|
【结 构 式】 
|
【药物名称】Acycloguanosine, Aciclovir, Acyclovir, W-248-U, BW-248-U, Maynar, Viropump(former Brand Name), Genvir, Zovirax 【化学名称】9-(2-Hydroxyethoxymethyl)guanine 【CA登记号】59277-89-3 【 分 子 式 】C8H11N5O3 【 分 子 量 】225.20857 |
【开发单位】GlaxoSmithKline (Originator), Biovail (Licensee), Ferrer (Licensee), Flamel (Formulation), SkyePharma (Formulation), Shionogi (Codevelopment) 【药理作用】Anti-Herpes Labialis Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Anti-Varicella Zoster Virus Drugs, Antiviral Drugs, Antiviral Ophthalmic Drugs, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs |
合成路线1
An efficient and selective process for the synthesis of acyclovir has been published: The reaction of guanine (I) with refluxing hexamethyldisilazane (HMDS) (II) by means of trifluoromethanesulfonic acid, elimination of the HMDS in excess and condensation of the resulting product with refluxing 1,3-dioxolane (III) gives 9-[2-(trimethylsilyloxy)ethoxymethyl]guanine (IV), which is finally hydrolyzed with refluxing acetic acid/water.
| 【1】 Han, Y.-K.; Harrington, P.J.; Schloemer, G.C. (F. Hoffmann-La Roche AG); Preparation of acyclovir. EP 0709385; JP 1996053451 . |
合成路线2
The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with NaNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.
| 【1】 Schaeffer, H.J.; et al.; 9-(2-Hydroxyethoxy)guanine activity aganist viruses of the herpes group. Nature 1978, 272, 583-585. |
| 【2】 Castaner, J.; Hillier, K.; Acycloguanosine. Drugs Fut 1978, 3, 11, 788. |
| 【3】 Schaeffer, H.J. (Glaxo Wellcome plc); Purine derivs.. US 4294831 . |
| 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) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (II) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 39965 | 2-hydroxyethyl benzoate | C9H10O3 | 详情 | 详情 | |
| (IV) | 39966 | 2-(chloromethoxy)ethyl benzoate | C10H11ClO3 | 详情 | 详情 | |
| (V) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (VI) | 39967 | 2-[(2,6-dichloro-9H-purin-9-yl)methoxy]ethyl benzoate | C15H12Cl2N4O3 | 详情 | 详情 | |
| (VII) | 39968 | 2-[(6-amino-2-chloro-9H-purin-9-yl)methoxy]-1-ethanol | C8H10ClN5O2 | 详情 | 详情 | |
| (VIII) | 39969 | 2-chloro-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol | C8H9ClN4O3 | 详情 | 详情 |
合成路线3
The condensation of guanine (IX) with refluxing hexamethyldisilazane followed by reaction with 1-benzoyloxy-2-chloromethoxyethane (IV) by means of triethylamine in refluxing benzene gives 9-(2-benzoyloxyethoxymethyl)guanine (X), which is finally hydrolyzed with ammonia in methanol at 80 C in a pressure vessel.
| 【1】 Castaner, J.; Hillier, K.; Acycloguanosine. Drugs Fut 1978, 3, 11, 788. |
| 【2】 Schaeffer, H.J. (Glaxo Wellcome plc); Purine derivs.. US 4294831 . |
合成路线4
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 |