|
【结 构 式】 
|
【分子编号】45339 【品名】 【CA登记号】 |
【 分 子 式 】C8H11N 【 分 子 量 】121.18208 【元素组成】C 79.29% H 9.15% N 11.56% |
合成路线1
该中间体在本合成路线中的序号：(V)The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.
| 【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071. |
| 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) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 33168 | (1R,3S)-4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (III) | 45374 | (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (IV) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (V) | 45339 | C8H11N | 详情 | 详情 | ||
| (VI) | 45400 | (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol | C11H18O3 | 详情 | 详情 | |
| (VII) | 45401 | tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether | C17H32O3Si | 详情 | 详情 | |
| (VIII) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (IX) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (X) | 45402 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol | C12H23ClO2Si | 详情 | 详情 | |
| (XI) | 45403 | tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane | C12H22O2Si | 详情 | 详情 | |
| (XII) | 45404 | ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol | C12H24O2Si | 详情 | 详情 | |
| (XIII) | 45405 | (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XIV) | 45406 | [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XV) | 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 |
| (XVI) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Treatment of [U-ring-14C] acetophenone (I) with O-methylhydroxylamine hydrochloride in pyridine/EtOH and catalytic MgSO4 yields labeled acetophenone oxime methyl ether (II), which is then subjected to Didier's enantioselective reduction with BH3·THF and 1S,2R-1-amino-indan-2-ol (III) to provide labeled (S)-(IV). Finally, phenylethylamine (S)-(IV) is coupled to chiral acid (V) with 1-hydroxybenzotriazole hydrate (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine (NMM).
| 【1】 Zhang, Y.S.; Synthesis of 14C-labeled S-(-)-1-phenylethylamine and its application to the synthesis of [14C] CI-1021, a potential antiemetic agent(1). J Label Compd Radiopharm 2000, 43, 11, 1087. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (I) | 45337 | C8H8O | 详情 | 详情 | ||
| (II) | 44172 | 1-phenyl-1-ethanone O-methyloxime | C9H11NO | 详情 | 详情 | |
| (II) | 45338 | C9H11NO | 详情 | 详情 | ||
| (III) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (IV) | 45339 | C8H11N | 详情 | 详情 | ||
| (V) | 44173 | (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid | C22H20N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)Cyclization of oxoester (I) with aqueous hydroxylamine at 0 C gave a mixture of two isoxazoles (II) and (III), which were separated by column chromatography. Methylation of (II) with ethereal diazomethane provided methyl ether (IV). This was regioselectively brominated with Br2 at 50 C to give bromomethyl compound (V). Further treatment with dimethyl acetamidomalonate (VI) and NaOMe in refluxing methanol gave (VII) (1). Then, hydrolysis and decarboxylation of malonate (VII) in refluxing 2 M HCl afforded racemic amino acid (VIII), and subsequent protection with di-tert-butyl dicarbonate gave carbamate (IX). Formation of the salt with (S)-1-phenylethylamine (X) and recrystallization from EtOH-Et2O provided pure (S)-amino acid as the phenylethylamine salt (XI). Free acid was obtained by treatment with acetic acid, and then a reflux in concentrated HBr effected hydrolysis of both methyl ether and carbamate groups to afford the target (S)-amino acid.
| 【1】 Johansen, T.N.; et al.; Excitatory amino acid receptor ligands: Resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid. J Med Chem 1998, 41, 6, 930-939. |
| 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) | 18096 | methyl 2-acetylhexanoate | C9H16O3 | 详情 | 详情 | |
| (II) | 18097 | 4-butyl-5-methyl-3-isoxazolol | C8H13NO2 | 详情 | 详情 | |
| (III) | 18098 | 4-butyl-3-methyl-5(2H)-isoxazolone | C8H13NO2 | 详情 | 详情 | |
| (IV) | 18099 | 4-butyl-3-methoxy-5-methylisoxazole; 4-butyl-5-methyl-3-isoxazolyl methyl ether | C9H15NO2 | 详情 | 详情 | |
| (V) | 18100 | 5-(bromomethyl)-4-butyl-3-isoxazolyl methyl ether; 5-(bromomethyl)-4-butyl-3-methoxyisoxazole | C9H14BrNO2 | 详情 | 详情 | |
| (VI) | 18101 | dimethyl 2-(acetamido)malonate | 60187-67-9 | C7H11NO5 | 详情 | 详情 |
| (VII) | 18102 | dimethyl 2-(acetamido)-2-[(4-butyl-3-methoxy-5-isoxazolyl)methyl]malonate | C16H24N2O7 | 详情 | 详情 | |
| (VIII) | 18103 | 3-(4-butyl-3-methoxy-5-isoxazolyl)alanine | C11H18N2O4 | 详情 | 详情 | |
| (IX) | 18104 | N-(tert-butoxycarbonyl)-3-(4-butyl-3-methoxy-5-isoxazolyl)alanine | C16H26N2O6 | 详情 | 详情 | |
| (X) | 45339 | C8H11N | 详情 | 详情 | ||
| (XI) | 18106 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-butyl-3-methoxy-5-isoxazolyl)propionic acid | C16H26N2O6 | 详情 | 详情 |