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【结 构 式】 
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【分子编号】11988 【品名】Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 【CA登记号】58-61-7 |
【 分 子 式 】C10H13N5O4 【 分 子 量 】267.24452 【元素组成】C 44.94% H 4.9% N 26.21% O 23.95% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound is prepared by two related ways: 1) The partial silylation of adenosine (I) with tert-butyldimethylsilyl chloride and imidazole gives 5'-O-(tert-butyldimethylsilyl)adenosine (II), which by reaction with 1,1'-thiocarbonyldiimidazole (III) in hot DMF is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-O-thionocarbonyladenosine (IV). The desulfurization of (IV) with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (V) or triethyl phosphite in THF yields 5'-O-(tert-butyldimethylsilyl)-2',3'-didehydro-2',3'-dideoxyadenosine (VI), which is deprotected with tetrabutylammonium fluoride in THF affording 2',3'-didehydro-2',3'-dideoxyadenosine (VII). Finally, this compound is hydrogenated with H2 over Pd/C in methanol. 2) The reaction of silylated adenosine (II) with CS2 and NaOH in DMSO, followed by methylation with methyl iodide gives 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-[(methylthio)thiocarbonyl]ad enosine (VIII), which is desulfurized with tributyltin hydride and AIBN in refluxing toluene to yield the dideoxy-didehydroadenosine (VI), already obtained.
| 【1】 Chu, C.K.; Bhadti, V.S.; Doboszewski, B.; Gu, Z.P.; Kosugi, Y.; Pullaiah, K.C.; Van Roey, P.; General syntheses of 2',3'-dideoxynucleosides and 2',3'-didehydro-2',3'-dideoxynucleosides. J Org Chem 1989, 54, 2217-25. |
| 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) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 11989 | (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-3,4-furandiol | C16H27N5O4Si | 详情 | 详情 | |
| (III) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (IV) | 11991 | (3aR,4R,6R,6aR)-4-(6-Amino-9H-purin-9-yl)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydrofuro[3,4-d][1,3]dioxole-2-thione | C17H25N5O4SSi | 详情 | 详情 | |
| (V) | 11992 | 1,3-Dimethyl-2-phenyl-1,3,2-diazaphospholane; 1,3-DIMETHYL-2-PHENYL-1,3,2-DIAZAPHOSPHOLIDINE 1,3-Dimethy?2-phenyl-1,3,2-diazaphospholidine | 22429-12-5 | C10H15N2P | 详情 | 详情 |
| (VI) | 11993 | 9-[(2R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-9H-purin-6-amine | C16H25N5O2Si | 详情 | 详情 | |
| (VII) | 11994 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methanol | 7057-48-9 | C10H11N5O2 | 详情 | 详情 |
| (VIII) | 11995 | O-((2R,3R,4R,5R)-2-(6-Amino-9H-purin-9-yl)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-[[(methylsulfanyl)carbothioyl]oxy]tetrahydro-3-furanyl) S-methyl carbonodithioate | C20H31N5O4S4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The reaction of adenosine (XIII) with 2-acetoxyisobutyryl bromide (XIV) in acetonitrile gives 3'-deoxy-3'-bromo-2'-O-acetyl-5'-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)adenosine (XV), which is submitted to hydrogenolysis with H2 over Pd/C in methanol containing triethylamine.
| 【1】 Russell, A.F.; et al.; Reaction of 2-acyloxyisobutyryl halides with nucleosides. II. Reactions of adenosine. J Am Chem Soc 1973, 95, 12, 4025-30. |
| 【2】 Castaner, J.; Hopkins, S.J.; Serradell, M.N.; Blancafort, P.; 2',3'-Dideoxyadenosine. Drugs Fut 1982, 7, 4, 244. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (XIV) | 12806 | 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide | 40635-67-4 | C6H9BrO3 | 详情 | 详情 |
| (XV) | 36390 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-bromo-2-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate | C18H22BrN5O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Adenosine-N1-oxide (II) was prepared by oxidation of adenosine (I) with meta-chloroperbenzoic acid in MeOH. After alkylation of (II) with 3-methoxybenzyl bromide (III), the resulting compound was treated with ammonium perchlorate to furnish the title perchlorate salt.
| 【1】 Montgomery, J.A.; Secrist, J.A. III; Krauth, C.A. (Southern Research Institute); Adenosine cpds. useful in the prevention and treatment of vaccinia virus infections. US 5102873 . |
| 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) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 49688 | 6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-1-ium-1-olate | C10H13N5O5 | 详情 | 详情 | |
| (III) | 34403 | 1-(bromomethyl)-3-methoxybenzene; 3-(bromomethyl)phenyl methyl ether | C8H9BrO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Direct chlorination of adenosine 3',5'-cyclic phosphate (I) was carried out by treatment with anhydrous HCl and m-chloroperbenzoic acid (m-CPBA) in DMF or with N-chlorosuccinimide and NaCl in aqueous HOAc. Chlorination of adenosine (II) was achieved by treatment with HCl in the presence of m-CPBA or in the absence of the oxidating reagent m-CPBA at a higher temperature and longer reaction times. The resultant 8-chloroadenosine (III) was converted to the monophosphate (IV) by means of POCl3, and this was further cyclized to the title compound using DCC. 8-Chloroadenosine monophosphate (IV) was also accessible by chlorination of adenosine monophosphate (V). Optionally, the chlorinated adenosine (III) was directly converted to the title cyclic phosphate by phosphorylation with POCl3 in the presence of NaOH in triethyl phosphate as the solvent.
