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【结 构 式】 
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【分子编号】26984 【品名】(2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate 【CA登记号】 |
【 分 子 式 】C28H24O9 【 分 子 量 】504.49316 【元素组成】C 66.66% H 4.8% O 28.54% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of thiazofurin has been described: The reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide and SnCl4 in dichloromethane gives 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl cyanide (II), which is treated with H2S gas and dimethylaminopyridine (DMAP) in ethanol yielding the corresponding thioamide (III). The carefully controlled cyclization of (III) with 3-bromopyruvic acid ethyl ester (IV) by means of NaHCO3 in dimethoxyethane, followed by treatment with trifluoroacetic anhydride and 2,6-lutidine in the same solvent affords 2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (V). Elimination of the benzoyl protecting groups of (V) with NaOEt in ethanol gives 2-(beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (VI). Which is finally treated with dry ammonia in methanol to afford the target amide.
| 【1】 Garcia-Munoz, G.; Stud, M.; Fuertes, M.; Synthesis of C-glycocyl thiazoles. J Org Chem 1976, 41, 4074. |
| 【2】 Ramasamy, K.S.; Averett, D.; A modified synthesis of tiazofurin. Nucleosides Nucleotides 1999, 18, 11-12, 2425. |
| 【3】 Eastland, G.; Tiazofurine. Drugs Fut 1985, 10, 4, 304. |
| 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) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (V) | 29145 | ethyl 2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C11H15NO6S | 详情 | 详情 | |
| (VI) | 34062 | ethyl 2-[(2R,3S,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C32H27NO9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)This compound has been obtained by two similar ways: 1) The condensation of 1-O-acetyl-2,3,5-O-tribenzoyl-beta-D-ribofuranose (I) with N6-benzoyl-9-(trimethylsilyl)adenine (II) by means of trimethylsilyl perchlorate or trimethylsilyl trifluoromethanesulfonate in dichloroethane gives the tetrabenzoyladenosine (III), which is finally debenzoylated with ammonia in methanol. 2) The reaction of tetraacetyl-D-ribofuranose (IV) with dry HCl in ethyl ether gives the 1-chloro derivative (V), which is condensed with the silver salt of 2,8-dichloroadenine (VI) in refluxing xylene yielding the acetylated dichloroadenosine (VII). The hydrolysis of (VII) with ammonia in methanol affords 2,8-dichloroadenosine (VIII), which is finally dechlorinated by hydrogenation with H2 over Pd/BaSO4 in aqueous NaOH.
| 【1】 Davoll, J.; et al.; Experiments on the synthesis of purine nucleosides. Part XIX. A synthesis of adenosine. J Chem Soc 1948, 967. |
| 【2】 Krolikiewicz, K.; Vorbrueggen, H.; New catalysts for the synthesis of nucleosides. Angew Chem. Int Ed Engl 1975, 14, 6, 421. |
| 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) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 34914 | N-[9-(trimethylsilyl)-9H-purin-6-yl]benzamide | C15H17N5OSi | 详情 | 详情 | |
| (III) | 34915 | (2R,3R,4R,5R)-2-[6-(benzoylamino)-9H-purin-9-yl]-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C38H29N5O8 | 详情 | 详情 | |
| (IV) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (V) | 34916 | (2R,3S,4R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-chlorotetrahydro-3-furanyl acetate | C11H15ClO7 | 详情 | 详情 | |
| (VI) | 34917 | C5H2AgCl2N5 | 详情 | 详情 | ||
| (VII) | 34918 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-amino-2,8-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17Cl2N5O7 | 详情 | 详情 | |
| (VIII) | 34919 | (2R,3R,4S,5R)-2-(6-amino-2,8-dichloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11Cl2N5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (X) with 1,2,4-triazole-3-carboxylic acid methyl ester (VII) by means of PNPP at 160 C C gives 1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XI), which is finally treated with NH4OH in methanol.
| 【1】 Witkowski, J.T.; et al.; Design, synthesis, and broad spectrum antiviral activity of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 1972, 15, 11, 1150. |
| 【2】 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 33827 | methyl 1H-1,2,4-triazole-3-carboxylate | 4928-88-5 | C4H5N3O2 | 详情 | 详情 |
| (X) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (XI) | 33830 | methyl 1-[(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate | C30H25N3O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The iodination of 1H-pyrazolo[3,4-d]pyrimidine-4-amine (I) with N-yodosuccinimide (NIS) gives 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (II), which is condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (III) by means of BF3/ethyl ether in nitromethane to yield the benzoylated adduct (IV). Finally this compound is deprotected with sodium methoxide.
