Process-intensified continuous-flow synthesis of azaperone via a microreactor system

Azaperone is a butyrophenone-type neuroleptic agent widely utilized in veterinary medicine for its potent sedative and anti-aggressive properties. This study reports the development of a streamlined, process-intensified synthesis of azaperone utilizing a continuous-flow microreactor system. In the first step, bis(2-chloroethyl)amine was synthesized via the chlorination of the hydroxyl groups of diethanolamine using thionyl chloride, affording an excellent yield of 96%. Subsequently, 2-aminopyridine underwent alkylation with the synthesized bis(2-chloroethyl)amine in the presence of tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst to produce 1-(pyridin-2-yl)piperazine in 75% yield. Finally, this key intermediate was alkylated with 4-chloro-1-(4-fluorophenyl)butan-1-one under solvent-free conditions to afford azaperone in 65% yield. The continuous-flow strategy successfully minimized reaction times and suppressed by-product formation compared to conventional batch methods.