N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide -Drug Synthesis Database

【结构式】

【分子编号】29162

【品名】N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide

【CA登记号】

【分子式】C₂₅H₂₇N₅O₅

【分子量】477.52008

【元素组成】C 62.88% H 5.7% N 14.67% O 16.75%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VII)

The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of NaOH in water gives 1,3-di-O-benzylglycerol (III), which is condensed with paraformaldehyde by means of HCl in methylene chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV). Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl-2-O-(acetoxymethyl)glycerol (V), which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]guanine (VII). Finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.

参考文献中间体

合成目标

【1】 Dvorak, C.A.; Matthews, T.R.; Martin, J.C.; Verheyden, P.H.; Smee, D.F.; 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: A new potent and selective antiherpes agent. J Med Chem 1983, 26, 5, 759-761.
【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61.
【3】 Verheyden, J.P.; Martin, J.C. (Roche Bioscience); 9-(1,3-Dihydroxy-2-propoxymethyl)guanine as antiviral agent. EP 0066208; JP 4217983; JP 57203086; US 4355032 .
【4】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365.

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)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(II)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情
(III)	29159	1,3-bis(benzyloxy)-2-propanol	6972-79-8	C₁₇H₂₀O₃	详情	详情
(IV)	24432	1-[[3-(benzyloxy)-2-(chloromethoxy)propoxy]methyl]benzene		C₁₈H₂₁ClO₃	详情	详情
(V)	29160	[2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate		C₂₀H₂₄O₅	详情	详情
(VI)	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
(VII)	29162	N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide		C₂₅H₂₇N₅O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The condensation of N2-acetylguanine (VIII) with (V) by means of ammonium sulfate in refluxing HMDS gives (VII). This compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.

参考文献中间体

合成目标

【1】 Kennell, W.L.; Ogilvie, K.K.; Cheriyan, U.O.; Smith, K.O.; Radatus, B.K.; Galloway, K.S.; Biologically active acylnucleoside analogs. II. The synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (BIOLF-62). Can J Chem 1982, 60, 24, 3005.
【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61.
【3】 Ogilvie, K.K. (Bio Logicals Inc.); Purine and pyrimidine compounds and their use as anti-viral agents. EP 0049072; EP 0243670; JP 57085373; US 4347360 .
【4】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	29160	[2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate	C₂₀H₂₄O₅	详情	详情
(VII)	29162	N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide	C₂₅H₂₇N₅O₅	详情	详情
(VIII)	29168	3-(acetoxy)-2-[(acetoxy)methoxy]propyl acetate	C₁₀H₁₆O₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The reaction of 1,3-dichloro-2-propanol (I) with Bn-ONa gives 1,3-dibenzyloxy-2-propanol (II), which by reaction with paraformaldehyde and HCl is converted into the chloromethyl ether (III). The reaction of (III) with potassium acetate affords the acetoxymethyl ether (IV), which is condensed with diacetylguanine (V) by means of TsOH to provide fully protected ganciclovir (VI). Finally, this compound is debenzylated to (VII) with Pd(OH)2/cyclohexene and deacetylated with ammonia in methanol.

参考文献中间体

合成目标

【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)	33378	1,3-dichloro-2-propanol	96-23-1	C₃H₆Cl₂O	详情	详情
(II)	29159	1,3-bis(benzyloxy)-2-propanol	6972-79-8	C₁₇H₂₀O₃	详情	详情
(III)	24432	1-[[3-(benzyloxy)-2-(chloromethoxy)propoxy]methyl]benzene		C₁₈H₂₁ClO₃	详情	详情
(IV)	29160	[2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate		C₂₀H₂₄O₅	详情	详情
(V)	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
(VI)	29162	N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide		C₂₅H₂₇N₅O₅	详情	详情
(VII)	46048	N-(9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide		C₁₁H₁₅N₅O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XVI)

The condensation of 2-(acetoxymethoxy)-1,3-bis(benzyloxy)propane (XIV) with N2-acetylguanine (XV) by means of hexamethyldisilazane (HMDS) and trifluoromethanesulfonic acid gives the N2-acetyl-O,O'-dibenzylganciclovir (XVI), which is selectively monodebenzylated with either H2 over Pd/C in methanol or cyclohexene and Pd(OH)2 in refluxing ethanol, yielding intermediate (XVII), which by deacetylation with NH4OH in methanol affords mono-O-benzylganciclovir (XVIII). The condensation of (XVIII) with N-benzyloxycarbonyl-L-valine (XIX) by means of DCC in dichloromethane gives the expected valine ester (XX), which is finally debenzylated with H2 over Pd/C in methanol as before.

参考文献中间体

合成目标

【1】 Nestor, J.J.; Womble, S.W.; Maag, H. (F. Hoffmann-La Roche AG); 2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol deriv.. CA 2154721; EP 0694547; ES 2083348; JP 1996041061; US 5840891; US 6083953 .
【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【3】 Dvorak, C.A.; Beard, C.C.; Wren, D.L.; Axt, S.D.; Han, Y.-K.; Fatheree, P.R.; Nguyen, S.L.; Lund, J.P.; Fisher, L.E.; Arzeno, H.B.; Humphreys, E.R. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. US 6040446; WO 9727198 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	29160	[2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate	C₂₀H₂₄O₅	详情	详情
(XV)	29163	N-(6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide	C₇H₇N₅O₂	详情	详情
(XVI)	29162	N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide	C₂₅H₂₇N₅O₅	详情	详情
(XVII)	35323	N-(9-[[2-(benzyloxy)-1-(hydroxymethyl)ethoxy]methyl]-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide	C₁₈H₂₁N₅O₅	详情	详情
(XVIII)	35324	2-amino-9-[[2-(benzyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one	C₁₆H₁₉N₅O₄	详情	详情
(XIX)	18092	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid	C₁₃H₁₇NO₄	详情	详情
(XX)	35325	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-(benzyloxy)propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate	C₂₉H₃₄N₆O₇	详情	详情

Extended Information