合成路线: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.
参考文献标题:6,9-Bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione and its dimaleate salt
文献作者:Spinelli,S.; DiDomenico,R.(Roche Diagnostics GmbH)
参考来源:JP 1997507674; JP 2001089454; US 5506232; WO 9526189
合成路线: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.
合成路线: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.
参考文献标题: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
文献作者:Krapcho,A.P.; Petry,M.E.; Getahun,Z.; Landi,J.J.Jr.; Stallman,J.; Polsenberg,J.F.; Gallagher,C.E.; Maresch,M.J.; Hacker,M.P.; Giuliani,F.C.; et al.
参考来源:J Med Chem 1994,37(6),828
产品链接: CAS No. 144510-96-3››