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【结 构 式】 
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【药物名称】Amotosalen hydrochloride, S-59 【化学名称】3-(2-Aminoethoxymethyl)-2,5,9-trimethyl-7H-furo[3,2-g]-1-benzopyran-7-one hydrochloride 【CA登记号】161262-29-9 (free base) 【 分 子 式 】C17H20ClNO4 【 分 子 量 】337.80625 |
【开发单位】Cerus (Originator), Baxter (Licensee) 【药理作用】Antithrombocytopenic, HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, IMMUNOMODULATING AGENTS, Treatment of Transplant Rejection |
合成路线1
Condensation of 7-hydroxy-4,8-dimethylcoumarin (I) with 3-chloro-2-butanone (II) affords the keto alkoxycoumarin (III), which is cyclized to the psoralen derivative (IV) under basic conditions. Benzylic bromination of (IV) by means of N-bromosuccinimide provides the bromomethyl compound (V) as the major isomer. Bromide (V) is then condensed with N-(2-hydroxyethyl)phthalimide (VI) to furnish ether (VII). The phthaloyl group of (VII) is removed by treatment with either primary amines or with hydrazine to produce the target free amine, which is finally isolated as the corresponding hydrochloride salt.
| 【1】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielmann, H.P. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. US 5399719; WO 9500141 . |
| 【2】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielman, H.P.; Niero, A. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. WO 9614739 . |
| 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) | 58850 | 4,8-Dimethyl-7-hydroxycoumarin | C11H10O3 | 详情 | 详情 | |
| (II) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (III) | 58851 | 4,8-dimethyl-7-(1-methyl-2-oxopropoxy)-2H-chromen-2-one | C15H16O4 | 详情 | 详情 | |
| (IV) | 58852 | 2,3,5,9-tetramethyl-7H-furo[3,2-g]chromen-7-one | C15H14O3 | 详情 | 详情 | |
| (V) | 58853 | 3-(bromomethyl)-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one | C15H13BrO3 | 详情 | 详情 | |
| (VI) | 58854 | 2-(2-hydroxyethyl)-1H-isoindole-1,3(2H)-dione;N-Hydroxyethylphthalimide;N-(2-Hydroxyethyl)phthalimide;2-(2-hydroxyethyl)isoindoline-1,3-dione | 3891-07-4 | C10H9NO3 | 详情 | 详情 |
| (VII) | 58855 | 2-{2-[(2,5,9-trimethyl-7-oxo-7H-furo[3,2-g]chromen-3-yl)methoxy]ethyl}-1H-isoindole-1,3(2H)-dione | C25H21NO6 | 详情 | 详情 |
合成路线2
A different method starts with the chloromethylation of trimethyl psoralen (I) to afford (II). Subsequent condensation of chloride (II) with ethylene glycol (III) yields the hydroxyethoxy derivative (IV). This is converted to mesylate (V) upon treatment with methanesulfonyl chloride and triethylamine. Mesylate displacement by NaN3 leads to azide (VI). Finally, azide reduction to the target amine is accomplished by treatment with triphenylphosphine in moist THF.
| 【1】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielmann, H.P. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. US 5399719; WO 9500141 . |
| 【2】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielman, H.P.; Niero, A. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. WO 9614739 . |
| 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) | 58856 | 2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one | C14H12O3 | 详情 | 详情 | |
| (II) | 58857 | 3-(chloromethyl)-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one | C15H13ClO3 | 详情 | 详情 | |
| (III) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (IV) | 58858 | 3-[(2-hydroxyethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one | C17H18O5 | 详情 | 详情 | |
| (V) | 58859 | 2-[(2,5,9-trimethyl-7-oxo-7H-furo[3,2-g]chromen-3-yl)methoxy]ethyl methanesulfonate | C18H20O7S | 详情 | 详情 | |
| (VI) | 58860 | 3-[(2-azidoethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one | C17H17N3O4 | 详情 | 详情 |