- Convenient synthesis of fluorinated nucleosides with perfluoroalkanesulfonyl fluorides
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Perfluoroalkanesulfonyl fluorides are effective dehydroxy-fluorination agents for the hydroxyl group at the sugar moiety of nucleoside derivatives and give the corresponding fluorinated nucleosides in good yield with an inversion of configuration in a sin
- Takamatsu, Satoshi,Katayama, Satoshi,Hirose, Naoko,De Cock, Etienne,Schelkens, Geert,Demillequand, Marc,Brepoels, Jozef,Izawa, Kunisuke
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- Practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) via a purine 3′-deoxynucleoside
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A practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-9-(3-deoxy-β-D-erythro-pentofuranosyl)-9H-purine (6) is described. Fluorination at the C2′-β position of the purine 3′-deoxynucleoside was improved
- Takamatsu, Satoshi,Maruyama, Tokumi,Katayama, Satoshi,Hirose, Naoko,Naito, Masaki,Izawa, Kunisuke
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- A stereoselective synthesis of 9-(3-O-benzyl-5-O-tetrahydropyranyl-β- D-arabinofuranosyl)adenine, a potentially useful intermediate for ribonucleoside synthesis
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A novel synthesis for preparing 9-(3-O-benzyl-5-O-tetrahydropyranyl-β- D-arabinofuranosyl)adenine (6) has been developed which does not require sub zero temperatures or exotic reagents. A key step in this synthesis is the selective protection of the 3′-OH of ara-A with a benzyl group. The 5′-OH is then selectively protected with DHP to yield 6, a potentially useful intermediate. A synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo- pentofuranosyl)adenine (1, FddA), an anti-viral compound, is given to illustrate the utility of this new approach.
- Woltermann, Christopher J.,Lapin, Yuri A.,Kunnen, Kevin B.,Tueting, David R.,Sanchez, Ignacio H.
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p. 3445 - 3449
(2007/10/03)
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- An industrial process for synthesizing lodenosine (FddA)
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Two industrial synthetic approaches to Lodenosine (1, FddA, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine) via a purine riboside or a purine 3′-deoxyriboside are described. Several novel applications of deoxygenation and fluorination methods are compared considering reaction yields, economy, safety and environmental concerns.
- Izawa, Kunisuke,Takamatsu, Satoshi,Katayama, Satoshi,Hirose, Naoko,Kozai, Shigetaka,Maruyama, Tokumi
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p. 507 - 517
(2007/10/03)
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- A concise synthesis of anti-viral agent F-ddA, starting from (S)-dihydro-5-(hydroxymethyl)-2(3H)-furanone
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Anti-HIV agent β-F-ddA (1) has been synthesized starting from readily available non-sugar, (S)-(+)-Dihydro-5-(hydroxymethyl)-2-(3H)-furanone (4). A highly syn-stereoselective fluorination of the hydroxy lactone 2 generates the key intermediate fluorolactone 5 in a short and concise synthetic sequence. Reduction of 5 followed by bromination generates the aglycon which is glycosylated to generate F-ddA by amination and deprotection. Steric bulk of the 5-protecting group has minimal effect on the steric course of glycosylation.
- Choudhury, Anusuya,Jin, Fuqiang,Wang, Dengjin,Wang, Zhe,Xu, Guoyou,Nguyen, Dieu,Castoro, John,Pierce, Michael E.,Confalone, Pat N.
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p. 247 - 250
(2007/10/03)
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- Improved synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) using triethylamine trihydrofluoride
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An improved synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, FddA) via a fluorination of 3′-O-benzoyl-5′-O-tritylriboside (4a) using noncorrosive triethylamine trihydrofluoride (Et3N·3HF) is described. The method is suitable for large-scale synthesis. In particular, the synthesis of the pivotal intermediate 4a was much improved in avoidance of the use of toxic tin reagent. Radical deoxygenation with several silanes was also studied. The total yield of FddA from 6-chloropurine riboside (2) in this study was greater than that we reported previously.
- Takamatsu, Satoshi,Maruyama, Tokumi,Katayama, Satoshi,Hirose, Naoko,Izawa, Kunisuke
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p. 2321 - 2324
(2007/10/03)
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- Synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) via a purine 3′-deoxynucleoside
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A synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro 9-(3-deoxy-β-D-erythro-pentofuranosyl)-9H-purine (9), which was readily obtained from inosine (5), is described. Fluorination at the C2′-β position of the purine 3′-deoxynucleoside with diethylaminosulfur trifluoride was improved by the introduction of a 6-chloro group and proceeded in moderate yield. Purine 3′-deoxynucleoside derivatives were also subjected to nucleophilic reactions with triethylamine trihydrofluoride and gave the desired fluorinated nucleoside in good yield. The safety and yield of the fluorination process were greatly improved by the use of triethylamine trihydrofluoride. The influence of the sugar ring conformation and 6-chloro group on the rate of the nucleophilic reaction against elimination are also discussed.
- Takamatsu,Maruyama,Katayama,Hirose,Naito,Izawa
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p. 7469 - 7477
(2007/10/03)
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- (2R,3S,5S)-2-Acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran: A key intermediate for the practical synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA)
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A highly efficient synthesis of (2R,3S,5S)-2-acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran (2a) was developed. As a key intermediate, 2a was effectively applied to the synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA), thus, providing a practical synthetic approach to FddA.