| 【1】 Woo, N.-T.; et al.; The facile and efficient synthesis of 8-chloroadenosine 3',5'-cyclic monophosphate by phosphorylative cyclization of 8-chloroadenosine and its characterization by 1H and 13C NMR spectroscopy. Arch Pharmacal Res 1997, 20, 2, 176. |
| 【2】 Robins, R.K.; Revankar, G.R.; Chang, Y. (Nucleic Acid Res. Inst., Costa Mesa); Treatment of malignant tumours with 8-chloroadenosine 3'-5'-cyclic phosphate, 8-aminoadenosine 3',5'-cyclic phosphate and preparation thereof. EP 0499291; WO 8905648 . |
| 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) | 28980 | (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-2,7-dihydroxytetrahydro-4H-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-2-one | 60-92-4 | C10H12N5O6P | 详情 | 详情 |
| (II) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (III) | 59293 | (3R,4S,5R)-2-(6-amino-8-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H12ClN5O4 | 详情 | 详情 | |
| (IV) | 59294 | [(2R,3S,4R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate | C10H13ClN5O7P | 详情 | 详情 | |
| (V) | 59295 | [(2R,3S,4R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate | C10H14N5O7P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of adenosine (I) 2-acetoxyisobutyryl bromide (A) in acetonitrile/water gives a mixture of the 3-bromo (II) and 2-bromo nucleosides (III), which is treated with Dowex (OH), Amberlite (OH) or methanolic NaOMe to yield the epoxide (IV). Finally, this compound is reduced with LiEt3BH in THF/DMSO or LiAlH4 in THF to afford a mixture of the 2'-deoxy nucleoside (V) and the target compound that are separated by chromatography. Alternatively, the mixture of the nucleosides (II) and (III) is debrominated by reaction with Bu3SnH and AIBN in refluxing toluene to give the same mixture of (V) and the target compound that is separated as before.
| 【1】 Russell, A.F.; et al.; Reactions of 2-acyloxyisobutyryl halides with nucleosides. II. Reactions of adenosine. J Am Chem Soc 1973, 95, 12, 4025. |
| 【2】 Hansske, F.; Robins, M.J.; Regiospecific and stereoselective conversion of ribonucleosides to 3'-deoxynucleosides. A high yield three-stage synthesis of cordycepin from adenosine. Tetrahedron Lett 1985, 26, 36, 4295. |
| 【3】 Bazin, H.; Chattopadhyaya, J.; A convenient preparation of 3'-deoxyadenosine (cordycepin) and 9-[3'(R)-deuterio-beta-D-2'(R)-pentofuranosyl]-adenine. Synthesis 1985, 1108. |
| 【4】 Robins, M.J.; et al.; Nucleic acid related compounds. 88. Efficient conversions of ribonucleosides into their 2',3'-anhydro, 2'(and 3')-deoxy, 2',3'-didehydro-2',3'-dideoxy, and 2',3'-dideoxynucleoside analogues. J Org Chem 1995, 60, 24, 7902. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 49211 | 1-(bromocarbonyl)-2-methylpropyl acetate | C7H11BrO3 | 详情 | 详情 | |
| (I) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 49212 | (2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate | C18H22BrN5O7 | 详情 | 详情 | |
| (III) | 36390 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-bromo-2-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate | C18H22BrN5O7 | 详情 | 详情 | |
| (IV) | 48061 | 1-[3-(2,3-dihydro-1H-inden-5-yloxy)-2-[(2-methoxyethoxy)methyl]-3-oxopropyl]cyclopentanecarboxylic acid | C22H30O6 | 详情 | 详情 | |
| (V) | 49213 | [(1S,2R,4R,5R)-4-(6-amino-9H-purin-9-yl)-3,6-dioxabicyclo[3.1.0]hex-2-yl]methanol | C10H11N5O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The reaction of adenosine (I) with triethyl orthoacetate (II) by means of Ts-OH in acetonitrile gives the bicyclic dioxolane (III), which is treated with acetyl bromide in dichloroethane to yield the acetylated bromonucleoside (IV). The debromination of (IV) by means of Bu3SnH in toluene affords the acetylated target compound (V), which is finally deprotected with ammonia in methanol.
| 【1】 Norman, D.G.; Reese, C.B.; A convenient preparation of 3'-deoxyadenosine. Synthesis 1983, 304. |
| 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) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (III) | 49214 | [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2-ethoxy-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C14H19N5O5 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 49215 | [(2S,4R,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C14H17N5O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The reaction of adenosine (I) with 2-acetoxyisobutyryl bromide (A) gives the 3'-bromonucleoside (II) along with some 3'-bromo regioisomer (III). The reaction of the desired isomer (II) with HCl in methanol yields the intermediate acetylated 3'-bromonucleoside (V) and finally the 3'-bromo-3'-deoxyadenosine (VI). This compound is then debrominated by hydrogenation with H2 over Pd/C in ethanol/water.
| 【1】 Aman, S.; et al.; From adenosine to 3'-deoxyadenosine: Development and scale up. Org Process Res Dev 2000, 4, 6, 601. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 49211 | 1-(bromocarbonyl)-2-methylpropyl acetate | C7H11BrO3 | 详情 | 详情 | |
| (I) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 49212 | (2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate | C18H22BrN5O7 | 详情 | 详情 | |
| (III) | 36390 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-bromo-2-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate | C18H22BrN5O7 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 49216 | (2R,3S,4R,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-(hydroxymethyl)tetrahydro-3-furanol | C10H12BrN5O3 | 详情 | 详情 |