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Transaminase-catalysis to produce trans-4-substituted cyclohexane-1-amines including a key intermediate towards cariprazine.

Emese FarkasPéter SátorhelyiZoltán SzakácsMiklós DékányDorottya VaskóGábor HornyánszkyLászló PoppeJános Éles
Published in: Communications chemistry (2024)
Cariprazine-the only single antipsychotic drug in the market which can handle all symptoms of bipolar I disorder-involves trans-4-substituted cyclohexane-1-amine as a key structural element. In this work, production of trans-4-substituted cyclohexane-1-amines was investigated applying transaminases either in diastereotope selective amination starting from the corresponding ketone or in diastereomer selective deamination of their diasteromeric mixtures. Transaminases were identified enabling the conversion of the cis-diastereomer of four selected cis/trans-amines with different 4-substituents to the corresponding ketones. In the continuous-flow experiments aiming the cis diastereomer conversion to ketone, highly diastereopure trans-amine could be produced (de > 99%). The yield of pure trans-isomers exceeding their original amount in the starting mixture could be explained by dynamic isomerization through ketone intermediates. The single transaminase-catalyzed process-exploiting the cis-diastereomer selectivity of the deamination and thermodynamic control favoring the trans-amines due to reversibility of the steps-allows enhancement of the productivity of industrial cariprazine synthesis.
Keyphrases
  • molecular docking
  • bipolar disorder
  • risk assessment
  • heavy metals
  • physical activity
  • depressive symptoms
  • ionic liquid
  • drug induced
  • structural basis