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【结 构 式】 
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【分子编号】57515 【品名】methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate 【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% |
合成路线1
该中间体在本合成路线中的序号：(IIIb)Ketal exchange between the chiral acetonide (I) and 2-(benzoyloxy)acetaldehyde (II) under acidic conditions affords the 2-(benzoyloxymethyl) dioxolane (III) as a diastereomeric mixture. Alternatively, diazotization of D-serine (IV) in the presence of NaNO2 and H2SO4 produces D-glyceric acid (V), which is further esterified with methanol to afford the methyl ester (VI). Condensation of dihydroxy ester (VI) with 2-(benzoyloxy)acetaldehyde dimethyl acetal (VII) then gives dioxolane (III).
| 【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 . |
| 【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 . |
| 【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 57514 | methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (IIIb) | 57515 | methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (I) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (II) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (IV) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (V) | 57516 | (2R)-2,3-dihydroxypropanoic acid | C3H6O4 | 详情 | 详情 | |
| (VI) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (VII) | 57517 | 2,2-dimethoxyethyl benzoate | C11H14O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IIIb),(X)Selective hydrolysis of the methyl esters (III) with LiOH provides the desired cis-dioxolane acid (IX) and the corresponding trans isomer (VIII), which are separated by column chromatography. Alternatively, ester (III) is subjected to enzymatic resolution with several different enzymes to provide a mixture of the undesired trans-dioxolane acid (VIII) and the unreacted cis-ester (X), separable by partition between H2O and EtOAc. The desired cis-ester (X) is then hydrolyzed with LiOH to the carboxylic acid (IX). Oxidative decarboxylation of acid (IX) employing lead tetraacetate furnishes the acetoxy dioxolane (XI). After silylation of 2-amino-6-chloropurine (XII) with hexamethyldisilazane in the presence of ammonium sulfate, coupling with the acetoxy dioxolane (XI), promoted by either trimethylsilyl triflate or by iodotrimethylsilane, gives rise to an anomeric mixture of adducts (XIII). Following chromatographic isolation of the target cis-anomer, chloride displacement with cyclopropylamine yields the diamino purine derivative (XIV). The benzoate ester group of (XIV) is finally hydrolyzed to the title compound by means of methanolic ammonia.
| 【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 . |
| 【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 . |
| 【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 57514 | methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (IIIb),(X) | 57515 | methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (XIa) | 57519 | [(2R,4R)-4-(acetyloxy)-1,3-dioxolan-2-yl]methyl benzoate | C13H14O6 | 详情 | 详情 | |
| (XIb) | 57520 | [(2R,4S)-4-(acetyloxy)-1,3-dioxolan-2-yl]methyl benzoate | C13H14O6 | 详情 | 详情 | |
| (XIIIa) | 57521 | [(2R,4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolan-2-yl]methyl benzoate | C16H14ClN5O4 | 详情 | 详情 | |
| (XIIIb) | 57522 | [(2R,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolan-2-yl]methyl benzoate | C16H14ClN5O4 | 详情 | 详情 | |
| (VIII) | 57518 | (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (IX) | 57524 | (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (XII) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (XIV) | 57523 | {(2R,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-1,3-dioxolan-2-yl}methyl benzoate | C19H20N6O4 | 详情 | 详情 |