6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and synthesis technology thereof

Abstract

The invention discloses a synthesis technology of 6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and relates to the technical field of antineoplastic drug synthesis. The synthesis technology comprises that 3, 4-pyridinedicarboxylic anhydride and hydroquinone undergo a reaction in the presence of a catalyst to produce a first intermediate, the first intermediate and N-t-butoxycarbonylethylenediamine undergo a reaction to produce a second intermediate, the second intermediate is subjected to deprotection, and the product and maleic acid undergo a salt forming reaction to produce a product. The prepared product has purity greater than 99.5% and known single impurity and unknown single impurity contents less than 0.1%. The important intermediate of the synthesis technology has stable properties and is convenient for storage. The synthesis technology allows mild reaction conditions, has simple processes, realizes a low cost and is suitable for industrial production. The invention also provides pixantrone dimaleate. The pixantrone dimaleate can be processed to form a freeze-dried powder injection for treating human aggressive non-Hodgkin's lymphoma with easy recurrence and high treatment difficulty.

Description

technical field [0001] The present invention relates to the technical field of synthesis of antineoplastic drugs, and in particular to a 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimer Salt and its synthesis process. Background technique [0002] The chemical name of Pixantrone Dimaleate is 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate, The chemical structure is The molecular weight is 557.5, and the properties are dark blue crystalline powder. The preparation form of picantron maleate is mostly freeze-dried powder for injection, each containing 29mg picantron, and after reconstitution, each milliliter solution contains picantron 5.8mg, which can be used as a single therapeutic drug for the treatment of adult relapse Treatment, aggressive non-Hodgkin's lymphoma (non-Hodgkin's lymphoma, NHL). [0003] Among them, picantron is a cytotoxic azaxanthenedione antibiotic drug, which is different from the approved anthracycline antibiot...

AI Technical Summary

Problems solved by technology

Route one and route two have the following disadvantages: (1) 3,4-pyridinecarboxylic acid anhydride will use a large amount of anhydrous aluminum chloride and high boiling point carcinogenic solvent nitrobenzene of strong acid corrosion when reacting p-difluorobenzene, This reaction is a heterogeneous reaction system, which is difficult to stir and is difficult to carry out industrial scale-up production; (2) when preparing the intermediate 6,9-difluorobenzo[g]isoquinoline-5,10-dione, 20 % of fuming sulfuric acid is reaction reagent and solvent, severe condition, serious pollution; (3) although the synthetic picantron maleate product purity can reach 99%, the individual impurity content of unknown structure is less than 0.2%, may still not Meet the increasingly stringent quality requirements for injection freeze-dried powder

The disadvantages of route 3 and route 4 are: 3,4-pyridine dichloride reacts with hydroquinone to prepare IV conversion rate is very low, purification is difficult, resulting in very low yield, and 3,4-pyridine dichloride is very easy to deteriorate , need to make and use

In addition, after the IV isomerization conversion, more impurities will be generated by reacting with ethylenediamine, and the stability of picantron in the reaction system is poor. When removing impurities, the free picantron will generate new impurities, making this The picantron generated in the step contains more impurities, and the purification cost is very high

[0015] In summary, there is not yet a kind of technology suitable for industrialized production of picantron maleate

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