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【结 构 式】 
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【分子编号】39673 【品名】diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate 【CA登记号】 |
【 分 子 式 】C12H20N5O4P 【 分 子 量 】329.295862 【元素组成】C 43.77% H 6.12% N 21.27% O 19.43% P 9.41% |
合成路线1
该中间体在本合成路线中的序号：(VI)PMEA was prepared by a straightforward route from readily available 2-acetoxyethoxymethyl chloride (I). The key intermediate, diethyl 2-bromoethylmethoxyphosphonate (IV), was coupled with adenine (V) in the presence of sodium hydride, followed by hydrolysis to afford PMEA.
| 【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163. |
| 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) | 63950 | 2-(chloromethoxy)ethyl acetate | C5H9ClO3 | 详情 | 详情 | |
| (II) | 39883 | 2-[(diethoxyphosphoryl)methoxy]ethyl acetate | C9H19O6P | 详情 | 详情 | |
| (III) | 39884 | diethyl (2-hydroxyethoxy)methylphosphonate | C7H17O5P | 详情 | 详情 | |
| (IV) | 39886 | diethyl (2-bromoethoxy)methylphosphonate | C7H16BrO4P | 详情 | 详情 | |
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VI) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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：(VII)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：(VI)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 |