Study On The Synthesis Process Of Several Steroid Targets And Urolithin A

The steroidal targets of this thesis include obeticholic acid,obeticholic acid intermediates,obeticholic acid impurities,and anecolta acetate.Obeticholic acid is mainly applied to the treatment of primary biliary cirrhosis,and the annual domestic and foreign demand reaches 400 tons.However,industrial production has not been realized in China because of the long route to synthesize Obeticholic acid,harsh conditions,and imperfect separation and characterization of impurities.Anacorta acetate is an intraocular pressure lowering agent and a key intermediate of steroid hormone drugs.Generally,the nucleophilic substitution reaction between potassium acetate and halide is used to prepare anacorta acetate,but there are problems such as long reaction time,high temperature,and difficulty in recovering the solvent DMF.Urolithin A has a variety of biological activities,high safety,and potential clinical medical value.However,the reported synthetic methods have disadvantages such as low yield,complicated experimental operations,and environmental pollution.Therefore,it is valuable to study the synthesis process of steroid targets（obeticholic acid,obeticholic acid intermediates,possible impurities produced in the synthesis of obeticholic acid,and anecortane acetate）and the synthesis process of urolithin A.The specific content of this thesis comes to the following steps:1.Using chenodeoxycholic acid as a raw material to synthesize obeticholic acid and its impurities and intermediates through oxidation,esterification,silylmethylation,and Mukaiyama reactions.In consideration of the selectivity,cost,environmental protection and other factors,the preparation of impurity7α-hydroxy-3-oxo-5β-cholanic acid was studied,and then it was decided to choose cheap,environmental friendly persulfate as the oxidant to realize the C-3 hydroxyl selective oxidation reaction conditions of deoxycholic acid.Hence,there are some optimal conditions from what have analyzed above:the equivalent ratio of chenodeoxycholic acid and potassium persulfate is 1.0∶2.0,in acetone,phase transfer catalyst,react for 10 h at 35℃,and oxidize the 3-position hydroxyl group.The yield is 62%.2.According to the principle that cesium ions can activate the anion that it is paired with,a method for preparing anacorta acetate using cesium acetate for nucleophilic substitution of the halide was developed.And systematically optimize the nucleophilic substitution reaction.In tetrahydrofuran solvent,1.1 equivalent of cesium acetate,at 70℃,reacted for 4 h,the yield was 98%.And the process was enlarged 100 times,and Anacorta acetate with the same high yield.This method has the merits of no column chromatography,brilliant productivity,and so on.3.The synthesis process of urolithin A is optimized.Due to the influence of comprehensive yield and environmental protection factors on the synthesis process,this paper chose m-methoxybenzoic acid as raw material,through bromination reaction,demethylation reaction,Ullmann coupling reaction to produce urolithin A.Systematic optimization of the key synthesis steps was carried out to obtain the best conditions for the bromination reaction,that the molar ratio of 3-methoxybenzoic acid,NBS,concentrated sulfuric acid is 1.0∶1.3∶1.0,and the reaction solvents were the mixed solution,acetonitrile and dichloromethane（5/1,v/v）,react for 5 h at room temperature.The best conditions for the demethylation reaction were the molar ratio of 2-bromo-5-methoxybenzoic acid,aluminum chloride is 1.0∶2.5,the reaction solvent is DMSO,and the reaction temperature is 130℃.The optimal reaction conditions for the Ullmann coupling reaction are that the molar ratio of2-bromo-5-hydroxybenzoic acid to resorcinol is 1.0:6.0,20 m L of 5.0%Na OH solution is refluxed for 1 h,and 20 m L of 15%Cu SO₄reacted for 30 min.This technical method avoids the use of column chromatography,simplifies the experimental operation,reduces the production cost,and increases the total yield from 25%to 74%,which is expected to realize industrial production.The structures of the compounds synthesized in the above studies have been confirmed by means of ¹H NMR,¹³C NMR,MS and melting point determination,and the industrialization research of obeticholic acid has entered the pilot stage.