CN104017043A - Method for purifying ursodesoxycholic acid by adopting silanization technology - Google Patents
Method for purifying ursodesoxycholic acid by adopting silanization technology Download PDFInfo
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- CN104017043A CN104017043A CN201410279478.2A CN201410279478A CN104017043A CN 104017043 A CN104017043 A CN 104017043A CN 201410279478 A CN201410279478 A CN 201410279478A CN 104017043 A CN104017043 A CN 104017043A
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- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The invention provides a method for purifying ursodesoxycholic acid by adopting a silanization technology. The method is characterized by comprising the following steps: 1, dissolving a mixture containing ursodesoxycholic acid in an organic solvent, adding a silanization reagent at 25-80 DEG C, and reacting to prepare a liquid containing ursodesoxycholic acid silanization derivatives, wherein R is alkyl with 1-5 carbon atoms and X is alkyl with 1-6 carbon atoms; 2, cooling the liquid containing the ursodesoxycholic acid silanization derivatives at 0-5 DEG C, crystallizing and separating to obtain the ursodesoxycholic acid silanization derivatives; and 3, adding the ursodesoxycholic acid silanization derivatives into inorganic acid, stirring, performing acid hydrolysis at 40-60 DEG C, and separating and drying to obtain pure ursodesoxycholic acid. According to the method, the reagent consumption is low, the selectivity is high, and obtained ursodesoxycholic acid is high in purity.
Description
Technical field
The present invention relates to medicine separation field, more specifically, relate to the separation purification method of ursodesoxycholic acid, particularly a kind of method of silyation technigue purifying ursodeoxycholic acid.
Background technology
Ursodesoxycholic acid (Ursodeoxycholic acid, UDCA, 3 α, 7 beta-dihydroxyl-5 β-cholestane-24-acid), is the main effective constituent of rare Chinese medicine bear gall, is unique medicine for the treatment of primary biliary cirrhosis (PBC).Clinical application both at home and abroad proves, ursodesoxycholic acid, at treatment various courage diseases, hepatopathy and various hyperlipidaemic conditions, is especially having good curative effect aspect dissolving cholesterol type gallbladdergallstonecholetithiasis; find again in recent years the curative effect that some are new; as cytoprotection, immunoregulation effect, antitumous effect etc.
In view of the importance of ursodesoxycholic acid, the demand of its clinical application constantly increases.But natural ursodesoxycholic acid derives from bile, the bear that kills is in the past got courage and present live body drainage, and not only source is few, and violates protection of animal principle.Therefore, synthetic ursodesoxycholic acid, and it is most important to extract highly purified ursodesoxycholic acid.(electroreduction is prepared the method for ursodesoxycholic acid to another patented product of research department, publication number CN102660755A) develop electroreduction 7-Ketolithocholsaeure (7-Ketolithocholic acid, 7K-LCA, 3 Alpha-hydroxies-7-oxygen-5 β-ursodeoxycholic acid) prepare the green synthesis method of ursodesoxycholic acid, in the electroreduction product that wherein obtained except ursodesoxycholic acid, also has raw material 7-Ketolithocholsaeure, and by product Chenodiol (Chenodeoxycholic acid, CDCA, 3 α, 7 alpha-dihydroxy--5 β-cholestane-24-acid).
At present, industrial employing organic solvent optionally dissolves away the impurity such as Chenodiol from the cholic acid mixture that contains ursodesoxycholic acid.Ethyl acetate, chloroform and ether etc. can optionally dissolve Chenodiol.But because both solubleness in above-mentioned solvent are all little, need to use a large amount of organic solvents, solvent recuperation power consumption is huge.Although the organic solvent such as ethanol, acetic acid is all larger to the solubleness of these two kinds of cholic acid, lacks selectivity, be also not suitable for industrial production.
So a kind of reagent consumption is few, selectivity is high, and the method for the purifying ursodeoxycholic acid that the ursodesoxycholic acid purity that obtains is high extremely has practical value.
Summary of the invention
Object of the present invention is exactly the problems and shortcomings for above existence, and the method for the silyation technigue purifying ursodeoxycholic acid that a kind of reagent consumption is few, selectivity is high, obtain ursodesoxycholic acid purity is high is provided.
