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【结 构 式】 
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【分子编号】37430 【品名】5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile 【CA登记号】 |
【 分 子 式 】C9H12N4O4 【 分 子 量 】240.21884 【元素组成】C 45% H 5.04% N 23.32% O 26.64% |
合成路线1
该中间体在本合成路线中的序号：(IV)This compound can be obtained in two different ways: 1) The acylation of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide (I) with propionic anhydride (A) in pyridine gives the corresponding tri-O-propionyl derivative (II), which by treatment with POCl3 and triethylamine in CHCl3 is converted into 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-beta-D-ribofuranosyl)imidazole (III). The hydrolysis of (III) with methanolic ammonia yields 5-amino-4-cyano-1-beta-D-ribofuranosylimidazole (IV), which is finally cyclized with phenylcyanamide (V) in methanolic ammonia at 180 C in a pressure vessel. This cyclization can also be performed with (III) and (V) directly, using the same procedure. 2) By reaction of 2-bromoadenosine (VI) with aniline (VII) in 2-methoxyethanol at 120 C.
| 【1】 Marumoto, R.; et al.; Synthesis and coronary vasodilating activity of 2-substituted adenosines. Chem Pharm Bull 1975, 23, 4, 759-774. |
| 【2】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); 2,6-Diaminonebularine derivs.. US 3936439 . |
| 【3】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); Production of 2,6-diaminonebularines. DE 2845435 . |
| 【4】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Thorpe, P.J.; CV-1808. Drugs Fut 1981, 6, 4, 222. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 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) | 37428 | [(2R,3R,4R,5R)-5-[5-amino-4-(aminocarbonyl)-1H-imidazol-1-yl]-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H26N4O8 | 详情 | 详情 | |
| (III) | 37429 | [(2R,3R,4R,5R)-5-(5-amino-4-cyano-1H-imidazol-1-yl)-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H24N4O7 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 37431 | phenylcyanamide | C7H6N2 | 详情 | 详情 | |
| (VI) | 37432 | (2R,3R,4S,5R)-2-(6-amino-2-bromo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H12BrN5O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |
合成路线3
该中间体在本合成路线中的序号：(V)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 |