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Preparation method of tauro ursodesoxy cholic acid

A technology for tauroursodeoxycholic acid and ursodeoxycholic acid is applied in the field of preparing tauroursodeoxycholic acid, which can solve problems such as environmental pollution and achieve the effects of cheap materials, short reaction time and improved yield.

Active Publication Date: 2013-07-03
山东天绿制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that raw materials containing sulfur and phosphorus are used, causing environmental pollution

Method used

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  • Preparation method of tauro ursodesoxy cholic acid
  • Preparation method of tauro ursodesoxy cholic acid
  • Preparation method of tauro ursodesoxy cholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation of embodiment 1 tauroursodeoxycholic acid

[0048] Add 39.2 g (0.1 mol) of ursodeoxycholic acid into 100 ml of N,N-dimethylformamide, and stir to dissolve (stir at 150 rpm for 10 minutes). Cool down to 10°C, add 12.66g (0.11mol) of N-hydroxysuccinimide, stir to dissolve (stir at 135rpm for 20 minutes), add 24.76g (0.12mol) of dicyclohexylcarbodiimide and 4-bis 0.12 g (0.001 mol) of methylaminopyridine, after adding all the materials, stirred and reacted at 12° C. for 2.5 hours at a rotation speed of 135 rpm. The content of ursodeoxycholic acid detected by HPLC was less than 0.1%, and the reaction was stopped. Another 12 g (0.12 mol) of taurine was dissolved in 500 ml of aqueous sodium hydroxide (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of sodium taurine. The above dimethylformamide solution was added to the sodium taurine aqueous solution, and 34ml (0.24mol) of triethylamine was added dropwise. After the dropwise add...

Embodiment 2

[0049]The preparation of embodiment 2 tauroursodeoxycholic acid

[0050] 39.2 g (0.1 mol) of ursodeoxycholic acid was added into 100 ml of tetrahydrofuran, stirred and dissolved (stirred at 150 rpm for 10 minutes). Cool down to 0°C, add 12.66g (0.11mol) of N-hydroxyphthalimide, stir to dissolve (stir at 150rpm for 20 minutes), add 15.14g (0.12mol) of diisopropylcarbodiimide and 0.12 g (0.001 mol) of 4-dimethylaminopyridine, after adding all the materials, react at 8° C. for 20 min, the content of ursodeoxycholic acid detected by HPLC is less than 0.1%, and the reaction is stopped. Another 12 g (0.12 mol) of taurine was dissolved in 500 ml of aqueous sodium hydroxide (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of sodium taurine. The above tetrahydrofuran solution was added to the aqueous sodium taurine solution, and 34ml (0.24mol) of triethylamine was added dropwise. After the dropwise addition, the mixture was reacted at 25°C for 2.5 hours a...

Embodiment 3

[0051] The preparation of embodiment 3 tauroursodeoxycholic acid

[0052] Add 39.2 g (0.1 mol) of ursodeoxycholic acid into 100 ml of dimethyl sulfoxide, and stir to dissolve (stir at 150 rpm for 10 minutes). Cool down to 10°C, add 12.66g (0.11mol) of N-hydroxysuccinimide, stir to dissolve (stir at 150rpm for 10), add 1-ethyl-3-(3-dimethylaminopropyl) carbon di 18.62g (0.12mol) of imine and 012g (0.001mol) of 4-dimethylaminopyridine, after adding all the materials, stir and react at 8°C for 20min, the rotation speed is 150rpm, and the content of ursodeoxycholic acid detected by HPLC is less than 0.1% , stop responding. Another 12 g (0.12 mol) of taurine was dissolved in 500 ml of aqueous sodium hydroxide (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of sodium taurine. The above dichloromethane solution was added to the aqueous sodium taurine solution, 34ml (0.24mol) of triethylamine was added dropwise, and the reaction was carried out at 22°C...

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Abstract

The invention discloses a preparation method of tauro ursodesoxy cholic acid. The method comprises the following steps: firstly, dissolving ursodesoxycholic acid in organic solvent, reducing the temperature of the ursodesoxycholic acid to 0 to 10 DEG C, adding amine compounds into the ursodesoxycholic acid, and stirring the ursodesoxycholic acid; secondly, adding condensing agent and 4-dimethylamino pyridine after stirring in the first step, and performing stirring reaction at room temperature, obtaining reaction liquid A; thirdly, adding the reaction liquid A obtained in the second step into sodium taurocholate salt water solution, and dropwise adding triethylamine at room temperature while stirring so as to ensure that the triethylamine is reacted with the reaction liquid A; and fourthly, adding methylene dichloride to perform extraction and liquid separation after the reaction in the third step, then washing a water layer through methylene dichloride, adjusting the pH value after washing, performing concentration after stirring, and then obtaining the tauro ursodesoxy cholic acid. The preparation method has the advantages that the tauro ursodesoxy cholic acid is prepared through a novel technical process, the reaction speed is high, the product quality is high, and raw material is cheap.

Description

technical field [0001] The invention relates to a method for preparing tauroursodeoxycholic acid. Background technique [0002] Tauroursodeoxycholic acid (tauroursodeoxycholic acid) is the active ingredient of bear bile, the chemical name is 2-[[(3α,5β,7β)-3,7-dihydroxy-24-oxocholestan-24-yl ]Amino]ethanesulfonic acid dihydrate, developed by Italy's Besti Pharmaceutical Factory, was first listed in Italy in 1991, and was approved to be sold in China under the trade name taurolite in 2007. Clinically, it is mainly used for the treatment of gallbladder cholesterol stones, primary sclerosing cholangitis, primary biliary cirrhosis and chronic hepatitis C virus. Due to the limitation of natural resources and animal protection, medicinal bezoar ursodeoxycholic acid is mainly obtained by chemical semi-synthesis: [0003] 1. Use ursodeoxycholic acid to react with ethyl chloroformate or pivaloyl chloride to form a mixed anhydride, react with taurine under alkaline conditions, and t...

Claims

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Application Information

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IPC IPC(8): C07J41/00
Inventor 秦笃伟
Owner 山东天绿制药有限公司
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