- A cedar Joan maleic acid salt preparation method
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The invention provides a pixantrone maleate synthesis method which has the advantages of high yield, low impurity content, simple process and easiness in large-scale production. In the method, pyridine-3,4-dicarboxylic acid is used as a starting raw material which reacts with acetic anhydride to obtain pyridine-3,4-dicarboxylic anhydride; the pyridine-3,4-dicarboxylic anhydride conducts an Friedel-Crafts acylation reaction with 1,4-difluorobenzene, and the obtained mixture is subjected to catalytic cyclization to obtain a key intermediate; the intermediate reacts with amino-protected ethylenediamine to obtain protecting group-containing pixantrone; and after that, deprotection and salifying are performed to obtain the target product. In the Friedel-Crafts acylation reaction of the method, an n-hexane solution of sulfuric acid is used as a catalyst, thus the use is convenient, the aftertreatment is simple, and the potential risk in production is eliminated; the Cbz or Fmoc protected ethylenediamine reacts with substituted anthraquinone and then the protecting group is removed through catalytic hydrogenation to obtain pixantrone; the process effectively inhibits side reactions and reduces the impurity content; and meanwhile, the aftertreatment is simplified, and the yield increase is facilitated.
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- 6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and synthesis technology thereof
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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.
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Paragraph 0068
(2017/03/18)
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- Preparation method of pixantrone dimaleate
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The invention relates to a preparation method of antitumor drug pixantrone dimaleate. The method includes the steps of: i) subjecting the compound 5(6, 9-bis[2-(N-Boc-amino)ethylamino]benzo[g]isoquinoline-5, 10-dione) to Boc protection removal reaction in dichloromethane (DCM) and trifluoroacetic acid (TFA), and letting the reaction generated reactant solution enter the next-step reaction directly without treatment; ii) employing a maleic acid ethanol solution to carry out acid exchange reaction on the reactant solution obtained in step i), and performing filtering to obtain a pixantrone dimaleate crude product. The method not only simplifies the operation process, greatly shortens the reaction time, improves production efficiency, but also can well control and remove impurities, especially a genotoxic impurities having potential serious hazard to the human body.
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Paragraph 0017; 0071-0082
(2017/03/17)
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- 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione and its dimaleate salt
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In the search for novel heteroanalogs of anthracendiones, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate salt (BBR 2778), was selected as the most promising compound. New methods of synthesis produce the compound in purity greater than 99%.
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