Design And Synthesis Of Isoxazole And Pyrazole Heterocyclic Derivatives Of Sinomenine

Sinomenine is a natural alkaloid isolated from the dried stems and rhizomes of Sinomenium acutum.Studies have found that Sinomenine exhibits some pharmacological activity in anti-inflammatory,analgesic,anti-cancer and neuroprotective.Currently,sinomenine is mainly used in the treatment of rheumatoid arthritis.However,sinomenine also has some defects,such as short biological half-life,high clinical therapeutic dose,and poor epidermal permeability,which limit its wide application.In order to improve the drug activity and reduce the side effects of the natural product sinomenine,scholars have conducted structural modification studies on sinomenine,and the results showed that most of the sinomenine derivatives synthesized achieved their objectives.Heterocyclic compounds have become important structural units in drug molecules because of their excellent pharmacological activities.Therefore,in this paper,we constructed isoxazole and pyrazole nitrogen heterocycles onto sinomenine and synthesized sinomenine isoxazole and pyrazole heterocyclic derivatives,which enriched the sinomenine derivative library and also provided an experimental basis for obtaining lead compounds in drug development.The research contents of this paper are as follows:（1）A synthetic method was designed and optimized for the construction of isoxazole heterocycles into the A-ring of sinomenine,and 16 new sinomenine A-ring isoxazole derivatives were synthesized in moderate to excellent yields.Sinomenine hydrochloride is neutralized with ammonia to obtain the parent sinomenine,which is substituted at the 1 position to obtain 1-iodosubstituted sinomenine,and1-iodosubstituted sinomenine is coupled with（trimethylsilyl）acetylene by Sonogashira and then deprotected to obtain the intermediate 1-ethynyl sinomenine.Finally,sinomenine A-ring isoxazole derivatives were synthesized by 1,3-dipole cycloaddition of 1-acetylene sinomenine and 1,3-dipoles generated from a series of benzaldehyde oximes.The synthesized derivatives were structurally characterized and analyzed by ¹H NMR,¹³C NMR,FT-IR and HRMS.（2）A synthetic method was designed and optimized for the construction of pyrazole heterocycles into the A-ring of sinomenine,and 13 new sinomenine A-ring pyrazole derivatives were synthesized in moderate yields.Sinomenine hydrochloride is neutralized with ammonia to obtain the parent sinomenine,which is substituted at the 1 position to obtain 1-iodosubstituted sinomenine,and 1-iodosubstituted sinomenine is coupled with（trimethylsilyl）acetylene by Sonogashira and then deprotected to obtain the intermediate 1-ethynyl sinomenine.Finally,sinomenine A-ring pyrazole derivatives were synthesized by 1,3-dipole cycloaddition of 1-acetylene sinomenine and 1,3-dipoles generated from a series of benzaldehyde.The synthesized derivatives were structurally characterized and analyzed by ¹H NMR,¹³C NMR,FT-IR and HRMS.（3）A synthetic method was designed and optimized for the construction of isoxazole-tetrazole hybrids into the D-ring of sinomenine,and 18 new sinomenine D-ring isoxazole-tetrazole derivatives were synthesized in moderate to excellent yields.The sinomenine undergoes von Braun reaction to obtain 17-cyano sinomenine,and the cyano group reacts with sodium azide to obtain the sinomenine D-ring N-（1H）-tetrazole derivative.And finally,carrying out alkylation reaction on a series of isoxazole derivatives generated by the 1,3-dipolar cycloaddition reaction of a series of benzaldehyde oximes and propargyl bromide and a sinomenine D-ring N-（1H）-tetrazole derivative to obtain the sinomenine D-ring isoxazole-tetrazole derivative.The synthesized derivatives were structurally characterized and analyzed by ¹H NMR,¹³C NMR,FT-IR,HMBC and HRMS.In this paper,we designed and optimized the synthesis of three series of new sinomenine derivatives,and synthesized a total of 48 new sinomenine derivatives in moderate to excellent yields,which enriched the library of sinomenine derivatives and provided lead compounds for the development of sinomenine drugs and also provided references for the structural modification studies of other natural products.