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Method for preparing chenodeoxycholic acid analogue

A technology of cholanic acid and cholanoic acid ester, which is applied in the field of organic synthesis of medicines, and achieves the effects of simple process operation, high yield, and avoiding ultra-low temperature reactions

Active Publication Date: 2016-07-20
YAOPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This method was optimized in patent WO2013192097, but no significant changes

Method used

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  • Method for preparing chenodeoxycholic acid analogue
  • Method for preparing chenodeoxycholic acid analogue
  • Method for preparing chenodeoxycholic acid analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Suspend 4.8g of potassium tert-butoxide (0.043mol) in 50ml of tetrahydrofuran at room temperature, add 16.0g of ethyltriphenylphosphine bromide (0.043mol) under stirring, the reaction solution turns blood red, stir for 30 minutes and then add dropwise A solution of 16.3 g of 3α,7α-dihydroxy-6-keto-5β-cholanoic acid methyl ester (0.040 mol) in 50 ml of tetrahydrofuran was reacted at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction is completed, add 100ml of water and adjust the pH value to 6~7 with 2M hydrochloric acid, add 200ml of ethyl acetate to extract, separate the liquids, and evaporate the solvent under reduced pressure to obtain 18.9g of the oily product 3α, 7α-dihydroxy-6-vinyl- 5β-methyl cholanoate, this product is directly subjected to the next reaction.

[0047]

[0048] 3α,7α-Dihydroxy-6-vinyl-5β-cholanoic acid methyl ester was analyzed by mass spectrometry, H NMR spectrum and carbon spectrum, and the following result...

Embodiment 2

[0053] Dissolve 18.9 g of the oily product obtained in Example 1 in 80 ml of methanol, add 8.0 g of 40% sodium hydroxide solution, heat to 30-40 ° C for about 1 hour, and monitor the reaction by TLC. After the reaction is completed, add 150ml of water and adjust the pH value to 4~5 with 2M hydrochloric acid, a large amount of white precipitates are formed, crystallize at about 10°C for 1 hour, filter, wash the filter cake with 50ml of water, and dry to obtain 3α,7α-dihydroxy - 14.8g of crude product of 6-vinyl-5β-cholanic acid. The resulting crude product was recrystallized with 50 ml of butyl acetate and dried to obtain 13.2 g of white powdery solid 3α, 7α-dihydroxy-6-vinyl-5β-cholanic acid, with an HPLC purity of 96.6%. The starting material 3α,7α- The calculated yield of methyl dihydroxy-6-keto-5β-cholanate was 81.0%.

[0054]

[0055] 3α,7α-dihydroxy-6-vinyl-5β-cholanic acid was analyzed by mass spectrometry, H NMR spectrum and carbon spectrum, and the following result...

Embodiment 3

[0060] Suspend 13.2g of 3α, 7α-dihydroxy-6-vinyl-5β-cholanic acid in 80ml of water, add 15g of 20% sodium hydroxide solution, stir to dissolve, then add 1g of 10% palladium carbon, heat to 80°C, Hydrogen was introduced to react at 3 atmospheres, and the reaction progress was monitored by HPLC. After the reaction is completed, cool down to room temperature, remove the catalyst by filtration, adjust the pH value to 4~5 with 2M hydrochloric acid, a large amount of white precipitates are formed, crystallize at 0°C~5°C for 1 hour, filter, wash the filter cake with 50ml of water, and dry 12.8 g of crude 3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid was obtained. The obtained crude product was recrystallized with 50 ml of butyl acetate and dried to obtain 11.5 g of white powdery solid 3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid, with an HPLC purity of 98.3% and a yield of 87.1%.

[0061]

[0062] 3α,7α-Dihydroxy-6α-ethyl-5β-cholanic acid was analyzed by mass spectrometry, H-NMR and C-N...

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Abstract

The invention discloses a new method for preparing 3 alpha, 7 alpha-dihydroxy-6 alpha-alkyl-5 beta-cholanic acid I and an intermediate thereof. The method requires no low-temperature reaction; reaction conditions are mild; a purification method is simple; and the method of the invention is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a preparation method of chenodeoxycholic acid analogue 3α, 7α-dihydroxy-6α-alkyl-5β-cholanic acid. Background technique [0002] Bile acids are cholesterol dissolvers in the body and emulsifiers of intestinal lipids, and play an important role in the absorption, clearance and transport of hydrophobic compounds in the liver and intestines. Normal bile acid metabolism plays an important role in maintaining the physiological functions of the human body. The metabolism of bile acids in the human body is regulated by many factors. Recent studies have found that farnesoid X receptor (FXR) is the core factor regulating bile acid metabolism. Under the regulation of corresponding ligands, synergistic activators and hormones, FXR precisely regulates various enzymes and bile salt carriers of bile acid metabolism. FXR was discovered as an orphan nuclear receptor in 1995. In rec...

Claims

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Application Information

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IPC IPC(8): C07J9/00
Inventor 李晶成功周浩然张贝陈英杰
Owner YAOPHARMA CO LTD
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