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Preparation method of tauroursodeoxycholic 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 low purity of crude products, many side reactions, and strong reactivity, and achieve operational Simple and post-processing, high product yield and purity, suitable for large-scale industrial production

Inactive Publication Date: 2019-11-22
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.
[0008] 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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  • Preparation method of tauroursodeoxycholic acid
  • Preparation method of tauroursodeoxycholic acid
  • Preparation method of tauroursodeoxycholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Tauroursodeoxycholic Acid

[0039] 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%.

[0040] The above oil was recrystallized from acetonitrile to obtain a white sticky substance, which was directly used in the next reaction.

[0041] 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

[0043] Preparation of Tauroursodeoxycholic Acid

[0044] 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.

[0045]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%.

[0046] The above oil was recrystallized from acetonitrile to obtain a white sticky substance, which was directly used in the next reaction.

[0047] 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,

[0048] The reaction system was cooled to room temperature, filtered and dried t...

Embodiment 3

[0050] Preparation of Tauroursodeoxycholic Acid

[0051] 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.

[0052] 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.

[0053] 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%.

[0054] 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 preparation method of tauroursodeoxycholic acid. A synthesis method comprises the following steps of (1) adding the ursodesoxycholic acid and a phenolic compound into a chloroalkane organic solvent at a room temperature, cooling to 10-20 DEG C, adding a condensing agent, reacting at 5-45 DEG C until the dropwise addition is completed, filtering, concentrating the filtrate to obtain a crude product, and recrystallizing to obtain a refined ursodesoxycholic acid phenolic ester product shown in a formula (II); and (2) at 50-80 DEG C, adding the ursodeoxycholic acid phenolic ester refined product and the taurine salt into an organic alcohol solvent for complete reaction, cooling to the room temperature, filtering, dissolving a filter cake into water, adjusting the pHvalue to 1.0-3.0 with acid, stirring and crystallizing to obtain the tauroursodeoxycholic acid shown as a formula (I). The synthesis method is low in cost, simple and controllable in operation, high in product yield and purity, is capable of well controlling the isomer impurity of taurochenodeoxycholic acid, and is suitable for industrial production.

Description

technical field [0001] This application is a divisional application of "a preparation method of tauroursodeoxycholic acid". The filing date of the original application is December 21, 2015, and the application number of the original application is 201510761902.1. [0002] 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 [0003] 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: . [0004] 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, tauroursod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
Inventor 倪晟陈鸿翔姜维斌赵航周亮华波杨政和
Owner HANGZHOU HEZE PHARMA TECH
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