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【结 构 式】 
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【分子编号】11639 【品名】6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione 【CA登记号】5617-70-9 |
【 分 子 式 】C8H10O4 【 分 子 量 】170.165 【元素组成】C 56.47% H 5.92% O 37.61% |
合成路线1
该中间体在本合成路线中的序号：(V)This compound can be obtained in the following way: 1) The reaction of N,N-dimethyl 4-methoxybenzamide (I) with 2-(methylthio)pyrrole) (II) by means of POCl3 in refluxing dichloromethane gives 5-(4-methoxyhenzoyl)-2-(methylthio)pyrrole (III), which is oxidized with m-chloroperbenzoic acid in dichloromethane to the corresponding sulfone (IV). The condensation of (IV) with 5,5-dimethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (V) by means of NaH in hot DMF affords the intermediate compound (VI), which by methanolysis with methanol and HCl is converted to 5-(4 methoxybenzoy)-1-[3,3-di-(methoxycarbonyl)propyl]-2-(methylsulfonyl)pyrrole (VII). The cyclization of (VII) by means of NaH in hot DMF gives dimethyl-5-(4-methoxybenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol-water.
| 【1】 Greenhouse, R.; Franco, F.; Novel syntheses of 5-aroyl-1,2-dihydro-3H-pyrrole-1-carboxilic acids. J Org Chem 1982, 47, 1682. |
| 【2】 Engler, H.; Schickaneder, H.; Szelenyi, I. (Heumann Pharma GmbH & Co.); Imidazoyl-substd. thiomethylpyridine derivs., method of administration thereof and medicaments containing them. DE 3216843; EP 0093252; US 4810715 . |
| 【3】 Muchowski, J.M.; Greenhouse, R. (Roche Bioscience); Process for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and novel intermediates therein. US 4347186 . |
| 【4】 Prous, J.; Castaner, J.; Anirolac. Drugs Fut 1986, 11, 6, 449. |
| 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) | 24830 | 4-methoxy-N,N-dimethylbenzamide | C10H13NO2 | 详情 | 详情 | |
| (II) | 24831 | 2-(methylsulfanyl)-1H-pyrrole | C5H7NS | 详情 | 详情 | |
| (III) | 24832 | (4-methoxyphenyl)[5-(methylsulfanyl)-1H-pyrrol-2-yl]methanone | C13H13NO2S | 详情 | 详情 | |
| (IV) | 24833 | (4-methoxyphenyl)[5-(methylsulfonyl)-1H-pyrrol-2-yl]methanone | C13H13NO4S | 详情 | 详情 | |
| (V) | 11639 | 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione | 5617-70-9 | C8H10O4 | 详情 | 详情 |
| (VI) | 24835 | 5-[2-[2-(4-methoxybenzoyl)-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C21H23NO8S | 详情 | 详情 | |
| (VII) | 24836 | dimethyl 2-[2-[2-(4-methoxybenzoyl)-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]malonate | C20H23NO8S | 详情 | 详情 | |
| (VIII) | 24837 | dimethyl 5-(4-methoxybenzoyl)-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate | C19H19NO6 | 详情 | 详情 | |
| (XI) | 24838 | 5-[2-[2-(4-methoxybenzoyl)-5-(methylsulfanyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C21H23NO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.
| 【1】 Muchowski, J.M.; Franco, F.; Greenhouse, R.; Novel syntheses of 5-aryl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids. J Org Chem 1982, 47, 9, 1682-88. |
| 【2】 Arrigoni-Martelli, E.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RS-37,619. Drugs Fut 1983, 8, 10, 871. |
| 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) | 24831 | 2-(methylsulfanyl)-1H-pyrrole | C5H7NS | 详情 | 详情 | |
| (II) | 30757 | N,N-dimethylbenzamide | 611-74-5 | C9H11NO | 详情 | 详情 |
| (III) | 30758 | [5-(methylsulfanyl)-1H-pyrrol-2-yl](phenyl)methanone | C12H11NOS | 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) | 30759 | 5-[2-[2-benzoyl-5-(methylsulfanyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C20H21NO5S | 详情 | 详情 | |
| (VI) | 30760 | 5-[2-[2-benzoyl-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C20H21NO7S | 详情 | 详情 | |
| (VII) | 30761 | dimethyl 2-[2-[2-benzoyl-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]malonate | C19H21NO7S | 详情 | 详情 | |
| (VIII) | 30762 | dimethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate | C18H17NO5 | 详情 | 详情 | |
| (IX) | 30763 | [5-(methylsulfonyl)-1H-pyrrol-2-yl](phenyl)methanone | C12H11NO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(IV)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 |