Study On Reuse Of The Byproducts In Chlorohvdrination Of 3?-Acetoxy-5-ene-androstan-17-one And Synthesis Of Bioactive Compound LH2-76

Steroidal drugs play an important and irreplaceable role in human health.This thesis carried out two parts research work about the synthesis of steroid compounds.Part 1:Study on reuse of the byproducts in chlorohydrination of 3?-acetoxy-5-ene-androstan-17-one.Chlorohydrination reaction of 3?-acetoxy-5-ene-androstan-17-one is one of the key synthetic reactions in manufacturing many important series steroidal drugs,the market demand is very large.However,the chlorohydrination reaction produces many hormone byproducts,wasting a lot of raw materials as well as causing serious environmental problem.In this thesis,we separated and purified the byproducts and elucidated their structures by HRMS spectroscopy for the first time.Two main byproduct structures has been confirmed,they are 3?-acetoxy-6a-chloro-5?-hydroxy-androstan-17-one and 3?-acetoxy-6?-chloro-5a-hydroxyl-androstan-17-one,respectively,which are isomers of the main product.On the basis of byproduct structure research,we further developed the transformation of 3?-acetoxy-6a-chloro-5?-hydroxy-androstan-17-one(byproduct ?)to the main product 3?-acetoxy-5a-chloro-6?-hydroxy-androstan-17-one via cyclization,ring opening process,realizing the efficient conversion from by product to the main product for the first time.At the same time,we developed the conversion 3?-acetoxy-6?-chloro-5?-hydroxy-androstan-17-one(byproduct ?)to 3?-acetoxy-5-ene-androstan-l 7-one via cyclization,reduction process,realizing the recycling of byproduct for the first time.Based on this research we achieved the reuse of two main byproducts of the chlorohydrination reaction of 3?-acetoxy-5-ene-androstan-17-one for the first time,which improved the reaction efficiency greatly,and reduced the pressure of hormonal solid wastes to the environment,made important application values.Part 2:Synthesis of LH2-76,a new HMGCR activity compoundWhile developing new lipid-lowering drugs our group had found a new active compound LH2-76 which could promote the degradation of HMGCR.This compound had been synthesized through fifteen steps with 9%overall yield using lithocholic acid as the starting material.Due to the high cost of lithocholic acid,searching new method for synthesis of LH2-76 in gram scale is very urgent to carry out the further biological studies and pharmacodynamic evaluation.In this part we developed a new route for synthesizing LH2-76 through thirteen steps using cheaper hyodeoxycholic as raw material.This new method has shortened the reaction procedure and avoided the use of toxic reagent PCC with the total yield remains unchanged.This method provides technical support for the study of new drug candidates.