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【结 构 式】 
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【药物名称】Dideoxyadenosine, NSC-98700, ddA 【化学名称】2',3'-Dideoxyadenosine 【CA登记号】4097-22-7 【 分 子 式 】C10H13N5O2 【 分 子 量 】235.24741 |
【开发单位】Ajinomoto (Originator), Bristol-Myers Squibb (Originator), National Cancer Institute (Originator) 【药理作用】AIDS Medicines, ANTIINFECTIVE THERAPY, Antiviral Drugs, Reverse Transcriptase Inhibitors |
合成路线1
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
A new synthesis of 2',3'-dideoxyadenosine has been described: The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C to the acetate (III). The reaction of (III) with acetic anhydride at temperatures over 120 C yields 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V).
| 【1】 Shiragami, H.; Shirae, H.; Irie, Y.; Yokozeki, K.; Yasuda, N.; The synthesis of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Nucl Acid Res Symp Ser 1988, 20, 20, 17-18. |
| 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) | 11996 | 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; Uridine | 58-96-8 | C9H12N2O6 | 详情 | 详情 |
| (I) | 12001 | 1-[(2R,5S)-5-(Hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | 5983-09-5 | C9H12N2O4 | 详情 | 详情 |
| (II) | 11997 | 1-[(3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C11H14N2O7 | 详情 | 详情 | |
| (III) | 11998 | [(3aR,4R,6R,6aR)-6-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate | C13H16N2O8 | 详情 | 详情 | |
| (IV) | 11999 | [(2S,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl acetate | C11H12N2O5 | 详情 | 详情 | |
| (V) | 12000 | [(2S,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl acetate | C11H14N2O5 | 详情 | 详情 | |
| (VI) | 12001 | 1-[(2R,5S)-5-(Hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | 5983-09-5 | C9H12N2O4 | 详情 | 详情 |
| (VII) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
合成路线3
The hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to transdeoxyribosilation with adenine (VII) by means of Escherichia coli AJ-2595 microorganisms.
| 【1】 Shiragami, H.; Shirae, H.; Irie, Y.; Yokozeki, K.; Yasuda, N.; The synthesis of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Nucl Acid Res Symp Ser 1988, 20, 20, 17-18. |
合成路线4
A new synthesis of 2',3'-dideoxyadenosine has been described: The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 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) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 12006 | (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid | 53558-93-3 | C5H6O4 | 详情 | 详情 |
| (III) | 12007 | ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone | 55094-96-7 | C7H10O4 | 详情 | 详情 |
| (IV) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 |
合成路线5
A new method for the synthesis of title compound has been reported: The reaction of 5'-O-triphenylmethyl-2'-deoxyadenosine (I) with CS2, methyl iodide and NaH gives the corresponding xanthate (II), which is reduced with tributyl hydrogen stannide to 5'-O-triphenylmethyl-2',3'-dideoxyadenosine (III). Finally, this compound is deprotected in the usual way.
| 【1】 Samukov, V.V.; Ofitserov, V.I.; Synthesis od 2',3'-dideoxynucleosides. Bioorg Khim 1983, 9, 1, 52-59. |
| 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) | 34204 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H27N5O3 | 详情 | 详情 | |
| (II) | 34205 | O-[(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanyl] S-methyl carbonodithioate | C31H29N5O3S2 | 详情 | 详情 | |
| (III) | 34206 | 9-[(2R,5S)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,5S)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H27N5O2 | 详情 | 详情 |
合成路线6
The elimination reaction of (III) with sodium ethoxide in DMF gives 2',3'-dideoxy-2',3'-didehydroadenosine (V), which is hydrogenated with H2 over Pd/C in ethanol.
| 【1】 McCarthy, J.R.; et al.; Purine nucleosides. XIV. Unsaturated furanosyl adenine nucleosides prepared via base-catalysed elimination reactions of 2'-deoxyadenosine derivatives. J Am Chem Soc 1966, 88, 7, 1549-53. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 34204 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H27N5O3 | 详情 | 详情 | |
| (II) | 36381 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanyl 4-methylbenzenesulfonate | C36H33N5O5S | 详情 | 详情 | |
| (III) | 36382 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanyl 4-methylbenzenesulfonate | C17H19N5O5S | 详情 | 详情 | |
| (V) | 11994 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methanol | 7057-48-9 | C10H11N5O2 | 详情 | 详情 |
合成路线7
The reaction of 5'-triphenylmethyl-2'-deoxyadenosine (I) with p-toluenesulfonyl chloride in pyridine gives 5'-triphenylmethyl-3'-(p-toluenesulfonyl)-2'-deoxyadenosine (II), which by partial hydrolysis with acetic acid yields 3'-p-toluenesulfonyl)-2'-deoxyadenosine (III). The reaction of (III) with ethylmercaptane (A) by means of sodium ethoxide affords 3'-ethylthio-2',3'-dideoxyadenosine (IV), which is finally desulfurized by treatment with Raney-Ni in refluxing methyl cellosolve - ethanol (100 C).
