5-fluorouracil (25) and other novel classes of 1,3-dioxolane nucleosides have been synthesized. Coupling of 2-methoxy-4-[[(tert-butyldiphenylsilyl)oxy]methyl]-1,3-dioxolane (23) or 2-methyl-1,3
- Liang,Lee,Newton,Chu
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p. 1546 - 1553
(2007/10/02)
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- Easy Synthesis and Different Conformational Behavior of Purine and Pyrimidine β-D-glycero-Pent-2'-enopyranosyl Nucleosides
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Condensation of 3,4-bis-O-(p-nitrobenzoyl)-D-xylal with purines and pyrimidines (A, C, 6-chloropurine, G, T, U) without externally added acid catalyst leads to the 2',3'-unsaturated pentopyranosyl nucleosides in preparatively acceptable yields of both β a
- Doboszewski, Bogdan,Blaton, Norbert,Herdewijn, Piet
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p. 7909 - 7919
(2007/10/03)
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