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【结 构 式】

【药物名称】Lodenosine, NSC-613792, DDG-1, 2'-F-dd-ara-A, FddA

【化学名称】2',3'-Dideoxy-2'beta-fluoroadenosine
　　　　　　9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine
　　　　　　9-(2,3-Dideoxy-2-fluoro-beta-D-arabinofuranosyl)adenine

【CA登记号】110143-10-7

【 分 子 式 】C10H12FN5O2

【 分 子 量 】253.23784

【开发单位】National Cancer Institute (Originator), US Department of Commerce (Originator), MedImmune Oncology (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

The selective tritylation of cordycepin (3'-deoxyadenosine) (I) with trityl chloride in pyridine gives the 5'-O-trityl derivative (II), which is then fluorinated with diethylamido sulfur trifluoride in refluxing dichloromethane and deprotected with hot 80% acetic acid.

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Baba, M.; De Clercq, E.; Herdewijn, P.; Pauwels, R.; Balzarini, J.; Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: A structure-activity analysis. J Med Chem 1987, 30, 11, 2131-7.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17627 (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol 73-03-0 C10H13N5O3 详情 详情
(II) 17628 (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol C29H27N5O3 详情 详情

合成路线2

The TLC monitored reaction of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (III) with 30% HBr in acetic acid gives the bromosugar (IV), which is condensed with 6-chloropurine (V) in refluxing dichloromethane, yielding the chloropurine derivative (VI). The reaction of (VI) with methanolic NH3 at 100 C in a steel bomb affords 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII), which is selectively silylated with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, giving the 5'-O-silyl derivative (VIII). The reaction of (VIII) with phenyl chlorothioformate by means of dimethylaminopyridine in DMF yields the thiocarbonate (IX), which is reduced with tributyltin hydride and AIBN in hot toluene, affording 9-[2,3-dideoxy-2-fluoro-5-O-(tert-butyldimethylsilyl)-beta-D-arabinofuranosyl]adenine (X). Finally, this compound is desilylated with tetrabutylammonium fluoride in THF.

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Ford, H. Jr.; Driscoll, J.S.; Aoki, S.; Kelley, J.A.; Johns, D.G.; Roth, J.S.; Tseng, C.K.-H.; Broder, S.; Marquez, V.E.; Mitsuya, H.; Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV. J Med Chem 1990, 33, 3, 978-85.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 17690 [(2R,3R,4S)-5-(acetoxy)-4-fluoro-3-[(1-hydroxyvinyl)oxy]tetrahydro-2-furanyl]methyl benzoate C16H17FO7 详情 详情
(IV) 17691 [(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate C14H14BrFO5 详情 详情
(V) 17692 6-Chloropurine; 6-chloro-9H-purine 87-42-3 C5H3ClN4 详情 详情
(VI) 17693 [(2R,3R,4S,5R)-3-(acetoxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C19H16ClFN4O5 详情 详情
(VII) 17694 (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol C10H12FN5O3 详情 详情
(VIII) 17695 (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanol C16H26FN5O3Si 详情 详情
(IX) 17696 O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanyl] O-phenyl carbonothioate C23H30FN5O4SSi 详情 详情
(X) 17697 9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine C16H26FN5O2Si 详情 详情

合成路线3

The reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XII), which is methylated with methanol/K2CO3 in THF, yielding the 1-O-methyl glucoside (XIII). The selective benzoylation of (XIII) with benzoyl chloride in pyridine at -30 C affords the 5-O-benzoyl glucoside (XIV), which is treated with CS2/methyl iodide and NaH in DMF, giving compound (XV). The reduction of (XV) with tributyltin hydride and AIBN in refluxing toluene yields the 3-deoxy glucoside (XVI), which is condensed with 6-chloropurine (V) in refluxing hexamethyldisylazane, affording 9-(5-O-benzoyl-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (XVII). Finally, this compound is debenzoylated with methanolic ammonia at 100 C in a sealed tube.

