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 requir

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