Study On New Process Of R-Praziquantel Synthesis

Praziquantel?PZQ?is indicated as the first line drug for the treatment of schistosomiasis,and this small molecule drug is commonly synthesized and administered as a racemate.However,only the R-enantiomer displays anti-parasite activities while the S-enantiomer is inactive with poor taste that affects patients.Therefore,it is of great significance to develop a reasonable and effective synthetic route to obtain R-PZQ.Given the limitations of the existing routes,we attempted to develop a“dual-routes”for mild and scalable preparation of R-PZQ.Firstly,we mainly introduced the pharmaceutical value of R-PZQ,summarized the synthetic methods of R-PZQ,as well as mechanochemistry and its application.This paper puts forward the idea of preparing R-PZQ by a“dual-path”methodology.Secondly,this work focused on the asymmetric resolution of the key intermediates of R-PZQ.1)1-nitromethyl-2-chloroacetyltetrahydroisoquinoline 2 was prepared starting from the readily available material 3,4-dihydroisoquinoline by mechanochemical solvent-free Aza-Henry reaction.The reaction conditions,involving chemical conditions and mechanical milling parameters were carefully examined to obtain the optimal reaction conditions,which provided the target compound with 83%yield.The reaction could be successfully scaled up to 50 mmol,and gave a constant product yield?82%?;2)1-aminomethyl-2-chloroacetyltetrahydroisoquinoline intermediate 3 was obtained by the reduction of 2.The reaction conditions,involving catalysts,solvent system,reaction temperature and time were examined in detail to obtain the 75%yield.The reaction was scaled up to 25 mmol and gave satisfacotry yield?74%?;3)R-3 was obtain via the kinetic resolution of 3,under a chiral acidic resolving agent.With the optimization of the resolving agent,solvent and time,the key intermediate R-3 was obtained in 26%yield and 99.9%ee.The reaction in this step can be scaled up 50 mmol?27%yield,95.1%ee?,and the remaining mother liquor can be recovered by racemization,and the yield based on the mother liquor recovery is 43.2%.In addition,the mechanochemical-enzymatic dynamic kinetic resolution of intermediate 3 was preliminary explored.Then,on the basis of the asymmetric resolution process,we proposed an asymmetric synthesis of key intermediates of R-PZQ.R-2 was synthesized via the introduction of chiral catalysts and liquid-assisted grinding reagents?LAGs?in the Aza-Henry reaction.After a detailed screening of the chemical conditions such as chiral catalysts,LAGs,base and mechanical milling parameters,R-2 was obtained in69%yield with 99.8%ee.The reaction was further scaled up to a gram scale?68%yield,99.6%ee?.Further reduction of R-2 was easily achieved under the Ni/H₂conditions gave R-3 in 74%yield and 99.7%ee.Finally,the preparation of R-PZQ was accomplished by the reaction of R-3 with cyclohexanoic acid.The optimal reaction conditions were obtained by a careful screening of the coupling agent as well as the mechanical milling parameters such as milling rotation speed,time and milling ball filling degree.The reaction can be scaled up to 50 mmol with good yield?80%?and enantioselectivity?>99.2%?.In addition,a preliminary calculation of the cost and“three wastes”of the two prodceures was carried out,and compared them with the representative processe in the literature.