参考文献 中间体
【1】 Siddiqui, M.A.; Marquez, V.E.; Driscoll, J.S.; Barchi, J.J. Jr.; Wysocki, R.J. Jr.; A more expedient approach to the synthesis of anti-HIV-active 2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl nucleosides. Synthesis 1991, 11, 11, 1005-8.
【2】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【3】 Driscoll, J.S.; Roth, J.S.; Broder, S.; Kelley, J.A.; Tseng, C.K.-H.; Mitsuya, H.; Marquez, V.E.; 2',3'-Dideoxy-2'-fluoro-ara-A, an acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem Pharmacol 1987, 36, 17, 2719-22.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 17692 6-Chloropurine; 6-chloro-9H-purine 87-42-3 C5H3ClN4 详情 详情
(XI) 17698 [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate C26H21FO7 详情 详情
(XII) 17699 (2R,3R,4S)-5-bromo-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol C5H8BrFO3 详情 详情
(XIII) 17700 (2R,3R,4S,5R)-4-fluoro-2-(hydroxymethyl)-5-methoxytetrahydro-3-furanol C6H11FO4 详情 详情
(XIV) 17701 [(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate C13H15FO5 详情 详情
(XV) 17702 ((2R,3R,4S,5R)-4-fluoro-5-methoxy-3-[[(methylsulfanyl)carbothioyl]oxy]tetrahydro-2-furanyl)methyl benzoate C15H17FO5S2 详情 详情
(XVI) 17703 [(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl benzoate C13H15FO4 详情 详情
(XVII) 17704 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C17H14ClFN4O3 详情 详情

合成路线4

The regioseletive deacetylation of 9-(2,5-diacetoxy-3-bromo-3-deoxy-beta-D-xylofuranosyl)adenine (XVIII) by means of beta-cyclodextrin/NaHCO3 in water or hydrazine monohydrate in ethanol gives 9-(5-acetoxy-3-bromo-3-deoxy-beta-D-xylofuranosyl)adenine (XIX), which is debrominated by hydrogenation over Pd/C in acetonitrile/water, affording 9-(5-acetoxy-3-deoxy-beta-D-xylofuranosyl)adenine (XX). Finally, this compound is fluorinated by means of diethylamido sulfur trifluoride in refluxing dichloromethane, yielding (XXI) and deacetylated with NH3 to the target compound.

参考文献 中间体
【1】 Tanaka, Y.; Uchida, Y.; Shiragami, H.; Yukawa, T.; Iwagami, H.; Izawa, K.; A novel method for the synthesis of ddA and F-ddA via regioselective 2'-O-deacetylation of 9-(2, 5-di-O-acetyl-3-bromo-3-deoxy-beta-D-xylofuranosyl)adenine. Nucleosides Nucleotides 1992, 1, 391-400.
【2】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 17629 [(2R,3S,4S,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)-3-bromotetrahydro-2-furanyl]methyl acetate C14H16BrN5O5 详情 详情
(XIX) 17630 [(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-3-bromo-4-hydroxytetrahydro-2-furanyl]methyl acetate C12H14BrN5O4 详情 详情
(XX) 17631 [(2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydro-2-furanyl]methyl acetate C12H15N5O4 详情 详情
(XXI) 17632 [(2S,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl acetate C12H14FN5O3 详情 详情

合成路线5

The controlled reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XXII), which is condensed with 6-chloropurine (V) as before, yielding 6-chloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-beta-D-arabinofuranosyl)purine (XXIII). Finally, this compound is treated with ammonia in methanol as before to afford intermediate 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII).

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Marquez, V.E.; Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. ACS Symp Ser 1989, 401, 140-55.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 17692 6-Chloropurine; 6-chloro-9H-purine 87-42-3 C5H3ClN4 详情 详情
(VII) 17694 (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol C10H12FN5O3 详情 详情
(XI) 17698 [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate C26H21FO7 详情 详情
(XXII) 17705 [(2R,3R,4S,5R)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate C19H16BrFO5 详情 详情
(XXIII) 17706 [(2R,3R,4S,5R)-3-(benzoyloxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C24H18ClFN4O5 详情 详情

合成路线6

The selective silylation of 2-deoxy-2-fluoro-1-O-methyl-beta-D-arabinofuranose (XIII) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) and imidazole in DMF gives the 5-O-silylated sugar (XXIV), which is treated with CS2/NaH/methyl iodide in DMF to yield compound (XXV). The reduction of (XXV) with tributyltin hydride and AIBN in refluxing toluene affords 2,3-dideoxy-2-fluoro-5-O-(tert-butyldiphenylsilyl)-beta-D-arabinofuranose (XXVI), which is treated with HBr in acetic acid to yield the bromosugar (XXVII). The condensation of (XXVII) with 6-chloropurine (V) in hot acetonitrile gives 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(tert-butyldiphenylsilyl)-beta-D-arabinofuranosyl]purine (XXVIII), which is desilylated with tetrabutylammonium fluoride in THF, yielding 6-chloro-9-[2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl]purine (XXIX). Finally, this compound is treated with methanolic ammonia at 105 C as before.

