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【结 构 式】 
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【分子编号】11646 【品名】triethyl 3-bromo-1,1,1-propanetricarboxylate 【CA登记号】 |
【 分 子 式 】C12H19BrO6 【 分 子 量 】339.18326 【元素组成】C 42.49% H 5.65% Br 23.56% O 28.3% |
合成路线1
该中间体在本合成路线中的序号：(VI)This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.
| 【1】 Jarvest, R.L.; Harnden, M.R.; An improved synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine. Tetrahedron Lett 1985, 26, 4265-68. |
| 【2】 Grose, W.F.A.; Pandit, U.K.; Eggelte, T.A.; A new class of nucleoside analogues. Synthesis of N1-pyrimidinyl- and N9-purinyl-4'-hydroxy-3'-(hydroxymethyl)butanes. Synth Commun 1972, 2, 345-351. |
| 【3】 Boyd, M.R.; Jarvest, R.L.; Bacon, T.H.; Harnden, M.R.; Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines. J Med Chem 1987, 30, 1636-42. |
| 【4】 Hardern, D.N.; Development of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines as potential therapeutic agents for treatment of human herpesvirus infections. Drugs Fut 1989, 14, 4, 347. |
| 【5】 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. |
| 【6】 Harnden, M.R.; Jarvest, R.L. (SmithKline Beecham plc); Guanine derivs.. EP 0141927; ES 8602791; ES 8603887; ES 8603888; JP 1994293764; US 5075445 . |
| 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) | 11639 | 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione | 5617-70-9 | C8H10O4 | 详情 | 详情 |
| (III) | 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 | |
| (IV) | 19782 | dimethyl 2-[2-(2-amino-6-methoxy-9H-purin-9-yl)ethyl]malonate | C13H17N5O5 | 详情 | 详情 | |
| (V) | 19783 | 2-[2-(2-amino-6-methoxy-9H-purin-9-yl)ethyl]-1,3-propanediol | C11H17N5O3 | 详情 | 详情 | |
| (VI) | 11646 | triethyl 3-bromo-1,1,1-propanetricarboxylate | C12H19BrO6 | 详情 | 详情 | |
| (VII) | 11647 | triethyl 3-(2-amino-6-chloro-9H-purin-9-yl)-1,1,1-propanetricarboxylate | C17H22ClN5O6 | 详情 | 详情 | |
| (VIII) | 19777 | dimethyl 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]malonate | C12H14ClN5O4 | 详情 | 详情 | |
| (IX) | 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2
该中间体在本合成路线中的序号：(XI)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3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(III)The sodium salt of triethyl methanetricarboxylate (I) was alkylated with 1,2-dibromoethane (II) to afford bromide (III). Subsequent condensation of 6-(methylamino)-2-chloropurine (IV) with bromide (III) in the presence of K2CO3 gave adduct (V). Mono-decarbethoxylation of tricarboxylate (V) upon treatment with NaOMe produced malonate (VI), which was further reduced to diol (VII) by means of NaBH4 in CH2Cl2-MeOH. Treatment of (VII) with tetrabenzyl pyrophosphate in the presence of LDA gave rise to the bis-phosphate ester (VIII). The benzyl groups of (VIII) were then cleaved employing boron trichloride, and the resulting phosphoric acid was purified through an ion-exchange resin in the presence of ammonium bicarbonate to furnish the title tetraammonium salt.
| 【1】 Boyer, J.L.; Nandanan, E.; Kim, Y.-C.; Adams, M.; Harden, T.K.; Jang, S.-Y.; Jacobson, K.A.; Gallo-Rodriguez, C.; Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y1 receptor antagonists. J Med Chem 2000, 43, 4, 746. |
| 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) | 47051 | triethyl methanetricarboxylate | 6279-86-3 | C10H16O6 | 详情 | 详情 |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 11646 | triethyl 3-bromo-1,1,1-propanetricarboxylate | C12H19BrO6 | 详情 | 详情 | |
| (IV) | 47052 | 2-chloro-N-methyl-9H-purin-6-amine; N-(2-chloro-9H-purin-6-yl)-N-methylamine | C6H6ClN5 | 详情 | 详情 | |
| (V) | 47053 | triethyl 3-[2-chloro-6-(methylamino)-9H-purin-9-yl]-1,1,1-propanetricarboxylate | C18H24ClN5O6 | 详情 | 详情 | |
| (VI) | 47054 | diethyl 2-[2-[2-chloro-6-(methylamino)-9H-purin-9-yl]ethyl]malonate | C15H20ClN5O4 | 详情 | 详情 | |
| (VII) | 47055 | 2-[2-[2-chloro-6-(methylamino)-9H-purin-9-yl]ethyl]-1,3-propanediol | C11H16ClN5O2 | 详情 | 详情 | |
| (VIII) | 47056 | dibenzyl 2-([[bis(benzyloxy)phosphoryl]oxy]methyl)-4-[2-chloro-6-(methylamino)-9H-purin-9-yl]butyl phosphate | C39H42ClN5O8P2 | 详情 | 详情 |