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【结 构 式】 
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【药物名称】Famciclovir, BRL-42810, Famvir 【化学名称】9-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine 【CA登记号】104227-87-4 【 分 子 式 】C14H19N5O4 【 分 子 量 】321.33863 |
【开发单位】Novartis (Proprietary), GlaxoSmithKline (Originator), Solvay (Licensee) 【药理作用】Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs |
合成路线1
A synthesis of famciclovir that corresponds to that previously published and studies on its oral bioavailability in rats and mice, identifying famciclovir as the preferred prodrug of BRL-39123 (penciclovir), have been published.
| 【1】 Choudary, B.M.; Geen, G.R.; Kincey, P.M.; Parratt, M.J.; Dales, J.R.M.; Johnson, G.P.; O'Donnell, S.; Tudor, D.W.; Woods, N.; A direct approach to the synthesis of famciclovir and penciclovir. Nucleosides Nucleotides 1996, 15, 5, 981. |
| 【2】 Harnden, M.R.; Boyd, M.R.; Vere Hodge, R.A.; Jarvest, R.L.; Sutton, D.; Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxy methyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 1989, 32, 1738-43. |
| 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) | 11636 | 6,8-Dichloro-9H-purin-2-ylamine; 6,8-Dichloro-9H-purin-2-amine | C5H3Cl2N5 | 详情 | 详情 | |
| (II) | 11637 | dimethyl 3-(2-iodoethyl)pentanedioate | C9H15IO4 | 详情 | 详情 | |
| (III) | 11638 | 2-[(acetoxy)methyl]-4-(2-amino-6,8-dichloro-9H-purin-9-yl)butyl acetate | C14H17Cl2N5O4 | 详情 | 详情 | |
| (IV) | 11639 | 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione | 5617-70-9 | C8H10O4 | 详情 | 详情 |
| (V) | 11640 | 5-[2-(2-amino-6,8-dichloro-9H-purin-9-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C13H13Cl2N5O4 | 详情 | 详情 | |
| (VI) | 11641 | 5-[2-(2-amino-9H-purin-9-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C13H15N5O4 | 详情 | 详情 | |
| (VII) | 11642 | dimethyl 2-[2-(2-amino-9H-purin-9-yl)ethyl]malonate | C12H15N5O4 | 详情 | 详情 | |
| (VIII) | 11643 | 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H15N5O2 | 详情 | 详情 | |
| (IX) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (X) | 11645 | 5-[2-(2-Amino-6-chloro-9H-purin-9-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C13H14ClN5O4 | 详情 | 详情 | |
| (XI) | 11646 | triethyl 3-bromo-1,1,1-propanetricarboxylate | C12H19BrO6 | 详情 | 详情 | |
| (XII) | 11647 | triethyl 3-(2-amino-6-chloro-9H-purin-9-yl)-1,1,1-propanetricarboxylate | C17H22ClN5O6 | 详情 | 详情 | |
| (XIII) | 11648 | triethyl 3-(2-amino-9H-purin-9-yl)-1,1,1-propanetricarboxylate | C17H23N5O6 | 详情 | 详情 | |
| (XIV) | 11649 | diethyl 2-[2-(2-amino-9H-purin-9-yl)ethyl]malonate | C14H19N5O4 | 详情 | 详情 |
合成路线2
The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (II) by means ofK2CO3 in DMF gives the expected condensation product (III), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (V), which is finally converted into famciclovir by reductive dechlorination with H2 over Pd/C in ethyl acetate/triethylamine.
| 【1】 Choudary, B.M.; Geen, G.R.; Kincey, P.M.; Parratt, M.J.; Dales, J.R.M.; Johnson, G.P.; O'Donnell, S.; Tudor, D.W.; Woods, N.; A direct approach to the synthesis of famciclovir and penciclovir. Nucleosides Nucleotides 1996, 15, 5, 981. |
| 【2】 Harnden, M.R.; Boyd, M.R.; Vere Hodge, R.A.; Jarvest, R.L.; Sutton, D.; Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxy methyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 1989, 32, 1738-43. |
| 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) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (II) | 11646 | triethyl 3-bromo-1,1,1-propanetricarboxylate | C12H19BrO6 | 详情 | 详情 | |
| (III) | 11647 | triethyl 3-(2-amino-6-chloro-9H-purin-9-yl)-1,1,1-propanetricarboxylate | C17H22ClN5O6 | 详情 | 详情 | |
| (IV) | 19777 | dimethyl 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]malonate | C12H14ClN5O4 | 详情 | 详情 | |
| (V) | 19778 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-[[(methoxycarbonyl)oxy]methyl]butyl methyl carbonate | C14H18ClN5O6 | 详情 | 详情 |
合成路线3
A new synthetic route to famciclovir has been described: The alkylation of 2,2-dimethyl-1,3-dioxan-5-one (I) with vinylmagnesium bromide (II) in THF gives the 2,2-dimethyl-5-vinyl-1,3-dioxan-5-ol derivative (II), which is treated with methyl chloroformate in the same solvent to yield the mixed carbonate (IV). Condensation of (IV) with 6-chloropurine-2-amine (V) by means of 1,2-bis(diphenylphosphino)ethane (dppe) and tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in DMF at 80 °C for 7.5 h affords a 5:95 mixture of the N-7 (VI) and N-9 (VII) regioisomers, respectively. Hydrogenation of regioisomer (VII) with H2 over Pd/C in THF eliminates the 6-chlorine atom and reduces the exocyclic double bond giving the 2-aminopurine derivative (VIII), which is treated with HCl in methanol to remove the acetonide group affording diol (IX). Finally, this compound is acylated with acetic anhydride and DMAP/TEA in dichloromethane.
| 【1】 Geen, G.R.; Share, A.C.; Slater, G.R.; Ramsay, T.W.; Smith, N.M.; Freer, R.; A new route to famciclovir via palladium catalysed allylation. Tetrahedron 2000, 56, 26, 4589. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 46539 | C8H13BrMgO3 | 详情 | 详情 | ||
| (IV) | 46540 | 2,2-dimethyl-5-vinyl-1,3-dioxan-5-yl methyl carbonate | C10H16O5 | 详情 | 详情 | |
| (V) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (VI) | 46541 | 6-chloro-7-[2-(2,2-dimethyl-1,3-dioxan-5-ylidene)ethyl]-7H-purin-2-ylamine; 6-chloro-7-[2-(2,2-dimethyl-1,3-dioxan-5-ylidene)ethyl]-7H-purin-2-amine | C13H16ClN5O2 | 详情 | 详情 | |
| (VII) | 46542 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-ylidene)ethyl]-9H-purin-2-ylamine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-ylidene)ethyl]-9H-purin-2-amine | C13H16ClN5O2 | 详情 | 详情 | |
| (VIII) | 46543 | 9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine; 9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine | C13H19N5O2 | 详情 | 详情 | |
| (IX) | 11643 | 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H15N5O2 | 详情 | 详情 |