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Marquez, V.E.; Siddiqui, M.A.; Driscoll, J.S.; Wysocki, R.J. Jr. (US Department of Health & Human Services); 2'-Fluorofuranosyl derivs. and methods for preparing 2'-fluoropyrimidine and 2'-fluoropurine nucleosides. US 5817799 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 17707 (2R,3R,4S,5R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-fluoro-5-methoxytetrahydro-3-furanol C22H29FO4Si 详情 详情
(XXV) 17708 O-[(2R,3R,4S,5R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-fluoro-5-methoxytetrahydro-3-furanyl] S-methyl carbonodithioate C24H31FO4S2Si 详情 详情
(XXVI) 17709 tert-butyl(diphenyl)silyl [(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl ether; tert-butyl[[(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methoxy]diphenylsilane C22H29FO3Si 详情 详情
(XXVII) 17710 [[(2S,4S)-5-bromo-4-fluorotetrahydro-2-furanyl]methoxy](tert-butyl)diphenylsilane; [(2S,4S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl tert-butyl(diphenyl)silyl ether C21H26BrFO2Si 详情 详情
(XXVIII) 17711 tert-butyl(diphenyl)silyl [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl ether; 9-[(2R,3S,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-6-chloro-9H-purine C26H28ClFN4O2Si 详情 详情
(XXIX) 17712 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol C10H10ClFN4O2 详情 详情

合成路线7

The treatment of 2,3-O-dimesyl-5-O-(4-methoxybenzyl)-1-O-methyl-alpha-D-xylofuranose (XXX) with NaBH4 gives 3-deoxy-5-O-(4-methoxybenzyl)-1-O-methyl-alpha-D-xylofuranose (XXXI), which is fluorinated with diethylamido sulfur trifluoride as before, yielding 2,3-dideoxy-2-fluoro-5-O-(4-methoxybenzyl)-alpha-D-arabinofuranose (XXXII). The condensation of (XXXII) with adenine (XXXIII) by means of acetyl bromide affords 9-[2,3-dideoxy-2-fluoro-5-O-(4-methoxybenzyl)-beta-D-arabinofuraosyl]adenine (XXXIV), which is finally deprotected by hydrogenation over Pd/C in ethanol.

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Stadelmann, B.; alpha-D-Pentofuranoside derivs., process for preparing the same and their use. WO 9606103 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX) 17713 (2S,3R,4S,5R)-2-methoxy-5-[[(4-methoxybenzyl)oxy]methyl]-4-[(methylsulfonyl)oxy]tetrahydro-3-furanyl methanesulfonate C16H24O10S2 详情 详情
(XXXI) 17714 (2S,3R,5S)-2-methoxy-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-3-furanol C14H20O5 详情 详情
(XXXII) 17715 (2S,3S,5S)-3-fluoro-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2-furanyl methyl ether; (2S,3S,5S)-3-fluoro-2-methoxy-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydrofuran C14H19FO4 详情 详情
(XXXIII) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(XXXIV) 17717 9-((2R,3S,5S)-3-fluoro-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2-furanyl)-9H-purin-6-amine; 9-((2R,3S,5S)-3-fluoro-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2-furanyl)-9H-purin-6-ylamine C18H20FN5O3 详情 详情

合成路线8

The reaction of 2,3-O-isopropylidene-D-ribofuranose (XXXV) with 4-methylbenzoyl chloride (XXXVI) by means of pyridine in butyl acetate gives 2,3-O-isopropylidene-5-O-(4-methylbenzoyl)-D-ribofuranose (XXXVII), which is methylated by means of NaH and dimethylsulfate in THF to yield the expected methyl ribofuranoside (XXXVIII). The hydrolysis of the acetonide group of (XXXVIII) with trifluoromethanesulfonic acid in acetonitrile affords 1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XXXIX), which is treated with SO2Cl2/triethylamine in butyl acetate to give the cyclic sulfate (XL). The reduction of (XL) with NaBH4 in THF yields 3-deoxy-1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XLI), which is treated with trifluoromethanesulfonic anhydride and tetrabutylammonium fluoride in dichloromethane/pyridine to afford 2,3-dideoxy-2-fluoro-1-O-methyl-alpha-D-arabinofuranose (XLII). The reaction of (XLII) with HBr in acetic acid as before gives the bromosugar (XLIII), which is condensed with 6-chloro-9-(trimethylsilyl)purine (XLIV) in dichloromethane to yield 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(4-methylbenzoyl)-beta-D-arabinofuranosyl]purine (XLV). Finally, this compound is treated with ammonia in methanol at 90 C.

