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【结 构 式】 
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【分子编号】29161 【品名】N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine 【CA登记号】3056-33-5 |
【 分 子 式 】C9H9N5O3 【 分 子 量 】235.20236 【元素组成】C 45.96% H 3.86% N 29.78% O 20.41% |
合成路线1
该中间体在本合成路线中的序号：(III)The acetylation of guanine (I) or guanosine (II) with acetic anhydride gives the diacetyl guanine (III), which is condensed with 1,4-diacetoxy-2-oxabutane (IV) by means of TsOH to yield N,O-diacetyl acyclovir (V). Finally, this compound is deacetylated with NH3, NaOH or pyrrolidine at room temperature, or also with refluxing glycol.
| 【1】 Gao, H.; Mitra, A.K.; Synthesis of acyclovir, ganciclovir and their prodrugs: A review. Synthesis 2000, 3, 329. |
| 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) | 10352 | 2-Amino-1,9-dihydro-6H-purin-6-one; Guanine | 73-40-5 | C5H5N5O | 详情 | 详情 |
| (II) | 38958 | Guanosine; 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one | 118-00-3 | C10H13N5O5 | 详情 | 详情 |
| (III) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (IV) | 46052 | [2-(acetoxy)ethoxy]methyl acetate | C7H12O5 | 详情 | 详情 | |
| (V) | 10784 | 2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]ethyl acetate; Acetic acid 2-(2-acetamido-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester | 75128-73-3 | C12H15N5O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of NaOH in water gives 1,3-di-O-benzylglycerol (III), which is condensed with paraformaldehyde by means of HCl in methylene chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV). Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl-2-O-(acetoxymethyl)glycerol (V), which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]guanine (VII). Finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
| 【1】 Dvorak, C.A.; Matthews, T.R.; Martin, J.C.; Verheyden, P.H.; Smee, D.F.; 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: A new potent and selective antiherpes agent. J Med Chem 1983, 26, 5, 759-761. |
| 【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61. |
| 【3】 Verheyden, J.P.; Martin, J.C. (Roche Bioscience); 9-(1,3-Dihydroxy-2-propoxymethyl)guanine as antiviral agent. EP 0066208; JP 4217983; JP 57203086; US 4355032 . |
| 【4】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (III) | 29159 | 1,3-bis(benzyloxy)-2-propanol | 6972-79-8 | C17H20O3 | 详情 | 详情 |
| (IV) | 24432 | 1-[[3-(benzyloxy)-2-(chloromethoxy)propoxy]methyl]benzene | C18H21ClO3 | 详情 | 详情 | |
| (V) | 29160 | [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate | C20H24O5 | 详情 | 详情 | |
| (VI) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (VII) | 29162 | N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide | C25H27N5O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The acetylation of 4-hydroxymethyl-1,3-dioxolane (XII) gives the corresponding acetate (XIII), which by reaction with acetic anhydride and ZnCl2 is converted to 1,3-diacetoxy-2-(acetoxymethoxy)propane (XIV). The condensation of (XIV) with diacetylguanine (VI) by means of ethanesulfonic acid (B) yields the triacetoxy precursor (XV), which is hydrolyzed with aqueous methylamine.
| 【1】 Field, A.K.; Tolman, R.L.; Ashton, W.A.; Karkas, J.D.; Activation by thymidine kinase and potent antiherpetic activity of 2'-nor-2'-deoxyguanosine (2'NDG). Biochem Biophys Res Commun 1982, 108, 4, 1716. |
| 【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61. |
| 【3】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365. |
| 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) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (B) | 29169 | 1-ethanesulfonic acid | 594-45-6 | C2H6O3S | 详情 | 详情 |
| (VI) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (XII) | 29166 | 1,3-dioxolan-4-ylmethanol | 4740-78-7 | C4H8O3 | 详情 | 详情 |
| (XIII) | 29167 | 1,3-dioxolan-4-ylmethyl acetate | C6H10O4 | 详情 | 详情 | |
| (XIV) | 29168 | 3-(acetoxy)-2-[(acetoxy)methoxy]propyl acetate | C10H16O7 | 详情 | 详情 | |
| (XV) | 29170 | 2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate | C15H19N5O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of 1,3-dichloro-2-propanol (I) with Bn-ONa gives 1,3-dibenzyloxy-2-propanol (II), which by reaction with paraformaldehyde and HCl is converted into the chloromethyl ether (III). The reaction of (III) with potassium acetate affords the acetoxymethyl ether (IV), which is condensed with diacetylguanine (V) by means of TsOH to provide fully protected ganciclovir (VI). Finally, this compound is debenzylated to (VII) with Pd(OH)2/cyclohexene and deacetylated with ammonia in methanol.
| 【1】 Gao, H.; Mitra, A.K.; Synthesis of acyclovir, ganciclovir and their prodrugs: A review. Synthesis 2000, 3, 329. |
| 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) | 33378 | 1,3-dichloro-2-propanol | 96-23-1 | C3H6Cl2O | 详情 | 详情 |
| (II) | 29159 | 1,3-bis(benzyloxy)-2-propanol | 6972-79-8 | C17H20O3 | 详情 | 详情 |
| (III) | 24432 | 1-[[3-(benzyloxy)-2-(chloromethoxy)propoxy]methyl]benzene | C18H21ClO3 | 详情 | 详情 | |
| (IV) | 29160 | [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate | C20H24O5 | 详情 | 详情 | |
| (V) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (VI) | 29162 | N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide | C25H27N5O5 | 详情 | 详情 | |
| (VII) | 46048 | N-(9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide | C11H15N5O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of diacetyl guanine (I) with 1,3-diacetoxy-2-(acetoxymethoxy)propane (II) by means of TsOH in hot DMF gives the target intermediate, N2-acetyl-9-[2-acetoxy-1-(acetoxymethyl)ethoxymethyl]guanine (III). (see Synthline Scheme no. 11147104a, intermediate no. (XV)).
| 【1】 Kumar, Y.; Khanduri, C.H.; Ray, P.C.; Babu, J.S. (Ranbaxy Laboratories Ltd.); A process for the preparation of ganciclovir intermediate N2-acetyl-9-(1,3-diacetoxy-2-propoxymethyl)guanine. WO 0333498 . |
| 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) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (II) | 64100 | 2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl acetate | C9H14O6 | 详情 | 详情 | |
| (III) | 29170 | 2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate | C15H19N5O7 | 详情 | 详情 |