| 【1】 Robins, R.K.; Potential purine antagonists. I. Synthesis of some 4,6-substituted pyrazolo[3,4-d]pyrimidines. J Am Chem Soc 1956, 78, 784-790. |
| 【2】 Cottam, H.B.; New adenosine kinase inhibitors with oral antiinflammatory activity. Drugs Fut 1994, 19, 5, 485. |
| 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) | 41249 | 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine | 2380-63-4 | C5H5N5 | 详情 | 详情 |
| (II) | 41250 | 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C5H4IN5 | 详情 | 详情 | |
| (III) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (IV) | 41251 | [(2R,3R,4R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C31H24IN5O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The hydrolysis of 6,7-dichloro-3-nitro-2-naphthoic acid ethyl ester (I) with NaOH in ethanol gives the expected free acid (II), which is treated with diphenylphosphoroazidate and triethylamine in DMF to yield 6,7-dichloro-3-nitro-2-naphthylamine (III). The reduction of (III) with H2 over RaNi in ehanol/ethyl acetate affords the corresponding diamine (IV), which is cyclized with thiocarbonyldi-imidazole (V) in refluxing benzene to give 6,7-dichloro-2,3-dihydro-1H-naphtho[2,3-d]imidazole-2-thione (VI). The methylation of (VI) with methyl iodide in dry DMF yields the corresponding methylsulfanyl derivative (VII), which is condensed with 1-O-acetyl-2,3,5-tri-O-ben-zoyl-beta-D-ribofuranose (VIII) by means of trimethylsilyl trifluoro-methanesulfonate (TMSOTf) and N,O-bis(trimethylsilyl)acetamide (BSA) in dichloromethane affording the benzoylated ribofuranoside (IX). The debenzoylation of (IX) with ammonia in methanol gives the free ribofuranoside (X), which is finally treated with Cl2/CCl4 in methanol to eliminate the methylsulfanyl group.
| 【1】 Zhu, Z.J.; et al.; Synthesis of 2,6, 7-trichloro-1-(beta-D-ribofuranosyl)naphtho[2, 3-d]imidazole: A linear dimensional analogue of the antiviral agent TCRB. J Org Chem 1998, 63, 4, 977. |
| 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) | 26976 | ethyl 6,7-dichloro-3-nitro-2-naphthoate | C13H9Cl2NO4 | 详情 | 详情 | |
| (II) | 26977 | 6,7-dichloro-3-nitro-2-naphthoic acid | C11H5Cl2NO4 | 详情 | 详情 | |
| (III) | 26978 | 6,7-dichloro-3-nitro-2-naphthalenamine | C10H6Cl2N2O2 | 详情 | 详情 | |
| (IV) | 26979 | 3-amino-6,7-dichloro-2-naphthylamine | C10H8Cl2N2 | 详情 | 详情 | |
| (V) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (VI) | 26980 | 6,7-dichloro-1,3-dihydro-2H-naphtho[2,3-d]imidazole-2-thione | C11H6Cl2N2S | 详情 | 详情 | |
| (VII) | 26981 | 6,7-dichloro-1H-naphtho[2,3-d]imidazol-2-yl methyl sulfide | C12H8Cl2N2S | 详情 | 详情 | |
| (VIII) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (IX) | 26982 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-[6,7-dichloro-2-(methylsulfanyl)-1H-naphtho[2,3-d]imidazol-1-yl]tetrahydro-3-furanyl benzoate | C38H28Cl2N2O7S | 详情 | 详情 | |
| (X) | 26983 | (2R,3R,4S,5R)-2-[6,7-dichloro-2-(methylsulfanyl)-1H-naphtho[2,3-d]imidazol-1-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C17H16Cl2N2O4S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Alternatively, condensation of 2,6-dichloropurine (VIII) with protected ribose (IX) at 140 C gave the ribofuranosyl purine (X). Subsequent displacement of the 6-chloro of (V) by amine (V), followed by hydrolysis of the benzoate esters afforded the intermediate (VII).
