[(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate -Drug Synthesis Database

【结构式】

【分子编号】25845

【品名】[(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate

【CA登记号】

【分子式】C₁₃H₁₄O₆

【分子量】266.25056

【元素组成】C 58.65% H 5.3% O 36.05%

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：(XIII)

In a related procedure, 1,6-anhydro-L-gulose (IX) was obtained from L-gulose (VIII) by treatment with 0.5 N HCl. Oxidative cleavage of (IX) by NaIO4, followed by reduction of the aldehyde groups with NaBH4, led to the dioxolane triol (X), which was further protected as the isopropylidene ketal (XI). Benzoylation of the free hydroxyl of (XI), followed by acidic hydrolysis of the acetonide group, furnished the benzoate diol (XII). Then, oxidation of the vicinal diol moiety of (XII), by means of RuO2 in the presence of NaIO4, afforded carboxylic acid (III). Oxidative decarboxylation of acid (III) with lead tetraacetate produced the key acetoxy dioxolane (XIII). This was coupled with the silylated N-acetylcytosine (XIV) in the presence of trimethylsilyl triflate to yield a mixture of anomers, which were separated by column chromatography. Final hydrolysis of the desired isomer (VII) was then performed by treatment with methanolic ammonia.

参考文献中间体

合成目标

【1】 Kim, H.O.; et al.; Potent anti-HIV and anti-HBV activities of (-)-L-beta-dioxolane-C and (+)-L-beta-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett 1992, 33, 46, 6899.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	25844	(2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid	C₁₂H₁₂O₆	详情	详情
(VII)	56696	{(2S,4S)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl}methyl benzoate	C₁₇H₁₇N₃O₆	详情	详情
(VIII)	36947	(3S,4S,5S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol	C₆H₁₂O₆	详情	详情
(IX)	25839	(1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol	C₆H₁₀O₅	详情	详情
(X)	56697	(1R)-1-[(2S,4S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-1,2-ethanediol	C₆H₁₂O₅	详情	详情
(XI)	56698		C₉H₁₆O₅	详情	详情
(XII)	56699	{(2S,4S)-4-[(1R)-1,2-dihydroxyethyl]-1,3-dioxolan-2-yl}methyl benzoate	C₁₃H₁₆O₆	详情	详情
(XIII)	25845	[(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate	C₁₃H₁₄O₆	详情	详情
(XIV)	56700	N-{2-[(trimethylsilyl)oxy]-4-pyrimidinyl}acetamide	C₉H₁₅N₃O₂Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

L-Gulono-gamma-lactone (I) was reduced with DIBAL and then protected as the diisopropylidene ketal (III). This was converted to 1,6-anhydrogulopyranose (IV) upon treatment with 0.5N HCl. Subsequent oxidative cleavage of (IV) with NaIO4, followed by reduction with NaBH4 provided triol (V), which was protected as the isopropylidene derivative (VI) with acetone and TsOH. Condensation of (VI) with benzoyl chloride in the presence of pyridine yielded benzoate ester (VII). Then, ketal deprotection of (VII) afforded diol (VIII). Oxidative treatment with NaIO4/RuO2 produced acid (IX), and further oxidative decarboxylation with Pb(OAc)4 furnished dioxolanyl acetate (X). 5-Iodouracil (XI) was silylated using hexamethyldisilazane and a catalytic amount of (NH4)2SO4. The resulting silylated uracil (XII) was coupled with dioxolanyl acetate (X) in the presence of trimethylsilyl triflate to afford an anomeric mixture of nucleosides (XIII). Title compound was then obtained by deprotection of the benzoate ester of the mixture (XIII) with methanolic ammonia, followed by chromatographic isolation of the desired L-anomer.

参考文献中间体

合成目标

【1】 Kim, H.O.; et al.; L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: Asymetric synthesis and structure - Activity relationships. J Med Chem 1993, 36, 5, 519.
【2】 Lin, J.-S.; et al.; Structure-activity relationships of L-dioxolane uracil nucleosides as anti-epstein barr virus agents. J Med Chem 1999, 42, 12, 2212.

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)	25836	(3S,4R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone		C₆H₁₀O₆	详情	详情
(II)	25837	(3S,4R)-5-[(1S)-1,2-dihydroxyethyl]tetrahydro-2,3,4-furantriol		C₆H₁₂O₆	详情	详情
(III)	25838	(3aS,6aS)-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol	14131-84-1	C₁₂H₂₀O₆	详情	详情
(IV)	25839	(1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol		C₆H₁₀O₅	详情	详情
(V)	25840	(1S)-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-1,2-ethanediol		C₆H₁₂O₅	详情	详情
(VI)	25841	4-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxqlan-2(S)-ymethanol		C₉H₁₆O₅	详情	详情
(VII)	25842	Benzoic acid 4-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxolan-2(S)-ylmethyl ester		C₁₆H₂₀O₆	详情	详情
(VIII)	25843	[(2S)-4-[(1S)-1,2-dihydroxyethyl]-1,3-dioxolan-2-yl]methyl benzoate		C₁₃H₁₆O₆	详情	详情
(IX)	25844	(2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid		C₁₂H₁₂O₆	详情	详情
(X)	25845	[(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate		C₁₃H₁₄O₆	详情	详情
(XI)	11876	1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione		C₉H₁₂I₂N₂O₅	详情	详情
(XII)	25846	5-iodo-2,4-bis[(trimethylsilyl)methyl]pyrimidine		C₁₂H₂₃IN₂Si₂	详情	详情
(XIII)	25847	[(2S)-4-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl]methyl benzoate		C₁₅H₁₃IN₂O₆	详情	详情

Extended Information