| 【1】 Robins, M.J.; et al.; The synthesis of 2',3'-dideoxyadenosine from 2'-deoxyadenosine. J Am Chem Soc 1964, 86, 17, 3585-86. |
| 【2】 Robins, M.J.; et al.; Purine nucleosides. XII. The preparation of 2',3'-dideoxyadenosine, 2',5'dideoxyadenosine and 2',3',5'-trideoxyadenosine from 2'-deoxyadenosine. Biochem J 1966, 5, 1, 224-231. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (A) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (I) | 34204 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H27N5O3 | 详情 | 详情 | |
| (II) | 36381 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanyl 4-methylbenzenesulfonate | C36H33N5O5S | 详情 | 详情 | |
| (III) | 36382 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanyl 4-methylbenzenesulfonate | C17H19N5O5S | 详情 | 详情 | |
| (IV) | 36383 | [(2R,3R,5R)-5-(6-amino-9H-purin-9-yl)-3-(ethylsulfanyl)tetrahydro-2-furanyl]methanol | C12H17N5O2S | 详情 | 详情 |
合成路线8
The reaction of 2',3'-dideoxy-2'chloro-3'-ethylthioadenosine (VI) with potassium thiocyanate gives 2',3'-dideoxy-2'-thiocyanato-3'-ethylthioadenosine (VII), which by treatment with Ni sponge in DMF at 100 C under H2 atmosphere is converted into compound (IV), which is finally treated with Raney-Ni in refluxing methyl cellosolve-ethanol (100 C).
| 【1】 Tong, L.; et al.; An alternative synthesis of 2',3'-dideoxyadenosine. J Org Chem 1965, 30, 8, 2854-55. |
| 【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 |
|---|---|---|---|---|---|---|
| (IV) | 36383 | [(2R,3R,5R)-5-(6-amino-9H-purin-9-yl)-3-(ethylsulfanyl)tetrahydro-2-furanyl]methanol | C12H17N5O2S | 详情 | 详情 | |
| (VI) | 36384 | [(2R,3S,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-chloro-3-(ethylsulfanyl)tetrahydro-2-furanyl]methanol | C12H16ClN5O2S | 详情 | 详情 | |
| (VII) | 36385 | (2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-(ethylsulfanyl)-5-(hydroxymethyl)tetrahydro-3-furansulfenyl cyanide | C13H16N6O2S2 | 详情 | 详情 |
合成路线9
The bromination of 2'-deoxyadenosine (VIII) with Br2 in dioxane - water by means of CaCO3 or sodium acetate gives 8-bromo-2'-deoxyadenosine (IX), which by reaction with triphenylmethyl chloride in pyridine - DMF is converted into 8-bromo-2'-deoxy-5'-O-triphenylmethyladenosine (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords 8-bromo-5'-O-triphenylmethyl-3'-O-(p-toluenesulfonyl)-2'-deoxyadenosine (XI), which by reaction with thiourea (A) in refluxing butanol and treatment with propanol-ammonia-water is converted into 2',3'-dideoxy-8-mercapto-8,3'-anhydroadenosine (XII). Finally, this compound is desulfurized by treatment with Raney-Ni in refluxing water.
| 【1】 Morio, I.; Masakatsu, K.; Nucleosides and nucleotides. XLIV. Purine cyclonucleosides. 2. Synthesis of cyclonucleosides having 8,3'-O- and -S-anhydro linkage derived from 2'-deoxyadenosine. Chem Pharm Bull 1970, 18, 12, 2441-46. |
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 18061 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol | 958-09-8 | C10H13N5O3 | 详情 | 详情 |
| (IX) | 36386 | (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol | C10H12BrN5O3 | 详情 | 详情 | |
| (X) | 36387 | (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H26BrN5O3 | 详情 | 详情 | |
| (XI) | 36388 | (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanyl 4-methylbenzenesulfonate | C36H32BrN5O5S | 详情 | 详情 | |
| (XII) | 36389 | [(1S,12S,13R)-7-amino-14-oxa-11-thia-2,4,6,9-tetraazatetracyclo[10.2.1.0(2,10).0(3,8)]pentadeca-3,5,7,9-tetraen-13-yl]methanol | C10H11N5O2S | 详情 | 详情 |
合成路线10
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 |