Asymmetric Synthesis Of Antipsychotic Drug （+）-Asenapine

In 2009,Organon Company discovered and developed the second-generation antipsychotic drug Asenapine,which has good curative effects and less side effects.The currently marketed drugs are racemates,and most of the patents are also for the synthesis of racemates.However,after studying and analyzing the pharmacokinetics of asenapine,a blood drug of（+）-isomer was found and the concentration is higher than the（-）-isomer.Therefore,choosing a strategy with stereoselectivity to control the optical isomers of asenapine has important research significance.Iridium catalysis plays an important role in the field of asymmetric synthesis.Among them,the combined dual iridium/amine catalysis using chiral ligands/chiral amines can control multiple chiral centers at one time,which greatly improves the construction efficiency of chiral centers.In this paper,the asymmetric catalytic reaction of iridium is used for the first time to explore the synthesis of（+）-asenapine.Through dual iridium/amine catalysis,using commercially available raw materials obromobenzaldehyde and 5-chloro-2-methoxybenzaldehyde as synthons,the target product with 1.4:1 dr and 81% ee was obtained.Then,the key intermediate was obtained by completing the construction of the intramolecular tetrahydropyrrole ring through reduction-amination.Finally,like most reported strategies,it is planned to complete the synthesis of（+）-asenapine through Ullmann condensation reaction.The method is simple to operate,has a short reaction time,does not use conditions such as highly toxic reagents,and completes the synthesis of molecules after 8 steps of reaction.