Multistep Mechanochemical Synthesis of PZ-1190, a Multitarget Antipsychotic Agent

A solid-state approach was used to synthesize compound PZ-1190, a multitarget ligand for serotonin and dopamine receptors with potential antipsychotic activity in rodents. Compared to the classical batch synthesis approach, the developed multistep mechanochemical protocol improved the overall yield (from 32% to 56%), reduced the reaction time (from 42 to 4 h), and decreased the use of toxic reagents and organic solvents. All synthesized intermediates and PZ-1190 were isolated in high purity by extraction without the requirement of chromatographic purification. PZ-1190 was obtained in high enantiomeric purity (>= 99% ee) with no impact of grinding processes on the integrity of the stereocenter. The described procedures represent rare examples of mechanochemical reduction of a carboxylic function, which might open up the possibility of obtaining crucial beta- and gamma-amino alcohols in a sustainable manner. The oxidation of an aliphatic alcohol into an aldehyde using mechanochemistry has also been reported for the first time. The obtained results confirmed the suitability of mechanochemistry as a sustainable and efficient method for synthesizing candidates for preclinical development.

Automated summary

A solid-state approach was used to synthesize compound PZ-1190, a multitarget ligand for serotonin and dopamine receptors with potential antipsychotic activity. The developed multistep mechanochemical protocol improved the overall yield, reduced the reaction time, and decreased the use of toxic reagents and organic solvents. The described procedures represent rare examples of mechanochemical reduction and aliphatic alcohol oxidation, which could be sustainable methods for obtaining crucial compounds.