To achieve these goals, the invention provides a kind of method of alkanisation technology purifying ursodeoxycholic acid, be characterized in, comprise the following steps:
Step 1: the mixture that contains ursodesoxycholic acid (A) is dissolved in organic solvent, adds silylating reagent to react at 25～80 DEG C, reaction formula is as follows, makes the solution that contains ursodesoxycholic acid Silylation thing (B),
Wherein, R is the alkyl that contains 1～5 carbon atom, and X is the alkyl that contains 1～6 carbon atom;
Step 2: the cooling described solution that contains ursodesoxycholic acid Silylation thing (B) at 0～5 DEG C, makes to obtain ursodesoxycholic acid Silylation thing (B) after its Crystallization Separation;
Step 3: described ursodesoxycholic acid Silylation thing (B) is added to mineral acid, stir, carry out acid hydrolysis at 40～60 DEG C, reaction formula is as follows, obtains ursodesoxycholic acid sterling (C) after separation is dry.
Preferably, the described mixture that contains ursodesoxycholic acid (A) is electroreduction 7-Ketolithocholsaeure product.The derivant structure formula that its reaction generates is as follows:
Preferably, the ursodeoxycholic acid content described in the described mixture that contains ursodesoxycholic acid (A) is 20～70wt%.Preferably, described organic solvent is aromatic hydrocarbon or chloride aliphatic category hydrocarbon.
More preferably, described aromatic hydrocarbon is at least one in benzene, toluene, nitrile, ester class, amides and their derivative;
Described chloride aliphatic category hydrocarbon is trichloromethane, methylene dichloride, tetracol phenixin, and at least one in aliphatics and aromatic ketone, as acetone, methyl iso-butyl ketone (MIBK) etc.
Preferably, described silylating reagent is that two substituted alkyl silicon halogenide, three substituted alkyl silicon halogenide, two replace silicon urea, three at least one that replace in silicon urea and dialkyl group silicon acid amides.
More preferably, no more than 5 of carbon atom in described silylating reagent alkyl.
Preferably, described mineral acid is at least one in 5% sulfuric acid, 5% hydrochloric acid and 5% phosphoric acid.
Preferably, described ursodesoxycholic acid sterling (C) purity is higher than 99.0%.
The beneficial effect of above-mentioned purification process is: on the basis that is ursodesoxycholic acid at electroreduction 7-Ketolithocholsaeure product, realize the isolation and purification of ursodesoxycholic acid, reagent consumption is few, and selectivity is high, and the ursodesoxycholic acid purity obtaining is high, can reach more than 99%.
Ursodeoxycholic acid derivative can be in organic solvent crystallization, and large polycomponent in the electroreduction 7-Ketolithocholsaeure product solubleness in organic solvent is larger, uncrystallizable separating out, thereby ursodesoxycholic acid derivatives selectively is separated efficiently.
The ursodeoxycholic acid derivative of gained, through acid hydrolysis, is sloughed to the silicon ether on molecule, regenerate ursodesoxycholic acid, after suction filtration separates, dry, just can obtain highly purified ursodesoxycholic acid.
Brief description of the drawings
Fig. 1 is the content schematic diagram of the front ursodesoxycholic acid of purifying in ursodeoxycholic acid crude in the embodiment of the present invention.
Fig. 2 is the content schematic diagram of ursodesoxycholic acid after purifying in the embodiment of the present invention.
Embodiment
In order more clearly to understand technology contents of the present invention, describe in detail especially exemplified by following examples by reference to the accompanying drawings.
Embodiment 1
Fig. 1 is the content schematic diagram of the front ursodesoxycholic acid of purifying in ursodeoxycholic acid crude in the embodiment of the present invention.As shown in Figure 1,10g is contained to 40% ursodesoxycholic acid dissolving crude product in 100ml acetonitrile, stirring and dissolving, and be warming up to 80 DEG C, add 15g hexamethyl two silicon ureas, react after two hours, be cooled to 0 DEG C, crystallization, suction filtration after 24h, and with appropriate acetonitrile flushing solid, obtain ursodesoxycholic acid Trimethylsilyl. derivative, m.p.124 DEG C; [α] D+49.4 ° (1% dioxane).
Fig. 2 is the content schematic diagram of ursodesoxycholic acid after purifying in the embodiment of the present invention.Above-mentioned ursodesoxycholic acid Trimethylsilyl. derivative adds in 100ml5% sulfuric acid, stir and be warming up to 50 DEG C, reaction 30min, be cooled to 0 DEG C, suction filtration, deionized water rinsing falls residual acid solution, collect dry, re-crystallizing in ethyl acetate, m.p.204 DEG C, [α] D+60.1 ° (1% ethanol).Obtain the ursodesoxycholic acid sterling shown in Fig. 2.
