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

Abstract

A synthesis process of 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-diketone dimaleate, which relates to the technical field of synthesis of antineoplastic drugs, In this synthesis process, 3,4-pyridinecarboxylic acid anhydride and hydroquinone are reacted under the action of a catalyst to obtain the first intermediate; secondly, the first intermediate is reacted with N-tert-butoxycarbonylethylenediamine to obtain the second Two intermediates; followed by deprotection of the second intermediate and salt formation with maleic acid to obtain the product. The purity of the obtained product is greater than 99.5%, and the content of known individual impurities and unknown individual impurities is less than 0.1%. The important intermediates involved in the synthesis process are stable in nature and easy to store, and the reaction conditions of the synthesis process are mild, simple, and low cost. Low, suitable for industrial production. The invention also provides picantron maleate, which can be made into freeze-dried powder for injection and used for treating relapsed, refractory and aggressive non-Hodgkin's lymphoma in adults.

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 Forate 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 antibi...

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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