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【结 构 式】 
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【分子编号】29876 【品名】9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine 【CA登记号】 |
【 分 子 式 】C29H26FN5O2 【 分 子 量 】495.5563432 【元素组成】C 70.29% H 5.29% F 3.83% N 14.13% O 6.46% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new synthesis of lodenosine has been described: The selective benzoylation of the 6-chloropurine riboside (I) with benzoyl chloride and triethylamine through the formation of a complex with dibutyl tin oxide, gives the 3'-O-benzoyl derivative (II), which is purified by crystallization (minor impurities, about 3%, of the 2'-O derivative are present). The protection of the primary OH group of (II) by reaction with trityl chloride, DMAP and Et3N in DMF yields the 5'-O-trityl derivative (III), which is treated with DAST and pyridine to afford the fluorinated arabinofuranoside (IV). The reaction of (IV) with ammonia in methanol displaces the 6-Cl atom and hydrolyzes the 3'-O-benzoyl group giving the fluorinated arabinofuranosyladenine (V). The reaction of (V) with phenyl chlorothionoformate and DMAP in acetonitrile yields the thiocarbonate (VI), which is treated with tris(trimethylsilyl)silane and AIBN in hot toluene to afford the 3'-deoxy compound (VII). Finally, this compound is deprotected by reaction with HCl in methanol/water.
| 【1】 Izawa, K.; Satoh, Y.; Takamatsu, S.; Kozai, S.; Maruyama, T.; Synthesis of 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine bearing selectively removable protecting group. Chem Pharm Bull 1999, 47, 7, 966. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 | |
| (I) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 29871 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydro-3-furanyl benzoate | C17H15ClN4O5 | 详情 | 详情 | |
| (III) | 29872 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H29ClN4O5 | 详情 | 详情 | |
| (IV) | 29873 | (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H28ClFN4O4 | 详情 | 详情 | |
| (V) | 29874 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H26FN5O3 | 详情 | 详情 | |
| (VI) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (VII) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)An improved synthesis of lodenosine has been reported: The reaction of the chloropurine derivative (I) with trityl chloride and diisopropylamine in DMF gives the 5'-O-trityl-purine (II), which is treated with benzoyl chloride and pyridine in toluene to afford the 3'-O-benzoyl-5'-O-trityl-purine (III) -- some of the 2'-O-benzyl regioisomer is also isolated and is recycled after acyl migration by reaction with TEA. The reaction of purine (III) with trifluoromethanesulfonyl chloride and DMAP in toluene yields the 3'-O-benzoyl-2'-O-sulfonyl-5'-O-trityl-purine (IV), which is treated with HF and TEA to provide the 2'-beta-fluoro-purine (V). The reaction of compound (V) with ammonia in methanol gives the adenosine derivative (VI), which is treated with O-phenyl chlorothioformate and DMAP in pyridine to yield the thiocarbonate (VIII). The deoxygenation of (VIII) is performed with diphenylsilane and AIBN affording 5'-O-trityl-lodenosine (IX), which is finally deprotected with 80% HOAc.
| 【1】 Katayama, S.; Hirose, N.; Izawa, K.; Takamatsu, S.; Maruyama, T.; Improved synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) using triethylamine trihydrofluoride. Tetrahedron Lett 2001, 42, 12, 2321. |
| 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) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 48718 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol | C29H25ClN4O4 | 详情 | 详情 | |
| (III) | 29872 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H29ClN4O5 | 详情 | 详情 | |
| (IV) | 48719 | (2R,3R,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C37H28ClF3N4O7S | 详情 | 详情 | |
| (V) | 29873 | (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H28ClFN4O4 | 详情 | 详情 | |
| (VI) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (VII) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VIII) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (IX) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)A practical synthesis of lodenosine has been reported: Selective tritylation of the chloropurine derivative (I) at the primary OH group by treatment with trityl chloride, TEA and DMAP in DMF gives the 5'-O-trityl ether (II), which is fluorinated with diethylamino sulfur trifluoride (DAST) and pyridine in dichloromethane to yield the 2'-beta-fluoro derivative (III). Reaction of compound (III) with ammonia in THF affords the tritylated lodenosine derivative (IV), which is finally deprotected with 37% HCl in methanol/water.
| 【1】 Hirose, N.; Takamatsu, S.; Katayama, S.; Naito, M.; Izawa, K.; Maruyama, T.; Practical synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. Tetrahedron Lett 2001, 42, 12, 2325. |
| 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) | 48720 | (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol | C10H11ClN4O3 | 详情 | 详情 | |
| (II) | 48721 | (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol | C29H25ClN4O3 | 详情 | 详情 | |
| (III) | 48722 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine | C29H24ClFN4O2 | 详情 | 详情 | |
| (IV) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The reaction of inosine (I) with trimethyl orthoacetate and AcOH, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is deacetylated with NaOMe in methanol to afford the dihydroxy compound (V). The selective tritylation of the primary OH group of (V) with Tr-Cl and collidine in acetonitrile provides the trityl ether (VI), which is fluorinated with diethylaminosulfur trifluoride (DAST) and pyridine in dichloromethane to give the 3'-beta-fluoro derivative (VII). The reaction of (VII) with ammonia in THF gives the tritylated fluoroadenosine (VIII), which is finally deprotected with HCl in methanol/water to provide the target lodenosine. Alternatively, conversion of (VII) into lodenosine can be performed by first removal of the trityl protecting group with HCl in MeOH/toluene yielding compound (IX), whose chlorine atom is finally displaced with ammonia in MeOH/toluene
| 【1】 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469. |
| 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) | 38013 | 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one | C10H12N4O5 | 详情 | 详情 | |
| (II) | 55505 | [(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C14H15BrN4O6 | 详情 | 详情 | |
| (III) | 55506 | (2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C14H16N4O6 | 详情 | 详情 | |
| (IV) | 55507 | [(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C14H15ClN4O5 | 详情 | 详情 | |
| (V) | 48720 | (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol | C10H11ClN4O3 | 详情 | 详情 | |
| (VI) | 48721 | (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol | C29H25ClN4O3 | 详情 | 详情 | |
| (VII) | 48722 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine | C29H24ClFN4O2 | 详情 | 详情 | |
| (VIII) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 | |
| (IX) | 17712 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol | C10H10ClFN4O2 | 详情 | 详情 |