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【结 构 式】 
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【分子编号】28279 【品名】2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one 【CA登记号】59277-89-3 |
【 分 子 式 】C8H11N5O3 【 分 子 量 】225.20724 【元素组成】C 42.67% H 4.92% N 31.1% O 21.31% |
合成路线1
该中间体在本合成路线中的序号：(I)Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid.
| 【1】 Tak, R.V.; et al.; Transport of acyclovir ester prodrugs through rabbit cornea and SIRC-rabbit corneal epithelial cell line. J Pharm Sci 2001, 90, 10, 1505. |
| 【2】 Krenitsky, T.A.; Beauchamp, L.M. (GlaxoSmithKline plc); Therapeutic nucleosides. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708 . |
| 【3】 Partin, J.M.; Winnike, R.A.; Carter, B.H.; Lake, P.G.; Varlashkin, P.G.; Grubb, W.B. III; Conway, G.A.; Skinner, D.M.; Whatrup, D.J. (GlaxoSmithKline plc); Guanine deriv.. WO 9622291 . |
| 【4】 Beauchamp, L.M.; et al.; Amino acid ester prodrugs of acyclovir. Antivir Chem Chemother 1992, 3, 3, 157. |
| 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) | 28279 | 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one | 59277-89-3 | C8H11N5O3 | 详情 | 详情 |
| (II) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (III) | 59532 | 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate | C21H26N6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.
| 【1】 Montoro, M.; Pirovano, S.; Process of preparation of valacyclovir and relevant intermediates. WO 9803553 . |
| 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) | 28279 | 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one | 59277-89-3 | C8H11N5O3 | 详情 | 详情 |
| (IV) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (V) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VI) | 59533 | sodium (2S)-2-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-3-methylbutanoate | C10H16NNaO4 | 详情 | 详情 | |
| (VII) | 59534 | 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl 4-methylbenzenesulfonate | C15H17N5O5S | 详情 | 详情 | |
| (VIII) | 59535 | methyl (E)-3-{[(1S)-1-({2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethoxy}carbonyl)-2-methylpropyl]amino}-2-butenoate | C18H26N6O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)By acylation of 9-(2-hydroxyethoxymethyl)guanine (I) with pentanoyl chloride (II) or pentanoyl anhydride (III).
| 【1】 Beauchamp, L.M.; Krenitsky, T.A.; Acyclovir prodrugs: The road to valaciclovir. Drugs Fut 1993, 18, 7, 619. |
合成路线4
该中间体在本合成路线中的序号：(I)The compound was prepared by condensation of acyclovir (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 . |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of acyclovir (I) with the cyclic chlorophosphane (II) in the presence of N,N-diisopropyl ethylamine afforded the acyclovir phosphite ester (III). This was then oxidized to the target phosphate using tert-butyl hydroperoxide.
| 【1】 Meier, C.; Habel, L.; Haller-Meier, F.; Lomp, A.; Herderich, M.; Klöcking, R.; Meerbach, A.; Wutzler, P.; Chemistry and anti-herpes simplex virus type 1 evaluation of cycloSal-nucleotides of acyclic nucleoside analogues. Antivir Chem Chemother 1998, 9, 389. |
| 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) | 28279 | 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one | 59277-89-3 | C8H11N5O3 | 详情 | 详情 |
| (II) | 41608 | 2-chloro-8-methyl-4H-1,3,2-benzodioxaphosphinine | C8H8ClO2P | 详情 | 详情 | |
| (III) | 41609 | 2-amino-9-([2-[(8-methyl-4H-1,3,2-benzodioxaphosphinin-2-yl)oxy]ethoxy]methyl)-1,9-dihydro-6H-purin-6-one | C16H18N5O5P | 详情 | 详情 |