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Synthesis of Panobinostat and Benzimidazolyl Sulfides

Author: LiuZuo
Tutor: JiYaFei
School: East China University of Science and Technology
Course: Pharmaceutical Engineering and Technology
Keywords: panobinostat small-molecule hydroxamic acid-based HDAC inhibitors benzimidazolyl sulfides one-pot synthesis
CLC: TQ463.53
Type: Master's thesis
Year: 2012
Downloads: 84
Quote: 0
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Abstract


Panobinostat, a novel class of small-molecule hydroxamic acid-based HDAC inhibitors developed by Novartis is now used for the treatment of CTCL as an orphan drug, It was prepared starting from phenylhydrazine,5-chloro-2-pentanone and methyl (E)-4-(methyl) cinnamate in 30.6% overall yield. Initially, the condensation of phenylhydrazine and 5-chloro-2-pentanone gave the corresponding hydrazone, ring formation of which and subsequent rearrangement afforded a key intermediate 2-methyltryptamine. Afterwards, another intermediate methyl (E)-4-(bromomethyl) cinnamate was obtained from methyl (E)-4-(methyl) cinnamate by bromination with NBS. Finally,2-methyltryptamine was performed N-alkylation with methyl (E)-4-(bromomethyl) cinnamate to give secondary amine, which was converted to the anticarcinogen drug panobinostat via aminolysis with hydroxylamine. The ready availability of raw materials and the mild conditions of this process make the route a valuable preparation for the drug.2-(Hetero)arylmethylthiobenzimidazoles, a basic skeleton as novel proton pump inhibitors (PPIs) frequently used for ulcer treatment by medicinal chemists have been synthesized starting from 2-nitroanilines by a novel one-pot procedure in good to excellent yields. The procedure involves a continuous sequence of reduction, cyclization and condensation assisted with only H2O and MeOH as the solvents, and the compatible Na2S and KOH as the reagents. It is distinguished by simple manipulation, environmental benignancy, inexpensive reagents and higher yields, comparing to corresponding batch reaction.The structures of all intermediates and products were confirmed by 1H NMR and MS. After optimization of reaction parameters with several experiments, the optimized reaction conditions for synthesis of panobinostat and benzimidazolyl sulfides were obtained.

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CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug > Heterocyclic compounds drugs > Five section heterocyclic
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