- Jin, Fuqiang,Wang, Dengjin,Confalone, Pat N.,Pierce, Michael E.,Wang, Zhe,Xu, Guoyou,Choudhury, Anusuya,Nguyen, Dieu
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p. 4787 - 4789
(2007/10/03)
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- α-D-pentofuranosides, and a process for preparing the same
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α-D-pentofuranoside derivatives have the general formula (D), in which R stands for (C1-C4)alkyl that is non-substituted or substituted one or several times by halogen, (C1-C4)alkyl, (C1-C4
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- Methods for producing nucleoside derivatives and intermediates therefor
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Novel intermediates of nucleoside derivatives, of which the 6-position of the nucleic acid base moiety is substituted with a halogen atom, are produced. Using those novel intermediates, even substrates, of which the 3'-position of the saccharide moiety is
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- Synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine bearing a selectively removable protecting group
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A facile and practical method to introduce fluorine at the up-side of the 2'-carbon of nucleosides is described. 6-Chloropurine riboside 3 was converted to the 3'-O-benzoate 4a via a stannylene complex, then converted to the 3'-O-benzoyl-5'-O-tritylriboside 5a. In the presence of pyridine, migration of the 3'-benzoyl groups of 4a and 5a to 2'-OH was rather slow. Hence, 5a was reacted with diethylaminosulfur trifluoride (DAST) in CH2Cl2 in the presence of pyridine to give the 2'-deoxy-2'-fluoroarabinoside 6 in good yield. The 3'-O-benzoyl-5'-O-trityl protecting system was easy to deprotect selectively. Thus, treatment of 6 with ammonia in MeOH gave the 5'- O-trityl compound 7, which was subjected to esterification with phenyl chlorothionoformate, radical deoxygenation with tris(trimethylsilyl)silane and acid treatment to afford 9-(2,3-dideoxy-2-fluoro-β-D-threo- pentofuranosyl)adenine (FddA) 2. In addition, acid treatment of 7 gave 9-(2- deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (FdaraA) 1.
- Maruyama, Tokumi,Takamatsu, Satoshi,Kozai, Shigetada,Satoh, Yoshiko,Izawa, Kunisuke
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p. 966 - 970
(2007/10/03)
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- A new synthetic approach to the clinically useful, anti-HIV-active nucleoside, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (β- FddA). Introduction of a 2'-β-fluoro substituent via inversion of a readily obtainable 2'-α-fluoro isomer
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A convenient route to the anti-HIV active compound, 9-(2,3-dideoxy-2- fluoro-β-D-threo-pentofuranosyl)adenine (1, β-FddA) started with the facile introduction of fluorine at C2' from the α-side of protected 9-(β-D- arabinofuranosyl)adenine (ara-A). Inversion of the stereochemistry at C2' was accomplished via a stable vinyl intermediate (6), which underwent stereoselective reduction of the double bond to give the desired 2'-F-threo isomer with the opposite β-fluoro stereochemistry.
- Siddiqui, Maqbool A.,Driscoll, John S.,Marquez, Victor E.
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p. 1657 - 1660
(2007/10/03)
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- Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-amino prodrugs of 2′-β-fluoro-2′,3′-dideoxyinosine
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A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV
- Driscoll, John S.,Siddiqui, Maqbool A.,Ford Jr., Harry,Kelley, James A.,Roth, Jeri S.,Mitsuya, Hiroaki,Tanaka, Masatoshi,Marquez, Victor E.
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p. 1619 - 1625
(2007/10/03)
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- 2'-fluorofuranosyl derivatives and novel method of preparing 2'-fluoropyrimidine and 2'-fluoropurine nucleosides
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A compound has the formula STR1 wherein R is selected from the group consisting of (C7 -C20)aroyl, (C6 -C20)aryl, aralkyl and alkylaryl, and (C1 -C10)alkyl-di(C6 -C20)aryl Si, R' is selected from the group consisting of (C1 -C10)alkyl, (C7 -C20)aroyl and (C2 -C12)acyl, all of which may be further substituted with O, S, N or alkyl, and R'" is selected from the group consisting of halogen, (C1 -C10)alkoxy, (C1 -C10)acyloxy, O-methane-sulfonyl and O-p-toluenesulfonyl. A composition of matter comprises 0.001 to 99.999 wt % of the above compound.
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- A more expedient approach to the synthesis of anti-HIV-active 2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl nucleosides
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Starting with 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose, a versatile method for the synthesis of 2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl nucleosides is described and illustrated with the synthesis of 9-(2,3-dideoxy-2-fluoro-β-D-threop
- Wysocki Jr.,Siddiqui,Barchi Jr.,Driscoll,Marquez
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p. 1005 - 1008
(2007/10/02)
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- Deoxyfluoronucleoside process
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There is disclosed a process for synthesizing 2?--fluoro-2?,3?-dideoxyarabinofuranose derivatives of inosine and adenine on a large scale which involves coupling of a fluorosugar derivative and a purine reactant to provide a purine nucleoside intermediate which is then deoxygenated. 6-Chloro or 6-benzamidopurine and 1,3,5-tri-O-benzoyl-2--deoxy-2-fluoroarabinofuranose are used as starting materials.
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- Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV
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2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo of isomer ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH1 at 37°C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.
- Marquez,Tseng,Mitsuya,Aoki,Kelley,Ford Jr.,Roth,Broder,Johns,Driscoll
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p. 978 - 985
(2007/10/02)
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- Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: A structure-activity analysis
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A systematic synthesis was undertaken of 2',3'-dideoxyadenosine analogues with either an azido, fluorine, or hydroxyl group substituted in the 'up' or 'down' position of C-2 or C-3 of the sugar moiety. The compounds were evaluated against the cytopathogen
- Herdewijn,Pauwels,Baba,Balzarini,De Clercq
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p. 2131 - 2137
(2007/10/02)
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