Valganciclovir hydrochloride, TA-9070, Ro-10-79070/194, RS-79070-194, RS-79070(free base), Valcyte, Valcyt, Cymeval, -Drug Synthesis Database

【结构式】

【药物名称】Valganciclovir hydrochloride, TA-9070, Ro-10-79070/194, RS-79070-194, RS-79070(free base), Valcyte, Valcyt, Cymeval

【化学名称】5-Amino-3-[1-(hydroxymethyl)-2-(L-valyloxy)ethoxymethyl]-6,7-dihydro-3H-imidazo[4,5-d]pyrimidin-7-one hydrochloride
　　　　　　L-Valine 2-(guanin-9-ylmethoxy)-3-hydroxypropyl ester hydrochloride

【CA登记号】175865-59-5, 175865-67-5 ((R)-isomer), 175865-62-0 ((R)-isomer, free base), 175865-63-1 ((R)-isomer, monoacetate salt), 175865-6

【分子式】C₁₄H₂₃ClN₆O₅

【分子量】390.82961

【开发单位】Roche (Originator), Tanabe Seiyaku (Marketer), Recordati (Licensee)

【药理作用】Anti-Cytomegalovirus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems

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1

The silylation of ganciclovir (I) with TMSCl and imidazole in DMF gives the N2-silylated compound (II), which by condensation with N-benzyloxycarbonyl-L-valine-N-carboxyanhydride (III) and subsequent treatment with 3M HCl yields the monoprotected valganciclovir derivative (IV). Finally, this compound is submitted to hydrogenolysis with H2 over Pd/C in methanol/HCl.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 Arzeno, H.B.; Beard, C.C.; Fisher, L.E.; Prince, A. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. WO 9727194 .

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)	35312	2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one		C₉H₁₃N₅O₄	详情	详情
(II)	35313	9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-2-[(trimethylsilyl)amino]-1,9-dihydro-6H-purin-6-one		C₁₂H₂₁N₅O₄Si	详情	详情
(III)	29555	benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	158257-41-1	C₁₄H₁₅NO₅	详情	详情
(IV)	35314	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₂₂H₂₈N₆O₇	详情	详情

合成路线2

The condensation of ganciclovir (I) with the activated L-valine derivative (III) by means of triethylamine in DMF gives the O,O'-bis(valyl)ganciclovir derivative (V), which by selective removal of one of the L-valine groups with propylamine in hexane yields the previously reported monoprotected valganciclovir derivative (IV).

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 Arzeno, H.B. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. US 5700936; WO 9727195 .

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)	35312	2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one		C₉H₁₃N₅O₄	详情	详情
(III)	29555	benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	158257-41-1	C₁₄H₁₅NO₅	详情	详情
(IV)	35314	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₂₂H₂₈N₆O₇	详情	详情
(V)	35315	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₃₅H₄₃N₇O₁₀	详情	详情

合成路线3

The reaction of ganciclovir (I) with trityl chloride in DMF in the presence of triethylamine and DMAP gives the N,O-bis(trityl) compound (VI), which is condensed with the activated L-valine derivative (III) by means of triethylamine in DMF/toluene to yield the expected valine ester (VII). Finally, the trityl groups of (VII) are removed with TFA in trifluoroethanol to afford the previously reported monoprotected compound (IV). The condensation of the tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine (VIII) by means of DCC in dichloromethane gives the expected valine ester (IX), which is finally deprotected with TFA in dichloromethane. The valine ester (IX) can also be obtained by condensation of tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine-N-carboxyanhydride (X) by means of triethylamine in DMF.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 Arzeno, H.B.; Humphreys, E.R. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. US 5756736; WO 9727196 .

