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药物详细合成路线

Name Acycloguanosine;Aciclovir;Acyclovir;W-248-U;BW-248-U;Maynar;Viropump(former Brand Name);Genvir;Zovirax
Chemical Name 9-(2-Hydroxyethoxymethyl)guanine;2-Amino-6-hydroxy-9-(2-hydroxyethoxymethyl)purine;2-Amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one
CAS 59277-89-3
Related CAS
Formula C8H11N5O3
Structure
Formula Weight 225.20857
Stage 上市-1981
Company GlaxoSmithKline (Originator), Biovail (Licensee), Ferrer (Licensee), Flamel (Formulation), SkyePharma (Formulation), Shionogi (Codevelopment)
Activity/Mechanism Anti-Herpes Labialis Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Anti-Varicella Zoster Virus Drugs, Antiviral Drugs, Antiviral Ophthalmic Drugs, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs
Syn. Route 4
Route 1
an efficient and selective process for the synthesis of acyclovir has been published:the reaction of guanine (i) with refluxing hexamethyldisilazane (hmds) (ii) by means of trifluoromethanesulfonic acid, elimination of the hmds in excess and condensation of the resulting product with refluxing 1,3-dioxolane (iii) gives 9-[2-(trimethylsilyloxy)ethoxymethyl]guanine (iv), which is finally hydrolyzed with refluxing acetic acid/water.
List of intermediates No.
n,n-dipropylamine; n-propyl-1-propanamine (i)
1,2-di(2-oxiranyl)-1,2-ethanediol (iii)
(7r)-3-[(acetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (iv)
Reference 1:
    han, y.-k.; harrington, p.j.; schloemer, g.c. (f. hoffmann-la roche ag); preparation of acyclovir. ep 0709385; jp 1996053451 .

Route 2
the reaction of benzonitrile (i) with refluxing ethylene glycol (ii) gives ethylene glycol monobenzoate (iii), which is chloromethylated with formaldehyde and dry hcl in ch2cl2 affording 1-benzoyloxy-2-chloromethoxyethane (iv). the condensation of (iv) with 2,6-dichloropurine (v) by means of triethylamine in dmf yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (vi), which is aminated and debenzoylated by treatment with nh3 in methanol at 95 c in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (vii). the sandmeyer reaction of (vii) with nano2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (viii), which is finally amonolyzed with ammonia in methanol at 125 c in a pressure vessel.
List of intermediates No.
(1r,4as,10ar)-7-isopropyl-1,4a-dimethyl-6-sulfo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid (ii)
(2s,3s)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxo-3-azetidinecarbaldehyde (v)
1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine (i)
2-[(4-isothiocyanatophenyl)oxy]-6-methyl-4-(methyloxy)tetrahydro-2h-pyran-3,5-diol (iii)
3,4-bis(phenylsulfonyl)-1,2,5-oxadiazol-2-ium-2-olate (iv)
4-[(3-hydroxypropyl)oxy]-3-(phenylsulfonyl)-1,2,5-oxadiazol-2-ium-2-olate (vi)
[(chlorocarbonyl)oxy]methyl 2-methylpropanoate (vii)
({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)methyl 2-methylpropanoate (viii)
Reference 1:
    schaeffer, h.j.; et al.; 9-(2-hydroxyethoxy)guanine activity aganist viruses of the herpes group. nature 1978, 272, 583-585.
Reference 2:
    castaner, j.; hillier, k.; acycloguanosine. drugs fut 1978, 3, 11, 788.
Reference 3:
    schaeffer, h.j. (glaxo wellcome plc); purine derivs.. us 4294831 .

Route 3
the condensation of guanine (ix) with refluxing hexamethyldisilazane followed by reaction with 1-benzoyloxy-2-chloromethoxyethane (iv) by means of triethylamine in refluxing benzene gives 9-(2-benzoyloxyethoxymethyl)guanine (x), which is finally hydrolyzed with ammonia in methanol at 80 c in a pressure vessel.
List of intermediates No.
3,4-bis(phenylsulfonyl)-1,2,5-oxadiazol-2-ium-2-olate (iv)
(ix)
tris(2,2,2-trifluoroethyl)phosphite (x)
Reference 1:
    castaner, j.; hillier, k.; acycloguanosine. drugs fut 1978, 3, 11, 788.
Reference 2:
    schaeffer, h.j. (glaxo wellcome plc); purine derivs.. us 4294831 .

Route 4
the acetylation of guanine (i) or guanosine (ii) with acetic anhydride gives the diacetyl guanine (iii), which is condensed with 1,4-diacetoxy-2-oxabutane (iv) by means of tsoh to yield n,o-diacetyl acyclovir (v). finally, this compound is deacetylated with nh3, naoh or pyrrolidine at room temperature, or also with refluxing glycol.
List of intermediates No.
n,n-dipropylamine; n-propyl-1-propanamine (i)
methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate (v)
4,8,8-trimethyl-1,8-dihydro-2h-pyrano[2,3-h]quinolin-2-one (iii)
1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone (ii)
{(1s,2s,3r,6s)-9-[(z)-(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.0~3,7~]dec-2-yl}methanol (iv)
Reference 1:
    gao, h.; mitra, a.k.; synthesis of acyclovir, ganciclovir and their prodrugs: a review. synthesis 2000, 3, 329.

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阿昔洛韦;英文名Acycloguanosine;Aciclovir;Acyclovir;W-248-U;BW-248-U;Maynar;Viropump(former Brand Name);Genvir;Zovirax;CAS[59277-89-3]

 
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