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Name Adefovir dipivoxil;GS-840;Bis(pom)PMEA;Piv2PMEA;Hepsera;Preveon(former TM)
Chemical Name 9-[2-[Bis(pivaloyloxymethoxy)phosphorylmethoxy]ethyl]adenine
CAS 142340-99-6
Related CAS
Formula C20H32N5O8P
Structure
Formula Weight 501.48054
Stage 上市-2002
Company Inst. Organic Chemistry Biochemistry (Originator), Rega Institute for Medical Research (Originator), Gilead (Licensee), GlaxoSmithKline (Licensee)
Activity/Mechanism AIDS Medicines, Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antiviral Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, DNA Polymerase Inhibitors
Syn. Route 3
Route 1
adefovir dipivoxil can be obtained by two similar ways:1) the reaction of adenine (i) with 2-(diisopropoxyphosphorylmethoxy)ethyl methanesulfonate (ii) by means of cesium carbonate in dmf gives the expected condensation product (iii), which is converted into the phosphonic acid (iv) by treatment with trimethylsilyl bromide in acetonitrile (1). finally, this compound is condensed with chloromethyl pivalate (v) by means of n,n-dicyclohexylmorpholine-4-carboxamidine in dmf.2) the final condensation of the phosphonic acid (iv) can also be performed with iodomethyl pivalate (vi) in pyridine.
List of intermediates No.
1-iodo-4-nitrobenzene (i)
diethyl 5-hydroxy-10-methoxybenzo[a]phenazine-6,9-dicarboxylate (vi)
1,4-difluoro-2-nitrobenzene (ii)
3-fluorophenoxathiin (iii)
3-fluoro-10h-10lambda(6)-phenoxathiin-10,10-dione (iv)
1,1,1-trifluoro-2-propanol (v)
Reference 1:
    benzaria, s.; pélicano, h.; johnson, r.; maury, g.; imbach, j.-l.; aubertin, a.-m.; obert, g.; gosselin, g.; synthesis, in vitro antiviral evaluation, and stability studies of bis(s-acyl-2-thioethyl) ester derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (pmea) as potential pmea prodrugs with improved oral bioavailability. j med chem 1996, 39, 25, 4958-65.
Reference 2:
    prous, j.; graul, a.; castaner, j.; adefovir dipivoxil. drugs fut 1997, 22, 8, 825.
Reference 3:
    starrett, j.e. jr.; mansuri, m.m.; martin, j.c.; tortolani, d.r.; bronson, j.j. (bristol-myers squibb co.); prodrug of phosphonates. ep 0481214; jp 1992230694 .
Reference 4:
    starrett, j.e. jr.; tortolani, d.r.; russell, j.; hitchcock, m.j.m.; whiterock, v.; martin, j.c.; mansuri, m.m.; synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (pmea). j med chem 1994, 37, 12, 1857-64.
Reference 5:
    starrett, j.e. jr.; et al.; synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. antivir res 1992, 19, 3, 267-73.

Route 2
an optimized process for large-scale production of adefovir dipivoxil has been reported:the reaction of adenine (i) with 1,3-dioxolan-2-one (ii) by means of naoh in hot dmf gives 9-(2-hydroxyethyl)adenine (iii), which is condensed with diethyl p-toluenesulfonyloxymethylphosphonate (iv) by means of sodium tert-butoxide, (instead of nah, originally used) in dmf yielding 9-[2-(diethylphosphonomethoxy)ethyl]adenine (v). the hydrolysis of intermediate (v) by means of tms-br in hot acetonitrile affords the phosphonic acid (vi), which is finally condensed with chloromethyl pivalate (vii) by means of triethylamine in hot n-methylpyrrolidine.
List of intermediates No.
1-iodo-4-nitrobenzene (i)
6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1h-1-benzothiophen-1-one (iv)
3-fluoro-10h-10lambda(6)-phenoxathiin-10,10-dione (vi)
1,1,1-trifluoro-2-propanol (vii)
[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]methanol (ii)
methyl 4-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate (iii)
methyl (2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate (v)
Reference 1:
    dudzinski, p.w.; kelly, d.e.; yu, r.h.; rohloff, j.c.; schultze, l.m.; process optimization in the synthesis of 9-[2-(diethylphosphonomethoxy)ethyl]adenine: replacement of sodium hydride with sodium tert-butoxide as the base for oxygen alkylation. org process res dev 1999, 3, 1, 53.
Reference 2:
    kelly, d.e.; lee, t.t.k.; prisbe, e.j.; schultze, l.m.; arimilli, m.n.; manes, l.v.; munger, j.d. jr. (gilead sciences inc.); nucleotide analog compsns.. wo 9904774 .
Reference 3:
    dahl, t.c.; yuan, l.-c.j. (gilead sciences inc.); pharmaceutical formulations. wo 0035460 .

Route 3
the 9-[2-(phosphonomethoxy)ethyl]adenine (viii), intermediate in the synthesis of adefovir has been obtained as follows:1) the partial hydrolysis of 2-acetoxyethoxymethylphosphonic acid diethyl ester (i) with dowex 50xb in ethanol gives the corresponding 2-hydroxyethoxymethylphosphonate (ii), which is treated with ccl4/pph3, with cbr4/pph3 or with tscl yielding 2-choroethoxy (iii), 2-bromoethoxy (iv) or 2-tosyloxyethoxy (v) derivatives, respectively (1). the condensation of (iii), (iv) or (v) with adenine (vi) by means of nah in hot dmf affords 9-[2-(diethoxyphosphorylmethoxy)ethyl]adenine (vii), which is finally treated with tms-br in acetonitrile to give the desired intermediate 9-[2-(phosphonomethoxy)ethyl]adenine (viii).2) the condensation of n6-benzoyl-9-(2-hydroxyethyl)adenine (ix) with tosyloxymethylphosphonic acid dimethyl ester (x) by means of nah in warm dmf gives 9-[2-(dimethoxyphosphorylmethoxy)ethyl]adenine (x), which is treated first with naoh in dmf/water and finally with tms-i in dmf to afford the desired intermediate 9-[2-(phosphonomethoxy)ethyl]adenine (viii).
List of intermediates No.
1-iodo-4-nitrobenzene (vi)
3-fluoro-10h-10lambda(6)-phenoxathiin-10,10-dione (viii)
methyl (2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate (vii)
(i)
(ii)
(iii)
(iv)
(v)
(ix)
(x)
(xi)
Reference 1:
    rosenberg, i.; holy, a.; synhtesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds. coll czech chem commun 1987, 52, 2801.
Reference 2:
    holy, a.; et al.; synthesi of n-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases. coll czech chem commun 1989, 54, 2190.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名阿德福韋酯;英文名Adefovir dipivoxil;GS-840;Bis(pom)PMEA;Piv2PMEA;Hepsera;Preveon(former TM);CAS[142340-99-6]

 
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