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【结 构 式】 
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【分子编号】38014 【品名】(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate 【CA登记号】 |
【 分 子 式 】C16H18N4O8 【 分 子 量 】394.34108 【元素组成】C 48.73% H 4.6% N 14.21% O 32.46% |
合成路线1
该中间体在本合成路线中的序号：(IV),(VI)The cyclization of the imidazolyl riboside (I) with [13C]-formic acid ethyl ester (II) by means of sodium ethoxide in refluxing ethanol gives labeled inosine (III), which is acetylated with Ac2O and pyridine yielding the triacetate (IV). The nitration of (IV) with ammonium nitrate and trifluoroacetic anhydride affords the 1-nitroinosine (V), which is rearranged with 15NH4Cl in acetonitrile/water to provide the doubly labeled inosine (VI). The reaction of (VI) with SOCl2 gives the chloropurine (VII), which is condensed with the dideuterated 2-aminocyclopentanol (rac-trans)-(VIII) (obtained by hydrogenation of the unsaturated analogue (rac-trans)-(IX)) by means of NaHCO3 in isopropanol providing a diastereomeric mixture (X). The deacetylation of (X) with tert-butylamine in methanol furnishes a mixture of the target compound along with its diastereomer, which is separated by preparative HPLC.
| 【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV),(VI) | 38014 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (I) | 37427 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboxamide | C9H14N4O5 | 详情 | 详情 | |
| (II) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (II) | 45175 | ethyl formate | C3H6O2 | 详情 | 详情 | |
| (III) | 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 | |
| (III) | 45176 | 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 | |
| (IV) | 45177 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (V) | 38015 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17N5O10 | 详情 | 详情 | |
| (V) | 45178 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17N5O10 | 详情 | 详情 | |
| (VI) | 45179 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (VII) | 38016 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17ClN4O7 | 详情 | 详情 | |
| (VII) | 45180 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17ClN4O7 | 详情 | 详情 | |
| (VIII) | 38010 | (1S,2S)-2-aminocyclopentanol | C5H11NO | 详情 | 详情 | |
| (VIII) | 45181 | (1S,2S)-2-aminocyclopentanol | C5H11NO | 详情 | 详情 | |
| (IX) | 38017 | (1S,2S)-2-amino-3-cyclopenten-1-ol | C5H9NO | 详情 | 详情 | |
| (X) | 38018 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C21H27N5O8 | 详情 | 详情 | |
| (X) | 45182 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C21H27N5O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The commercially available 8-[14C]-inosine (I) with Ac2O in hot pyridine gives the triacetate (II), which is treated with SOCl2 and DMF in dichloromethane yielding the chloropurine (III). The condensation of (III) with (1S-trans)-2-aminocyclopentanol by means of NaHCO3 in hot isopropanol affords the acetylated target compound (V), which is finally deacetylated with t-Bu-NH2 in methanol.
| 【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11. |
| 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 | |
| (I) | 63751 | 9-[3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one | C10H12N4O5 | 详情 | 详情 | |
| (II) | 38014 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (II) | 63752 | 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (III) | 38015 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17N5O10 | 详情 | 详情 | |
| (III) | 63753 | 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17ClN4O7 | 详情 | 详情 | |
| (IV) | 38017 | (1S,2S)-2-amino-3-cyclopenten-1-ol | C5H9NO | 详情 | 详情 | |
| (V) | 38018 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C21H27N5O8 | 详情 | 详情 | |
| (V) | 63754 | 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{6-[(2-hydroxycyclopentyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate | C21H27N5O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Acylation of inosine (I) with Ac2O in the presence of pyridine yields inosine triacetate (II), which is then protected as the N-MEM derivative (III) using chloromethyl methyl ether and DIEA in CH2Cl2. Deacetylation of compound (III) with NH3 in MeOH affords 1-MEMinosine (IV), which finally undergoes purine ring opening in refluxing NaOH .
In a related method, acadesine is obtained by MEM protection of inosine acetate (II) with chloromethyl methyl ether by means of NaH in dioxane, and subsequent purine ring hydrolysis with NaOH in refluxing EtOH .
Similarly, direct hydrolysis of unprotected inosine (I) with KOH in water at 130 °C produces a mixture of acadesine and 9-β-D-ribopyranosylhypoxanthine, from which acadesine can be isolated using column chromatography .
An alternative strategy is the hydrolysis of the imidazolecarbonitrile (V) with NaOH at 100 °C .
In a different approach, reaction of 2’,3’-O-isopropylideneinosine (VI) with 2,4-dinitrochlorobenzene (DNCB) by means of K2CO3 at 80 °C yields N1-(2,4-dinitrophenyl)-2’,3’-O-isopropylideneinosine (VII), which is then O-deprotected with HCOOH in H2O to give 1-(2,4-dinitrophenyl) inosine (VIII). Regioselective attachment of the triol (VIII) to MMTCl resin in the presence of DMAP in pyridine provides the resin-bound compound (IX), which is then submitted to purine ring hydrolysis with EDA in DMF, and subsequent deprotection of the obtained intermediate with TFA in CH2Cl2 .
| 【1】 Kohyama, N., Yamamoto, Y. A facile synthesis of AICAR from inosine. Synthesis 2001, 17: 2639-42. |
| 【2】 Shaw, E. A chemical preparation of 5-amino-4-imidazolecarboxamide ribotide. J Am Chem Soc 1961, 83(23): 4770-2. |
| 【3】 Suzuki, Y. Action of alkali on inosine - Formation of 5-amino-1-beta-Dribofuranosyl-4-imidazolecarboxamide and 9-beta-D-ribopyranosyl hypoxanthine. Bull Chem Soc Jpn 1974, 47(4): 898-903. |
| 【4】 Ferris, J.P., Devadas, B., Huang, C.H., Ren, W.Y. Novel synthesis of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide and 5-amino-1-(beta-D-ribopyranosyl)imidazole-4-carboxamide. J Org Chem 1985, 50(6): 747-54. |
| 【5】 Oliviero, G., Amato, J., Borbone, N., D’Errico, S., Piccialli, G., Mayol, L. Synthesis of N-1 and ribose modified inosine analogues on solid support. Tetrahedron Lett 2007, 48(3): 397-400. |
| 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) | 12795 | (2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-3,4-furandiol; Inosine | 58-63-9 | C10H12N4O5 | 详情 | 详情 |
| (II) | 38014 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18N4O8 | 详情 | 详情 | |
| (III) | 68809 | (2R,3R,4S,5R)-2-(acetoxymethyl)-5-(1-((2-methoxyethoxy)methyl)-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3,4-diyl diacetate | C20H26N4O10 | 详情 | 详情 | |
| (IV) | 68810 | 9-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1-((2-methoxyethoxy)methyl)-1H-purin-6(9H)-one | C14H20N4O7 | 详情 | 详情 | |
| (V) | 37430 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile | C9H12N4O4 | 详情 | 详情 | |
| (VI) | 68811 | 9-((3aS,4S,6S,6aS)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)-1H-purin-6(9H)-one | C13H16N4O5 | 详情 | 详情 | |
| (VII) | 68812 | 1-(2,4-dinitrophenyl)-9-((3aS,4S,6S,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-purin-6(9H)-one | C19H18N6O9 | 详情 | 详情 | |
| (VIII) | 68813 | 9-((2S,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1-(2,4-dinitrophenyl)-1H-purin-6(9H)-one | C16H14N6O9 | 详情 | 详情 | |
| (IX) | 68814 | C16H13N6O9 | 详情 | 详情 |