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A kind of method for preparing obeticholic acid intermediate and obeticholic acid thereof

A technology of obeticholic acid and intermediates, applied in the field of drug synthesis, can solve problems such as difficult quality control and unfavorable initial quality control, and achieve the effects of easy tracking of reactions, reduced difficulty of refining, and high reaction yields

Active Publication Date: 2021-06-04
ZENJI RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this route uses ethyl ester compounds as starting materials, which is not conducive to initial quality control, and uses -MOM as a hydroxyl protecting group, and most of the intermediates involved exist in oily form, which is difficult to achieve quality control in the scale-up production process

Method used

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  • A kind of method for preparing obeticholic acid intermediate and obeticholic acid thereof
  • A kind of method for preparing obeticholic acid intermediate and obeticholic acid thereof
  • A kind of method for preparing obeticholic acid intermediate and obeticholic acid thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] carbonyl reduction reaction

[0036] Preparation of Compound XIV

[0037]

[0038] In a 100ml round-bottomed flask, add 20ml of ethanol and 4.2g of compound XIII in sequence. After the solution is stirred and dissolved, add 0.95g of sodium borohydride in batches at a temperature of 10°C. The full reaction time is 8h. After the reaction is completed, add acetic acid Quench the reaction, add toluene and water, stir and separate layers, remove the water phase, wash the organic phase once with 5% acetic acid aqueous solution, dry, and spin dry to obtain the crude compound XIV, which is directly used in the next reaction, with a yield of 100%.

Embodiment 2

[0040] hydroxyl protection reaction

[0041] Preparation of Compound XV

[0042]

[0043] Add the crude compound XIV prepared in Example 1 to a 100ml round-bottomed flask and completely dissolve it in N,N-dimethylformamide solvent, then add 0.46g of potassium carbonate, and finally add 3.4g of benzyl bromide, heat at 40°C, and stir Reacted for 8 hours, cooled after the reaction, added toluene and 5% acetic acid aqueous solution, stirred and separated, removed the water phase, dried the organic phase and then spin-dried, recrystallized with toluene to obtain 5.5 g of intermediate XV, with a yield of 92%.

Embodiment 3

[0045] palladium carbon reduction reaction

[0046] Preparation of obeticholic acid I

[0047]

[0048] 1) In a 100ml hydrogenation kettle, sequentially add 3.0 g of compound XV, 50ml of methanol, 0.005g of 10% Pd / C, 0.02g of sodium hydroxide and 100ml of water. After the mixture is evenly stirred, seal the hydrogenation kettle and use N 2 and H 2 Replace the air in the system, control the temperature at 20°C, control the hydrogen pressure at 0.5MPa, and react the mixture system for 2 hours under stirring;

[0049] 2) To terminate the reaction, use N in turn 2 and air displacement system H 2 ;

[0050] 3) After the mixture was filtered to separate Pd / C, the solvent was spun off to obtain a crude product of obeticholic acid, which was crystallized and purified with ethyl acetate to obtain 1.8 g of a refined product with a yield of 85%.

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Abstract

The invention discloses a method for preparing an obeticholic acid intermediate and obeticholic acid, wherein the obeticholic acid intermediate uses 3A-hydroxy-6-vinyl-7-oxo-cholic acid as a raw material Carbonyl reduction and hydroxyl protection. The obtained obeticholic acid intermediate contains two benzene ring structures and has strong ultraviolet absorption. It is convenient to use ultraviolet detectors for quality research, so as to ensure that the quality of raw materials in the last step is controllable. It is in a solid state at room temperature and can be refined by conventional purification methods such as recrystallization; and then further reduced by palladium carbon to obtain obeticholic acid. From the perspective of the reaction process, the palladium carbon reduction process first completes the reduction of olefinic bonds, which is convenient The reaction is tracked, and the reaction yield is high, and the conversion is relatively complete, which reduces the difficulty of refining the final product.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a method for preparing an obeticholic acid intermediate and the obeticholic acid. Background technique [0002] Obeticholic acid has attracted wide attention due to its good therapeutic effect on a variety of chronic liver diseases, including primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NASH), primary cirrhosis Cholangitis (PSC) and biliary atresia. Its structure is as follows: [0003] [0004] In 2002, WO2002072598 disclosed the synthesis route of obeticholic acid for the first time. As shown below, compound II was reacted with ethyl iodide under strong alkali conditions to obtain compound III, and then the target compound I was obtained through reductive hydrolysis. The synthesis route is simple, but direct use of ethyl iodide for alkylation has many side reactions, and the yield is low, so it is not suitable for scale-up production. [0005]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 葛敏胡春晨李令超李亮
Owner ZENJI RES LAB
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