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Novel synthesizing method for preparing ursodesoxycholic acid (UDCA) from chenodeoxycholic acid

The technology of ursodeoxycholic acid and chenodeoxycholic acid is applied in the field of treating gallstones and preparing liver-protecting drugs, and can solve the problems of poor stereoselectivity and the like

Active Publication Date: 2012-10-24
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, most of them use alcohol + metal sodium system for hydrogenation reduction reaction. This system has poor stereoselectivity during hydrogenation reduction reaction. Only about 80% of 7-ketodeoxycholic acid is reduced to ursodeoxycholic acid. In addition, 20% is reduced to chenodeoxycholic acid. After the reaction is completed, it needs to be separated and purified. The final ursodeoxycholic acid product is only about 60% of chenodeoxycholic acid.

Method used

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  • Novel synthesizing method for preparing ursodesoxycholic acid (UDCA) from chenodeoxycholic acid
  • Novel synthesizing method for preparing ursodesoxycholic acid (UDCA) from chenodeoxycholic acid

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Experimental program
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Effect test

Embodiment 1

[0011] Synthesis of methyl chenodeoxycholic acid

[0012] Dissolve chenodeoxycholic acid (39.2g, 0.1mol) in 100ml of methanol, add 1ml of concentrated sulfuric acid, heat and reflux and stir for 10h, after the reaction is complete, after concentration, add 200ml of ethyl acetate and 100ml of water, adjust with saturated potassium carbonate solution pH to neutral, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure, and recrystallized to obtain 37.2 g of a white solid, with a yield of 91.6%; mp: 156-157 °C; NMR (CDCl 3 300MHz) δppm 0.63(3H,s,C-18Me),0.94(3H,s,C-19Me),3.66(3H,s,COOMe),3.65(2H,brm,C-3 and C-7 C H OH) The rest are cholic acid mother nucleus peaks.

Embodiment 2

[0014] Synthesis of 3-ethylcarbonate-chenodeoxycholic acid methyl ester

[0015] Methyl chenodeoxycholic acid (20.3g, 0.05mol), 20ml of dichloromethane, 6ml of pyridine, 6g of ethyl chloroformate was added dropwise at 0-5°C, stirred at room temperature for 2h, diluted with water, extracted with dichloromethane, The organic layers were combined, washed successively with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain 17.6 g of an off-white solid with a yield of 73.6%; mp136-137°C; NMR (CDCl 3 300MHz) δppm: 0.66(3H,s,C-18Me),0.91(3H,s,C-19Me)1.28(3H,t,OCOCH 2 C H 3 )3.64(3H,s,COOMe)3.82(1H,m,C-7CHOH),4.14(2H,q,OCOC H 2 CH 3 ),4.44(1H,brm,C-3 CH OCOCH 2 CH 3 ) and the rest are cholic acid mother nucleus peaks.

Embodiment 3

[0017] Synthesis of 3-ethylcarbonate-7-methanesulfonate-chenodeoxycholic acid methyl ester

[0018] 3-Ethyl carbonate-chenodeoxycholic acid methyl ester (4.78g, 0.01mol) was dissolved in 5ml of pyridine, and methanesulfonyl chloride (8g, 0.011mol) was slowly added dropwise at room temperature, stirred overnight, and after the reaction was completed, pour In ice water, extract twice with 50ml dichloromethane, combine the organic layers, wash with 10% hydrochloric acid, 5% sodium bicarbonate solution, and water successively, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure to dryness, and recrystallize to obtain prism 4.6g of needle-like crystals, yield 82.7%, mp107-108°C; NMR (CDCl 3 300MHz) δppm: 0.67 (3H, s, C-18Me), 0.94 (3H, s, C-19Me), 1.33 (3H, t, OCOCH2C H 3 ),3.04(3H,s,SO 2 Me), 3.61 (3H, s, COOMe), 4.17 (2H, q, OCOC H 2 CH 3 ),4.43(1H,brm,C-3 CH OCOEt), 4.89 (1H,brm,C-7 CH OSO 2 CH 3 ) and the rest are cholic acid mother nucleus ...

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Abstract

The invention relates to a novel method for preparing UDCA from chenodeoxycholic acid. The method includes taking the chenodeoxycholic acid as a raw material, performing protection on carboxyl and selective protection on 3-carboxyl, then subjecting carboxyl at position 7 to a reaction through Mitsunobu or producing ester from paratoluensulfonyl chloride, methanesulfonyl chloride and paranitrobenzenesulfonyl chloride, and stripping off a protecting group to prepare the UDCA. Compared with other processes, the method has the advantages of being mild in reaction condition, simple in operation, high in efficiency, yield and optical purity and the like, and provided with a bright industrial production prospect.

Description

1. Technical field [0001] The invention relates to a preparation method of a drug for treating gallstones and protecting the liver, and a new synthesis method for preparing ursodeoxycholic acid from chenodeoxycholic acid. 2. Background technology [0002] The chemical name of ursodeoxycholic acid is: 3a,7β-dihydroxy-5β-cholestane-24-acid, which has the same molecular formula as chenodeoxycholic acid and bovine cholic acid, but different three-dimensional structures. The structural relationship of two compounds is called isomers. This product is white crystalline powder, odorless, bitter taste. Soluble in ethanol, glacial acetic acid, dilute lye, slightly soluble in ether, insoluble in water and dilute mineral acid, melting point 203 ° C, ursodeoxycholic acid (UDCA) is a non-toxic hydrophilic bile acid, can compete with It can selectively inhibit the absorption of toxic endogenous bile acid in the ileum, activate the signaling network composed of calcium ions and protein ki...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCY02P20/55
Inventor 何勇陈仕云余三喜高永好江浩方宗华吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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