【结 构 式】 |
【分子编号】65235 【品名】 【CA登记号】 |
【 分 子 式 】C22H28ClN6O4P 【 分 子 量 】506.928822 【元素组成】C 52.13% H 5.57% Cl 6.99% N 16.58% O 12.62% P 6.11% |
合成路线1
该中间体在本合成路线中的序号:(XI)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 |