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Method for preparing 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 many side reactions, low purity of the crude product, strong reactivity, etc., and achieve the product High yield and purity, simple operation and post-treatment, suitable for large-scale industrial production

Inactive Publication Date: 2016-02-03
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 low purity of the crude product.
[0007] In summary, in the existing synthesis process of tauroursodeoxycholic acid, due to the many side reactions of the synthesis method and the low purity of the crude product, most of them failed to effectively control the isomer impurity taurochenodeoxycholic acid; Or it is necessary to introduce controlled products or highly toxic drugs during the synthesis process to achieve effective control of the isomer impurity taurochenodeoxycholic acid, but it is not suitable for industrial production

Method used

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  • Method for preparing tauro ursodesoxy cholic acid
  • Method for preparing tauro ursodesoxy cholic acid
  • Method for preparing tauro ursodesoxy cholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of Tauroursodeoxycholic Acid

[0038] At room temperature, add 20.0 g (50.9 mmol) of ursodeoxycholic acid and 4.79 g (50.9 mmol) of phenol into 100 mL of dichloromethane, stir and cool down to 10-20°C. Slowly add the dichloromethane solution of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine dropwise, after the dropwise addition, react at 30-45°C for 2 hours, filter to remove insoluble matter, and concentrate the filtrate Obtained 22.68 g of light yellow oily substance, yield 95.0%.

[0039] The above oil was recrystallized from acetonitrile to obtain a white sticky substance, which was directly used in the next reaction.

[0040] At room temperature, 12.55 g (76.4 mmol) of potassium taurate and the above oil were added to n-butanol and stirred. After heating to 80°C and keeping it warm for 6 hours, TLC (ethyl acetate:petroleum ether=1:1) monitored that the reaction was complete. The reaction system was cooled to room temperature, filtered and d...

Embodiment 2

[0042] Preparation of Tauroursodeoxycholic Acid

[0043] At room temperature, 10.0 g (25.4 mmol) of ursodeoxycholic acid and 3.90 g (28.0 mmol) of p-nitrophenol were added to 80 mL of dichloromethane, stirred and cooled to 15°C.

[0044] At 10-20°C, slowly add the dichloromethane solution of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine dropwise, after the addition is complete, react at 5-20°C for 2 hours, then filter. The insoluble matter was removed, and the filtrate was concentrated to obtain 12.03 g of a light yellow oil, with a yield of 92.0%.

[0045] The above oil was recrystallized from acetonitrile to obtain a white sticky substance, which was directly used in the next reaction.

[0046] At room temperature, 6.28 g (38.2 mmol) of potassium taurate and the above-mentioned oil were added to n-butanol, and stirred. After heating to 80°C and keeping the temperature for 6 hours,

[0047] The reaction system was cooled to room temperature, filtered and dried to...

Embodiment 3

[0049] Preparation of Tauroursodeoxycholic Acid

[0050] At room temperature, 50.0 g (127.4 mmol) of ursodeoxycholic acid and 21.04 g (140.1 mmol) of 4-hydroxypropiophenone were added to 200 mL of dichloromethane, stirred and cooled to 15°C.

[0051] At 10-20°C, slowly add the dichloromethane solution of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine dropwise, after the addition is complete, react at 30-45°C for 2 hours, then filter. Insoluble matter was removed, and the filtrate was concentrated to obtain 65.63 g of light yellow oil.

[0052] The above oil was added into acetonitrile for recrystallization to obtain 65.03 g of white solid tauroursodeoxycholic acid 4-propionylphenol ester, with a yield of 97.3% and a purity of 99.6%.

[0053] At room temperature, 30.53 g (0.19 mol) of potassium taurate and the above-mentioned white solid were added to n-butanol and stirred. After heating to 80°C and keeping it warm for 6 hours, the reaction system was cooled to roo...

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Abstract

The invention discloses a method for preparing tauro ursodesoxy cholic acid. The synthetic method comprises the following steps: a step (1) of adding ursodeoxycholic acid and phenolic compounds into chloralkane organic solvent at room temperature, performing cooling to 10-20 DEG C, adding a condensing agent; after the condensing agent is added dropwise, reacting completely at 5-45 DEG C, performing filtration and then concentrating filtrate to obtain a crude product, performing recrystallization and then obtaining high-finished product ursodesoxycholic acid phenolic ester as shown in a formula (II); a step (2) of adding the high-finished product ursodesoxycholic acid phenolic ester and taurine salt into an organic alcohol solvent to undergo the reaction completely, lowering the temperature to room temperature and then performing filtration, dissolving filter cake in water, using acid to adjust the pH to 1.0-3.0, and performing stirring and crystallization to obtain tauro ursodesoxy cholic acid as shown in a formula (I). The synthetic method is low cost, simple to operate, controllable and high in product yield and purity, an isomer impurity taurochenodeoxycholic acid of tauro ursodesoxy cholic acid can be controlled well, and the 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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Patent Type & Authority Applications(China)
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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