5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione -Drug Synthesis Database

【结构式】

【分子编号】38073

【品名】5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione

【CA登记号】69304-49-0

【分子式】C₆H₅BrN₂O₂

【分子量】217.02198

【元素组成】C 33.21% H 2.32% Br 36.82% N 12.91% O 14.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

The reaction of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of sodium ethoxide in refluxing ethanol gives the 3-oxa-2-oxobicyclic compound (III), which by reduction with NaBH4 in ethanol yields (1S,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The reaction of (IV) with diphenyldiazomethane by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloroethane affords (1R,7R)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylic acid ethyl ester (V), which is reduced with LiBH4 in THF giving the carbinol (VI). The reaction of (VI) with CBr4 and triphenylphosphine in dichloromethane yields the bromomethyl derivative (VII), which is condensed with 5-(2-(E)-bromovinyluracil (VIII) by means of K2CO3 and 18-crown-6 in hot DMF affording the expected addition compound (IX). Finally, this compound is deprotected with HCl in methanol.

参考文献中间体

合成目标

【1】 Onishi, T.; Mukai, C.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Bis(hydroxymethyl)cyclopropylmethyl pyrimidine derivs.,their preparation and their use as anti-viral agents. EP 0649840; JP 1995165731; US 5496824 .
【2】 Onishi, T.; Mukai, C.; Nakagawa, R.; et al.; Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety. J Med Chem 2000, 43, 2, 278.

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)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(II)	38067	(2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin	51594-55-9	C₃H₅ClO	详情	详情
(III)	38068	ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate		C₈H₁₀O₄	详情	详情
(IV)	38069	ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate		C₈H₁₄O₄	详情	详情
(V)	38070	ethyl (1R,7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate		C₂₁H₂₂O₄	详情	详情
(VI)	38071	[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol		C₁₉H₂₀O₃	详情	详情
(VII)	38072	(1R,7S)-1-(bromomethyl)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane		C₁₉H₁₉BrO₂	详情	详情
(VIII)	38073	5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione	69304-49-0	C₆H₅BrN₂O₂	详情	详情
(IX)	38074	5-[(E)-2-bromoethenyl]-1-[[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl]-2,4(1H,3H)-pyrimidinedione		C₂₅H₂₃BrN₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The condensation of the chiral dioxolane (I) with 5(E)-(2-bromovinyl)uracil (II) by means of Tbdms-OTf and lutidine gives the silylated nucleoside (II), which is purified by chromatography. Finally, this compound is deprotected by means of TBAF in acetonitrile. (1,2)

参考文献中间体

合成目标

【1】 Gumina, G.; Li, L.; Lee, C.S.; Cheng, Y.-C.; Choi, Y.; Tsujii, E.; Grill, S.; Gullen, E.; Chu, C.K.; Structure-activity relationships of (E)-5-(2-bromovinyl)uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses. J Med Chem 2000, 43, 13, 2538.
【2】 Chu, C.K.; Cheng, Y.-C.; Li, L.; Chai, Y. (University of Georgia; Yale University); 5-(E)-Bromovinyl uracil analogues and related pyrimidine nucleosides as anti-viral agents and methods of use. CA 2378370; EP 1204415; US 6653318; WO 0106986 .

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)	51553	(2R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl acetate		C₁₂H₂₄O₅Si	详情	详情
(II)	38073	5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione	69304-49-0	C₆H₅BrN₂O₂	详情	详情
(III)	51554	5-[(E)-2-bromoethenyl]-1-[(2R,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-2,4(1H,3H)-pyrimidinedione		C₁₆H₂₅BrN₂O₅Si	详情	详情

Extended Information