Resource Utilization Of A Steroidal Waste And Preliminary Investigation Of Some Cholesteroids As SHP-1 Agonist

Pharmaceuticals and the environment are two themes which closely related to human health.Steroid drugs are the second largest class of drugs after antibiotics,and they play a vital role in maintaining human life and health.However,the structural characteristics of steroids with multi-chiral centers and multi-reaction sites lead to the side reactions during the synthesis process which may form environmental problems and harms to human health.Therefore,the research and development of steroidal new drugs as well as harmless and recycling of waste in the process of steroidal drug manufacturing are of great significance to human health.This thesis focuses on two parts of research work:Resource utilization of a steroidal waste and Preliminary investigation of some cholesteroids as SHP-1 agonist.Part Ⅰ:Study on resource utilization of a steroidal waste in DHEA manufacturing process.3β-Hydroxyandrost-5-en-17-one(DHEA)is a steroidal drug,and it is also a basic key intermediate for many important steroidal drugs.Our research group had developed a new efficient method for preparation of DHEA from androst-4-ene-3,17-dione(4AD),but a by-product with high content and unknown structure has been produced in the process.After a large-scale industrialization,a large amount of hazardous solid waste was generated,and it is urgent to find a scientific resource utilization method.This thesis starts with the structure determination of the unknown byproduct.With a variety of spectroscopy methods and theoretical analysis,the possible structure of the byproduct was determined.Then through derivatization reaction,single crystal cultivation and single crystal X-ray diffraction,the structure and configuration of the byproduct was confirmed as 3β-hydroxyandrost-17-one-6α-boronic acid.On the basis of the structure confirmation,this thesis carried out the further research on the resource utilization of the byproduct.Through a reasonable synthetic design,a new method for preparing 3β-acetoxyandrost-5-en-17-one,an important intermediate for steroid drugs,was developed using the byproduct as raw material through a four-step reaction,in which the sulfonation-elimination at C-6 position can be carried out by "one-pot" method.This new recycling method of 3β-hydroxyandrost-17-one-6α-boronic acid has been successfully industrialized in our cooperative factory,which not only reduces the harm of steroid solid waste emissions to the environment,but also reduces the production cost,and further enhances the competitive power of DHEA’s synthetic process.Part Ⅱ:Preliminary investigation of cholesteroids as SHP-1 agonist.Our research group have designed and synthesized a batch of bile acid derivatives in the preliminary research.The activity screening revealed that the compound MSW83 is of SHP-1 agonistic activity.The second part of this thesis focuses on optimization upon the synthetic method of the hit compound MSW-83.What’s more,design and synthesis of some derivatives with amino/amido substitution at C-3 position as well as SHP-1 agonistic activity were initially investigated.Aimed at the shortcomings in the synthetic method of MSW-83,we optimized the procedure for preparation of key intermediate 3-amino-4,4-dimethyl bile acid methyl ester.The reaction route was shortened from 7-step to 5-step,and the reaction selectivity problem and the usage of highly toxic reagents were solved and avoided.Based on the more effective method for construction of this kind of compound,nine new structures with amino/amido substitution at C-3 position were designed,synthesized and characterized.The preliminary activity test showed that the EC50 value of 2-17 on SHP-1 is 20.60 ± 1.3 μM,which is better than that of the hit compound MSW-83(EC50=47.34 ±0.34 μM).This work provides some useful information for discovery of cholesteroidal candidate of anti-tumor drugs.