Process Study Of High Value Utilization Of Hyodeoxycholic Acid

Natural chenodeoxycholic acid is one of the most widely used drugs for treating gallstones in the world.Using hyodeoxycholic acid as raw material to synthesize chenodeoxycholic acid has certain research value.On one hand,it can improve the utilization rate of pig bile,on the other hand,it can meet the demand for chenodeoxycholic acid in domestic and foreign markets,and can also produce economic benefits.The currently reported process route for synthesis of chenodeoxycholic acid using hyodeoxycholic acid as a raw material is difficult to control,and the overall yield is not high.It lacks practicality and is difficult to produce on a large scale in industry.Therefore,this article has studied the route of synthesizing chenodeoxycholic acid from hyodeoxycholic acid as raw material,mainly including the following two aspects:1.Hyodeoxycholic acid is used as a raw material,which undergoes an esterification reaction,selectively oxidize C-6 hydroxyl reaction,C-3 hydroxyl protection reaction,C-7hydrogen bromine substitution reaction,C-6 carbonyl reduction reaction,double bond elimination reaction,double bond epoxidation reaction,epoxy ring opening reaction,hydrolysis,nine steps to synthesize chenodeoxycholic acid with a total yield of 9%.In addition,the key reaction steps of the reaction were explored: 1)Complement the peak time of products that may be produced by the selective oxidation of the C-6 hydroxyl group,and the best oxidant in this reaction is 2-iodoacylbenzoic acid;2)The type of protecting group is explored,and the best reaction effect is obtained using acetic anhydride as a protecting agent;3)The epoxidizing agent is explored,and monoperoxy phthalic acid is finally obtained is better for epoxidation reaction;4)The method of epoxy ring-opening reaction is explored,and it is concluded that epoxy substrate reacts with 10% palladium carbon under hydrogen,can stereoselective ring-opening generate 7α-OH.2.Exploring the synthesis of key intermediate 3α-acetoxy 6-vinyl-5β-cholic acid methyl ester(H4).(1)Shapiro reaction was carried out using intermediate H3 as a substrate.Intermediate H4 was obtained in two steps.The two-step reaction yield was 51%,and the total yield of the route was 34%;(2)It is obtained that H3 is used as a starting material,afterC-6 carbonyl reduction reaction occurs,sulfonate formation reaction,and the elimination reaction,there are 3 steps reaction to generate intermediate H4.The three-step reaction yield is 90%,and the total yield of the route reaches 60%;(3)H1 is the starting material.After selective oxidation reaction,sulfonate formation reaction,elimination reaction,there are three steps to generate the compound 3-carbonyl-4-vinylcholine methyl ester(D3),and the total yield in three steps is 66%;(4)Using H1 as a starting material,after sulfonate formation reaction,elimination reaction,there are two steps to generate the compound3α-hydroxy-5-vinylcholic acid methyl ester(E2).The total yield of the two steps is 91%.Finally,three routes for synthesizing chenodeoxycholic acid from hyodeoxycholic acid were developed.The total yield of the route was increased from 9% to 34%,and then to 60%.The structure of the synthesized product was confirmed by spectroscopic methods such as1H-NMR,13C-NMR,and HRMS.Some compounds w ere further confirmed by X-ray single crystal diffraction.