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Preparation method for obeticholic acid

A technology for obeticholic acid and cholanoic acid, which is applied in the field of preparation of obeticholic acid, can solve the problems of low yield, cumbersome process route and the like, and achieves the effects of simple operation, high yield and mild reaction

Inactive Publication Date: 2015-09-23
ZHEJIANG TIANSHUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, obeticholic acid is still in the research and development stage, the process route is cumbersome, and the yield is not high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of Methyl 3α-Hydroxy-7-keto-5β-cholanate

[0026] Add 17kg of 3α-hydroxy-7-keto-5β-cholanic acid and 50kg of methanol into the reaction vessel, add 0.5kg of sulfuric acid to carry out esterification reaction, the reaction temperature is 35-55°C, and react for 2 hours to obtain 3α-hydroxy-7- Keto-5β-cholanoic acid methyl ester, the yield is 85%.

Embodiment 2

[0028] The hydroxyl group is protected with a tetrahydropyranyl ether group

[0029] Add 40kg3,4-dihydro-2H-pyran, 0.5kg p-toluenesulfonic acid, and 8.5kg dioxane to 20kg3α-hydroxyl-7-keto-5β-cholanoic acid methyl ester, and replace the hydroxyl group with tetrahydro Pyranyl ether for protection.

Embodiment 3

[0031] 15kg of the intermediate after the hydroxyl group is protected with a tetrahydropyranyl ether group, 18kg of bromoethane, 0.21kg of lithium diisopropylamide, and 50kg of tetrahydrofuran are added to the reaction vessel, and the diastereomethylated ketone The alpha position of the carbonyl.

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PUM

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Abstract

The invention provides a preparation method for obeticholic acid. The preparation method comprises the following steps of: adding 3alpha-hydroxyl-7-keto-5beta-cholanic acid and methanol into a reaction container and carrying out esterification reaction in an acidic environment to obtain 3alpha-hydroxyl-7-keto-5beta-methyl cholanate; adding 3,4-dihydro-2H-pyran and dioxane and protecting hydroxyl by tetrahydropyrane ether; adding bromoethane, lithium diisopropylamide and site alpha of diastereomeric methylated keto-carbonyl; then adding methanol, removing the protecting group which protects tetrahydropyrane ether and reducing hydroxyl in the acidic environment; adding sodium borohydride and reducing the mixture to 3alpha-hydroxyl-6beta-methyl-7-hydroxyl-5beta-methyl cholanate; and adding methanol and carrying out alkali hydrolysis to obtain 3alpha-hydroxyl-6beta-methyl-7-hydroxyl-5beta-cholanic acid, namely the target product obeticholic acid. According to the preparation method provided by the invention, the process line is mild in reaction, simple to operate and high in yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of obeticholic acid. Background technique [0002] Non-alcoholic fatty liver disease (NAFLD) refers to a clinicopathological syndrome characterized by excessive fat deposition in liver cells caused by alcohol and other definite liver damage factors. It is associated with insulin resistance and genetic Acquired metabolic stress liver injury closely related to susceptibility, including simple fatty liver (SFL), non-alcoholic steatohepatitis (Non-alcoholic steatohepatitis, NASH) and its related cirrhosis (Cirrhosis of Liver). Worldwide, nonalcoholic fatty liver disease (NAFLD) affects 10-24% of the population and has become an epidemic. [0003] Farnesoid X receptor (FR / FXR) is a member of the nuclear receptor superfamily. Farnesoid X receptors are highly expressed in the liver, intestines, kidneys, adrenal glands, etc., and are key regulators of cholesterol ho...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005Y02P20/55
Inventor 张胜
Owner ZHEJIANG TIANSHUN BIOTECH
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