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The synthetic method of obeticholic acid

A technology of obeticholic acid and its synthesis method, which is applied in the field of synthesis technology of obeticholic acid, can solve the problems of low yield, immature synthesis route, harsh reaction conditions, etc., and achieve high cost, improved low temperature environment, and equipment less demanding effect

Active Publication Date: 2017-02-22
NANJING UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide a synthetic method of obeticholic acid in order to solve the problems of harsh reaction conditions, low yield and immature synthetic route. to industrial production

Method used

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  • The synthetic method of obeticholic acid
  • The synthetic method of obeticholic acid
  • The synthetic method of obeticholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、13

[0045] Embodiment 1, the synthesis of 13α-hydroxyl-7-ketone-5β-cholanic acid-24-methyl ester (Ⅲ)

[0046]Take 2g (5.1mmol) chenodeoxycholic acid (I), 1.3g (7.3mmol) N-bromosuccinimide in a 100mL single-necked round bottom flask, add 48mL acetone-water (3:1, volume ratio) , The reaction was stirred at room temperature for 4 h, and the reaction was detected by TLC. Add 10mL of 20% (mass fraction) sodium bisulfite to the flask, evaporate the acetone to dryness, then acidify with 5mL hydrochloric acid solution (5%), filter after solid precipitation, wash the filter residue with water until neutral, dry, and weigh with absolute ethanol After crystallization and drying, 1.84 g of white solid was obtained.

[0047] Take the obtained white solid in a 150mL single-necked round bottom flask, add 60mL of methanol, heat to 60°C, add dropwise 1mL of 98% concentrated sulfuric acid, reflux and stir for 12h, after the reaction is completed by TLC, add 2g of sodium bicarbonate, and wait until...

Embodiment 2、3

[0051] Example 2, 3α, the synthesis of 7-bis(tert-butyldimethylsilyloxy)-6-ene-5β-cholanic acid-24-methyl ester (Ⅳ)

[0052] Take 5g (12.4mmol) of compound (Ⅲ) in a 150mL single-necked round bottom flask, add 25mL of dry tetrahydrofuran and dissolve it, take 4.1g (27.3mmol) of tert-butyldimethylsilyl chloride and 2g (29.8mmol) of imidazole Add it into the constantly stirring solution, take 10mL triethylamine and slowly add it into the solution after 0.5h, and stir at room temperature for 4h after all the addition, and the reaction is completed by TLC detection. Add 25 mL of saturated sodium bicarbonate solution to the solution, and after the temperature of the solution returns to room temperature, extract the organic phase with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and rotary evaporate to obtain 6.63 g of a brown oily solid that is the compound ( Ⅳ), yield 84%. 1 H NMR (CDCl 3 ,500MHz)δ:0~0.2(12H,m,3,7-OSi(t-Bu)Me 2 ), 0.66 (3H, s, 18-...

Embodiment 3

[0062] Embodiment 3, the synthesis of 3α-hydroxyl-6-ethylene-7-ketone-5β-cholanic acid-24-methyl ester (Ⅴ)

[0063] Take 12.7g (23.2mmol) of compound (Ⅳ) and dichloromethane (20mL) in a 150mL single-necked round bottom flask, cool down to -30°C, add 1.7mL (0.121mol) of paraldehyde and keep stirring, slowly drop Add 2.2mL (0.09mol) boron trifluoride diethyl ether, react for 1h under stirring, and then heat up to 0°C. Then add 20mL of dichloromethane to the solution, stir overnight, after TLC detects that the reaction is complete, add 6.5g (25mmol) tetrabutylammonium fluoride to the solution, after stirring for 1h, add 50mL of saturated sodium bicarbonate solution to the solution and then statically Place, extract the organic phase with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, distill under reduced pressure, and separate by flash column chromatography (petroleum ether: ethyl acetate = 7:3, v / v) to obtain a white solid 6.7 g is the compound ...

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Abstract

The invention discloses a synthetic method of 6-ethylchenodeoxycholic acid. The synthetic method comprises steps as follows: chenodeoxycholic acid and an oxidizing agent are subjected to an oxidizing reaction and an esterification reaction, and a compound with a structure represented as a formula III is prepared; hydroxyl and carbonyl on rings of the compound with the structure represented as the formula III are protected with tert-butyldimethylsilyl chloride, and a compound with a structure represented as a formula IV is obtained; the compound with the structure represented as the formula IV and paraldehydeare are subjected to an electrophilic addition reaction and then are subjected to deprotection, and a compound with a structure represented as a formula V is obtained; the compound with the structure represented as the formula V is subjected to catalytic hydrogenation and is subjected to reduction and hydrolysis finally, and the compound 6-ethylchenodeoxycholic acid with a structure represented as a formula VI is obtained. The method is simple and convenient to operate, adopts mild conditions, has higher yield and is suitable for being popularized to industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis process of obeticholic acid (6-ethylchenodeoxycholic acid). Background technique [0002] Liver cirrhosis is a common clinical chronic progressive liver disease, which is diffuse liver damage caused by long-term or repeated effects of one or more etiologies. Nonalcoholic fatty liver disease is a new challenge in the field of contemporary medicine, and the harm of nonalcoholic fatty liver disease to human health will continue to increase in the near future. Obeticholic acid is a farnesoid X receptor agonist, which indirectly inhibits the gene expression of cytochrome 7A1 (CYP7A1) by activating farnesoid X receptor. Since CYP7A1 is the rate-limiting enzyme of bile acid biosynthesis, obeticholic acid can promote bile acid synthesis for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. [0003] At present, obeticholic acid is stil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 姚绎炎杜杨
Owner NANJING UNIV OF SCI & TECH
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