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Name Ganciclovir;DHPG;RS-21592;BW-795;2-NDG;BIOLF-62;BW-759U;Cymeven;Cymevan;Citovirax;Vitrasert;Cymevene;Cytovene;Virgan
Chemical Name 2-Amino-1,9-dihydro-9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]-6H-purin-6-one
      9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine
CAS 82410-32-0
Related CAS 107910-75-8 (Na salt)
Formula C9H13N5O4
Structure
Formula Weight 255.23506
Stage 上市-1988
Company Roche (Originator), Roche Bioscience (Originator), Recordati (Not Determined), Ranbaxy (Generic)
Activity/Mechanism Anti-Cytomegalovirus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, DNA Polymerase Inhibitors
Syn. Route 7
Route 1
the reaction of epichlorohydrin (i) with benzyl alcohol (ii) by means of naoh in water gives 1,3-di-o-benzylglycerol (iii), which is condensed with paraformaldehyde by means of hcl in methylene chloride to yield 1,3-di-o-benzyl-2-o-(chloromethyl)glycerol (iv). acetylation of (iv) with potassium acetate in acetone affords 1,3-di-o-benzyl-2-o-(acetoxymethyl)glycerol (v), which is condensed with diacetylguanine (vi) by means of p-toluenesulfonic acid in sulfolane giving n2-acetyl-9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]guanine (vii). finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (i)
4,5-dimethyl-1,3-dioxol-2-one (ii)
methyl (2r,3r,6s)-3-(acetoxy)-6-[[tert-butyl(dimethyl)silyl]oxy]tricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate (iv)
7-hydroxy-4-methyl-2(1h)-quinolinone (iii)
7-[(1,1-dimethyl-2-propynyl)oxy]-4-methyl-2(1h)-quinolinone (v)
4,8,8-trimethyl-1,8-dihydro-2h-pyrano[2,3-h]quinolin-2-one (vi)
tert-butyl 4,8,8-trimethyl-2-oxo-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (vii)
Reference 1:
    dvorak, c.a.; matthews, t.r.; martin, j.c.; verheyden, p.h.; smee, d.f.; 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. j med chem 1983, 26, 5, 759-761.
Reference 2:
    galloway, k.s.; radatus, b.k.; kennell, w.l.; smith, k.o.; ogilvie, k.k.; a new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. antimicrob agents chemother 1982, 22, 1, 55-61.
Reference 3:
    verheyden, j.p.; martin, j.c. (roche bioscience); 9-(1,3-dihydroxy-2-propoxymethyl)guanine as antiviral agent. ep 0066208; jp 4217983; jp 57203086; us 4355032 .
Reference 4:
    pento, j.t.; serradell, m.n.; castaner, j.; biolf-62. drugs fut 1985, 10, 5, 365.

Route 2
the condensation of n2-acetylguanine (viii) with (v) by means of ammonium sulfate in refluxing hmds gives (vii). this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
List of intermediates No.
7-[(1,1-dimethyl-2-propynyl)oxy]-4-methyl-2(1h)-quinolinone (v)
tert-butyl 4,8,8-trimethyl-2-oxo-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (vii)
4-[([1,1-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoyl chloride (viii)
Reference 1:
    kennell, w.l.; ogilvie, k.k.; cheriyan, u.o.; smith, k.o.; radatus, b.k.; galloway, k.s.; biologically active acylnucleoside analogs. ii. the synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (biolf-62). can j chem 1982, 60, 24, 3005.
Reference 2:
    galloway, k.s.; radatus, b.k.; kennell, w.l.; smith, k.o.; ogilvie, k.k.; a new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. antimicrob agents chemother 1982, 22, 1, 55-61.
Reference 3:
    ogilvie, k.k. (bio logicals inc.); purine and pyrimidine compounds and their use as anti-viral agents. ep 0049072; ep 0243670; jp 57085373; us 4347360 .
Reference 4:
    pento, j.t.; serradell, m.n.; castaner, j.; biolf-62. drugs fut 1985, 10, 5, 365.

Route 3
the condensation of 6-chloroguanine (ix) with (v) by means of ammonium sulfate in refluxing hmds gives 9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]-6-chloroguanine (xi), which is treated with sodium methoxide and mercaptoethanol in refluxing methanol to yield 9-[[1,3-bisbenzyloxy)-2-propoxy]methyl]guanine (xi), which is finally deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
List of intermediates No.
(2s,4r)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid (ix)
7-[(1,1-dimethyl-2-propynyl)oxy]-4-methyl-2(1h)-quinolinone (v)
tert-butyl (9r,10r)-4,8,8-trimethyl-2-oxo-9,10-bis([[(4s)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]oxy)-9,10-dihydro-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (x)
(1r,4s)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride (xi)
Reference 1:
    kennell, w.l.; ogilvie, k.k.; cheriyan, u.o.; smith, k.o.; radatus, b.k.; galloway, k.s.; biologically active acylnucleoside analogs. ii. the synthesis of 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (biolf-62). can j chem 1982, 60, 24, 3005.
Reference 2:
    galloway, k.s.; radatus, b.k.; kennell, w.l.; smith, k.o.; ogilvie, k.k.; a new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. antimicrob agents chemother 1982, 22, 1, 55-61.
Reference 3:
    pento, j.t.; serradell, m.n.; castaner, j.; biolf-62. drugs fut 1985, 10, 5, 365.

