Research On High-value Products Of Hyodeoxycholic Acid

Hyodeoxycholic acid(HDCA)is mainly a kind of cholic acid extracted from pig bile,which has the advantages of high content,wide source and low cost.Synthesis of high-value chenodeoxycholic acid,?-muricholic acid and bile acid derivatives from hyodeoxycholic acid has the advantages of wide source of raw materials,good stereoselectivity,short route,high yield and environmental friendliness,and it is of great significance for the development of CDCA,?-MCA and biochemical standards.Synthesis of chenodeoxycholic acid,?-MCA and two different bile acids derivatives from hyodeoxycholic acid was carried out in the article.These derivatives were evaluated for biological activity.The paper mainly includes the following aspects:1?The structure,properties,physiological functions,pharmacological activities,clinical application of cholic acid compounds,advances in research on pre-synthesis of chenodeoxycholic acid and ?-MCA and the interaction of Farnesoid X Receptor(FXR)with cholic acid compounds were briefly introduced.2?A synthetic route for synthesis of chenodeoxycholic acid from hyodeoxycholic acid was explored.Using hyodeoxycholic acid as raw material,the target was synthesized via esterification,selective oxidation,hydroxylation of C-7-methylene,C-6-carbonyl reduction methylation and hydrolysis reactions.The overall yield of this route is 10.7%.The synthetic route has the advantages of easy availability of raw materials,simple separation and purification,and easy operation.Three key reactions in this route were studied: 1)it was confirmed that the oxidant 2-iodobenzoic acid(IBX)can selectively oxidize the hydroxyl group at the C-6 position of H2 to obtain H3.2)After Rubottom oxidation,a hydroxyl group can be introduced at the C-7 position of H3 and the hydrogen configuration at the C-5position can be maintained to obtain H5.3)The reductive methyleneation of carbonyl group at the C-6 position of H5 is carried out by reacting benzenesulfonylhydrazide with carbonyl group at the C-6 position of H5 to reduce the methylene group to obtain H7.3 ? A synthetic route for synthesis of ?-muricholic acid from hyodeoxycholic acid was explored.?-Muricholic acid was synthesized from hyodeoxycholic acid via esterification,selective oxidation,hydroxylation of C-7-methylene,C-6-carbonyl reduction and hydrolysisreactions.The overall yield of this route is 28.9%.Synthesis method has the advantages of mild conditions,short steps and high yield.4?Based on the exploration of synthesis route of chenodeoxycholic acid and ?-muricholic acid from hyodeoxycholic acid,in order to develop highly active bile acid derivatives and biological standards,two cholic acid analogues were designed and synthesized and bio-evaluation.Using hyodeoxycholic acid as raw material,the effects of different hydroxyl oxidation on the activity were investigated.The cholic acid analogues N1 and H1 were designed and synthesized,and the absolute configuration of N1 was determined through crystal structure.Two key reactions in this route were studied during synthesis of compounds N1: 1)Hydroxylation of the C-7 position of intermediate N4 to obtain N5 is achieved by?-bromination rehydrolysis of carbonyl group at the C-6 position of N4.2)The reductive methyleneation of carbonyl group at the C-6 position of compound N5 is carried out by reacting p-toluenesulfonhydrazide with carbonyl group at the C-6 position of N5 to reduce the methylene group to obtain N7.During synthesis of compound H1,the key intermediate H11 is synthesized via ?-bromo rehydrolysis of carbonyl group at the C-6 position of H9,and its structure was determined by crystal structure.It was found that the configuration of H-5 in compound H11 was reversed from ? to ?.The mechanism was discussed in this paper,which is consistent with Favorski rearrangement.The two bile acid analogs N1 and H1 were subjected to agonistic activity assay on Farnesyl X Receptor(FXR).Cell experiments showed that the compounds N1 and H1 had no agonistic activity on the FXR receptor.All the structures of the above synthesized compounds were confirmed by NMR and HRMS,the structures of some of the key intermediates and final products were further confirmed by X-ray single crystal diffraction.