Acceleration of Anti-Markovnikov Hydroamination in the Synthesis of an Active Pharmaceutical Ingredient

Aleksandar Mitic, Tommy Skovby, Kim Dam-Johansen, Krist Gernaey

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Slow chemical reactions are a big challenge in the modern pharmaceutical industry. Their accelerations together with the introduction of continuous manufacturing modes are major drivers for future development. One example reaction is hydroamination, a reaction between unsaturated hydrocarbons and amines. Such a reaction type is the main focus of this work. More precisely, the anti-Markovnikov hydroamination reaction between cis/trans 9H-thioxanthene-2-chloro-9-(2-propenylidene)-(9CI) and 1-(2-hydroxyethyl)piperazine (HEP) is investigated in detail. It has been traditionally performed in toluene with a huge excess of HEP and reaction times of up to 24h. Acceleration of the reaction from 24 down to 4h is achieved by switching from batch operation mode in toluene to either solvent-free batch mode or microwave-assisted hydroamination with tetrahydrofuran as a solvent.
Original languageEnglish
JournalChemical Engineering and Technology
Issue number10
Pages (from-to)1821–1827
Publication statusPublished - 2016


  • Active pharmaceutical ingredient
  • Hydroamination reaction
  • Microwave-assisted organic synthesis
  • Solvent-free synthesis

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