【药物名称】Adefovir dipivoxil, GS-840, Bis(pom)PMEA, Piv2PMEA, Hepsera, Preveon(former TM)
化学结构式(Chemical Structure):
参考文献No.17522
标题:Prodrug of phosphonates
作者:Starrett, J.E. Jr.; Mansuri, M.M.; Martin, J.C.; Tortolani, D.R.; Bronson, J.J. (Bristol-Myers Squibb Co.)
来源:EP 0481214; JP 1992230694
合成路线图解说明:

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.

参考文献No.44382
标题:Nucleotide analog compsns.
作者: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.)
来源:WO 9904774
合成路线图解说明:

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.

参考文献No.44383
标题:Pharmaceutical formulations
作者:Dahl, T.C.; Yuan, L.-C.J. (Gilead Sciences Inc.)
来源:WO 0035460
合成路线图解说明:

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.

参考文献No.190632
标题:Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine
作者:Starrett, J.E. Jr.; et al.
来源:Antivir Res 1992,19(3),267-73
合成路线图解说明:

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.

参考文献No.275785
标题:Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)
作者:Starrett, J.E. Jr.; Tortolani, D.R.; Russell, J.; Hitchcock, M.J.M.; Whiterock, V.; Martin, J.C.; Mansuri, M.M.
来源:J Med Chem 1994,37(12),1857-64
合成路线图解说明:

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.

参考文献No.416898
标题:Adefovir Dipivoxil
作者:Prous, J.; Graul, A.; Casta馿r, J.
来源:Drugs Fut 1997,22(8),825
合成路线图解说明:

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.

参考文献No.433266
标题: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
作者:Benzaria, S.; P閘icano, H.; Johnson, R.; Maury, G.; Imbach, J.-L.; Aubertin, A.-M.; Obert, G.; Gosselin, G.
来源:J Med Chem 1996,39(25),4958-65
合成路线图解说明:

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.

参考文献No.563492
标题: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
作者:Dudzinski, P.W.; Kelly, D.E.; Yu, R.H.; Rohloff, J.C.; Schultze, L.M.
来源:Org Process Res Dev 1999,3(1),53
合成路线图解说明:

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.

参考文献No.592171
标题:Synthesi of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases
作者:Hol? A.; et al.
来源:Coll Czech Chem Commun 1989,542190
合成路线图解说明:

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).

参考文献No.592172
标题:Synhtesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds
作者:Rosenberg, I.; Hol? A.
来源:Coll Czech Chem Commun 1987,522801
合成路线图解说明:

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).

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