Obeticholic acid preparation method

Abstract

The invention discloses an obeticholic acid preparation method, which comprises that (1) hyodeoxycholic acid II reacts with an alcohol compound III under the action of a catalyst to generate an ester compound IV; (2) the ester compound IV is subjected to PDC oxidation in dichloromethane to generate a compound V; (3) the compound V and trimethyl chlorosilane are subjected to a reaction at a temperature of -70 to -20 DEG C in tetrahydrofuran by using lithium diisopropylamide as an alkali to generate a silyl enol ether compound VI; (4) the silyl enol ether compound VI is subjected to m-chloroperoxybenzoic acid oxidation and deprotection in dichloromethane to generate a compound VII: (5) the compound VII and Yield generated from ethyltriphenylphosphonium bromide under the action of a strong alkali are subjected to a Wittig alkenylation reaction at a temperature of 0-70 DEG C to convert the ketone into the vinyl so as to generate a compound VIII; (6) the double bond of the compound VIII is subjected to catalytic hydrogenation reduction in a mixing solvent to generate a compound IX; and (7) the compound IX is hydrolyzed under an alkaline condition to generate the obeticholic acid.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of obeticholic acid. Background technique [0002] Obeticholic acid, chemical name 3α, 7α-dihydroxy-6α-ethyl-5β-cholanic acid, is a new drug with excellent efficacy in various phases of clinical trials under development by Intercept Pharmaceuticals, also known as INT747 or 6α -Ethyl chenodeoxycholic acid, which is a derivative of semi-synthetic chenodeoxycholic acid (CDCA), can activate farnesoid X receptor (FXR), and has anti-cholestasis and anti-fibrosis effects. The research indications include primary biliary cirrhosis (PBC), nonalcoholic fatty liver disease (NASH), primary sclerosing cholangitis (PSC), portal hypertension and diarrhea. Among them, primary biliary cirrhosis (PBC) has successfully completed phase III clinical trials, and is currently in the pre-registration state in the United States and the European Union (Pre-regis...

AI Technical Summary

Problems solved by technology

[0005] The process uses 7-ketolithocholic acid (7-KLCA) as the starting material, and sequentially undergoes four steps of 3α-hydroxyl protection, carboxylic acid formation into ethyl ester, 6α-ethylation, 7-carbonyl reduction and ester hydrolysis. Deobeticholic acid contains fewer synthetic steps, but there are two important defects: first, in all steps, the reaction product needs to be separated and purified by chromatographic columns, which will greatly increase its preparation cost and is difficult to use Industrialized production: the 2nd, the reaction yield of second step is very low, only has about 12%, causes the total yield of this technique to be only about 3%, and yield is too low and has reduced the practicability of this method greatly

[0019] This method has been improved on the basis of the method reported in the document J.Med.Chem.2012, 55, 84-93, and the cost has been reduced, but it involves a low-temperature reaction in the selective reduction of the fourth step carbonyl, which increases the cost. Energy consumption is also not conducive to industrial production

[0020] In the prior art for the preparation of obeticholic acid, the starting materials are chenodeoxycholic acid or its oxidation product 7-KLCA, the raw materials are not easy to obtain, and the cost is high, which restricts the scale-up production of obeticholic acid

Images