CN102911235A - Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material - Google Patents
Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material Download PDFInfo
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- ursodesoxycholic
- chenodiol
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Abstract
The invention relates to a method for producing ursodesoxycholic acid by using chenodeoxycholic acid as a raw material. The method comprises the steps of performing selective oxidation on the chenodeoxycholic acid to obtain 7-O-lithocholic acid; performing selective reduction on the 7-O-lithocholic acid to obtain the ursodesoxycholic acid containing a certain amount of the chenodeoxycholic acid; reacting the obtained ursodesoxycholic acid with a silicified agent to form ursodesoxycholic acid silicide which is insoluble in organic solvents, wherein the chenodeoxycholic acid contained in the ursodesoxycholic acid reacts with the silicified agent to form chenodeoxycholic acid silicide which is soluble in organic solvents; and acidizing and hydrolyzing the obtained ursodesoxycholic acid silicide to obtain a high pure ursodesoxycholic acid product.
Description
Technical field
Ursodesoxycholic acid is important medical material, also is to treat clinically the most widely used medicine of cholesterol type gallbladdergallstonecholetithiasis disease.The present invention relates to take Chenodiol as raw material production high purity ursodesoxycholic acid method.
Background technology
Chenodiol (chenodeoxycholic acid is called for short CDCA) chemistry 3 α by name, 7 alpha-dihydroxy-s-5 β-ursodeoxycholic acid, molecular formula C
24H
40O
4, molecular weight 392.58.From goose bile, to extract first in 1848 to obtain.Chenodiol has the dissolving ability of gallbladdergallstonecholetithiasis and other pharmacy function, since last century the seventies, be used as clinically treating the medicine of gallbladdergallstonecholetithiasis, but its side effect is stronger.Research afterwards finds that aspect the dissolving gallbladdergallstonecholetithiasis, the clinical application effect of the isomers ursodesoxycholic acid of Chenodiol is better, and is free from side effects.At present, aspect the treatment of cholesterol type gallbladdergallstonecholetithiasis disease, ursodesoxycholic acid is the most a kind of medicine of clinical application.
Ursodesoxycholic acid (ursodeoxycholic acid is called for short UDCA) chemistry 3 α by name, 7 beta-dihydroxyies-5 β-ursodeoxycholic acid, molecular formula C
24H
49O
4, molecular weight is 392.58, for white or micro-yellow powder, is soluble in ethanol, glacial acetic acid slightly is dissolved in chloroform, is dissolved in hardly ether and water.Ursodesoxycholic acid is at first to find from Fel Ursi nineteen twenty, and nineteen twenty-seven Shoda separates from Fel Ursi and obtains crystal, and nineteen thirty-seven is determined its chemical structure.
Natural ursodesoxycholic acid derives from Fel Ursi, and along with the demand of clinical application constantly increases, natural ursodesoxycholic acid can not be met the need of market far away.Kill bear and get courage and prohibited by country, therefore, obtain ursodesoxycholic acid by chemical synthesis process and become more and more important.At first, people's success synthesized ursodesoxycholic acid, but this kind method reactions steps is many take cholic acid, Deoxycholic Acid etc. as raw material, complex process, and productive rate is low, is difficult to carry out industrialization scale operation.In recent years, investigators find, take Chenodiol as raw material, carry out chemosynthesis ursodesoxycholic acid technological process and greatly simplify.
Chenodiol is the major ingredient of the poultry bile such as chicken, duck and goose, can directly from the bile of duck, goose and chicken, extract to obtain, and mature production technology, cheap.Take Chenodiol as the raw material production ursodesoxycholic acid, can create obvious economic benefit and social value.This patent report is take the method for Chenodiol as the raw material production ursodesoxycholic acid.The prepared ursodeoxycholic acid product of the inventive method can be used in preparation dissolving gallbladdergallstonecholetithiasis medicine or other medicines intermediate.
