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A kind of preparation method of obeticholic acid dimer

A technology of obeticholic acid dimer and dimer, which is applied in the field of preparation of obeticholic acid dimer, can solve the problems of many by-products, inability to use impurities for research, and low product purity

Active Publication Date: 2021-06-22
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Two molecules of obeticholic acid are directly reacted in an acidic environment, resulting in many by-products, low product purity, difficult separation, and cannot be used for impurity research

Method used

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  • A kind of preparation method of obeticholic acid dimer
  • A kind of preparation method of obeticholic acid dimer
  • A kind of preparation method of obeticholic acid dimer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Step a: Preparation of benzyl 3α,7α-dihydroxy-6α-ethyl-5β-cholanate (VI)

[0058] At room temperature, add 10.0 g of 3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid (VII), 5.0 g of potassium carbonate and 100 ml of N,N-dimethylformamide into the reaction flask, 6.1 g of benzyl bromide (1.5 eq) was added with stirring, and the reaction was stirred for 10 h. The reaction solution was poured into 100 ml of saturated sodium chloride solution, 100 ml of ethyl acetate was added for extraction, and the organic phase was collected. Wash the organic phase twice with 50ml of 10% sodium chloride aqueous solution, wash once with 50ml of water, add 20g of anhydrous magnesium sulfate to dry for 2h, filter, and concentrate the organic phase to obtain 11.24g of 3α,7α-dihydroxy-6α-ethyl-5β - Benzyl cholanoate (VI), content 96.7%, yield 92.4%.

[0059] Step b: Preparation of 3α,7α-bis-(4-methoxytriphenylmethyl)-6α-ethyl-5β-cholanoic acid benzyl ester (Ⅴ)

[0060] Control the temperature at ...

Embodiment 2

[0070] Step a: Preparation of benzyl 3α,7α-dihydroxy-6α-ethyl-5β-cholanate (VI)

[0071] 10.0 g of 3α, 7α-dihydroxy-6α-ethyl-5β-cholanic acid (VII), 11.2 g of cesium carbonate and 100 ml of acetonitrile were added to the reaction flask, and 6.1 g of benzyl bromide (1.5 eq), the reaction was stirred for 10h. After the reaction solution was concentrated under reduced pressure, 100 ml of saturated sodium chloride solution was added, and extracted with 100 ml of ethyl acetate. Wash the organic phase twice with 50ml of 10% sodium chloride aqueous solution, and once with 50ml of water, add 20g of anhydrous magnesium sulfate to dry for 3h, filter, and concentrate the organic phase to obtain 11.36g of 3α,7α-dihydroxy-6α-ethyl-5β - benzyl cholanoate (VI), content 97.6%, yield 93.4%.

[0072] Step b: Preparation of 3α,7α-bis-(4-methoxytriphenylmethyl)-6α-ethyl-5β-cholanoic acid benzyl ester (Ⅴ)

[0073] Control the temperature at -5~0°C, add 7g of 3α,7α-dihydroxy-6α-ethyl-5β-benzyl c...

Embodiment 3

[0083] Step a: Preparation of benzyl 3α,7α-dihydroxy-6α-ethyl-5β-cholanate (VI)

[0084] Add 10.0 g of 3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid (VII), 5.4 g of DBU and 100 ml of N,N-dimethylformamide into the reaction flask, and add 6.1 g of benzyl bromide (1.5eq), the reaction was stirred for 10h. After the reaction solution was concentrated under reduced pressure, 100 ml of saturated sodium chloride solution was added, and extracted with 100 ml of ethyl acetate. The organic phase was washed twice with 50ml of 10% sodium chloride aqueous solution, washed once with 50ml of water, dried with 20g of anhydrous magnesium sulfate for 2.5h, filtered, and the organic phase was concentrated to obtain 11.31g of 3α,7α-dihydroxy-6α-ethyl- Benzyl 5β-cholanoate (Ⅵ), content 96.9%, yield 93%.

[0085] Step b: Preparation of 3α,7α-bis-(4-methoxytriphenylmethyl)-6α-ethyl-5β-cholanoic acid benzyl ester (Ⅴ)

[0086] Control the temperature at -5~0°C, add 7g of 3α,7α-dihydroxy-6α-ethyl-5β-ch...

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Abstract

The present invention relates to a preparation method of obeticholic acid dimer. The carboxyl group and hydroxyl group of obeticholic acid are protected to obtain benzyl 3α,7α-dihydroxy-6α-ethyl-5β-cholanoate ( Ⅵ) and 3α, 7α-bis-(4-methoxytriphenylmethyl)-6α-ethyl-5β-cholanic acid (IV), and then esterify compounds Ⅳ and Ⅵ under alkaline conditions , and finally remove the protective groups of the hydroxyl group and the carboxyl group in turn to obtain the obeticholic acid dimer (I). The obeticholic acid dimer prepared in the present invention has high purity and can be well used for the research on impurities of obeticholic acid without further purification.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of obeticholic acid dimer. Background technique [0002] Obeticholic acid was developed by Intercept Pharmaceuticals of the United States, and its main indications are primary biliary cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH). Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with a prevalence of 10% to 20%. The etiology is not yet clear. It causes chronic inflammation and leads to liver cirrhosis. There are currently no FDA-approved medications to treat this condition. Ursodeoxycholic acid (UDCA) 13-15mg / kg / d is currently the only drug approved for the treatment of PBC patients, but up to 50% of patients do not respond adequately to it. Now there is an urgent need for a new drug to fill the gap in the treatment of NASH in China and to provide new and effective drugs for PBC patients. [0003] Currently, obeticholic ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 李亚楠赵晶晶王芹芳左明昊冯国龙胡军平朱秀良刘贺钦郭洪茹齐志良刘魏
Owner NCPC NEW DRUG RES & DEV
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