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【结 构 式】 
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【分子编号】55533 【品名】[(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol 【CA登记号】 |
【 分 子 式 】C11H14N6O 【 分 子 量 】246.272 【元素组成】C 53.65% H 5.73% N 34.13% O 6.5% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of the commercially available (1S-cis)-2-cyclopentan-1,4-diol 4-acetate (I) with methyl pyrocarbonate and DMAP in THF gives the carbonate ester (II), which by reaction with nitromethane (III), triisopropyl phosphite and a Pd catalyst, yields (1R-cis)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (IV). The hydrolysis of (IV) by means of Ts-OH in methanol affords the corresponding alcohol (V), which by treatment with O3, NaOMe and NaBH4 in methanol provides (1R-cis)-4-(hydroxymethyl)-2-cyclopenten-1-ol (VI). The selective monotritylation of the primary OH group of (VI) with trityl chloride (VII) in pyridine gives the trityl ether (VIII), which is condensed with 2-amino-6-chloropurine (IX) by means of Pd(PPh3)4 in THF to yield the adduct (X). The destritylation of (X) with HOAc/water affords the hydroxymethyl compound (XI), which is finally dechlorinated by hydrolysis with hot HCl or NaOH to provide the target (-)-carbovir. Alternatively, the dechlorination of (XI) can be performed by reaction of (XI) with liquid ammonia at 75-80 C in a Parr bomb to give the diaminopurine (XII), which is finally submitted to an enzymatic deamination with adenosine deaminase (from calf intestinal mucosa).
| 【1】 Vince, R.; Peterson, M.L.; Lackey, J.W.; Mook, R.A. Jr.; Partridge, J.J. (GlaxoSmithKline plc); Synthesis of purine substd. cyclopentene derivs.. US 5126452 . |
| 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) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (II) | 55528 | (1R,4S)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl acetate | C9H12O5 | 详情 | 详情 | |
| (III) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (IV) | 55529 | (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl acetate | C8H11NO4 | 详情 | 详情 | |
| (V) | 55530 | (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-ol | C6H9NO3 | 详情 | 详情 | |
| (VI) | 45405 | (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VII) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (VIII) | 55531 | (1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-ol | C25H24O2 | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 55532 | 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-amine; 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-ylamine | C30H26ClN5O | 详情 | 详情 | |
| (XI) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XII) | 55533 | [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H14N6O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The selective silylation of (-)-aristeromycin (I) with Hdms-Cl and imidazole gives the monosilyl ether (II), which is treated with thiocarbonyl dimidazole (TCDI) in hot ethyl acetate to yield the cyclic thiocarbonate (III). The reaction of (III) with 1,3-dimethyl-1,3,2-diazaphospholidine (DMPDP) in refluxing THF affords the desired cyclopentene derivative (IV). In an alternative method, the reaction of (II) with methyl orthoformate provides the cyclic orthoester (V), which undergoes thermal elimination with acetic acid at high temperature giving the desired cyclopentene derivative (IV). The oxidation of (IV) with MCPBA in chloroform yields the N-oxide (VI), which by reaction with Br-CN in methanol affords the oxadiazole derivative (VII). The cleavage of the oxadiazole ring of (VII) and simultaneous methylation with TEA and Me-I provided the cyanoimino derivative (VIII), which is submitted to a Dimroth rearrangement by means of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in refluxing aqueous ethanol to give the methoxylated diaminopurine (IX). The reductive cleavage of the methoxyamino group of (IX) with Al/Hg in aqueous THF yields the silylated diaminopurine (X), which is deprotected with HCl in ethanol to afford the free diaminopurine precursor (XI). Finally, this compound is enzymatically deaminated by means of adenosine deaminase to furnish the target (-)-carbovir.
| 【1】 Exall, A.M.; et al.; Synthesis from (-)-aristeromycin and x-ray structure of (-)-carbovir. J Chem Soc - Perkins Trans I 1991, 10, 2467. |
| 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) | 55534 | (1R,2S,3R,5R)-3-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)-1,2-cyclopentanediol | C11H15N5O3 | 详情 | 详情 | |
| (II) | 55535 | (1R,2S,3R,5R)-3-(6-amino-9H-purin-9-yl)-5-({[hexyl(dimethyl)silyl]oxy}methyl)-1,2-cyclopentanediol | C19H33N5O3Si | 详情 | 详情 | |
| (III) | 55536 | (4R,6R)-4-(6-amino-9H-purin-9-yl)-6-({[hexyl(dimethyl)silyl]oxy}methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxole-2-thione | C20H31N5O3SSi | 详情 | 详情 | |
| (IV) | 55537 | 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-amine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-ylamine | C19H31N5OSi | 详情 | 详情 | |
| (V) | 55538 | 9-[(4R,6R)-6-({[hexyl(dimethyl)silyl]oxy}methyl)-2-methoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(4R,6R)-6-({[hexyl(dimethyl)silyl]oxy}methyl)-2-methoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C21H35N5O4Si | 详情 | 详情 | |
| (VI) | 55539 | 6-amino-9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-1-ium-1-olate | C19H31N5O2Si | 详情 | 详情 | |
| (VII) | 55540 | 7-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl][1,2,4]oxadiazolo[3,2-i]purin-2(7H)-imine | C20H30N6O2Si | 详情 | 详情 | |
| (VIII) | 55541 | 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-1-methoxy-1,9-dihydro-6H-purin-6-ylidenecyanamide | C21H32N6O2Si | 详情 | 详情 | |
| (IX) | 55542 | 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-6-(methoxyamino)-9H-purin-2-ylamine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-6-(methoxyamino)-9H-purin-2-amine | C20H34N6O2Si | 详情 | 详情 | |
| (X) | 55543 | 2-amino-9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-ylamine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purine-2,6-diamine | C19H32N6OSi | 详情 | 详情 | |
| (XI) | 55533 | [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H14N6O | 详情 | 详情 |