参考文献 中间体
【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Saischek, E.; Dax, K.; Braun, W.; Fuchs, F.; Saischek, G. (Chevron Research Co.); D-Xylofuranose derivs., method of preparing them, their use, and novel intermediate compounds for the method. WO 9606851 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXL) 17722 [(2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate C14H18O6 详情 详情
(XXXV) 17718 (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol C8H14O5 详情 详情
(XXXVI) 17719 p-Toluoyl chloride; 4-methylbenzoyl chloride 874-60-2 C8H7ClO 详情 详情
(XXXVII) 17720 [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate C16H20O6 详情 详情
(XXXVIII) 17721 [(3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate C17H22O6 详情 详情
(XL) 17723 [(3aR,4R,6S,6aR)-6-methoxy-2,2-dioxotetrahydro-2lambda(6)-furo[3,4-d][1,3,2]dioxathiol-4-yl]methyl 4-methylbenzoate C14H16O8S 详情 详情
(XLI) 17724 [(2S,4R,5S)-4-hydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate C14H18O5 详情 详情
(XLII) 17725 [(2S,4S,5S)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate C14H17FO4 详情 详情
(XLIII) 17726 [(2S,4S,5S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate C13H14BrFO3 详情 详情
(XLIV) 17727 6-chloro-9-(trimethylsilyl)-9H-purine C8H11ClN4Si 详情 详情
(XLV) 17728 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate C18H16ClFN4O3 详情 详情

合成路线9

A new synthesis of lodenosine has been described: The selective benzoylation of the 6-chloropurine riboside (I) with benzoyl chloride and triethylamine through the formation of a complex with dibutyl tin oxide, gives the 3'-O-benzoyl derivative (II), which is purified by crystallization (minor impurities, about 3%, of the 2'-O derivative are present). The protection of the primary OH group of (II) by reaction with trityl chloride, DMAP and Et3N in DMF yields the 5'-O-trityl derivative (III), which is treated with DAST and pyridine to afford the fluorinated arabinofuranoside (IV). The reaction of (IV) with ammonia in methanol displaces the 6-Cl atom and hydrolyzes the 3'-O-benzoyl group giving the fluorinated arabinofuranosyladenine (V). The reaction of (V) with phenyl chlorothionoformate and DMAP in acetonitrile yields the thiocarbonate (VI), which is treated with tris(trimethylsilyl)silane and AIBN in hot toluene to afford the 3'-deoxy compound (VII). Finally, this compound is deprotected by reaction with HCl in methanol/water.

参考文献 中间体
【1】 Izawa, K.; Satoh, Y.; Takamatsu, S.; Kozai, S.; Maruyama, T.; Synthesis of 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine bearing selectively removable protecting group. Chem Pharm Bull 1999, 47, 7, 966.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(I) 18716 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 2004-06-0 C10H11ClN4O4 详情 详情
(II) 29871 (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydro-3-furanyl benzoate C17H15ClN4O5 详情 详情
(III) 29872 (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate C36H29ClN4O5 详情 详情
(IV) 29873 (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate C36H28ClFN4O4 详情 详情
(V) 29874 (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanol C29H26FN5O3 详情 详情
(VI) 29875 O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate C36H30FN5O4S 详情 详情
(VII) 29876 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine C29H26FN5O2 详情 详情

合成路线10

An improved synthesis of lodenosine has been reported: The reaction of the chloropurine derivative (I) with trityl chloride and diisopropylamine in DMF gives the 5'-O-trityl-purine (II), which is treated with benzoyl chloride and pyridine in toluene to afford the 3'-O-benzoyl-5'-O-trityl-purine (III) -- some of the 2'-O-benzyl regioisomer is also isolated and is recycled after acyl migration by reaction with TEA. The reaction of purine (III) with trifluoromethanesulfonyl chloride and DMAP in toluene yields the 3'-O-benzoyl-2'-O-sulfonyl-5'-O-trityl-purine (IV), which is treated with HF and TEA to provide the 2'-beta-fluoro-purine (V). The reaction of compound (V) with ammonia in methanol gives the adenosine derivative (VI), which is treated with O-phenyl chlorothioformate and DMAP in pyridine to yield the thiocarbonate (VIII). The deoxygenation of (VIII) is performed with diphenylsilane and AIBN affording 5'-O-trityl-lodenosine (IX), which is finally deprotected with 80% HOAc.

