Ganciclovir, DHPG, RS-21592, BW-795, 2'-NDG, BIOLF-62, BW-759U, Cymeven, Cymevan, Citovirax, Vitrasert, Cymevene, Cytovene, Virgan, -Drug Synthesis Database

【结构式】

【药物名称】Ganciclovir, DHPG, RS-21592, BW-795, 2'-NDG, BIOLF-62, BW-759U, Cymeven, Cymevan, Citovirax, Vitrasert, Cymevene, Cytovene, Virgan

【化学名称】2-Amino-1,9-dihydro-9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]-6H-purin-6-one
　　　　　　9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine

【CA登记号】82410-32-0, 107910-75-8 (Na salt)

【分子式】C₉H₁₃N₅O₄

【分子量】255.23506

【开发单位】Roche (Originator), Roche Bioscience (Originator), Recordati (Not Determined), Ranbaxy (Generic)

【药理作用】Anti-Cytomegalovirus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, DNA Polymerase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

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

【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

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

【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

The condensation of 6-chloroguanine (IX) with (V) by means of ammonium sulfate in refluxing HMDS gives 9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]-6-chloroguanine (XI), which is treated with sodium methoxide and mercaptoethanol in refluxing methanol to yield 9-[[1,3-bisbenzyloxy)-2-propoxy]methyl]guanine (XI), which is finally deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.

参考文献中间体

【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】 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
(IX)	10913	6-Chloro-6,9-dihydro-1H-purin-2-ylamine; 6-Chloro-6,9-dihydro-1H-purin-2-amine	C₅H₆ClN₅	详情	详情
(X)	29164	9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-chloro-9H-purin-2-ylamine	C₂₃H₂₄ClN₅O₃	详情	详情
(XI)	29165	2-amino-9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-1,9-dihydro-6H-purin-6-one	C₂₃H₂₅N₅O₄	详情	详情

合成路线4

The acetylation of 4-hydroxymethyl-1,3-dioxolane (XII) gives the corresponding acetate (XIII), which by reaction with acetic anhydride and ZnCl2 is converted to 1,3-diacetoxy-2-(acetoxymethoxy)propane (XIV). The condensation of (XIV) with diacetylguanine (VI) by means of ethanesulfonic acid (B) yields the triacetoxy precursor (XV), which is hydrolyzed with aqueous methylamine.

参考文献中间体

【1】 Field, A.K.; Tolman, R.L.; Ashton, W.A.; Karkas, J.D.; Activation by thymidine kinase and potent antiherpetic activity of 2'-nor-2'-deoxyguanosine (2'NDG). Biochem Biophys Res Commun 1982, 108, 4, 1716.
【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】 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
(A)	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(B)	29169	1-ethanesulfonic acid	594-45-6	C₂H₆O₃S	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
(XII)	29166	1,3-dioxolan-4-ylmethanol	4740-78-7	C₄H₈O₃	详情	详情
(XIII)	29167	1,3-dioxolan-4-ylmethyl acetate		C₆H₁₀O₄	详情	详情
(XIV)	29168	3-(acetoxy)-2-[(acetoxy)methoxy]propyl acetate		C₁₀H₁₆O₇	详情	详情
(XV)	29170	2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate		C₁₅H₁₉N₅O₇	详情	详情

合成路线5

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

【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6

The reaction of 4-(chloromethyl)-1,3-dioxolane (I) with Ac2O, HOAc and ZnCl2 gives the diacetoxy compound (II), which is treated with KOAc to yield the triacetoxy compound (III). The condensation of (III) with diacetyl guanine (IV) by means of ethylsulfonic acid affords the triacetyl ganciclovir (V), which is finally deacetylated with methylamine in methanol.

参考文献中间体

【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)	46049	4-(chloromethyl)-1,3-dioxolane		C₄H₇ClO₂	详情	详情
(II)	46050	[2-(acetoxy)-1-(chloromethyl)ethoxy]methyl acetate		C₈H₁₃ClO₅	详情	详情
(III)	46051	3-(acetoxy)-2-(2-oxopropoxy)propyl acetate		C₁₀H₁₆O₆	详情	详情
(IV)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(V)	29170	2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate		C₁₅H₁₉N₅O₇	详情	详情

合成路线7

The condensation of diacetyl guanine (I) with 1,3-diacetoxy-2-(acetoxymethoxy)propane (II) by means of TsOH in hot DMF gives the target intermediate, N2-acetyl-9-[2-acetoxy-1-(acetoxymethyl)ethoxymethyl]guanine (III). (see Synthline Scheme no. 11147104a, intermediate no. (XV)).

参考文献中间体

【1】 Kumar, Y.; Khanduri, C.H.; Ray, P.C.; Babu, J.S. (Ranbaxy Laboratories Ltd.); A process for the preparation of ganciclovir intermediate N2-acetyl-9-(1,3-diacetoxy-2-propoxymethyl)guanine. WO 0333498 .

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)	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
(II)	64100	2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl acetate		C₉H₁₄O₆	详情	详情
(III)	29170	2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate		C₁₅H₁₉N₅O₇	详情	详情

Extended Information