Ursodeoxycholic acid (3α, 7β-dihydroxy-5β-cholanic acid, UDCA) is a dihydroxy-cholic acid that makes up 3% of the total bile in humans. The name was first isolated from Chinese bear bile by Shoda of Okayama University in Japan。It is a white powder; Odorless, bitter taste. This product is easily soluble in ethanol, but insoluble in chloroform; It is soluble in glacial acetic acid and dissolved in sodium hydroxide test solution. The melting point of this product is 200 ~ 204℃. This product is obtained by rotation ratio, precision weighing, adding anhydrous ethanol to dissolve and quantitative dilution to make a solution containing 40mg per 1ml. According to the law, the specific curl is +59.0 degrees to +62.0 degrees.
There are three generations of bile acids in normal bile, which are the primary bile acids, chenodeoxycholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid.
Chenodeoxycholic acid is a hydrophobic primary bile acid, but cholesterol calculi have a good dissolution effect, but there are adverse reactions to increase ALT, diarrhea and liver toxicity, as the first generation of oral bile acid, due to poor safety, basically has been eliminated.
Ursodeoxycholic acid (UDCA) is the 7-β isomer of goosedeoxycholic acid (the primary bile acid in normal bile), this small difference in structure makes ursodeoxycholic acid hydrophilic.
Ursodeoxycholic acid (UDCA) is the second generation of hydrophilic bile acid, and has the following characteristics :
1. increase the secretion of bile acid, resulting in changes in the composition of bile acid, so that its content in bile is increased, which is beneficial to bile action.
2. can inhibit liver cholesterol synthesis, significantly reduce the amount of cholesterol and cholesterol esters in bile and cholesterol saturation index, which is conducive to the gradual dissolution of cholesterol in stones. UDCA also promotes the formation of liquid cholesterol crystal complexes, which accelerate the excretion and clearance of cholesterol from the gallbladder to the intestine.
3. Relax Oddi sphincter and strengthen gallbladder action.
4. Reduce liver fat, increase liver catalase activity, promote liver glycogen accumulation, and improve liver anti-toxin and detoxification ability; It can also reduce the concentration of triglyceride in the liver and blood.
5. Inhibit the secretion of digestive enzymes and digestive fluid.
6. Foreign studies have also shown that UDCA has an immunomodulatory effect on chronic liver diseases, can significantly reduce the expression of type I human leukocyte histocompatibility antigen (HLA) in hepatocytes, and reduce the number of activated T cells, with good safety and few side effects
Compared with the primary bile acid, ursodeoxycholic acid has the following characteristics:
1. the dissolution effect of ursodeoxycholic acid is faster than CDCA.
2. Unlike CDCA, patient weight is not a predictor of treatment success.
3. The dissolution rate of large stones was higher than that of CDCA.
4. The efficacy was dose-independent.
Tauroursodeoxycholic acid is the third generation bile acid, ursodeoxycholic acid and taurine conjugated, hydrophilicity is stronger than UDCA, faster than UDCA dissolution, total dissolution rate is higher, better safety.
Ursodeoxycholic acid has the following two main production methods:
Method 1.
Anhydrous methanol 36ml was prepared by using andeoxycholic acid as raw material 3α and 7α-diacetylcholic acid methyl ester, adding 1g dry hydrogen chloride gas, adding cholic acid 12g, stirring, heating reflux for 20-30min, leaving at room temperature for several hours, crystallizing, freezing, filtering, washing with ether and drying to obtain methyl cholic acid methyl ester. Take methyl cholic acid 2g, add benzene 9.6ml, pyridine 2.4ml, and acetic anhydride 2.4ml, shake for 10-15min, leave at room temperature for 20h, pour the reaction liquid into 100ml water, remove the benzene layer, wash with distilled water repeatedly, recover the solvent, wash the solid residue with petroleum ether once, recrystallize with methanol-aqueous solution to obtain 3α. 7 alpha-diacetylcholic acid methyl ester. Bile acid to cholic acid methyl ester, 3 alpha, 7 alpha diacetyl cholic acid methyl ester chenodeoxycholic acid system be on the waiting list of diacetyl cholic acid methyl ester, 1.5 g and 24 ml, acetic acid and potassium chromate solution (0.76 g take potassium chromate in 1.8 ml water), heating up to 40 ℃, reaction 8 h, 120 ml of water, vibration wave for a moment, 12 h, filtration, washed with distilled water to neutral, After drying, 3α, 7α-diacetoxy-12-ketocholanate methyl ester, referred to as 12-ketone, was obtained. Take 15g of 12-ketone, add 150ml of diethylene glycol ether, 15ml of 80% hydrazine hydrate solution, 15g of potassium hydroxide hydrohydrate, heating to 30℃ for 15h, heating to 195-200℃, reflux for 2.5h, heating to 217℃ for a moment, cooling to 190℃, adding 0.7ml hydrazine hydrate solution. The temperature was raised from 215℃ to 220℃ within 3h of the chemical store, then cooled, distilled water was added to 600ml, and 10% sulfuric acid was added to adjust pH3, crystallization was precipitated, filtration was done, water was washed to neutral, the water layer was added to ethyl acetate, the water layer was discarded, the organic layer was washed with water 1-2 times, and pressure reduction distillation was carried out to obtain white 3α, 7α-dihydroxycholic acid, that is, goose deoxycholic acid. 3α, 7α-diacetoxy-12-ketocholic acid methyl ester →3α, 7α-diacetoxy-12-ketocholic acid methyl ester →3α, 7α-dihydroxy-cholic acid (channedeoxycholic acid) ursodeoxycholic acid preparation of channedeoxycholic acid 2g, add 100ml acetic acid, add 20g potassium acetate, shake to dissolve, add 1.5g potassium chromate (dissolved in 10ml water), Place at room temperature overnight, add 200ml water, crystallized, filtered, washed, dried to obtain 3α-hydroxy-7-ketocholanic acid. Take 4g of 3α-hydroxy-7-ketocholic acid, add 100ml n-butanol, heat to about 115℃, add 8g sodium metal in batches, and gradually precipitate white slurry, continue to react for 30min, add 120ml water, stir to heat up, dissolve transparent, steam off the organic layer under reduced pressure, add 500ml water, dissolve and filter the residue. The filtrate was added with 10% sulfuric acid to adjust pH3, white flocculent precipitated, filtered, washed to neutral, dried, washed with ethyl acetate, and crystallized with dilute ethanol to obtain 3α, 7β-dihydroxycholic acid, namely ursodeoxycholic acid. Chenodeoxycholic acid [potassium chromate]→ 3α-hydroxy-7-ketocholic acid [Sodium metal, 115℃]→3α, 7β-dihydroxy-cholic acid (ursodeoxycholic acid).
Method 2.
Ursodeoxycholic acid was isolated from pig bile salt or pig bile by thin layer chromatography. The content of free and bound UDCA in pig bile salt is about 30%. The content of binding UDCA in pig bile was about 0.6%.
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