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【结 构 式】 
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【分子编号】16165 【品名】[2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid 【CA登记号】 |
【 分 子 式 】C8H12N5O4P 【 分 子 量 】273.188342 【元素组成】C 35.17% H 4.43% N 25.64% O 23.43% P 11.34% |
合成路线1
该中间体在本合成路线中的序号：(IV)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.
| 【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. |
| 【2】 Prous, J.; Graul, A.; Castaner, J.; Adefovir Dipivoxil. Drugs Fut 1997, 22, 8, 825. |
| 【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 . |
| 【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. |
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 16163 | 2-[(diisopropoxyphosphoryl)methoxy]ethyl methanesulfonate | C10H23O7PS | 详情 | 详情 | |
| (III) | 16164 | diisopropyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C14H24N5O4P | 详情 | 详情 | |
| (IV) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (V) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
| (VI) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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.
| 【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. |
| 【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 . |
| 【3】 Dahl, T.C.; Yuan, L.-C.J. (Gilead Sciences Inc.); Pharmaceutical formulations. WO 0035460 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (III) | 39672 | 2-(6-amino-9H-purin-9-yl)-1-ethanol | C7H9N5O | 详情 | 详情 | |
| (IV) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (V) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 | |
| (VI) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (VII) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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).
| 【1】 Rosenberg, I.; Holý, A.; Synhtesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds. Coll Czech Chem Commun 1987, 52, 2801. |
| 【2】 Holý, A.; et al.; Synthesi of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases. Coll Czech Chem Commun 1989, 54, 2190. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 39883 | 2-[(diethoxyphosphoryl)methoxy]ethyl acetate | C9H19O6P | 详情 | 详情 | |
| (II) | 39884 | diethyl (2-hydroxyethoxy)methylphosphonate | C7H17O5P | 详情 | 详情 | |
| (III) | 39885 | diethyl (2-chloroethoxy)methylphosphonate | C7H16ClO4P | 详情 | 详情 | |
| (IV) | 39886 | diethyl (2-bromoethoxy)methylphosphonate | C7H16BrO4P | 详情 | 详情 | |
| (V) | 39887 | diethyl [2-[(4-methylphenyl)sulfonyl]ethoxy]methylphosphonate | C14H23O6PS | 详情 | 详情 | |
| (VI) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VII) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 | |
| (VIII) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (IX) | 39888 | N-[9-(2-hydroxyethyl)-9H-purin-6-yl]benzamide | C14H13N5O2 | 详情 | 详情 | |
| (X) | 39889 | (dimethoxyphosphoryl)methyl 4-methylbenzenesulfonate | C10H15O6PS | 详情 | 详情 | |
| (XI) | 39890 | dimethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C10H16N5O4P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The condensation of 9-[2-(phosphonomethoxy)ethyl]adenine (I) with butenolide (II) by means of NaHCO3 in hot DMF gives the target phosphonate monoester.
| 【1】 Hakimelahi, G.H.; et al.; Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses. J Med Chem 2001, 44, 22, 3710. |
合成路线5
该中间体在本合成路线中的序号：(VII)Treatment of adenosine (I) with ethylene carbonate (II) in the presence of NaOH in refluxing DMF gives 9-(2-hydroxyethyl)adenosine (III). Diethyl phosphite (IV) is then condensed with formaldehyde, followed by reaction with p-toluenesulfonyl chloride and Et3N to afford diethyl (tosyloxymethyl)phosphonate (V). Subsequent condensation of tosylate (V) with (III) in the presence of t-BuONa gives the phosphonyloxymethoxyethyl adenosine (PMEA) diethyl ester (VI), which is hydrolyzed to the corresponding phosphonic acid adefovir (VII) by means of in situ-generated iodotrimethylsilane. The condensation of phosphonic acid (VII) with 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) utilizing DCC/pyridine leads to the cyclic phosphonate (IX) as a roughly equimolecular mixture of diastereoisomers, which can be chromatographically separated to furnish the title cis-isomer pradefovir. In an improved procedure, activation of adefovir (VII) with oxalyl chloride and N,N-diethylformamide generates the formamidine-protected phosphonyl dichloridate (X), which upon condensation with diol (VIII) at low temperature gives the cyclic phosphonate (XI) as a mixture in which the desired cis-diastereoisomer predominates. After hydrolysis of the formamidine (XI) with ethanolic AcOH, recrystallization as the corresponding mesylate salt provides the title adefovir prodrug in high diastereomeric excess (1-5). Scheme 1.
| 【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665. |
| 【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161. |
| 【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27. |
| 【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729. |
| 【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (III) | 39672 | 2-(6-amino-9H-purin-9-yl)-1-ethanol | C7H9N5O | 详情 | 详情 | |
| (IV) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (V) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (VI) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 | |
| (VII) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (VIII) | 65232 | 1(S)-(3-chlorophenyl)-1,3-propanediol | C9H11ClO2 | 详情 | 详情 | |
| (IX) | 65233 | C17H19ClN5O4P | 详情 | 详情 | ||
| (X) | 65234 | C13H19Cl2N6O2P | 详情 | 详情 | ||
| (XI) | 65235 | C22H28ClN6O4P | 详情 | 详情 |