| Obeticholic acid is a farnesyl X nuclear receptor agonist developed by Intercept Pharmaceuticals.It is mainly used to treat primary bile cholangitis and non-alcoholic fatty liver disease.Pyridoxal phosphate can promote transaminase transamination and increase dopamine content in the body,and is used clinically to treat Parkinson’s syndrome.Both of them have broad market prospects,and therefore the optimization of their synthesis process has high economic value.The main work in this thesis can be summarized as follows:（1）Synthesis process optimization of Obeticholic acid: Using chenodeoxycholic acid as a raw material,obeticholic acid is prepared by a total of six steps of oxidation reaction,esterification reaction,nucleophilic addition,catalytic hydrogenation,hydrolysis and selective reduction The reaction mechanism and reaction conditions of the synthesis units involved were analyzed and discussed,and the route technology was optimized.The results show that the optimal condition for sodium hypochlorite to oxidize chenodeoxycholic acid is in methanol solution,the molar ratio of sodium hypochlorite to chenodeoxycholic acid is 1: 3,the reaction temperature is 15℃,the reaction time is 2 h,and the yield is 91.8%.In the esterification reaction,the reaction time using methanesulfonic acid as the catalyst was shortened from 12 hours to 4 hours.In nucleophilic addition reaction,first use trimethylchlorosilane for group protection,and then add with acetaldehyde,3α-hydroxy-7-one-5β-cholanoic acid-24-methyl ester,trimethylchlorosilane The molar ratio to acetaldehyde is 1: 8: 2.The optimal condition for catalytic hydrogenation is that the mass ratio of 10% palladium carbon to3α-hydroxy-6-methylene-7-one-5β-cholanoic acid-24-methyl ester is 0.2: 1,and the hydrolysis reaction time is from 10 The hours were shortened to 8 hours.In the selective reduction reaction,the molar ratio of 6α-ethyl-3α-hydroxy-7-one-5β-cholanoic acid to sodium borohydride was 1: 5,and the yield was 89.6%.The purity of the final product obeticholic acid reached 99.0%,and the total yield of the reaction reached 35.9%.（2）Synthesis process optimization of Pyridoxal phosphate: Pyridoxal phosphate was synthesized from pyridoxine hydrochloride（VB6）by oxidation,aldehyde protection,phosphate esterification and hydrolysis.The conditions of oxidizing VB6 by MnO2,phosphate esterification of the pyridoxine Schiff base and crystallization of pyridoxal phosphate from water were discussed.The result shows that optimal oxidation of VB6 is carried out in 6% hydrochloric acid solution,the molar ratio of VB6 and MnO2 is 1:2,the reaction temperature is 15℃,and the reaction time is 6 h.Polyphosphoric acid with a small amount of water（3% w/w）is the optimal phosphate esterification reagent for the pyridoxine Schiff base（The molar ratio of pyridoxal hydrochloride Schiff base to polyphosphoric acid is 1: 3.5）.The hydrolysis solution of pyridoxal phosphate Schiff base is acidified with strong acid cation exchange resin,followed by freeze-drying to give pyridoxal phosphate,which solves the problem of difficult crystallization of pyridoxal phosphate from water.The entire process is easy to industrialize,and the total yield of pyridoxal phosphate reaches 61.6%. |
