|
【结 构 式】 
|
【药物名称】Fosquidone, GR-63178X, GR-63178A, NSC-D-611615, GR-63178G(sodium salt) 【化学名称】(R,S)-9-[Benzyloxy(hydroxy)phosphoryloxy]-14-methyl-5,14-dihydrobenz[5,6]isoindolo[2,1-b]isoquinoline-8,13-dione 【CA登记号】114517-02-1, 114517-04-3 (Na salt) 【 分 子 式 】C28H22NO6P 【 分 子 量 】499.46444 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Oncolytic Drugs |
合成路线1
This compound can be obtained by two related ways: 1) The cyclization of 2-formyl-4-methyl-1,2,3,4-tetrahydroisoquinolone-3-carboxylic acid (I) with 2-chloro-5-hydroxy-1,4-naphthoquinone (II) by means of sodium acetate in hot acetic anhydride gives 9-hydroxy-14-methyl-5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b] isoquinoline-8,13-dione (III), which is condensed with dibenzyl phosphonate (IV) by means of N-chlorosuccinimide (NClS) and NaH in benzene to afford (14-methyl-8,13-dioxo-5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b] isoquinolin-9-yl)phosphoric acid dibenzyl ester (V). Finally, this compound is partially hydrolyzed with NaI in refluxing acetone, and the resulting sodium salt treated with aqueous HCl. 2) The condensation of 5-hydroxy-1,4-naphthoquinone (VI) with phosphonate (IV) by means of Cl2SO2 followed by a treatment with NaHCO3 gives (1,4-naphthoquinon-5-yl)phosphoric acid dibenzyl ester (VII), which is then cyclized with isoquinoline (I) in hot acetic anhydride to compound (V), already obtained.
| 【1】 Phillips, G.H.; Jones, P.S.; Cooper, M.E. (Glaxo Wellcome plc); Dioxobenz[5,6]isoindolo[2,1-b]isoquinoline derivs. AU 8776203; BE 1002110; CH 672489; DE 3725185; FR 2602233; JP 1988093783; JP 1990000187; US 4851399 . |
| 【2】 Phillips, G.H.; Cowley, B.R. (Glaxo Wellcome plc); Preparation of 5,8,13,14-tetrahydrobenz(5,6)isoindolo(2,1-b)isoquinolin-8,13-dione derivs. EP 0323907 . |
| 【3】 Castaner, J.; Pento, J.T.; Fosquidone. Drugs Fut 1993, 18, 10, 891. |
| 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) | 12504 | 2-Formyl-4-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C12H13NO3 | 详情 | 详情 | |
| (II) | 12505 | 2-Chloro-5-hydroxy-2,3-dihydro-1,4-naphthalenedione | C10H7ClO3 | 详情 | 详情 | |
| (III) | 12506 | 9-Hydroxy-14-methyl-5,14-dihydrobenzo[5,6]isoindolo[2,1-b]isoquinoline-8,13-dione | C21H15NO3 | 详情 | 详情 | |
| (IV) | 12507 | dibenzyl phosphonate; Dibenzyl phosphite | 17176-77-1 | C14H15O3P | 详情 | 详情 |
| (V) | 12508 | dibenzyl 14-methyl-8,13-dioxo-5,8,13,14-tetrahydrobenzo[5,6]isoindolo[2,1-b]isoquinolin-9-yl phosphate | C35H28NO6P | 详情 | 详情 | |
| (VI) | 63439 | 5-hydroxynaphthoquinone | C10H6O3 | 详情 | 详情 | |
| (VII) | 12510 | dibenzyl 5,8-dioxo-5,8-dihydro-1-naphthalenyl phosphate | C24H19O6P | 详情 | 详情 |