4-(2-amino-6-chloro-9H-purin-9-yl)-2-[[(methoxycarbonyl)oxy]methyl]butyl methyl carbonate -Drug Synthesis Database

【结构式】

【分子编号】19778

【品名】4-(2-amino-6-chloro-9H-purin-9-yl)-2-[[(methoxycarbonyl)oxy]methyl]butyl methyl carbonate

【CA登记号】

【分子式】C₁₄H₁₈ClN₅O₆

【分子量】387.77972

【元素组成】C 43.36% H 4.68% Cl 9.14% N 18.06% O 24.76%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

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.

参考文献中间体

合成目标

【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：(V)

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.

参考文献中间体

合成目标

【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

Extended Information