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Synthesis method of obeticholic acid

A technology of obeticholic acid and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of easy configuration inversion, many impurities, difficult purification and the like, and achieves the effects of improving the total yield, convenient purification and good economy.

Inactive Publication Date: 2017-01-04
合肥诺瑞吉医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this method is 16%, and the intermediate needs to be purified by column chromatography. In the process of direct catalytic hydrogenation, there are many impurities, the configuration is easy to reverse, and the purification is difficult.

Method used

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  • Synthesis method of obeticholic acid
  • Synthesis method of obeticholic acid
  • Synthesis method of obeticholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of 3α-Hydroxy-7-keto-5β-cholestane-24-acid (III)

[0046] Dissolve the compound (118.0 g, 0.31 mol) shown in formula (II) in dichloromethane (500 ml), add 30% sulfuric acid (80 ml) solution and sodium bromide (800 mg) and stir at room temperature, and control the temperature at 30 ° C Add 16% sodium bromate (162.4g, 1.06mol) solution dropwise, and react for 6h after the dropwise addition, add 10% sodium bisulfite solution (200ml), extract and retain the organic layer, and use ethyl acetate (200ml) to re- extraction. The organic phases were combined, concentrated to dryness, added ethyl acetate (200ml), heated to reflux for 0.5h, cooled down and crystallized for 24h, filtered, and the filter cake was air-dried at 50°C for 10h to obtain a white solid of the compound shown in formula (III) ( 112.5 g, yield 96.1%).

Embodiment 2

[0048] Preparation of 3α-hydroxy-7-keto-5β-cholestane-24-ethyl ester (IV)

[0049] The compound represented by formula (III) (100.0 g, 0.26 mol) was dissolved in ethanol (500 ml), concentrated sulfuric acid (5 ml) was added, heated to reflux for 10 h, and cooled to room temperature. Add 1mol / L sodium hydroxide solution (about 30ml) to adjust the pH to 7, slowly add purified water (1L) dropwise, stir at room temperature, a white solid precipitates, and let it stand overnight. After suction filtration, the filter cake was vacuum-dried at 50° C. to obtain a white solid of the compound represented by formula (IV) (105.5 g, 98.4%).

Embodiment 3

[0051] Preparation of 3α,7-bis(trimethylsilyloxy)-6-ene-5β-cholestane-24-ethyl ester formula (V)

[0052] Anhydrous THF (400ml), 2mol / LLDA THF solution (150ml) and trimethylchlorosilane (110ml, 0.9mol) were added to the reaction flask under nitrogen protection. Stir at -50~-30°C for 15min, slowly add dropwise anhydrous THF solution (100ml) containing the compound (80.3g, 0.2mol) shown in (IV), and add dropwise at -50~-30°C under temperature control. Keep stirring at this temperature for 6h, add saturated sodium bicarbonate solution (100ml) to quench the reaction. Slowly rise to room temperature, continue stirring for 2 h, add saturated sodium bicarbonate solution (1 L), extract with ethyl acetate (1 L × 2), combine organic layers, wash with water (1 L) and saturated sodium chloride solution (1 L) successively, After drying with anhydrous sodium sulfate and filtering, the filtrate was concentrated to dryness to obtain a tan solid (120.7 g) of the compound represented by formul...

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Abstract

The invention discloses a synthesis method of obeticholic acid. The synthesis method takes 3alpha,7alpha-dihydroxyl-5beta-cholestane-24-acid as a starting material and comprises the following steps: carrying out hydroxyl oxidation and carboxylic acid ethyl esterification, and reacting with trimethylsilyl chloride to synthesize silyl enol ether; then enabling the silyl enol ether and acetaldehyde to subject to Mukaiyama hydroxyaldehyde condensation to obtain 6-ethylidene-3alpha-hydroxyl-7-one-5beta-cholestane-24-ethyl; carrying out catalytic hydrogenation, hydroxyl protection and ester group hydrolysis; carrying out selective reduction through sodium borohydride; finally, carrying out de-protection to obtain the obeticholic acid. By optimizing synthesis steps and selecting different protection reagents to protect hydroxyl and carboxyl for a plurality of times, and adopting a selective hydrogenation reduction reaction, the problems in a synthesis reaction of the obeticholic acid that more impurities are caused, a structure is easy to overturn, the yield in a 6alpha-ethylation process is low, purification is difficult to realize and the like are effectively solved; the total yield of an obeticholic acid product is greatly improved; the synthesis method has good economical efficiency and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for synthesizing obeticholic acid. Background technique [0002] The structural formula of obeticholic acid is as formula (I), [0003] [0004] Its trade name is OCALIVA, and its chemical name is 6α-ethyl-3α,7α-dihydroxy-5β-cholestane-24-acid. The drug was first developed by the University of Perugia, and Intercept Pharmaceuticals was authorized to develop it and was released in 2016. Launched in the US in May. Obeticholic acid is a potent inhibitor of farnesoid X receptor agonist. It plays a role in regulating bile level and has anti-cholestasis and anti-fibrosis effects. Clinically, this drug is effective for primary The curative effect of biliary cirrhosis exceeded expectations. In 2008, it was granted orphan drug qualification in the United States. In 2015, it was granted breakthrough therapy designation by FDA. Therefore, obeticholic acid has huge mark...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCY02P20/55C07J9/005
Inventor 吴云
Owner 合肥诺瑞吉医药科技有限公司
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