参考文献 中间体
【1】 Katayama, S.; Hirose, N.; Izawa, K.; Takamatsu, S.; Maruyama, T.; Improved synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) using triethylamine trihydrofluoride. Tetrahedron Lett 2001, 42, 12, 2321.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18716 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 2004-06-0 C10H11ClN4O4 详情 详情
(II) 48718 (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol C29H25ClN4O4 详情 详情
(III) 29872 (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate C36H29ClN4O5 详情 详情
(IV) 48719 (2R,3R,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate C37H28ClF3N4O7S 详情 详情
(V) 29873 (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate C36H28ClFN4O4 详情 详情
(VI) 29875 O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate C36H30FN5O4S 详情 详情
(VII) 25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(VIII) 29875 O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate C36H30FN5O4S 详情 详情
(IX) 29876 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine C29H26FN5O2 详情 详情

合成路线11

A practical synthesis of lodenosine has been reported: Selective tritylation of the chloropurine derivative (I) at the primary OH group by treatment with trityl chloride, TEA and DMAP in DMF gives the 5'-O-trityl ether (II), which is fluorinated with diethylamino sulfur trifluoride (DAST) and pyridine in dichloromethane to yield the 2'-beta-fluoro derivative (III). Reaction of compound (III) with ammonia in THF affords the tritylated lodenosine derivative (IV), which is finally deprotected with 37% HCl in methanol/water.

参考文献 中间体
【1】 Hirose, N.; Takamatsu, S.; Katayama, S.; Naito, M.; Izawa, K.; Maruyama, T.; Practical synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. Tetrahedron Lett 2001, 42, 12, 2325.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 48720 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol C10H11ClN4O3 详情 详情
(II) 48721 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol C29H25ClN4O3 详情 详情
(III) 48722 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine C29H24ClFN4O2 详情 详情
(IV) 29876 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine C29H26FN5O2 详情 详情

合成路线12

A practical synthetic approach to lodenosine has been developed: Acylation of the chiral carbinol (I) with 4-methylbenzoyl chloride (II) and pyridine in dichloromethane gives the ester (III), which is diastereoselectively hydrogenated with H2 over Pd/C in ethyl acetate to yield the tetrahydrofuranone (IV). Surprisingly, the diastereoselectivity of this reaction depends on the hydrogen pressure: while at 40 psi it is very poor, at 10 psi it increases to 98%. The reduction of lactone (IV) with red-Al and 2-hydroxypyridine in THF at -30 C affords the lactol (V), which is treated with Ac2O and catalytic concentrated H2SO4 to provide the acetate ester (VI). Reaction of compound (VI) with HBr in AcOH gives the bromo derivative (VII), which is condensed with N6-benzoyl adenine (VIII) by means of NaH in refluxing THF to give the acylated adenosine derivative (IX). Finally, this compound is deprotected with NaOMe in refluxing methanol.

参考文献 中间体
【1】 Xu, G.Y.; Wang, D.J.; Pierce, M.E.; Choudhury, A.; Nguyen, D.; Jin, F.Q.; Confalona, P.N.; Wang, Z.; (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-beta-D-threo-pentofuranosyl)adenine (FddA). Tetrahedron Lett 2001, 42, 29, 4787.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 48723 (5S)-3-fluoro-5-(hydroxymethyl)-2(5H)-furanone C5H5FO3 详情 详情
(II) 17719 p-Toluoyl chloride; 4-methylbenzoyl chloride 874-60-2 C8H7ClO 详情 详情
(III) 48724 [(2S)-4-fluoro-5-oxo-2,5-dihydro-2-furanyl]methyl 4-methylbenzoate C13H11FO4 详情 详情
(IV) 48725 [(2S,4S)-4-fluoro-5-oxotetrahydro-2-furanyl]methyl 4-methylbenzoate C13H13FO4 详情 详情
(V) 48726 [(2S,4S)-4-fluoro-5-hydroxytetrahydro-2-furanyl]methyl 4-methylbenzoate C13H15FO4 详情 详情
(VI) 48727 [(2S,4S,5R)-5-(acetoxy)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate C15H17FO5 详情 详情
(VII) 48728 [(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate C13H14BrFO3 详情 详情
(VIII) 10035 N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine 4005-49-6 C12H9N5O 详情 详情
(IX) 48729 [(2S,4S,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate C25H22FN5O4 详情 详情