Route 4
the acetylation of 4-hydroxymethyl-1,3-dioxolane (xii) gives the corresponding acetate (xiii), which by reaction with acetic anhydride and zncl2 is converted to 1,3-diacetoxy-2-(acetoxymethoxy)propane (xiv). the condensation of (xiv) with diacetylguanine (vi) by means of ethanesulfonic acid (b) yields the triacetoxy precursor (xv), which is hydrolyzed with aqueous methylamine.
List of intermediates No.
5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde (a)
4,8,8-trimethyl-1,8-dihydro-2h-pyrano[2,3-h]quinolin-2-one (vi)
methyl 4-[([1,1-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoate (xii)
4-[([1,1-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoic acid (xiii)
4-[([1,1-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoyl chloride (xiv)
1-acetyl-2-pyrrolidinone (b)
3-[(e)-1,3-benzodioxol-5-ylmethylidene]-2-pyrrolidinone (xv)
Reference 1:
    field, a.k.; tolman, r.l.; ashton, w.a.; karkas, j.d.; activation by thymidine kinase and potent antiherpetic activity of 2-nor-2-deoxyguanosine (2ndg). biochem biophys res commun 1982, 108, 4, 1716.
Reference 2:
    galloway, k.s.; radatus, b.k.; kennell, w.l.; smith, k.o.; ogilvie, k.k.; a new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. antimicrob agents chemother 1982, 22, 1, 55-61.
Reference 3:
    pento, j.t.; serradell, m.n.; castaner, j.; biolf-62. drugs fut 1985, 10, 5, 365.

Route 5
the reaction of 1,3-dichloro-2-propanol (i) with bn-ona gives 1,3-dibenzyloxy-2-propanol (ii), which by reaction with paraformaldehyde and hcl is converted into the chloromethyl ether (iii). the reaction of (iii) with potassium acetate affords the acetoxymethyl ether (iv), which is condensed with diacetylguanine (v) by means of tsoh to provide fully protected ganciclovir (vi). finally, this compound is debenzylated to (vii) with pd(oh)2/cyclohexene and deacetylated with ammonia in methanol.
List of intermediates No.
methyl (2r,3r,6s)-3-(acetoxy)-6-[[tert-butyl(dimethyl)silyl]oxy]tricyclo[6.2.1.0(2,7)]undeca-4,9-diene-2-carboxylate (iii)
7-hydroxy-4-methyl-2(1h)-quinolinone (ii)
7-[(1,1-dimethyl-2-propynyl)oxy]-4-methyl-2(1h)-quinolinone (iv)
4,8,8-trimethyl-1,8-dihydro-2h-pyrano[2,3-h]quinolin-2-one (v)
tert-butyl 4,8,8-trimethyl-2-oxo-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (vi)
ethyl (2r)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate (i)
methyl (1s,2s,3r,6s)-9-[(z)-(tributylstannyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate (vii)
Reference 1:
    gao, h.; mitra, a.k.; synthesis of acyclovir, ganciclovir and their prodrugs: a review. synthesis 2000, 3, 329.

Route 6
the reaction of 4-(chloromethyl)-1,3-dioxolane (i) with ac2o, hoac and zncl2 gives the diacetoxy compound (ii), which is treated with koac to yield the triacetoxy compound (iii). the condensation of (iii) with diacetyl guanine (iv) by means of ethylsulfonic acid affords the triacetyl ganciclovir (v), which is finally deacetylated with methylamine in methanol.
List of intermediates No.
(2r)-2-cyclopentyl-2-hydroxy-2-phenyl-n-(4-piperidinyl)ethanamide (iv)
3-[(e)-1,3-benzodioxol-5-ylmethylidene]-2-pyrrolidinone (v)
methyl (1s,2s,3r,6s)-9-[(e)-(tributylstannyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate (i)
1-bromo-2-chloro-4-iodobenzene (ii)
methyl (1s,2s,3r,6s)-9-[(z)-(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]decane-2-carboxylate (iii)
Reference 1:
    gao, h.; mitra, a.k.; synthesis of acyclovir, ganciclovir and their prodrugs: a review. synthesis 2000, 3, 329.

Route 7
the condensation of diacetyl guanine (i) with 1,3-diacetoxy-2-(acetoxymethoxy)propane (ii) by means of tsoh in hot dmf gives the target intermediate, n2-acetyl-9-[2-acetoxy-1-(acetoxymethyl)ethoxymethyl]guanine (iii). (see synthline scheme no. 11147104a, intermediate no. (xv)).
List of intermediates No.
4,8,8-trimethyl-1,8-dihydro-2h-pyrano[2,3-h]quinolin-2-one (i)
3-[(e)-1,3-benzodioxol-5-ylmethylidene]-2-pyrrolidinone (iii)
Reference 1:
    kumar, y.; khanduri, c.h.; ray, p.c.; babu, j.s. (ranbaxy laboratories ltd.); a process for the preparation of ganciclovir intermediate n2-acetyl-9-(1,3-diacetoxy-2-propoxymethyl)guanine. wo 0333498 .

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更昔洛韦;英文名Ganciclovir;DHPG;RS-21592;BW-795;2-NDG;BIOLF-62;BW-759U;Cymeven;Cymevan;Citovirax;Vitrasert;Cymevene;Cytovene;Virgan;CAS[82410-32-0]

 
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