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【结 构 式】 
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【药物名称】MDL-201449A 【化学名称】(1R,3R)-trans-9-(3-Hydroxycyclopentyl)adenine hydrochloride 【CA登记号】149342-61-0 【 分 子 式 】C10H14ClN5O 【 分 子 量 】255.70898 |
【开发单位】Aventis Pharma (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants |
合成路线1
The reaction of cyclopentadiene (I) with Br2 gives 1,4-dibromo-2-cyclopentene (II), which is treated with potassium acetate in tert-butanol yielding 1,4-diacetoxy-2-cyclopentene (III). The hydrolysis of (III) with KHCO3 in methanol affords 2-cyclopentene-1,4-diol (IV) as a mixture of the cis and trans isomers. The treatment of (cis/trans) (IV) or (cis) (IV) with pancreatin, vinyl acetate (V) and triethylamine gives (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is hydrogenated with H2 over RaNi in ethanol to yield the corresponding saturated (1S,3R)-3-acetoxycyclopentanol (VII). The reaction of (VII) with methanesulfonyl chloride and TEA in dichloromethane affords the corresponding mesylate (VIII), which is condensed with adenine (IX) by means of NaH in hot DMF providing the final intermediate (X). Finally, this compound is deacetylated with HCl in refluxing ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (cis/trans)(IV) | 21533 | 4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (cis)(IV) | 33168 | (1R,3S)-4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (I) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 33167 | 3,5-dibromo-1-cyclopentene | C5H6Br2 | 详情 | 详情 | |
| (III) | 21534 | 4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 |
合成路线2
The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)(XIV) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 | |
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (XII) | 33173 | 4-hydroxy-2-cyclopenten-1-one | C5H6O2 | 详情 | 详情 | |
| (XIII) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XV) | 33175 | (1S)-2-cyclopenten-1-yl acetate | C7H10O2 | 详情 | 详情 | |
| (XVI) | 64705 | (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XVII) | 33176 | (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol | C11H24O2Si | 详情 | 详情 | |
| (XVIII) | 33177 | (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate | C12H24O4SSi | 详情 | 详情 | |
| (XIX) | 33178 | 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine | C16H27N5OSi | 详情 | 详情 |