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Preparing method for tauro ursodesoxy cholic acid

A technology of tauroursodeoxycholic acid and ursodeoxycholic acid, which is applied in the field of preparation of tauroursodeoxycholic acid, can solve the problems of inapplicability to industrial production, low purity of crude products, inconvenient use, etc., and achieve The effect of low cost, simple operation and post-processing, and increased controllability

Active Publication Date: 2016-02-17
HANGZHOU HEZE PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the chloroformic esters used in this method are chemical control products or highly toxic substances, which are inconvenient to use and difficult to store; meanwhile, the intermediates are active acid anhydrides, which have strong reactivity, many side reactions, and the crude product is not high in purity.
[0007] In summary, in the existing synthetic process of tauroursodeoxycholic acid, due to the many side reactions of the synthetic method and the low purity of the crude product, the isomer impurity taurochenodeoxycholic acid is mostly not effectively controlled, even if Effective control is carried out, but other controlled products or highly toxic substances are also introduced during the synthesis process, which is not suitable for industrial production

Method used

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  • Preparing method for tauro ursodesoxy cholic acid
  • Preparing method for tauro ursodesoxy cholic acid
  • Preparing method for tauro ursodesoxy cholic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Preparation of Taurate Complex

[0041] At room temperature, dissolve 100.00 g (0.61 mol) of potassium taurine in water, then add complexing agent 18-crown-6161.92 g, and stir to dissolve. The above clear liquid was concentrated at 60°C to obtain 260.59 g of potassium taurate 18-crown-6 complex as a white solid.

Embodiment 2

[0043] Preparation of Taurate Complex

[0044] At room temperature, dissolve 100.00 g (0.68 mol) of sodium taurine in water, then add complexing agent 15-crown-5149.53 g, and stir to dissolve. The above clear liquid was concentrated at 60°C to obtain 248.52 g of sodium taurate 15-crown-5 complex as a white solid.

Embodiment 3

[0046] Preparation of Tauroursodeoxycholic Acid

[0047] At room temperature, add 10.0 g (25.4 mmol) of ursodeoxycholic acid and 2.39 g (25.4 mmol) of phenol into 100 mL of dichloromethane, stir and cool down to 10-20°C. Add 5.25g (25.4mmol) of N,N'-dicyclohexylcarbodiimide solution in dichloromethane dropwise. After the dropwise addition, react at 5-20°C for 2 hours, filter to remove insoluble matter, and concentrate the filtrate to obtain a light yellow oil The product was 11.45g, and the yield was 96.0%.

[0048] The above oil was recrystallized from acetonitrile to obtain a white sticky substance, which was directly used in the next reaction.

[0049] At room temperature, 15.68 g (36.7 mmol) of potassium taurate 18-crown-6 complex and the above-mentioned oily substance were added to dichloromethane, and stirred. After reacting at room temperature for 5 hours, TLC (ethyl acetate:petroleum ether=1:1) monitored that the reaction was complete. Add 0.19 g of glacial acetic aci...

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Abstract

The invention discloses a preparing method for tauro ursodesoxy cholic acid. The method comprises the following steps that firstly, ursodesoxycholic acid and a phenolic compound are added into a chloralkane organic solvent at the room temperature, the temperature is lowered to 10-20 DEG C, a condensing agent is added, thorough reaction is carried out under the temperature of 5-45 DEG C in a heat preservation mode after dripping is completed, filter liquor is concentrated after filtering to obtain a crude product, and the crude product is recrystallized to obtain a ursodesoxycholic acid phenolic ester refined product; secondly, taurine salt and a crown ether complexing agent are added into water to be dissolved, a taurine salt crown ether complex is obtained after concentration, the ursodesoxycholic acid phenolic ester refined product and the taurine salt crown ether complex are added into an organic solvent to be reacted, acid is added after thorough reaction and stirred, solids are separated out and filtered, a filter cake is dissolved in water, stirred and subjected to crystallization, and tauro ursodesoxy cholic acid is obtained. The synthetic method is low in cost, operation is simple and controllable, the product is high in yield and purity, meanwhile, the isomer impurity taurochenodeoxycholic acid of tauro ursodesoxy cholic acid can be well controlled, and the preparing method is suitable for industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical raw material drug and a preparation method thereof, and specifically discloses a preparation method of tauroursodeoxycholic acid. Background technique [0002] The chemical name of tauroursodeoxycholic acid is 2-[[(3α,5β,7β)-3,7-dihydroxy-24-oxocholestan-24-yl]amino]ethanesulfonic acid dihydrate , the structural formula is as follows: . [0003] Tauroursodeoxycholic acid is an active ingredient of natural bear bile, which has a variety of physiological and pharmacological effects, and is mainly used for sterol-induced gallstones, cholestatic liver disease, bile reflux gastritis, etc. Clinical studies have found that compared with ursodeoxycholic acid, tauroursodeoxycholic acid has a faster rate of stone dissolution, improved total dissolution, and no obvious adverse reactions. Due to the limitation of natural resources and animal protection, medicinal tauroursodeoxycholic acid is mainly obtained by chemical...

Claims

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Application Information

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IPC IPC(8): C07J41/00
Inventor 倪晟翁德英陈鸿翔姜维斌赵航周亮华波杨政和
Owner HANGZHOU HEZE PHARMA TECH
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