Summary of the invention
The present invention relates to take the method for Chenodiol as the raw material production ursodesoxycholic acid.Chenodiol and ursodesoxycholic acid are isomerss, use the methods such as common recrystallization, chromatographic separation and they can't be separated.The method that Chenodiol is converted into ursodesoxycholic acid comprises that the selective oxidation of A. Chenodiol is the 7-O-lithocholic acid; B.7-O-lithocholic acid is reduced to ursodesoxycholic acid; C. three steps of ursodeoxycholic acid treating.In the Chenodiol selective oxidation step, the weak oxidants such as application NBS can be converted into Chenodiol the lithocholic acid into 7-O-fully; In the 7-O-lithocholic acid reduction step, do not have reductive agent the 7-O-lithocholic acid can be converted into ursodesoxycholic acid fully, always contain 10%～40% Chenodiol in the ursodeoxycholic acid product that reduction obtains.In order to remove the Chenodiol in the ursodesoxycholic acid, the purification process of usually using is difficult to realize.We find containing silicon derivative and can generating of some ursodesoxycholic acids and Chenodiol under identical condition, also be hydrolyzed under acidity or alkaline condition easily and slough, and their solubleness in many organic solvents has than big difference.Therefore, use this character and can remove Chenodiol in the ursodesoxycholic acid.
The ursodesoxycholic acid that the present invention relates to and Chenodiol contain silicon derivative suc as formula (X in the formula can be the alkyl that contains 1～6 carbon atom shown in (1), aromatic alkyl etc., R can be the alkyl etc. that contains 1～5 carbon atom), can in organic solvent, obtain with suitable silication agent reaction by ursodesoxycholic acid and Chenodiol.The silication agent of using here can be that two replacements or trisubstituted alkyl silicon halogenide, two replace or trisubstituted silicon urea or dialkyl group silicon acid amides etc.
The organic solvent of using in the reaction process can be benzene, toluene, oil of mirbane, chloroform, methylene dichloride, tetracol phenixin, tetrahydrofuran (THF) etc.
Formula (1)
Ursodesoxycholic acid shown in the formula (1) contains silicon derivative can separate out with precipitation forms in organic solvent, obtains by filtration.And that the Chenodiol shown in the formula (1) contains silicon derivative solubleness in organic solvent is larger, can not separate out from solution, thereby separates with ursodesoxycholic acid.
With the ursodesoxycholic acid shown in the formula (1) contain silicon derivative in the aqueous solution with acid-respons, can slough silicon, generate ursodesoxycholic acid.Chenodiol discharges Chenodiol after containing silicon derivative and acid-respons, can reclaim and use.
The implementation step:
The ursodesoxycholic acid 50g that will contain 15%～25% Chenodiol puts into the ethyl acetate of 400mL drying, after stirring, to wherein adding the 50mL trimethylchlorosilane, mixture slowly is heated to boiling, and keep little 1h of boiling, at this moment be cooled to 0 ℃, treat that precipitation does not increase, and filters collecting precipitation.Get ursodesoxycholic acid trimethylchloro-silicane alkane derivatives, m.p.:126 ℃, [α]
D=49.3 ° (1% dioxane).
The ursodesoxycholic acid trimethylchloro-silicane alkane derivatives that obtains is added in the hydrochloric acid soln of 150mL 5%, stirs to get suspension liquid; This suspension liquid is heated to 45～50 ℃, and keeps this temperature 10min., be cooled to 0 ℃; Filter, collecting precipitation washes neutrality with water, and drying is used re-crystallizing in ethyl acetate.M.p.:204～205 ℃, [α]
D=59.8～60.2 ° (1%, ethanol).
Claims (7)
1. one kind take the method for Chenodiol as the raw material production ursodesoxycholic acid.Ursodesoxycholic acid is the medicine that is used for the treatment of clinically gallbladdergallstonecholetithiasis, also is important medical material, is widely used at field of medicaments.
2. claimed in claim 1 take the method for Chenodiol as the raw material production ursodesoxycholic acid, it is characterized in that it comprises the steps: oxidation, reduction, purifying.
3. the oxidation step in take Chenodiol as raw material production ursodesoxycholic acid method claimed in claim 2 is characterised in that, adds weak oxidant in the CDCA acid solution, makes Chenodiol be converted into the 7-O-lithocholic acid.
4. the solvent of dissolving Chenodiol claimed in claim 3 is a certain proportion of acetone/water mixture, and weak oxidant is the N-bromo-succinimide.
