1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione -Drug Synthesis Database

【结构式】

【分子编号】31154

【品名】1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione

【CA登记号】54-42-2

【分子式】C₉H₁₁IN₂O₅

【分子量】354.10129

【元素组成】C 30.53% H 3.13% I 35.84% N 7.91% O 22.59%

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：(I)

The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.

参考文献中间体

合成目标

【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 .
【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 .
【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139.
【4】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
	19171	1-(Chloromethyl)benzene; Benzyl chloride	100-44-7	C₇H₇Cl	详情	详情
(I)	31154	1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione	54-42-2	C₉H₁₁IN₂O₅	详情	详情
(II)	31155	[(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₁₆H₁₅IN₂O₆	详情	详情
(III)	31156	benzyl 2,2,2-trichloroethanimidoate	81927-55-1	C₉H₈Cl₃NO	详情	详情
(IV)	31157	[(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₁IN₂O₆	详情	详情
(V)	31158	1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione		C₁₆H₁₇IN₂O₅	详情	详情
(IX)	11875	1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine	951-78-0	C₉H₁₂N₂O₅	详情	详情
(X)	31159	1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₂₈H₂₆N₂O₅	详情	详情
(XI)	31160	1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₃₅H₃₂N₂O₅	详情	详情
(XII)	31161	1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione		C₃₆H₃₁F₃N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Coupling of 5-iodo-2'-deoxyuridine (I) with 1-decyne (II) in the presence of cuprous iodide and tetrakis(triphenylphosphine)palladium furnished the 5-decynyl uridine derivative (III). This was then cyclized to the title furopyrimidinone by treatment with cuprous iodide and triethylamine in refluxing methanol.

参考文献中间体

合成目标

【1】 Balzarini, J.; McGuigan, C.; Andrei, G.; Srinivasan, S.; Snoeck, R.; De clercq, E.; Bicyclic nucleoside inhibitors of varicella-Zoster virus (VZV): The effect of terminal unsaturation in the side chain. Bioorg Med Chem Lett 2001, 11, 3, 391.
【2】 Brancale, A.; Snoeck, R.; Yarnold, C.J.; Barucki, H.; Velázquez, S.; Jones, G.; Andrei, G.; McGuigan, C.; De Clercq, E.; Balzarini, J.; Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base. J Med Chem 1999, 42, 22, 4479.
【3】 Jones, G.; Balzarini, J.; McGuigan, C.; Yarnold, C.; De Clercq, E. (University College, Cardiff); Anti-viral pyrimidine nucleoside analogues. EP 0980377; WO 9849177 .

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)	31154	1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione	54-42-2	C₉H₁₁IN₂O₅	详情	详情
(II)	42585	1-decyne	764-93-2	C₁₀H₁₈	详情	详情
(III)	42586	5-(1-decynyl)-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione		C₁₉H₂₈N₂O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

5-Iodo-2'-deoxyuridine (I) is protected at the primary hydroxyl group with 4,4'-dimethoxytrityl chloride to afford the 5'-O-trityl derivative (II). Subsequent esterification of the remaining hydroxyl group of (II) with succinic anhydride (III) yields the succinate mono-ester (IV). Acid (IV) is then coupled with diethylene glycol in the presence of DCC to produce (V). The O-trityl group of (V) is finally removed by treatment with formic acid, to give the title compound.

参考文献中间体

合成目标

【1】 Bonina, F.P.; et al.; New oligoethylene ester derivatives of 5-iodo-2'-deoxyuridine as dermal prodrugs: Synthesis, physicochemical properties, and skin permeation studies. J Pharm Sci 2002, 91, 1, 171.

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)	31154	1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione	54-42-2	C₉H₁₁IN₂O₅	详情	详情
(II)	57566	1-((2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxytetrahydro-2-furanyl)-5-iodo-2,4(1H,3H)-pyrimidinedione		C₃₀H₂₉IN₂O₇	详情	详情
(III)	11291	Dihydro-2,5-furandione; Succinic anhydride	108-30-5	C₄H₄O₃	详情	详情
(IV)	57567	4-({(2R,3S,5R)-2-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl}oxy)-4-oxobutanoic acid		C₃₄H₃₃IN₂O₁₀	详情	详情
(V)	57568	1-{(2R,3S,5R)-2-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl} 4-[2-(2-hydroxyethoxy)ethyl] succinate		C₃₈H₄₁IN₂O₁₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

5-Iodo-2'-deoxyuridine (I) is protected at the primary hydroxyl group with 4,4'-dimethoxytrityl chloride to afford the 5'-O-trityl derivative (II). Subsequent esterification of the remaining hydroxyl group of (II) with succinic anhydride (III) yields the succinate mono-ester (IV). Acid (IV) is then coupled with triethylene glycol in the presence of DCC to produce (V). The O-trityl group of (V) is finally removed by treatment with formic acid, to give the title compound.

参考文献中间体

合成目标

【1】 Bonina, F.P.; et al.; New oligoethylene ester derivatives of 5-iodo-2'-deoxyuridine as dermal prodrugs: Synthesis, physicochemical properties, and skin permeation studies. J Pharm Sci 2002, 91, 1, 171.

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)	31154	1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione	54-42-2	C₉H₁₁IN₂O₅	详情	详情
(II)	57566	1-((2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxytetrahydro-2-furanyl)-5-iodo-2,4(1H,3H)-pyrimidinedione		C₃₀H₂₉IN₂O₇	详情	详情
(III)	11291	Dihydro-2,5-furandione; Succinic anhydride	108-30-5	C₄H₄O₃	详情	详情
(IV)	57567	4-({(2R,3S,5R)-2-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl}oxy)-4-oxobutanoic acid		C₃₄H₃₃IN₂O₁₀	详情	详情
(V)	57569	1-{(2R,3S,5R)-2-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl} 4-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl} succinate		C₄₀H₄₅IN₂O₁₃	详情	详情

Extended Information