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)	35312	2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one		C₉H₁₃N₅O₄	详情	详情
(III)	29555	benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	158257-41-1	C₁₄H₁₅NO₅	详情	详情
(IV)	35314	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₂₂H₂₈N₆O₇	详情	详情
(VI)	35316	9-([2-hydroxy-1-[(trityloxy)methyl]ethoxy]methyl)-2-(tritylamino)-1,9-dihydro-6H-purin-6-one		C₄₇H₄₁N₅O₄	详情	详情
(VII)	35319	2-[[6-oxo-2-(tritylamino)-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(trityloxy)propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₆₀H₅₆N₆O₇	详情	详情
(VIII)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(IX)	35317	2-[[6-oxo-2-(tritylamino)-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(trityloxy)propyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate		C₅₇H₅₈N₆O₇	详情	详情
(X)	35318	tert-butyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	141468-55-5	C₁₁H₁₇NO₅	详情	详情

合成路线4

The reaction of ganciclovir (I) with trimethyl orthoformate and TFA in DMF gives the cyclic orthoester (XI), which is treated with formic acid in DMF/water to yield ganciclovir O-monoformate (XII). The condensation of (XII) with N-benzyloxycarbonyl-L-valine-N-carboxyanhydride (III) by means of triethylamine in DMF affords the expected monovalinate (XIII), which is deformylated with HCl in methanol/dichloromethane to give the previously reported monoprotected valganciclovir derivative (IV). The preceding reaction sequence can also be performed by substituting trimethyl orthoformate with other orthoesters such as benzyl orthoformate, ethyl orthoacetate, methyl orthoacetate or ethyl orthopropionate.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 Arzeno, H.B.; Humphreys, E.R.; Wong, J.-W.; Roberts, C.R. (F. Hoffmann-La Roche AG); Process for preparing ganciclovir derivs.. US 5840890; WO 9727197 .

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)	35312	2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one		C₉H₁₃N₅O₄	详情	详情
(III)	29555	benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	158257-41-1	C₁₄H₁₅NO₅	详情	详情
(IV)	35314	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₂₂H₂₈N₆O₇	详情	详情
(XI)	35320	2-amino-9-[[(2-methoxy-1,3-dioxan-5-yl)oxy]methyl]-1,9-dihydro-6H-purin-6-one		C₁₁H₁₅N₅O₅	详情	详情
(XII)	35320	2-amino-9-[[(2-methoxy-1,3-dioxan-5-yl)oxy]methyl]-1,9-dihydro-6H-purin-6-one		C₁₁H₁₅N₅O₅	详情	详情
(XIII)	35322	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-(formyloxy)propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₂₃H₂₈N₆O₈	详情	详情

合成路线5

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

【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

合成路线6

The condensation of 1-acetoxy-2-(acetoxymethoxy)-3-(benzyloxy) propane (XXI) with guanine (XXII) by means of HMDS and trifluoromethanesulfonic acid gives O-acetyl-O'-benzylganciclovir (XXIII), which is deacetylated with NaOH in methanol to yield the previously reported mono-O-benzylganciclovir (XVIII). The preceding reaction sequence can also be performed by using 1-(benzyloxy)-2-(propionyloxymethoxy)-3-(propionyloxy)propane (XXIV) instead of compound (XXI), yielding intermediate (XXV) and finally the previously reported mono-O-benzylganciclovir (XVIII).

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 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	CAS号	分子式	供应商	用于合成
(XVIII)	35324	2-amino-9-[[2-(benzyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one		C₁₆H₁₉N₅O₄	详情	详情
(XXI)	35326	[2-(acetoxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate		C₁₅H₂₀O₆	详情	详情
(XXII)	10352	2-Amino-1,9-dihydro-6H-purin-6-one; Guanine	73-40-5	C₅H₅N₅O	详情	详情
(XXIII)	35327	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-(benzyloxy)propyl acetate		C₁₈H₂₁N₅O₅	详情	详情
(XXIV)	35328	3-(benzyloxy)-2-[(propionyloxy)methoxy]propyl propionate		C₁₇H₂₄O₆	详情	详情
(XXV)	35329	2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-(benzyloxy)propyl propionate		C₁₉H₂₃N₅O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)