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【结 构 式】 
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【药物名称】Pixantrone maleate, BBR-2778 【化学名称】6,9-Bis(2-aminoethylamino)-5,10-dihydrobenz[g]isoquinoline-5,10-dione dimaleate 【CA登记号】144510-96-3 (free base) 【 分 子 式 】C25H27N5O10 【 分 子 量 】557.52144 |
【开发单位】Cell Therapeutics (Originator) 【药理作用】Immunologic Neuromuscular Disorders, Treatment of, Lymphoma Therapy, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Antimitotic Drugs, DNA-Intercalating Drugs |
合成路线1
3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine (VII) in pyridine provided the target bis(2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.
| 【1】 Spinelli, S.; DiDomenico, R. (Roche Diagnostics GmbH); 6,9-Bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione and its dimaleate salt. JP 1997507674; JP 2001089454; US 5506232; WO 9526189 . |
| 【2】 Krapcho, P.A. (University of Vermont); 6,9-Bis(substd.-amino)benzo-[g]isoquinoline-5,10-diones. EP 0503537; EP 0575526; JP 1994511230; WO 9215300 . |
| 【3】 Krapcho, A.P.; et al.; 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5, 10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: Synthesis and antitumor evaluations. J Med Chem 1994, 37, 6, 828. |
| 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) | 52805 | 3,4-Pyridinedicarboxylic acid; Cinchomeronic acid; Pyridin-3,4-dicarboxylic acid; Pyridine-3,4-dicarboxylic acid | 490-11-9 | C7H5NO4 | 详情 | 详情 |
| (II) | 52806 | 3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride | 4664-08-8 | C7H3NO3 | 详情 | 详情 |
| (III) | 52807 | 1,4-Difluorobenzene; p-Difluorobenzene | 540-36-3 | C6H4F2 | 详情 | 详情 |
| (IV) | 52808 | 4-(2,5-difluorobenzoyl)nicotinic acid | C13H7F2NO3 | 详情 | 详情 | |
| (V) | 52809 | 3-(2,5-difluorobenzoyl)isonicotinic acid | C13H7F2NO3 | 详情 | 详情 | |
| (VI) | 52810 | 6,9-difluorobenzo[g]isoquinoline-5,10-dione | C13H5F2NO2 | 详情 | 详情 | |
| (VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VIII) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (IX) | 52811 | tert-butyl 2-{[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-9-yl]amino}ethylcarbamate | C27H35N5O6 | 详情 | 详情 |
合成路线2
Friedel-Crafts bis-acylation of p-dimethoxybenzene (X) with anhydride (II) in molten aluminum chloride/sodium chloride afforded the benzoisoquinoline (XI). This compound was reduced with sodium dithionite to generate an intermediate leuco form (XII). Subsequent addition of Boc-ethylenediamine (VIII) to (XII) produced, after air oxidation during the work-up, the protected tetraamino compound (IX). Alternatively, addition of ethylenediamine (VII) to the intermediate (XII) led to the free base of BBR-2778, which was converted to the maleate.
| 【1】 Krapcho, A.P.; et al.; 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5, 10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: Synthesis and antitumor evaluations. J Med Chem 1994, 37, 6, 828. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (II) | 52806 | 3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride | 4664-08-8 | C7H3NO3 | 详情 | 详情 |
| (VII) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (IX) | 52811 | tert-butyl 2-{[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-9-yl]amino}ethylcarbamate | C27H35N5O6 | 详情 | 详情 | |
| (X) | 21946 | 1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether | 150-78-7 | C8H10O2 | 详情 | 详情 |
| (XI) | 52812 | 6,9-dihydroxybenzo[g]isoquinoline-5,10-dione | C13H7NO4 | 详情 | 详情 | |
| (XII) | 52813 | 5,10-dihydroxy-7,8-dihydrobenzo[g]isoquinoline-6,9-dione | C13H9NO4 | 详情 | 详情 |