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【结 构 式】 
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【分子编号】29160 【品名】[2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate 【CA登记号】 |
【 分 子 式 】C20H24O5 【 分 子 量 】344.40756 【元素组成】C 69.75% H 7.02% O 23.23% |
合成路线1
该中间体在本合成路线中的序号：(V)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2
该中间体在本合成路线中的序号：(V)The condensation of N2-acetylguanine (VIII) with (V) by means of ammonium sulfate in refluxing HMDS gives (VII). This compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
| 【1】 Kennell, W.L.; Ogilvie, K.K.; Cheriyan, U.O.; Smith, K.O.; Radatus, B.K.; Galloway, K.S.; Biologically active acylnucleoside analogs. II. The synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (BIOLF-62). Can J Chem 1982, 60, 24, 3005. |
| 【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】 Ogilvie, K.K. (Bio Logicals Inc.); Purine and pyrimidine compounds and their use as anti-viral agents. EP 0049072; EP 0243670; JP 57085373; US 4347360 . |
| 【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 |
|---|---|---|---|---|---|---|
| (V) | 29160 | [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate | C20H24O5 | 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 | |
| (VIII) | 29168 | 3-(acetoxy)-2-[(acetoxy)methoxy]propyl acetate | C10H16O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation of 6-chloroguanine (IX) with (V) by means of ammonium sulfate in refluxing HMDS gives 9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]-6-chloroguanine (XI), which is treated with sodium methoxide and mercaptoethanol in refluxing methanol to yield 9-[[1,3-bisbenzyloxy)-2-propoxy]methyl]guanine (XI), which is finally deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
| 【1】 Kennell, W.L.; Ogilvie, K.K.; Cheriyan, U.O.; Smith, K.O.; Radatus, B.K.; Galloway, K.S.; Biologically active acylnucleoside analogs. II. The synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (BIOLF-62). Can J Chem 1982, 60, 24, 3005. |
| 【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 |
|---|---|---|---|---|---|---|
| (V) | 29160 | [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate | C20H24O5 | 详情 | 详情 | |
| (IX) | 10913 | 6-Chloro-6,9-dihydro-1H-purin-2-ylamine; 6-Chloro-6,9-dihydro-1H-purin-2-amine | C5H6ClN5 | 详情 | 详情 | |
| (X) | 29164 | 9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-chloro-9H-purin-2-ylamine | C23H24ClN5O3 | 详情 | 详情 | |
| (XI) | 29165 | 2-amino-9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-1,9-dihydro-6H-purin-6-one | C23H25N5O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)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：(XIV)The condensation of 2-(acetoxymethoxy)-1,3-bis(benzyloxy)propane (XIV) with N2-acetylguanine (XV) by means of hexamethyldisilazane (HMDS) and trifluoromethanesulfonic acid gives the N2-acetyl-O,O'-dibenzylganciclovir (XVI), which is selectively monodebenzylated with either H2 over Pd/C in methanol or cyclohexene and Pd(OH)2 in refluxing ethanol, yielding intermediate (XVII), which by deacetylation with NH4OH in methanol affords mono-O-benzylganciclovir (XVIII). The condensation of (XVIII) with N-benzyloxycarbonyl-L-valine (XIX) by means of DCC in dichloromethane gives the expected valine ester (XX), which is finally debenzylated with H2 over Pd/C in methanol as before.
| 【1】 Nestor, J.J.; Womble, S.W.; Maag, H. (F. Hoffmann-La Roche AG); 2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol deriv.. CA 2154721; EP 0694547; ES 2083348; JP 1996041061; US 5840891; US 6083953 . |
| 【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474. |
| 【3】 Dvorak, C.A.; Beard, C.C.; Wren, D.L.; Axt, S.D.; Han, Y.-K.; Fatheree, P.R.; Nguyen, S.L.; Lund, J.P.; Fisher, L.E.; Arzeno, H.B.; Humphreys, E.R. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. US 6040446; WO 9727198 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 29160 | [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate | C20H24O5 | 详情 | 详情 | |
| (XV) | 29163 | N-(6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide | C7H7N5O2 | 详情 | 详情 | |
| (XVI) | 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 | |
| (XVII) | 35323 | N-(9-[[2-(benzyloxy)-1-(hydroxymethyl)ethoxy]methyl]-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide | C18H21N5O5 | 详情 | 详情 | |
| (XVIII) | 35324 | 2-amino-9-[[2-(benzyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one | C16H19N5O4 | 详情 | 详情 | |
| (XIX) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XX) | 35325 | 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-(benzyloxy)propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C29H34N6O7 | 详情 | 详情 |