|
【结 构 式】 
|
【药物名称】Dexrazoxane hydrochloride, ADR-529(free base), NSC-169780(free base), ICRF-187, TopoTect, Zinecard, Cardioxane 【化学名称】(+)-(S)-4,4'-(Propane-1,2-diyl)bis(piperazine-2,6-dione) hydrochloride 【CA登记号】24584-09-6 (free base) 【 分 子 式 】C11H17ClN4O4 【 分 子 量 】304.73554 |
【开发单位】Pfizer (Orphan Drug), Cancer Research UK (Originator), National Research Development (Originator), TopoTarget (Not Determined), Chiron (Licensee), Pfizer (Licensee), National Cancer Institute (Codevelopment) 【药理作用】Cardioprotectants, Chemoprotective Agents, ONCOLYTIC DRUGS, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, DNA Topoisomerase II Inhibitors |
合成路线1
The chiral diamine (II) was obtained by resolution of racemic 1,2-diaminopropane (I) with D-tartaric acid. Condensation of diamine (II) with formaldehyde and NaCN produced the tetranitrile (III). Acidic hydrolysis of tetranitrile (III) produced tetraamide (VI). The cyclization of (VI) upon heating in phenol furnished the title bis-piperazinedione. The cyclization of tetraamide (VI) has also been reported using polyphosphoric acid or sodium (methylsulfinyl)methyde. Alternatively, the synthesis of Dexrazoxane can be performed by by alkylation of diamine (II) with chloroacetic acid (IV) by means of NaOH in water to afford tetraacid (V), which is then subjected to cyclization in hot formamide.
| 【1】 Miller, W.D.; Process for preparing (S)(+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione). EP 0284594 . |
| 【2】 Tu, C.-Y.J.; Clark, G.W.; Borsotti, G.; Process for preparing bis(3,5-dioxopiperazinyl)alkanes or alkenes. EP 0330381 . |
| 【3】 Creighton, A.M. (National Research Development Corp.); (3,5,3',5'-Tetraoxo)-1,2-dipiperazinoalkane cpds. and process for their preparation. DE 1910283; DE 1967027 . |
| 【4】 Holthuis, J.J.M.; MacDonald, P.L.; Stradi, R.; Rossetto, P. (EuroCetus BV); Process for preparing (S)(+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione). WO 9308172 . |
| 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) | 30691 | 1,2-propanediamine; 2-amino-1-methylethylamine | 78-90-0 | C3H10N2 | 详情 | 详情 |
| (II) | 27996 | (1S)-2-amino-1-methylethylamine | C3H10N2 | 详情 | 详情 | |
| (III) | 55629 | 2-[{(1S)-2-[bis(cyanomethyl)amino]-1-methylethyl}(cyanomethyl)amino]acetonitrile | C11H14N6 | 详情 | 详情 | |
| (IV) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (V) | 27997 | 2-[[(1S)-2-[bis(carboxymethyl)amino]-1-methylethyl](carboxymethyl)amino]acetic acid | C11H18N2O8 | 详情 | 详情 | |
| (VI) | 55630 | 2-((2-amino-2-oxoethyl){(1S)-2-[bis(2-amino-2-oxoethyl)amino]-1-methylethyl}amino)acetamide | C11H22N6O4 | 详情 | 详情 |