Synthesis Of Sinomenine Triazole And Isoxazole Derivatives

Sinomenine is an active ingredient of the medicinal plant Sinomenium acutum,an isoquinoline alkaloid with a structure similar to morphine,and a natural drug molecule with multiple biological activities.It is commonly used in rheumatoid joints in clinic Inflammation(RA)and anti-arrhythmia and other diseases.Clinical experiments have shown that sinomenine has anti-inflammatory and analgesic,immunosuppressive,tumor cell proliferation and other drug activities,which can effectively improve the disease;at the same time,although sinomenine is similar to morphine in structure,patients will not be addicted to sinomenine,So sinomenine is expected to be used in detoxification drugs.Sinomenine also has defects such as large side effects,instability to light and heat,and large dosage.Therefore,it is necessary to modify the structure of sinomenine matrix in order to obtain highly efficient and low-toxic derivatives.Heterocycles are often the key active sites of drug molecules.Modifying and synthesizing heterocyclic substituted part on sinomenine,synthesis of heterocyclic substituted sinomenine derivatives is the main work of this thesis.The series of sinomenine derivatives synthesized in the paper enriched the sinomenine derivative library and also provided basic research for the discovery of potential new drugs.The main research contents of this paper are as follows.(1)A new method for the synthesis of sinomenine derivatives substituted with A ring 1,2,3-triazole was developed,and a total of 14 compounds were synthesized.Using sinomenine as the raw material,chloropropyne is used to replace the active hydroxy hydrogen at the C4 position of sinomenine to obtain 4-alkynyl sinomenine;afterwards,the synthesized benzyl azide compound and 4-Fourteen target products were obtained through the reaction of sinomenine derivatives,and the structure was characterized by nuclear magnetic,infrared,mass spectrometry and other instruments.Compared with the traditional synthetic sinomenine triazole derivatives,this article uses tert-butanol and water as the solvent,the solvent is more environmentally friendly,and the post-processing is easy.(2)The synthetic method of sinomenine derivatives substituted with A-cycloisoxazole was developed,and 19 new sinomenine isoxa derivatives were synthesized.Starting from sinomenine,4-alkynyl sinomenine is synthesized;benzaldehyde compounds are oximated to obtain a variety of benzaldehyde oximes,chlorinated with NCS to obtain chloroximes,and then dehydrochlorinated with acid binding agents 1,3-dipole;1,3-dipole undergoes "1,3-dipolar cycloaddition" reaction with 4-alkynyl sinomenine to obtain sinomenine isoxazole derivatives.,Infrared,mass spectrometry and other instruments for structural characterization.The reaction does not require any catalyst,the operation is simple,the raw material price is low,and the yield is excellent.(3)The synthesis method of C-cycloquinoxaline substituted A-cycloisoxazole substituted sinomenine derivatives was developed,and a total of 15 new C-cycloquinoxaline substituted sinomenine derivatives were synthesized.Taking sinomenine as the lead,firstly the C-ring of sinomenine was modified to obtain an ?-diketone structure,and the reaction with o-phenylenediamine was continued to obtain a C-cycloquinoxaline substituted sinomenine derivative This is an intermediate product.Continued structural modification of the A ring.After replacing the active hydroxy hydrogen at the C4 position with chloropropyne,the terminal alkyne was successfully grafted at the C4 position and reacted with 1,3-dipole to obtain 15 target products.Nuclear magnetic,infrared,mass spectrometry and other instruments were used for structural characterization.There are many studies on sinomenine structure modification,but there are few reports on double substitution.The synthesis method of sinomenine double heterocyclic substituted derivatives provided in this paper provides a new direction for the study of sinomenine structure modification.