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【结 构 式】

【分子编号】52806

【品名】3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride

【CA登记号】4664-08-8

【 分 子 式 】C7H3NO3

【 分 子 量 】149.10576

【元素组成】C 56.39% H 2.03% N 9.39% O 32.19%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

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

该中间体在本合成路线中的序号:(II)

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
Extended Information