A kind of preparation method of obeticholic acid

Abstract

The invention belongs to the field of medicine, particularly relates to a preparation method of 6-ethylchenodeoxycholic acid. The method comprises the following steps of using HDCA (hyodesoxycholic acid) as starting raw materials; sequentially performing esterification reaction, oxidation reaction, hydroxy group protection reaction, reaction with ethyl zinc bromide or diethyl zinc reagent, dewatering reaction, oxidation reaction, reduction reaction and hydroxyl removal and carboxyl group protection reaction to obtain the 6-ethylchenodeoxycholic acid. The method provided by the invention has the advantages that the raw material problem can be solved; the severe reaction conditions of strong alkalinity, high temperature and the like can be avoided; the synthesis efficiency of the 6-ethylchenodeoxycholic acid is greatly improved, so that the provided novel preparation method has the advantages that the byproducts are few; the operation is simple and convenient; the reaction conditions are mild; the cost is low; the method is suitable for the large-scale production of the 6-ethylchenodeoxycholic acid.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a preparation method of obeticholic acid. Background technique [0002] Obeticholic acid (shown in chemical formula I) is a semi-synthetic chenodeoxycholic acid derivative, which has been proven to be a highly active farnesoid X receptor agonist. It is used to treat portal hypertension and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, and non-alcoholic steatohepatitis. Obeticholic acid works by activating the FXR receptor. FXR is a nuclear receptor, which is mainly expressed in the liver, intestine and kidney. It can regulate the expression of genes related to bile acid, fat and sugar metabolism, and can also regulate immune response. Activating FXR can inhibit bile acid synthesis and prevent toxic reactions caused by excessive bile acid accumulation. [0003] [0004] WO2002072598 discloses for the first time a method for preparing obeticholic acid. The ...

AI Technical Summary

Problems solved by technology

Difficult to scale up due to poor selectivity and low yields of direct alkylation with ethyl iodide

[0005] Although WO2006122977 and WO2016045480 have improved the above synthesis process, they still use chenodeoxycholic acid as the starting raw material to prepare obeticholic acid through complex chemical reactions. The total yield of this method is low and the cost is high

[0006] CN101203526 also uses the selective oxide 3α-hydroxyl-7-carbonyl-5β-cholanic acid of CDCA as the starting material to prepare obeticholic acid through 7 steps of reaction, the process route is long, the product yield is low, and the cost is high

[0007] In summary, the current methods for preparing obeticholic acid are all limited to using chenodeoxycholic acid as the starting material, and the resources of chenodeoxycholic acid are limited, and its market price is increasing year by year, resulting in the use of chenodeoxycholic acid The cost of synthetic routes for raw materials remains high

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