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Name Penciclovir;BRL-39123;Denavir;Vectavir
Chemical Name 9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine
CAS 39809-25-1
Related CAS 97845-62-0 (Na salt)
Formula C10H15N5O3
Structure
Formula Weight 253.26275
Stage 上市-1996
Company Novartis (Proprietary), GlaxoSmithKline (Originator), CollaGenex (Marketer)
Activity/Mechanism Anti-Herpes Labialis Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs
Syn. Route 2
Route 1
the synthesis of penciclovir by two related ways has been reported:1) the reaction of 2-(hydroxymethyl)butane-1,4-diol (i) with formaldehyde (or an aldehyde such as trimethylacetaldehyde) (ii) by means of h2so4 (or p-toluenesulfonic acid, tsoh) gives the dioxane (iii), which by reaction first with methanesulfonyl chloride and triethylamine and then with nai in acetone affords the corresponding 5-(2-iodoethyl)-1,3-dioxane (iv). the reaction of (iv) with 2-amino-6-chloropurine (v) by means of k2co3 in dmf gives the corresponding condensation product (vi), which is finally hydrolyzed and deprotected with refluxing 2m aqueous hcl.2) the reaction of triol (i) with 2,2-dimethoxypropane (vii) by means of tsoh gives the corresponding 1,3-dioxane (viii), which by reaction with triphenylphosphine and cbr4 is converted to the 5-(2-bromoethyl) derivative (ix). the reaction of (ix) with the purine (v) by means of k2co3 as before affords the corresponding condensation product (x), which is hydrolyzed and deprotected with 2m hcl as before.
List of intermediates No.
4-nitrobenzyl (5r,6s)-3-[(diphenoxyphosphoryl)oxy]-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (i)
4-nitrobenzyl (2s,4s)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate (iiia)
1-(chloromethyl)-4-nitrobenzene (iva)
(2s,4r)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid (v)
2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2s,4r)-4-hydroxy-1,2-pyrrolidinedicarboxylate (via)
2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2s,4s)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate (vii)
4-nitrobenzyl (2s,4s)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate (viii)
4-nitrobenzyl (5s,6s)-3-[((3s,5s)-5-[(dimethylamino)carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (ix)
n-[(benzyloxy)carbonyl]valine (x)
Reference 1:
    grinter, t.j.; choudary, b.m.; macbeath, f.s.; parratt, m.j.; geen, g.r.; influence of remote structure upon regioselectivity in the n-alkylation of 2-amino-6-chloropurine: application to the synthesis of penciclovir. nucleosides nucleotides 1994, 13, 4, 979.

Route 2
this compound has been obtained by two similar ways:1) the reaction of 6-chloropurine-2-amine (i) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (ii) by means of k2co3 in dmf gives the expected condensation product (iii), which is methanolized with hcl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (iv). the reduction of (iv) with nabh4 in tert-butanol/methanol affords the corresponding diol (v), which is finally converted into pecnciclovir by hydrolysis with 2n naoh.2) the reaction of purine (i) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (vi) by means ofk2co3 in dmf gives the expected condensation product (vii), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (viii). the reduction of (viii) with nabh4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (ix), which is finally converted into penciclovir by hydrlysis with 2n hcl.
List of intermediates No.
4-(4-pyridinyl)heptanedioic acid (ii)
4-bromopyridine (i)
8-(4-pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol (iii)
4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (vi)
(1r,5r)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene (vii)
(1r,3as,3br,5as,6as,7as,8as,8bs,10as)-1-hydroxy-8a,10a-dimethylhexadecahydro-2h-cyclopenta[7,8]phenanthro[2,3-b]oxiren-2-one (viii)
(2s,3s,5s,8r,9s,10s,13s,14s,16s,17r)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1h-cyclopenta[a]phenanthrene-3,17-diol (ix)
(e)-1,4-dichloro-2-butene (iv)
diethyl 2-vinyl-1,1-cyclopropanedicarboxylate (v)
Reference 1:
    jarvest, r.l.; harnden, m.r.; an improved synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine. tetrahedron lett 1985, 26, 4265-68.
Reference 2:
    grose, w.f.a.; pandit, u.k.; eggelte, t.a.; a new class of nucleoside analogues. synthesis of n1-pyrimidinyl- and n9-purinyl-4-hydroxy-3-(hydroxymethyl)butanes. synth commun 1972, 2, 345-351.
Reference 3:
    boyd, m.r.; jarvest, r.l.; bacon, t.h.; harnden, m.r.; synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines. j med chem 1987, 30, 1636-42.
Reference 4:
    hardern, d.n.; development of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines as potential therapeutic agents for treatment of human herpesvirus infections. drugs fut 1989, 14, 4, 347.
Reference 5:
    choudary, b.m.; geen, g.r.; kincey, p.m.; parratt, m.j.; dales, j.r.m.; johnson, g.p.; odonnell, s.; tudor, d.w.; woods, n.; a direct approach to the synthesis of famciclovir and penciclovir. nucleosides nucleotides 1996, 15, 5, 981.
Reference 6:
    harnden, m.r.; jarvest, r.l. (smithkline beecham plc); guanine derivs.. ep 0141927; es 8602791; es 8603887; es 8603888; jp 1994293764; us 5075445 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名喷昔洛韦;英文名Penciclovir;BRL-39123;Denavir;Vectavir;CAS[39809-25-1]

 
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