Valaciclovir, Valacyclovir, ValACV, BW-256U, 256U87, Virval, Zelitrex, Valtrex(HCl), -Drug Synthesis Database

【结构式】

【药物名称】Valaciclovir, Valacyclovir, ValACV, BW-256U, 256U87, Virval, Zelitrex, Valtrex(HCl)

【化学名称】L-Valine 2-(guanin-9-ylmethoxy)ethyl ester

【CA登记号】124832-26-4, 124832-27-5 (monoHCl)

【分子式】C₁₃H₂₀N₆O₄

【分子量】324.34215

【开发单位】GlaxoSmithKline (Originator), Aventis Pharma (Licensee), Theraplix (Licensee), Shionogi (Codevelopment)

【药理作用】Anti-Herpes Labialis Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Anti-Varicella Zoster Virus Drugs, Antiviral Drugs

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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

Extended Information