超大码男鞋:泛昔洛韦 [CAS:104227-87-4]合成路线图解??有机化学网

药物详细合成路线

Chemical Name： 9-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine Generic Name： 泛昔洛韦;Famciclovir Other Names： Famciclovir;BRL-42810;Famvir CAS： 104227-87-4 Formula： C₁₄H₁₉N₅O₄ Mole Weight： 321.33863 structure： Company： Novartis (Proprietary), GlaxoSmithKline (Originator), Solvay (Licensee) Usage： Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs Route 1 A synthesis of famciclovir that corresponds to that previously published and studies on its oral bioavailability in rats and mice, identifying famciclovir as the preferred prodrug of BRL-39123 (penciclovir), have been published. Intermediates: Serial No. 8-chloro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol (I) 2-(4-pyridinyl)acetonitrile (II) dimethyl 4-cyano-4-(4-pyridinyl)heptanedioate (III) 4-(4-pyridinyl)heptanedioic acid (IV) 4-(4-pyridinyl)cyclohexanone (V) 2-acetyl-4-(4-pyridinyl)cyclohexanone (VI) 3-oxobutanamide (VII) 1-methyl-3-oxo-7-(4-pyridinyl)-2,3,5,6,7,8-hexahydro-4-isoquinolinecarbonitrile (VIII) 4-bromopyridine (IX) 8-(4-pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol (X) 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (XI) (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene (XII) 2-[(1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]-1-ethanol (XIII) 2-[3-[(1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]propoxy]tetrahydro-2H-pyran; 3-[(1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]propyl tetrahydro-2H-pyran-2-yl ether (XIV) Reference 1:     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 2:     Harnden, M.R.; Boyd, M.R.; Vere Hodge, R.A.; Jarvest, R.L.; Sutton, D.; Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxy methyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 1989, 32, 1738-43.
Route 2 The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (II) by means ofK2CO3 in DMF gives the expected condensation product (III), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (V), which is finally converted into famciclovir by reductive dechlorination with H2 over Pd/C in ethyl acetate/triethylamine. Intermediates: Serial No. 4-bromopyridine (I) 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (II) (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene (III) (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 (IV) (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 (V) Reference 1:     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 2:     Harnden, M.R.; Boyd, M.R.; Vere Hodge, R.A.; Jarvest, R.L.; Sutton, D.; Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxy methyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 1989, 32, 1738-43.
Route 3 A new synthetic route to famciclovir has been described: The alkylation of 2,2-dimethyl-1,3-dioxan-5-one (I) with vinylmagnesium bromide (II) in THF gives the 2,2-dimethyl-5-vinyl-1,3-dioxan-5-ol derivative (II), which is treated with methyl chloroformate in the same solvent to yield the mixed carbonate (IV). Condensation of (IV) with 6-chloropurine-2-amine (V) by means of 1,2-bis(diphenylphosphino)ethane (dppe) and tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in DMF at 80 °C for 7.5 h affords a 5:95 mixture of the N-7 (VI) and N-9 (VII) regioisomers, respectively. Hydrogenation of regioisomer (VII) with H2 over Pd/C in THF eliminates the 6-chlorine atom and reduces the exocyclic double bond giving the 2-aminopurine derivative (VIII), which is treated with HCl in methanol to remove the acetonide group affording diol (IX). Finally, this compound is acylated with acetic anhydride and DMAP/TEA in dichloromethane. Intermediates: Serial No. 1-methyl-3-oxo-7-(4-pyridinyl)-2,3,5,6,7,8-hexahydro-4-isoquinolinecarbonitrile (IX) 4-bromopyridine (V) benzhydryl (6R,7R)-7-[((2R,3S)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) 1-(5-bromo-2-methoxyphenyl)adamantane; 2-(1-adamantyl)-4-bromophenyl methyl ether (I) [3-(1-adamantyl)-4-methoxyphenyl](bromo)magnesium (III) 6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate (IV) methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (VI) tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate (VII) tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate (VIII) Reference 1:     Geen, G.R.; Share, A.C.; Slater, G.R.; Ramsay, T.W.; Smith, N.M.; Freer, R.; A new route to famciclovir via palladium catalysed allylation. Tetrahedron 2000, 56, 26, 4589.