| 【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 . |
| 【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (IX) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (X) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (XI) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (XII) | 38963 | ((2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl benzoate | C45H36ClN5O7 | 详情 | 详情 | |
| (XIII) | 38961 | (2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C24H24ClN5O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIV)Condensation of 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl bromide (X) with diaminomaleonitrile (XI) yields the ribofuranosyl diamine (XII), which is alternatively prepared by N-protection of diamine (XI) with TMSCl in the presence of HMDS in refluxing acetonitrile and subsequent coupling of the obtained bis(silylamine) (XIII) with the D-ribofuranosyl acetate (XIV) by means of TMSOTf in CH2Cl2. Cyclization of diamine (XII) with HC(OEt)3 in the presence of NaOMe in anisole affords the 4,5-dicyanoimidazole derivative (XV), which undergoes regioselective addition of NaOMe in MeOH to give imidate (XVI). Finally, Hofmann rearrangement of imidate (XVI) with NaOCl in the presence of NaOH yields imidazolecarbonitrile (V) .
Alternatively, formylation of diaminomaleonitrile (XI) with HCOOH in benzene leads to N-formyldiaminomaleonitrile (XVII) , which is then silylated with TMSCl in the presence of HMDS to yield the protected amine (XVIII). Finally, amine (XVIII) is condensed with the ribofuranosyl acetate (XIV) in the presence of TMSOTf in CH2Cl2 to give compound (XIX), which undergoes cyclization using AcOH in refluxing benzene yielding nitrile (XV) .
| 【1】 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. |
| 【2】 Ohtsuka, Y. Chemistry of diaminomaleonitrile. 1. Selective preparations of monoformyldiaminomaleonitrile and imidazoles by reaction with formicacid. J Org Chem 1976, 41(4): 713-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 | |
| (X) | 33832 | [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate | C26H21BrO7 | 详情 | 详情 | |
| (XI) | 16903 | (Z)-2,3-diamino-2-butenedinitrile;diaminomaleonitrile | 1187-42-4 | C4H4N4 | 详情 | 详情 |
| (XII) | 68818 | (2R,3R,4S,5R)-2-((benzoyloxy)methyl)-5-(((Z)-1,3-diamino-1-cyanoprop-1-en-2-yl)amino)tetrahydrofuran-3,4-diyl dibenzoate | C30H24N4O7 | 详情 | 详情 | |
| (XIII) | 68815 | (Z)-4-amino-2,3-bis((trimethylsilyl)amino)but-2-enenitrile | C10H20N4Si2 | 详情 | 详情 | |
| (XIV) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (XV) | 68819 | (2R,3R,4S,5R)-2-(5-(aminomethyl)-4-cyano-1H-imidazol-1-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate | C31H22N4O7 | 详情 | 详情 | |
| (XVI) | 68821 | methyl 4-cyano-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-5-carbimidate | C11H14N4O5 | 详情 | 详情 | |
| (XVII) | 68816 | N-formyldiaminomaleonitrile;(Z)-N-(1,3-diamino-1-cyanoprop-1-en-2-yl)formamide | C5H4N4O | 详情 | 详情 | |
| (XVIII) | 68817 | (Z)-N-(3-amino-1-cyano-2-((trimethylsilyl)amino)prop-1-en-1-yl)formamide | C8H12N4OSi | 详情 | 详情 | |
| (XIX) | 68820 | (2R,3R,4S,5R)-2-(((Z)-3-amino-1-cyano-2-formamidoprop-1-en-1-yl)amino)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate | C31H24N4O8 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIV)Methylation of D-ribose (XX) with MeOH using HCl yields methyl Dribofuranoside (XXI), which is then benzoylated with BzCl in CHCl3/pyr to give the protected intermediate (XXII). Bromination of methyl ether (XXII) with HBr in AcOH furnishes bromide (X). Acetylation of methyl ether (XXII) with Ac2O and AcOH produces acetate (XIV) .
| 【1】 Recondo, E.F., Rinderknecht, H. Eine neue, einfache Synthese des 1-OAcetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranosides. Helv Chim Acta 1959, 42(4): 1171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 33832 | [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate | C26H21BrO7 | 详情 | 详情 | |
| (XIV) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (XX) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (XXI) | 41258 | (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydro-3,4-furandiol | C6H12O5 | 详情 | 详情 | |
| (XXII) | 12247 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 |