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【结 构 式】 
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【药物名称】Didanosine, Dideoxyinosine, ddIno, BMY-40900, d2I, NSC-612049, DDI, Videx 【化学名称】2',3'-Dideoxyinosine 【CA登记号】69655-05-6 【 分 子 式 】C10H12N4O3 【 分 子 量 】236.23214 |
【开发单位】Bristol-Myers Squibb (Orphan Drug), Bristol-Myers Squibb (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
1) 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 and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 【2】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 【3】 Taniguchi, M.; Koga, K.; Yamada, S.; Stereoselective synthesis of D-ribose from L-glutamic acid. Tetrahedron 1974, 30, 3547-52. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (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 | |
| (XI) | 12787 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)tetrahydro-2-furanyl]methanol; Dideoxyadenosine | 4097-22-7 | C10H13N5O2 | 详情 | 详情 |
合成路线2
2) 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, yielding the 5'-acetoxy derivative (III). The reaction of (III) with acetic anhydride at temperatures over 120 C affords 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V). Hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to a transdideoxyribosylation with hypoxanthine (VII) by incubation in an appropriate medium with Escherichia coli AJ 2595 resting cells.
| 【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. |
| 【2】 Shirae, H.; Kobayashi, K.; Shiragami, H.; Irie, Y.; Yasuda, N.; Yokozeki, K.; Production of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine from 2',3'-dideoxyuridine and the corresponding purine bases by resting cells of Escherichia coli AJ 2595. Appl Environ Microbiol 1989, 55, 2, 419-24. |
| 【3】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (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 |
| (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) | 12794 | 9H-Purin-6-ol; Hypoxanthine | 68-94-0 | C5H4N4O | 详情 | 详情 |
合成路线3
3) The reaction of inosine (I) with tert-butyldimethylsilyl chloride by means of imidazole in DMF gives the 5'-O-silyl derivative (II), which by reaction with CS2 and 3-bromopropionitrile by means of NaOH in DMSO is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-(2-cyanoethyldithiocarbonyl)inosine (III). The reaction of (III) with tri-n-butyltin hydride and AIBN in refluxing toluene affords 5'-O-(tert-butyldimethylsilyl-2',3'-dideoxy-2',3'-didehydroinosine (IV), which is deprotected with tetrabutylammonium fluoride in THF to 2',3'-dideoxy-2',3'-didehydroinosine (V). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol - water. 4) The reaction of (II) with 1,1'-thiocarbonyldiimidazole (DTI) in DMF gives 5'-O-(tert-butyldimethylsilyl)-2',3'-O-(thionocarbonyl)inosine (VI), which by reaction with refluxing triethyl phosphite is converted into the didehydro derivative (IV), already obtained (5).
| 【1】 Webb, R.R. II, Wos, J.A.; Martin, J.C.; Brodfuehrer, P.R.; Synthesis of 2',3'-dideoxyinosine. Nucleosides Nucleotides 1988, 7, 2, 147-53. |
| 【2】 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. |
| 【3】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 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) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 详情 | 详情 |
| (II) | 12796 | (2R,3S,4R,5R)-2-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol | C16H26N4O5Si | 详情 | 详情 | |
| (III) | 12797 | O-[(2R,3R,4R,5R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-([[(2-cyanoethyl)sulfanyl]carbothioyl]oxy)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3-furanyl] S-(2-cyanoethyl) carbonodithioate | C24H32N6O5S4Si | 详情 | 详情 | |
| (IV) | 12798 | 9-[(2R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C16H24N4O3Si | 详情 | 详情 | |
| (V) | 12799 | 9-[(2R,5S)-5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C10H10N4O3 | 详情 | 详情 | |
| (VI) | 12800 | (3aR,4R,6R,6aR)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-6-(6-hydroxy-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxole-2-thione | C17H24N4O5SSi | 详情 | 详情 |
合成路线4
5) The benzoylation of 2'-deoxyinosine (I) with benzoyl chloride in pyridine gives the 5'-O-benzoyl derivative (II), which is treated with 1,1'-thiocarbonyldiimidazole (DTI) in DMF to afford the 2'-O-thiocarbonyl derivative (III). The reaction of (III) with bis(tributyltin)oxide, polymethylhydroxysilane and AIBN in refluxing dioxane yields 5'-O-benzoyl-2',3'-dideoxyinosine (IV), which is finally deprotected with anhydrous NH3 in methanol. Another microbial conversion of 2',3'-dideoxyuridine to 2',3'-dideoxyinosine by transdideoxyribosylation with hypoxanthine in a culture medium of Escherichia coli ATCC 10798 is described, and industrially applicable methods for the purification of enzymatically or microbially obtained dideoxyinosines are reported.