It is 5. claimed in claim 2 that reduction step in the synthetic ursodesoxycholic acid method is characterised in that take Chenodiol as raw material, take sec-butyl alcohol as solvent, sodium Metal 99.5 is reductive agent, under reflux state, the 7-O-lithocholic acid is reduced to ursodesoxycholic acid and chenodeoxycholic acid mixture.
It is 6. claimed in claim 2 that purification step in the synthetic ursodesoxycholic acid method is characterised in that take Chenodiol as raw material, with the ursodesoxycholic acid of 5 gained and chenodeoxycholic acid mixture in organic solvent, react with the silication agent under the certain temperature, generate ursodesoxycholic acid silicon ether solid precipitation, with this solid at a certain temperature with acid-respons, obtain the ursodesoxycholic acid sterling.The organic solvent of herein using can be benzene, toluene, oil of mirbane, chloroform, methylene dichloride, tetracol phenixin, tetrahydrofuran (THF) etc.
7. the silication agent described in the ursodesoxycholic acid purification step claimed in claim 6 is that two replacements or trisubstituted alkyl silicon halogenide, two replace or trisubstituted silicon urea or dialkyl group silicon acid amides etc., and the temperature of silicon etherification reaction is that acid is 75～85 ℃; The acid of using in the acidification step is 5% sulfuric acid or 5% hydrochloric acid, and the temperature of acidification reaction is 40～50 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201110217907 CN102911235A (en) | 2011-08-01 | 2011-08-01 | Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material |
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| CN 201110217907 CN102911235A (en) | 2011-08-01 | 2011-08-01 | Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804453A (en) * | 2013-09-30 | 2014-05-21 | 淮北市恒通生物科技有限公司 | Method for preparing ursodesoxycholic acid with pig bile as raw material |
| CN104017043A (en) * | 2014-06-20 | 2014-09-03 | 华东理工大学 | Method for purifying ursodesoxycholic acid by adopting silanization technology |
| CN105503987A (en) * | 2015-12-28 | 2016-04-20 | 成都市新功生物科技有限公司 | Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method |
| CN106928306A (en) * | 2017-03-15 | 2017-07-07 | 眉山市新功生物科技有限公司 | A kind of purification process of urso |
| CN113480589A (en) * | 2021-07-09 | 2021-10-08 | 华东师范大学 | Purification method of ursodeoxycholic acid |
| CN116497081A (en) * | 2023-02-09 | 2023-07-28 | 新沂大江化工有限公司 | Lithocholic acid production process |
-
2011
- 2011-08-01 CN CN 201110217907 patent/CN102911235A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804453A (en) * | 2013-09-30 | 2014-05-21 | 淮北市恒通生物科技有限公司 | Method for preparing ursodesoxycholic acid with pig bile as raw material |
| CN104017043A (en) * | 2014-06-20 | 2014-09-03 | 华东理工大学 | Method for purifying ursodesoxycholic acid by adopting silanization technology |
| CN107915767A (en) * | 2014-06-20 | 2018-04-17 | 华东理工大学 | The method of silyation technigue purifying ursodeoxycholic acid |
| CN105503987A (en) * | 2015-12-28 | 2016-04-20 | 成都市新功生物科技有限公司 | Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method |
| CN105503987B (en) * | 2015-12-28 | 2017-05-31 | 成都市新功生物科技有限公司 | A kind of Activated Carbon with Cu catalytic oxidation-reduction method synthesizes the method for urso with chenodeoxycholic acid |
| CN106928306A (en) * | 2017-03-15 | 2017-07-07 | 眉山市新功生物科技有限公司 | A kind of purification process of urso |
| CN106928306B (en) * | 2017-03-15 | 2018-04-24 | 眉山市新功生物科技有限公司 | A kind of purification process of urso |
| CN113480589A (en) * | 2021-07-09 | 2021-10-08 | 华东师范大学 | Purification method of ursodeoxycholic acid |
| CN113480589B (en) * | 2021-07-09 | 2023-08-25 | 华东师范大学 | Purification method of ursodeoxycholic acid |
| CN116497081A (en) * | 2023-02-09 | 2023-07-28 | 新沂大江化工有限公司 | Lithocholic acid production process |
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Application publication date: 20130206 |