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【结 构 式】

【分子编号】12191

【品名】((2R,3S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[[methyl(methylene)oxo-lambda(6)-sulfanyl]oxy]tetrahydro-2-furanyl)methyl methanesulfonate

【CA登记号】

【 分 子 式 】C13H20N2O8S2

【 分 子 量 】396.44248

【元素组成】C 39.39% H 5.08% N 7.07% O 32.29% S 16.18%

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:(II)

1) The first method ever reported involves the mesylation of thymidine (I) to give dimesylate (II), which is treated with sodium hydroxide in ethanol to yield oxetane (III). Finally, (III) is converted to stavudine by means of potassium tert-butoxide in DMSO. This process has been modified in order to obtain large quantities or to obtain [2-14C]-stavudine starting from [2-14C]-thymidine. 2) A second closely related method, but using a different protecting group strategy, involves tritylation of the primary hydroxyl group of thymidine to give (IVa), which is then mesylated to give (Va). Elimination with TBAF/THF or t-BuOK/DMSO yields compound (VI), which is finally deprotected with acetic acid. 3) A third synthesis starting from thymidine involves its protection with monomethoxytrityl chloride or picolyl chloride to give (IVb) or (IVc), respectively, which are mesylated to give (Vb) or (Vc). These are treated with phenyl diselenide and lithium aluminum hydride in tetrahydrofuran to yield compounds (VIIb) or (VIIc), which are treated with m-chloroperbenzoic acid in dichloromethane to afford (VIIIb) or (VIIIc). Finally, (VIIIb) is deprotected with methylamine in water and (VIIIc) is deprotected with acetic acid.

1 Martin, J.C.; Hitchcock, M.J.M.; Starrett, J.E. Jr.; Ghazzouli, I.; Mansuri, M.M.; Ho, H.-T.; Sommadossi, J.-P.; Brankovan, V.; Synthesis, anti-HIV activity, and biological properties of 2',3'-didehydro-2',3'-dideoxythymidine (D4T). Nucleosides Nucleotides 1989, 32, 461-6.
2 Starret, J.E. Jr.; Mansuri, M.M.; Martin, J.C.; Fuller, C.E.; Howell, H.G. (Bristol-Myers Squibb Co.); Production of 2',3'-dideoxy-2',3'-didehydronucleosides. EP 0334368 .
3 Lin, T.-S.; Prusoff, W.H. (Yale University); Pharmaceutical compsn. comprising 3'-deoxythymidin-2'-ene (3'-deoxy-2',3'-didehydrothymidine) in treating patients infected with retrovirus. EP 0273277 .
4 Mansuri, M.M.; Ghazzouli, I.; Starrett, J.E. Jr.; Hitchcock, M.J.; Sterzycki, R.Z.; Brankovan, V.; Lin, T.S.; August, E.M.; Prusoff, W.H.; Sommadossi, J.P.; et al.; 1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent. J Med Chem 1989, 32, 2, 461-6.
5 Lin, T.-S.; Gao, Y.-S.; August, E.M.; Prusoff, W.H.; Qian, H.-Y.; Synthesis of [2-14C]3'-deoxythymidin-2'-ene (d4T) and [5-125I]3'-azido-2',3'-dideoxy-5-iodouridine: Potent inhibitors of human immunodeficiency virus (HIV-1). J Label Compd Radiopharm 1989, 27, 6, 669-74.
6 Da Rooge, M.A.; Noel, M.; Horwitz, J.P.; Chua, J.; Klundt, I.L.; Nucleosides. IX. The formation of 2',3'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. J Org Chem 1966, 31, 205-11.
7 Chattopadhyaya, J.; Agback, P.; Vial, J.M.; A new synthesis of 1-(2,3-dideoxy-beta-D-glycero-pent-2-enofuranosyl)-thymine. A highly potent and selective anti-HIV agent. Nucleosides Nucleotides 1990, 9, 2, 245-58.
8 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.
9 Robinson, C.; Castaner, J.; Stavudine. Drugs Fut 1994, 19, 10, 925.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVa) 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
(IVb) 12194 1-((2R,4S,5R)-4-Hydroxy-5-[[(4-methoxyphenyl)(diphenyl)methoxy]methyl]tetrahydro-2-furanyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C30H30N2O6 详情 详情
(IVc) 12195 [(2R,3S,5R)-3-hydroxy-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl 2-pyridinecarboxylate C16H17N3O6 详情 详情
(Va) 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
(Vb) 12197 (2R,3S,5R)-2-[[(4-methoxyphenyl)(diphenyl)methoxy]methyl]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl methanesulfonate C31H32N2O8S 详情 详情
(Vc) 12198 [(2R,3S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl]methyl 2-pyridinecarboxylate C17H19N3O8S 详情 详情
(VIa) 12199 5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C29H26N2O4 详情 详情
(VIIb) 12200 1-[(2R,4R,5R)-5-[[(4-Methoxyphenyl)(diphenyl)methoxy]methyl]-4-(phenylselanyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C36H34N2O5Se 详情 详情
(VIIc) 12201 [(2R,3R,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-(phenylselanyl)tetrahydro-2-furanyl]methyl 2-pyridinecarboxylate C22H21N3O5Se 详情 详情
(VIIIb) 12202 1-((2R,5S)-5-[[(4-Methoxyphenyl)(diphenyl)methoxy]methyl]-2,5-dihydro-2-furanyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C30H28N2O5 详情 详情
(VIIIc) 12203 1-[(2R,5S)-5-(Methoxymethyl)-2,5-dihydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C11H14N2O4 详情 详情
(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) 12191 ((2R,3S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[[methyl(methylene)oxo-lambda(6)-sulfanyl]oxy]tetrahydro-2-furanyl)methyl methanesulfonate C13H20N2O8S2 详情 详情
(III) 12192 1-[(1R,3R,5R)-2,6-Dioxabicyclo[3.2.0]hept-3-yl]-5-methyl-2,4(1H,3H)-pyrimidinedione C10H12N2O4 详情 详情
Extended Information