Accelerated flow synthesis of aripiprazole and brexpiprazole in environmentally benign solvents

Aripiprazole and Brexpiprazole are both second-generation atypical antipsychotic medications to treat a wide range of psychiatric disorders, the retail sales of which reached $1.35 billion and $2.07 billion in 2023, respectively. The greenness and efficiency of reported synthetic pathways diminished due to the use of toxic solvents, the extended reaction time, and low yields. Herein, facilitated by the employment of flow technology, all 4 steps proceeded smoothly in environmentally benign solvents. The reaction time of two steps towards aripiprazole was reduced from over 18 ​h to 1.5 ​h, with an increase in yield, the reaction time for brexpiprazole was reduced from over 19 ​h to 65 ​min, without yield decline. The significantly smaller volume of microtubing allowed us to conduct the DDQ-mediated dehydrogenation at a higher temperature, thus the 5 ​min residence time effectively minimized the risk of hydrogen cyanide release. The flow synthesis protocols for Aripiprazole and Brexpiprazole, two blockbuster antipsychotic medications with annual sales exceeding $1 billion, have been developed to utilize environmentally benign solvents. The streamlined processes deliver Aripiprazole in just 90 ​min with an impressive 86.5 ​% yield, and Brexpiprazole in 65 ​min with an 87.2 ​% yield, demonstrating both efficiency and sustainability.