|
【结 构 式】 
|
【分子编号】25844 【品名】(2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid 【CA登记号】 |
【 分 子 式 】C12H12O6 【 分 子 量 】252.22368 【元素组成】C 57.14% H 4.8% O 38.06% |
合成路线1
该中间体在本合成路线中的序号：(III)Displacement of the chlorine atom of (I) with potassium benzoate in boiling DMF afforded benzoate ester (II). The hydroxymethyl group of (II) was subsequently oxidized to carboxylic acid (III) employing pyridinium dichromate. Conversion of acid (III) to the corresponding mixed anhydride with ethyl chloroformate, followed by Baeyer-Villiger oxidation with m-chloroperbenzoic acid, gave rise to the m-chlorobenzoyloxy dioxolane (IV). This was then coupled to cytosine (V) following a previously reported procedure to produce adduct (VI) as a cis/trans mixture. After acetylation with Ac2O, the desired cis-isomer (VII) was isolated by flash chromatography. The title compound was finally obtained by basic hydrolysis (VII).
| 【1】 Belleau, B.; Dixit, D.; Nguyen-Ba, N. (Shire BioChem Inc.); 2-Substd.-4-substd.-1,3-dioxolanes, synthesis and use thereof. EP 0337713 . |
| 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) | 56692 | [(2S,4R)-2-(chloromethyl)-1,3-dioxolan-4-yl]methanol | C5H9ClO3 | 详情 | 详情 | |
| (II) | 56693 | [(2S,4R)-4-(hydroxymethyl)-1,3-dioxolan-2-yl]methyl benzoate | C12H14O5 | 详情 | 详情 | |
| (III) | 25844 | (2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (IV) | 56694 | (2S)-2-[(benzoyloxy)methyl]-1,3-dioxolan-4-yl 3-chlorobenzoate | C18H15ClO6 | 详情 | 详情 | |
| (V) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (VI) | 56695 | {(2S)-4-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl}methyl benzoate | C15H15N3O5 | 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 |
合成路线2
该中间体在本合成路线中的序号：(III)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.
| 【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 | CAS号 | 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3
该中间体在本合成路线中的序号：(IX)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.
| 【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 |