5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione -Drug Synthesis Database

【结构式】

【分子编号】12199

【品名】5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione

【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%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VIa)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 5-methyl-5'-O-(triphenylmethyl)uridine (I) with MsCl and pyridine gives the dimesylate (II), which is treated with Li2Te in THF to yield the tritylated derivative (III) of the target compound.

参考文献中间体

合成目标

【1】 Clive, D.L.J.; et al.; Synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides by reaction of 5'-protected nucleoside 2',3'-dimesylates with telluride dianion: A general route from cis vicinal diols to olefins. J Org Chem 1996, 61, 21, 7426.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	41905	1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	C₂₉H₂₈N₂O₆	详情	详情
(II)	41906	1-[(2R,3R,4R,5R)-3,4-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	C₃₅H₄₀N₂O₆S₂	详情	详情
(III)	12199	5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione	C₂₉H₂₆N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The reaction of 5-methyluridine (I) with TrCl and pyridine gives the 5'-O-trityl derivative (II), which is oxidized with NaIO4 in ethanol/water to yield the dialdehyde (III). The Wittig reaction of (III) with methyltriphenylphosphonium bromide (IV) and t-BuOK in toluene to afford the bis vinyl compound (V), which is submitted to a ring closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to provide the unsaturated nucleoside (VI). Finally, this compound is deprotected by means of AcOH in water to furnish the target Stavudine.

参考文献中间体

合成目标

【1】 Ewing, D.F.; et al.; Synthesis of acyclic bis-vinyl pyrimidines: A general route to d4T via metathesis. Tetrahedron 2003, 59, 7, 941.

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)	12206	1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine	1463-10-1	C₁₀H₁₄N₂O₆	详情	详情
(II)	41905	1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione		C₂₉H₂₈N₂O₆	详情	详情
(III)	62190	(2R)-2-({(1R)-1-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-oxoethyl}oxy)-3-(trityloxy)propanal		C₂₉H₂₆N₂O₆	详情	详情
(IV)	30484	Methyl(triphenyl)phosphonium bromide	1779-49-3	C₁₉H₁₈BrP	详情	详情
(V)	62191	5-methyl-1-[(1R)-1-({(1S)-1-[(trityloxy)methyl]-2-propenyl}oxy)-2-propenyl]-2,4(1H,3H)-pyrimidinedione		C₃₁H₃₀N₂O₄	详情	详情
(VI)	12199	5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₂₉H₂₆N₂O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

The reaction of 5-methyluridine (I) with trityl chloride (II) and pyridine gives the 5'-O-trityl analogue (III), which is submitted to an oxidative cleavage of the vicinal dihydroxy group by means of NaIO4 in EtOH/water to yield the dialdehyde (IV). The double Wittig olefination of (IV) by means of methyltriphenylphosphonium bromide (V) and t-BuOK in toluene affords the bis alkene (VI), which is submitted to a ring closing metathesis by means of the Grubb's catalyst in dichloromethane to provide the unsaturated nucleoside (VII). Finally, this compound was deprotected by means of 80% AcOH to furnish the target Stavudine.

参考文献中间体

合成目标

【1】 Ewing, D.; Glacon, V.; Mackenzie, G.; Postel, D.; Len, C.; A novel approach to unsaturated acyclic nucleoside analogues and the first synthesis of d4T by ring closure metathesis. Tetrahedron Lett 2002, 43, 19, 3503.

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)	12206	1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine	1463-10-1	C₁₀H₁₄N₂O₆	详情	详情
(II)	28630	Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride	76-83-5	C₁₉H₁₅Cl	详情	详情
(III)	41905	1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione		C₂₉H₂₈N₂O₆	详情	详情
(IV)	62190	(2R)-2-({(1R)-1-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-oxoethyl}oxy)-3-(trityloxy)propanal		C₂₉H₂₆N₂O₆	详情	详情
(V)	30484	Methyl(triphenyl)phosphonium bromide	1779-49-3	C₁₉H₁₈BrP	详情	详情
(VI)	62191	5-methyl-1-[(1R)-1-({(1S)-1-[(trityloxy)methyl]-2-propenyl}oxy)-2-propenyl]-2,4(1H,3H)-pyrimidinedione		C₃₁H₃₀N₂O₄	详情	详情
(VII)	12199	5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₂₉H₂₆N₂O₄	详情	详情

Extended Information