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【结 构 式】 
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【分子编号】36958 【品名】1,4-dithiane-2,5-diol 【CA登记号】40018-26-6 |
【 分 子 式 】C4H8O2S2 【 分 子 量 】152.23832 【元素组成】C 31.56% H 5.3% O 21.02% S 42.13% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of 1,4-dithiane-2,5-diol (XII) with 2-(benzoyloxy)acetaldehyde (XIII) in hot pyridine gives 5-acetoxy-2-(benzoyloxymethyl)-1,3-oxathiolane (XIV), which is condensed with fully silylated cytosine (XV) (obtained by silylation of cytosine (XVI) with HMDS) by means of TBDMS-OTf, yielding, after acetylation with Ac2O, a mixture of the desired racemic-cis substituted fluorocytosine (XVII) along with its racemic trans isomer, which are separated by flash chromatography. The deacylation of (XVII) with ammonia in methanol gives the racemic cis-2-(hydroxymethyl)-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (XVIII), which is phosphorylated with POCl3 and water in trimethyl phosphate yielding the racemic phosphate (XIX). The enantioselective dephosphorylation of (XIX) with 5'-nucleotidase (Sigma), affords a mixture of the (+)-(cis)-dephosphorylated compound (XXI) and unreacted (-)-(cis)-compound (XX) that are separated by column chromatography. Finally, (XX) is dephosphorylated by means of alkaline phosphatase (Sigma) to afford the target compound.
| 【1】 Dionne, G. (BioChem Pharma Inc.); 1,3-Oxathiolane nucleoside analogues. EP 0526253; JP 1995500317; US 5538975; WO 9303027 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 36958 | 1,4-dithiane-2,5-diol | 40018-26-6 | C4H8O2S2 | 详情 | 详情 |
| (XIII) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (XIV) | 36964 | [5-(acetoxy)-1,3-oxathiolan-2-yl]methyl benzoate | C13H14O5S | 详情 | 详情 | |
| (XV) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (XVI) | 16747 | 4-amino-5-fluoro-2(1H)-pyrimidinone; 5-fluorocytosine | 2022-85-7 | C4H4FN3O | 详情 | 详情 |
| (XVII) | 36960 | [(2R,5S)-5-[4-(acetamido)-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl benzoate | C17H16FN3O5S | 详情 | 详情 | |
| (XVIII) | 36961 | 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H10FN3O3S | 详情 | 详情 | |
| (XIX) | 64685 | (rac)-({(2R*,5S*)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl}methyl dihydrogen phosphate) | C8H11FN3O6PS | 详情 | 详情 | |
| (XX) | 36962 | [(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl dihydrogen phosphate | C8H11FN3O6PS | 详情 | 详情 | |
| (XXI) | 36963 | 4-amino-5-fluoro-1-[(2S,5R)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone | C8H10FN3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)
| 【1】 Mansour T,Jin H.et al.1997.Processes for the diastereoselective synthesisof nucleoside analogues. US 5696254 |
| 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) | 36958 | 1,4-dithiane-2,5-diol | 40018-26-6 | C4H8O2S2 | 详情 | 详情 |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 66301 | (2S,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylic acid | C4H6O4S | 详情 | 详情 | |
| (IV) | 66302 | (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylic acid | 147027-04-1 | C4H6O4S | 详情 | 详情 |
| (V) | 15620 | (2R,5R)-5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid | 147027-05-2 | C6H8O5S | 详情 | 详情 |
| (VI) | 66303 | (2R,5S)-2-isopropyl-5-methylcyclohexanol | C10H20O | 详情 | 详情 | |
| (VII) | 55067 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(acetyloxy)-1,3-oxathiolane-2-carboxylate | C16H26O5S | 详情 | 详情 | |
| (VIII) | 66304 | C16H26O5S | 详情 | 详情 | ||
| (IX) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (X) | 66305 | (2S,5R)-(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate | C18H26FN3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【1】 Ren D．2005．Inclustrial scale preparation of emtricitabine.发明专利申请公开说明书，CN 1563002 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII） | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (I) | 36958 | 1,4-dithiane-2,5-diol | 40018-26-6 | C4H8O2S2 | 详情 | 详情 |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (VI) | 66303 | (2R,5S)-2-isopropyl-5-methylcyclohexanol | C10H20O | 详情 | 详情 | |
| (X) | 66305 | (2S,5R)-(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate | C18H26FN3O4S | 详情 | 详情 | |
| (XI) | 66306 | (2R,5S)-2-isopropyl-5-methylcyclohexyl 2-oxoacetate | C12H20O3 | 详情 | 详情 | |
| (XII) | 66308 | (5R)-(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate | C14H24O4S | 详情 | 详情 | |
| (XIII) | 66307 | (5R)-(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate | C16H26O5S | 详情 | 详情 |