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【结 构 式】

【分子编号】12165

【品名】[(2R,3S,5R)-3-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl methanesulfonate

【CA登记号】

【 分 子 式 】C11H15FN2O6S

【 分 子 量 】322.3143832

【元素组成】C 40.99% H 4.69% F 5.89% N 8.69% O 29.78% S 9.95%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

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
Extended Information