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Preparation method of mixed anhydride and industrial preparation method of tauroursodeoxycholic acid dihydrate

A technology of oxycholic acid dihydrate and ursodeoxycholic acid, which is applied in the field of tauroursodeoxycholic acid synthesis, can solve the problems affecting the yield and product quality, and easy to generate impurities, so as to achieve recovery and recycling , avoid the generation of impurities, and reduce the use of solvents

Active Publication Date: 2022-05-27
成都百途医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when this method is prepared, impurities are easily produced, which affects the final yield and product quality.

Method used

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  • Preparation method of mixed anhydride and industrial preparation method of tauroursodeoxycholic acid dihydrate
  • Preparation method of mixed anhydride and industrial preparation method of tauroursodeoxycholic acid dihydrate
  • Preparation method of mixed anhydride and industrial preparation method of tauroursodeoxycholic acid dihydrate

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specific Embodiment 1

[0035] This embodiment provides a method for preparing a mixed acid anhydride, including the following steps: using ursodeoxycholic acid and alkyl chloroformate as raw materials to react in an organic solvent to generate a mixed acid anhydride, the key is that the alkyl chloroformate includes chloroformic acid Propyl and / or isopropyl chloroformate; organic solvents include propanol and / or isopropanol.

[0036] The key technical core of the present invention is: using propanol or isopropanol as the organic solvent for reaction, and using UDCA and alkyl chloroformate (formula (1)) as starting materials to prepare UDCA mixed acid anhydride. The prepared mixed acid anhydride is used for alkaline water-soluble reaction with taurine to prepare TUDCA. R in the formula (1) is propyl group or isopropyl group, and the solvent in the mixed anhydride preparation system is corresponding propanol or isopropanol (Table 1); the UDCA mixed anhydride is prepared without further treatment, and c...

specific Embodiment 2

[0043] This embodiment provides a tauroursodeoxycholic acid dihydrate (TUDCA.2H) suitable for industrial production 2 O) production process, emphasizing that ursodeoxycholic acid (Ursodeoxycholic acid, UDCA) is used as the starting material, and propanol or isopropanol, propyl chloroformate or isopropyl chloroformate are used as reagents to prepare UDCA mixed acid anhydride; UDCA The mixed acid anhydride is directly reacted with sodium taurine in water to obtain the crude product of TUDCA. The crude TUDCA product is purified by water+alcohol+acetone system to obtain TUDCA dihydrate. The whole process has mild and controllable reaction, high yield and high product purity (above 99.5%). The solvent recovery is convenient, reducing the pressure on environmental protection.

[0044] TUDCA purification: The obtained crude TUDCA (more than 99%) was purified according to EP1985622A1 and JPH07267985A. The invention is further improved by adding a certain proportion of alcohol to th...

Embodiment 1

[0046] The present embodiment provides an industrialized preparation method of tauroursodeoxycholic acid dihydrate, and the specific steps are as follows:

[0047] Get UDCA 20.0kg, n-propanol 180kg and triethylamine 8kg, add in the 1000L reactor, stir, and be cooled to -10 ℃ (± 2 ℃); Slowly add propyl chloroformate 7kg, dropwise process temperature Must not exceed -5°C. After dripping, the temperature should not exceed -10°C, and the reaction of tracking UDCA was completed. Keeping the temperature, a pre-cooled aqueous solution of taurine sodium hydroxide (containing 7.5 kg of taurine, 2.6 kg of NaOH, and 80 kg of water) was added dropwise. After the dropwise addition was completed, the temperature was raised to 20-25° C. to continue the reaction until the mixed anhydride disappeared. The temperature was raised to 50°C, and the TUDCA oil was obtained by distillation under reduced pressure. Cool to 20°C (±2°C), add 80kg of pure water, stir to dissolve, add concentrated hydro...

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Abstract

The invention discloses a preparation method of mixed anhydride and an industrial preparation method of tauroursodesoxycholic acid dihydrate, ursodesoxycholic acid and alkyl chloroformate are used as raw materials to react in an organic solvent to generate the mixed anhydride, and the alkyl chloroformate comprises propyl chloroformate and / or isopropyl chloroformate; the organic solvent comprises propyl alcohol and / or isopropyl alcohol. Furthermore, the mixed anhydride is prepared by adopting the preparation method of the mixed anhydride; the method comprises the following steps: carrying out alkaline water-soluble reaction on mixed anhydride and taurine to prepare a TUDCA crude product, and refining to obtain high-quality TUDCA dihydrate. The method disclosed by the invention is beneficial to reducing impurities, improving the quality of the TUDCA, reducing the cost and being beneficial to industrial production of the TUDCA.

Description

technical field [0001] The invention relates to the technical field of tauroursodeoxycholic acid synthesis, in particular to a preparation method of a mixed acid anhydride and an industrialized preparation method of tauroursodeoxycholic acid dihydrate. Background technique [0002] Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), which is the main bile acid component in bear bile, and exists in trace amounts in human bile acid. The use of bear bile powder as medicine has a long history in traditional Chinese medicine. Modern medical research shows that TUDCA not only plays an important role in the dissolution of gallstones and liver protection, but also plays an important role in neuroprotection, immune regulation, oxidative stress and metabolism. Physiological and pathological regulation. The single component of TUDCA was launched in Italy in 1992 as a medicine; TUDCA is also widely used in European and American markets as a health...

Claims

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Application Information

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IPC IPC(8): C07J9/00C07J41/00
CPCC07J9/005C07J41/0061Y02P20/55
Inventor 彭宇蒋宁钟丕
Owner 成都百途医药科技有限公司
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