| 【1】 Tanabe, T.; Otani, M.; Arai, M.; Yukawa, T. (Ajinomoto Co., Inc.); Method for the purification of dideoxyinosine. JP 1989175991 . |
| 【2】 Tanabe, T.; Otani, M.; Yukawa, T. (Ajinomoto Co., Inc.); Method for the purification of dideoxyinosine. JP 1989165390 . |
| 【3】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 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) | 12801 | 9-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-6-ol | 890-38-0 | C10H12N4O4 | 详情 | 详情 |
| (II) | 12802 | [(2R,3S,5R)-3-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H16N4O5 | 详情 | 详情 | |
| (III) | 12803 | [(2R,3S,5R)-5-(6-hydroxy-9H-purin-9-yl)-3-[(1H-imidazol-1-ylcarbothioyl)oxy]tetrahydro-2-furanyl]methyl benzoate | C21H18N6O5S | 详情 | 详情 | |
| (IV) | 12804 | [(2S,5R)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H16N4O4 | 详情 | 详情 |
合成路线5
A new synthesis of ddI has been described: The reaction of inosine (I) with 2-acetoxyisobutyryl bromide (II) gives a mixture of two bromodiacyloxy derivatives (IIIa) and (IIIb) that, without separation, are hydrolyzed either with ammonia in methanol or with the pair Zn-Cu in the same solvent, yielding a mixture of the 2- and 3-bromo derivatives (IVa) and (IVb). The acylation of this mixture with chlorothionoformic acid O-phenyl ester and dimethylaminopyridine (DMAP) in acetonitrile gives a new mixture of the thiono esters (Va) and (Vb), which is treated with tributyltin hydride and azoisobutyronitrile (AIBN) in refluxing benzene to yield 5'-O-(2-acetoxyisobutyryl)-2',3'-didehydro-2',3'-dideoxyinosine (VI). The hydrolysis of (VI) with ammonia in methanol affords 2',3'-didehydro-2',3'-dideoxyinosine (VII), which is finally hydrogenated with H2 over Pd/C.
| 【1】 Dorland, E.; Serafinowski, P.; A convenient method for the synthesis of 2',3'-dideoxynucleosides. Antivir Res 1992, 17, (Suppl. 1), Abst 26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 12807 | [(2R,3S,4S,5R)-4-(acetoxy)-3-bromo-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C18H21BrN4O8 | 详情 | 详情 | |
| (IIIb) | 12808 | [(2R,3R,4S,5R)-3-(acetoxy)-4-bromo-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C18H21BrN4O8 | 详情 | 详情 | |
| (IVa) | 12809 | [(2R,3R,4S,5R)-3-bromo-4-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H19BrN4O7 | 详情 | 详情 | |
| (IVb) | 12810 | [(2R,3R,4S,5R)-4-bromo-3-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H19BrN4O7 | 详情 | 详情 | |
| (Va) | 12811 | [(2R,3S,4S,5R)-3-bromo-5-(6-hydroxy-9H-purin-9-yl)-4-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C23H23BrN4O8S | 详情 | 详情 | |
| (Vb) | 12812 | [(2R,3R,4S,5R)-4-bromo-5-(6-hydroxy-9H-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C23H23BrN4O8S | 详情 | 详情 | |
| (I) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 详情 | 详情 |
| (II) | 12806 | 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide | 40635-67-4 | C6H9BrO3 | 详情 | 详情 |
| (VI) | 12813 | [(2S,5R)-5-(6-hydroxy-9H-purin-9-yl)-2,5-dihydro-2-furanyl]methyl 2-(acetoxy)-2-methylpropanoate | C16H18N4O6 | 详情 | 详情 | |
| (VII) | 12799 | 9-[(2R,5S)-5-(Hydroxymethyl)-2,5-dihydro-2-furanyl]-9H-purin-6-ol | C10H10N4O3 | 详情 | 详情 |
合成路线6
A new synthesis of didanosine has been described: Treatment of 2'-deoxyadenosine (I) with adenosine deaminase (ADA) in water gives 2'-deoxyinosine (II), which is treated with vinyl acetate (III) and Candida antarctica lipase (CAL) in hot pyridine yielding 5'-O-acetyl-2'-deoxyinosine (IV). The reaction of (IV) with phenyl chlorothionoformate (V) and DMAP in acetonitrile affords the corresponding thiocarbonate (VI), which is treated with tributylstannane and AIBN in hot toluene to provide 5'-O-acetyl-2',3'-dideoxyinosine (VII). Finally, this compound is deacetylated with NH3 in methanol.
| 【1】 Santaniello, E.; Ciuffreda, P.; Casati, S.; Lipase-catalyzed protection of the hydroxy groups of the nucleosides inosine and 2'-deoxyinosine: A new chemoenzymatic synthesis of the antiviral drug 2',3'-dideoxyinosine. Bioorg Med Chem Lett 1999, 9, 11, 1577. |
| 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) | 18061 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol | 958-09-8 | C10H13N5O3 | 详情 | 详情 |
| (II) | 12801 | 9-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-6-ol | 890-38-0 | C10H12N4O4 | 详情 | 详情 |
| (III) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (IV) | 37609 | [(2R,3S,5R)-3-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C12H14N4O5 | 详情 | 详情 | |
| (V) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VI) | 37610 | [(2R,3S,5R)-5-(6-hydroxy-9H-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate | C19H18N4O6S | 详情 | 详情 | |
| (VII) | 37611 | [(2S,5R)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C12H14N4O4 | 详情 | 详情 |