A convenient and practical synthesis of the cis isomer of the first orally active dopamine D₃-Preferring D₃-D₂ receptor partial agonist cariprazine

Abstract

A convenient and practical synthetic route was here developed for the preparation of the cis isomer of cariprazine (2), a dopamine D₃-preferring D₃-D₂ receptor partial agonist for the treatment of schizophrenia. The key step is the concise preparation of 2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid in the cis configuration via a recrystallization separation tactic. The entire synthetic procedure was performed under mild conditions avoiding any need for expensive material, hazardous conditions, ultralow temperatures or tedious purification processes. The cis configuration of 2 confirmed via X-ray crystallography.

Graphical Abstract

Keywords:

• Cariprazine
• Cis isomer Cis-cariprazine
• convenient and practical synthesis
• recrystallization
• X-ray crystallography

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant No. 81803371; the Shanghai Rising-Star Program under Grant No. 19QB1406200; and the National Science and Technology Major Project under Grant No. 2019ZX09301116.