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【结 构 式】 
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【分子编号】35312 【品名】2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one 【CA登记号】 |
【 分 子 式 】C9H13N5O4 【 分 子 量 】255.23352 【元素组成】C 42.35% H 5.13% N 27.44% O 25.07% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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
该中间体在本合成路线中的序号：(I)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).
| 【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
该中间体在本合成路线中的序号：(I)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.
| 【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
该中间体在本合成路线中的序号：(I)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.
| 【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
该中间体在本合成路线中的序号：(I)The title compound was prepared by condensation of ganciclovir (I) with elaidic acid chloride (II) in the presence of pyridine.
| 【1】 Dalen, A.; Myhren, F.; Borretzen, B.; Stokke, K.T. (Norsk Hydro AS); Chemical cpds.. GB 2260319; WO 9307163 . |