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Synthetic method of tauroursodeoxycholic acid

A technology of tauroursodeoxycholic acid and tauroursodeoxycholic acid, which is applied in the field of synthesis of tauroursodeoxycholic acid, can solve the problems of complex substances, large pollution, high production cost, etc., and achieve good application Prospect, easy industrialization, high purity effect

Inactive Publication Date: 2018-07-20
GUANGZHOU YINGYU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a kind of simple and convenient synthetic method of tauroursodeoxycholic acid raw material drug for the deficiencies in existing raw material drug production technology such as high production cost, large pollution, poor safety, complex related substances, the synthetic method It has the advantages of low cost, high efficiency, simple and controllable process, high purity of the target product, safety, and environmental protection.

Method used

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  • Synthetic method of tauroursodeoxycholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Take 100g of chicken gall paste, add 500mL of water and stir to dissolve, centrifuge, filter, wash the filtrate three times with ethyl acetate (200mL*3), collect the lower layer solution; add 2-3 times of ethanol to the filtrate, centrifuge, filter, and filtrate Concentrate to dryness, add 200ml ethanol, centrifuge, filter, adjust the pH of the filtrate to 2-5 with hydrochloric acid, evaporate to dryness, add pure water to dissolve the concentrate completely, and collect taurine goose with a purity of more than 90% The fraction of deoxycholic acid was concentrated to obtain 10.3 g of the target compound with a purity greater than 90%.

[0026] (2) Dissolve taurochenodeoxycholic acid (10.0 g, 18.4 mmol) in 50 mL of acetone aqueous solution (acetone (V) / water (V) = 4 / 1), and slowly add N in batches after the dissolution is complete. -Bromosuccinimide (5.6g, 30mmol), stirred at room temperature for 4h; sampled on TLC plate, and the reaction was completed after the disa...

Embodiment 2

[0033] (1) The steps are the same as in Example 1 (1).

[0034] (2) Dissolve taurochenodeoxycholic acid (10.0g, 18.4mmol) in 50mL of acetone aqueous solution (acetone (V) / water (V) = 4 / 1), and slowly add hydrogen peroxide in batches after the dissolution is complete (3ml, 30mmol), stirred at room temperature for 4h; sampling TLC plate, until the raw material point disappears to end the reaction, distill off acetone under reduced pressure, extract with ethyl acetate, separate the organic layer, concentrate the aqueous phase to dryness to obtain the crude product, further water / Acetone (1:10 (v:v)) mixed solvent was recrystallized to obtain 7.3 g of 3α-hydroxy-7-carbonyl-cholanoyl-N-taurine.

[0035] (3) The steps are the same as in Example 1 (3).

[0036] (4) The steps are the same as in Example 1 (4).

[0037] (5) The steps are the same as in Example 1 (5).

[0038] (6) The steps are the same as in Example 1 (6).

[0039] (7) The steps are the same as in Example 1 (7).

Embodiment 3

[0041] (1) The steps are the same as in Example 1 (1).

[0042] (2) Dissolve taurochenodeoxycholic acid (10.0g, 18.5mmol) in 50ml of acetone aqueous solution (acetone (V) / water (V)=4 / 1), and slowly add in batches after the dissolution is complete. Chloroperoxybenzoic acid (80%, 6.5g, 30mmol), stirred at room temperature for 4h; sampled on TLC plate, and the reaction was completed after the disappearance of the raw material point, the acetone was evaporated under reduced pressure, extracted with ethyl acetate, the organic layer was separated, and the aqueous phase was Concentrate to dryness to obtain a crude product, which is further recrystallized from a mixed solvent of water / acetone (1:10 (v:v)) to obtain 7.0 g of 3α-hydroxy-7-carbonyl-cholanoyl-N-taurine.

[0043] (3) The steps are the same as in Example 1 (3).

[0044] (4) The steps are the same as in Example 1 (4).

[0045] (5) The steps are the same as in Example 1 (5).

[0046] (6) The steps are the same as in Exampl...

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Abstract

The invention discloses a synthetic method of tauroursodeoxycholic acid. The synthetic method comprises the following steps: taking extracted or synthetic taurochenodeoxycholic acid as a raw material,obtaining a target product tauroursodeoxycholic acid crude product through 7 alpha-hydroxyl selective oxidation, 3 alpha-hydroxyl protection, 7-carbonyl selective oxidation, 7 alpha-hydroxyl sulfonylation, detosylation and alkaline hydrolysis reactions of the taurochenodeoxycholic acid, and finally obtaining the high-purity tauroursodeoxycholic acid through recrystallization purification. The tauroursodeoxycholic acid is obtained by using low-cost poultry bile as the raw material, the traditional steps of hydrolyzing and then condensing combined chenodeoxycholic acid are omitted, and a taurylamine structure is obtained directly; the target configuration product is obtained through selective oxidation, selective reduction and stereoselectivity elimination; in the whole technology, using high alkali, metallic sodium or valuable catalysts is avoided, and the whole technology presents a relatively efficient and safe chemical synthetic route. The technological process has the advantages ofbeing simple and controllable, high in purity, efficient, safe, environmentally-friendly and easy for industrialization, and has good application prospects in the field of pharmacy.

Description

technical field [0001] The invention relates to the field of pharmaceutical raw materials, in particular to a safe and effective method for synthesizing tauroursodeoxycholic acid. Background technique [0002] Tauroursodeoxycholic acid (TUDCA), the chemical name is 3α, 7β-dihydroxy-cholanoyl-N-taurine, which is mainly used clinically to treat gallbladder cholesterol stones, primary sclerosing cholangitis, primary bile Liver cirrhosis and chronic hepatitis C virus, etc., were developed by Italy's Besti Pharmaceuticals in 1991, and were first listed in Italy. The currently reported synthesis method is formed by combining ursodeoxycholic acid and taurine through amide bonds. The key technology difference lies in the use of different condensing agents or the formation of different active intermediates. For example, using ursodeoxycholic acid as a raw material, first form mixed anhydride or active ester with ethyl chloroacetate, and then react with taurine to synthesize taurours...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
CPCC07J41/0061
Inventor 康健
Owner GUANGZHOU YINGYU PHARMA TECH CO LTD
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