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【结 构 式】 
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【分子编号】12168 【品名】(1R,9R,10R)-4-Methyl-10-[(trityloxy)methyl]-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one 【CA登记号】 |
【 分 子 式 】C29H26N2O4 【 分 子 量 】466.53652 【元素组成】C 74.66% H 5.62% N 6% O 13.72% |
合成路线1
该中间体在本合成路线中的序号：(IV)1) The mesylation of 5'-O-tritylthymidine with mesyl chloride gives the corresponding 3'-O-mesyl derivative (II), which is cyclized by means of potassium phthalimide (III) in hot DMF water, yielding 5'-O-trityl-2,3'-anhydrothymidine (IV). The reaction of (IV) with sodium azide in refluxing DMF - water affords 5'-O-trityl-3'-azido-3'-deoxy thymidine (V), which is finally deprotected with 80% aqueous acetic acid at 100 C.
| 【1】 Glinski, R.P.; et al.; Nucleotide synthesis. IV. Phosphorylated 3'-amino-3'-deoxythymidine and 5'-amino-5'-deoxythymidine and derivatives. J Org Chem 1973, 38, 25, 4299. |
| 【2】 Castaner, J.; Prous, J.; BW-A 509 U. Drugs Fut 1986, 11, 12, 1017. |
| 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) | 12166 | 1-[(2R,4S,5R)-4-Hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C29H28N2O5 | 详情 | 详情 | |
| (II) | 12196 | (2R,3S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[(trityloxy)methyl]tetrahydro-3-furanyl methanesulfonate | C30H30N2O7S | 详情 | 详情 | |
| (III) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IV) | 12168 | (1R,9R,10R)-4-Methyl-10-[(trityloxy)methyl]-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one | C29H26N2O4 | 详情 | 详情 | |
| (V) | 24469 | 1-[4-azido-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C29H27N5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Alovudine can be obtained by several related ways: 1) The acylation of thymidine (I) with 4-chlorobenzoylchloride (II) in pyridine gives 5'-O-(4-chlorobenzoyl)thymidine (IX), which is then treated with diethylamino sulfur trifluoride in methylene chloride at -79 C, and finally with NaHCO3 in refluxing methanol. 2) By reaction of 2,3'-anhydro-1-(2'-deoxy-beta-D-xylofuranosyl)thymine (III) with AlF3 and 1% HF in anhydrous dioxan at 150-7 C. 3) By reaction of (III) with KHF2 or NH4F in diethylene glycol at 190C, or in ethanol at 150 C. 4) The reaction of 2,3'-anhydro-5'-O-(methylsufonyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (IV) with AlF3 and HF as before gives 3'-deoxy-3'-fluoro-5'-O-(methylsulfonyl)thymidine (V), which is then treated with NaOH in refluxing ethanol. 5) By reaction of 5'-O-(triphenylmethyl)thymidine (VI) with diethylamino sulfur trifluoride in THF, and then with aqueous, NaHCO3. 6) By reaction of 3'-O-(methylsulfonyl)thymidine (VII) with KHF2 or NH4F in diethylene glycol at 190 C. 7) By reaction of 2,3'-anhydro-5'-O-(triphenylmethyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (VIII) with 4-6% HF in anhydrous dioxan at 90 C.
| 【1】 Selway, J.W.T.; Beacham III, L.M.; Daluge, S.M.; Tuttle, J.V.; Krenitsky, T.A. (Glaxo Wellcome plc); 2,3-Dideoxy-3'-fluorothymidine and related cpds. for the treatment of adenovirus infections. AU 8821429; EP 0305117; EP 0479336; JP 1989068325; US 5070078 . |
| 【2】 Etzold, G.; Hintsche, R.; Langen, P. (Akademie der Wissenschaften der DDR); Cytostatically-active 2',3'-didesoxy-3'-fluoropyrimidine nucleosides. GB 1189973 . |
| 【3】 Castaner, J.; Hoshi, A.; Alovudine. Drugs Fut 1994, 19, 3, 221. |
| 【4】 Baba, M.; De Clercq, E.; Pauwels, R.; Herdewijn, P.; Balzarini, J.; Vanderhaeghe, H.; Broder, S.; 3'-Substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J Med Chem 1987, 30, 8, 1270-8. |
| 【5】 Kowollik, G.; Etzold, G.; Hintsche, R.; Langen, P.; Synthesis and reactivity of 3'-fluoro and 3'-chloro-3'-desoxy-thymidine. Tetrahedron 1971, 27, 2463-72. |
| 【6】 Langen, P.; Von Janta-Lipinski, M.; Gaertner, K.; Etzold, G.; Von Kowollik, G.; A novel access to 1-(2,3-didesoxy-3-fluoro-beta-D-ribofuranosyl)-pyrimidines. J Prakt Chem 1973, 315, 5, 895-900. |
| 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) | 12161 | Thymidine; 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 50-89-5 | C10H14N2O5 | 详情 | 详情 |
| (II) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (III) | 12163 | (1R,9R,10R)-10-(Hydroxymethyl)-4-methyl-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one | C10H12N2O4 | 详情 | 详情 | |
| (IV) | 12164 | [(1R,9R,10R)-4-methyl-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-10-yl]methyl methanesulfonate | C11H14N2O6S | 详情 | 详情 | |
| (V) | 12165 | [(2R,3S,5R)-3-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl methanesulfonate | C11H15FN2O6S | 详情 | 详情 | |
| (VI) | 12166 | 1-[(2R,4S,5R)-4-Hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C29H28N2O5 | 详情 | 详情 | |
| (VII) | 12167 | (2R,3S,5R)-2-(hydroxymethyl)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl methanesulfonate | C11H16N2O7S | 详情 | 详情 | |
| (VIII) | 12168 | (1R,9R,10R)-4-Methyl-10-[(trityloxy)methyl]-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one | C29H26N2O4 | 详情 | 详情 | |
| (IX) | 63321 | methyl 4-[2-(tert-butylamino)acetyl]-7-hydroxy-1H-indole-2-carboxylate | C16H20N2O4 | 详情 | 详情 |