合成路线13

The reaction of inosine (I) with trimethyl orthoacetate and AcOH, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is deacetylated with NaOMe in methanol to afford the dihydroxy compound (V). The selective tritylation of the primary OH group of (V) with Tr-Cl and collidine in acetonitrile provides the trityl ether (VI), which is fluorinated with diethylaminosulfur trifluoride (DAST) and pyridine in dichloromethane to give the 3'-beta-fluoro derivative (VII). The reaction of (VII) with ammonia in THF gives the tritylated fluoroadenosine (VIII), which is finally deprotected with HCl in methanol/water to provide the target lodenosine. Alternatively, conversion of (VII) into lodenosine can be performed by first removal of the trityl protecting group with HCl in MeOH/toluene yielding compound (IX), whose chlorine atom is finally displaced with ammonia in MeOH/toluene

参考文献 中间体
【1】 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38013 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(II) 55505 [(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15BrN4O6 详情 详情
(III) 55506 (2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C14H16N4O6 详情 详情
(IV) 55507 [(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15ClN4O5 详情 详情
(V) 48720 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol C10H11ClN4O3 详情 详情
(VI) 48721 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol C29H25ClN4O3 详情 详情
(VII) 48722 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine C29H24ClFN4O2 详情 详情
(VIII) 29876 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine C29H26FN5O2 详情 详情
(IX) 17712 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol C10H10ClFN4O2 详情 详情

合成路线14

The reaction of inosine (I) with trimethyl orthoacetate and HOAc, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is regioselectively monodeacetylated with TEA in methanol to afford the hydroxy compound (V). The fluorination of (V) with morpholinosulfur trifluoride (MOST) and pyridine in dichloromethane gives the 3'-beta-fluoro derivative (VI), which is finally deprotected with ammonia in THF to provide the target lodenosine.

参考文献 中间体
【1】 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38013 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(II) 55505 [(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15BrN4O6 详情 详情
(III) 55506 (2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C14H16N4O6 详情 详情
(IV) 55507 [(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15ClN4O5 详情 详情
(V) 55509 [(2S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxytetrahydro-2-furanyl]methyl acetate C12H13ClN4O4 详情 详情
(VI) 55508 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl acetate C12H12ClFN4O3 详情 详情

合成路线15

The protection of 5(S)-(hydroxymethyl)tetrahydrofuran-2-one with Tbdps-Cl and imidazole gives the silyl ether (II), which is oxidized by means of LiHMDS and MoOPH in THF to yield 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(R)-hydroxytetrahydrofuran-2-one (III). The fluorination of (III) by means of Et2N-SF3 (DAST) in dichloromethane affords 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(S)-fluorotetrahydrofuran-2-one (IV), which is reduced with DIBAL to provide the alcohol (V). The acylation of (V) with Ac2O and pyridine gives the acetate (VI), which is converted into the bromide (VII) by reaction with Tms-Br and BiBr3. The condensation of (VII) with 6-chloro-9-(trimethylsilyl)purine (VIII) yields the glycosylated chloropurine (IX), which is then desilylated by means of TBAF in THF to afford the chloronucleoside (X). Finally, this compound is treated with ammonia in methanol at 100 C in a pressure vessel to provide the target Lodenosine.

参考文献 中间体
【1】 Choudhury, A.; et al.; A concise synthesis of anti-viral agent F-ddA, starting from (S)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. Tetrahedron Lett 2003, 44, 2, 247.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12008 (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone 32780-06-6 C5H8O3 详情 详情
(II) 12215 (5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone C21H26O3Si 详情 详情
(III) 61756 (3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxydihydro-2(3H)-furanone C21H26O4Si 详情 详情
(IV) 61757 (3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorodihydro-2(3H)-furanone C21H25FO3Si 详情 详情
(V) 61758 (3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanol C21H27FO3Si 详情 详情
(VI) 61759 (2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl acetate C23H29FO4Si 详情 详情
(VII) 61760 [(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl tert-butyl(diphenyl)silyl ether; {[(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methoxy}(tert-butyl)diphenylsilane C21H26BrFO2Si 详情 详情
(VIII) 17727 6-chloro-9-(trimethylsilyl)-9H-purine C8H11ClN4Si 详情 详情
(IX) 61761 9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine; 9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine C26H30FN5O2Si 详情 详情
(X) 17712 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol C10H10ClFN4O2 详情 详情
Extended Information