Embodiment 2
10g contains 40% ursodesoxycholic acid dissolving crude product in 100ml DMF, stirring and dissolving, and be warming up to 80 DEG C, add 20g hexamethyldisilazane, react after two hours, be cooled to 0 DEG C, crystallization, suction filtration after 24h, and rinse solid with appropriate DMF, obtain ursodesoxycholic acid Trimethylsilyl. derivative, m.p.126 DEG C; [α] D+49.3 ° (1% dioxane).
Above-mentioned ursodesoxycholic acid Trimethylsilyl. derivative adds in 100ml5% hydrochloric acid, stir and be warming up to 50 DEG C, reaction 30min, be cooled to 0 DEG C, suction filtration, deionized water rinsing falls residual acid solution, collect dry, re-crystallizing in ethyl acetate, m.p.203 DEG C, [α] D+61.0 ° of (1% ethanol) ursodesoxycholic acid sterling.
Embodiment 3
10g contains 40% ursodesoxycholic acid dissolving crude product in 100ml ethyl acetate, and stirring and dissolving, adds after 2.5g triethylamine, then adds 7.5g N, the two trimethylsilyl ethanamides of O-, react after five hours at 30 DEG C, are cooled to 0 DEG C, crystallization, suction filtration, ethyl acetate rinse, obtains Silylation thing.Subsequent step, with embodiment 1, obtains the ursodesoxycholic acid after purifying.
Embodiment 4
10g contains 40% ursodesoxycholic acid dissolving crude product in 80ml ethyl acetate, and stirring and dissolving adds after 5ml trimethylchlorosilane and 5ml hexamethyldisilazane, stirs and be warming up to 80 DEG C, react after one hour, be cooled to 0 DEG C, crystallization, suction filtration, ethyl acetate rinse, obtains Silylation thing.Use 5% phosphoric acid to be hydrolyzed, other subsequent steps, with embodiment 1, obtain the ursodesoxycholic acid after purifying.
The beneficial effect of the embodiment of the present invention is: reagent consumption is few, and selectivity is high, and the ursodesoxycholic acid purity obtaining is high, can reach more than 99%.
Ursodeoxycholic acid derivative can be in organic solvent crystallization, and the solubleness of the large polycomponent of electroreduction 7-Ketolithocholsaeure product in organic solvent is larger, uncrystallizable separating out, thereby ursodesoxycholic acid derivatives selectively is separated efficiently.
The ursodeoxycholic acid derivative of gained, through acid hydrolysis, is sloughed to the silicon ether on molecule, regenerate ursodesoxycholic acid, after suction filtration separates, dry, just can obtain highly purified ursodesoxycholic acid.
In this specification sheets, the present invention is described with reference to its specific embodiment.But, still can make various amendments and conversion obviously and not deviate from the spirit and scope of the present invention.Therefore, specification sheets is regarded in an illustrative, rather than a restrictive.
Claims (9)
1. a method for silyation technigue purifying ursodeoxycholic acid, is characterized in that, comprises the following steps:
Step 1: the mixture that contains ursodesoxycholic acid (A) is dissolved in organic solvent, adds silylating reagent to react at 25～80 DEG C, reaction formula is as follows, makes the solution that contains ursodesoxycholic acid Silylation thing (B),
Wherein, R is the alkyl that contains 1～5 carbon atom, and X is the alkyl that contains 1～6 carbon atom;
Step 2: the cooling described solution that contains ursodesoxycholic acid Silylation thing (B) at 0～5 DEG C, makes to separate and obtain ursodesoxycholic acid Silylation thing (B) after its crystallization;
Step 3: described ursodesoxycholic acid Silylation thing (B) is added to mineral acid, stir, carry out acid hydrolysis at 40～60 DEG C, reaction formula is as follows, obtains ursodesoxycholic acid sterling (C) after separation is dry.
2. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, is characterized in that, the described mixture that contains ursodesoxycholic acid (A) is electroreduction 7-Ketolithocholsaeure product.
3. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, is characterized in that, the ursodeoxycholic acid content described in the described mixture that contains ursodesoxycholic acid (A) is 20～70wt%.
4. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, is characterized in that, described organic solvent is aromatic hydrocarbon or chloride aliphatic category hydrocarbon.
5. the method for silyation technigue purifying ursodeoxycholic acid according to claim 4, is characterized in that, described aromatic hydrocarbon is at least one in benzene, toluene, nitrile, ester class, amides and their derivative;
Described chloride aliphatic category hydrocarbon is trichloromethane, methylene dichloride, tetracol phenixin, at least one in aliphatics and aromatic ketone.
6. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, it is characterized in that, described silylating reagent is that two substituted alkyl silicon halogenide, three substituted alkyl silicon halogenide, two replace silicon urea, three at least one that replace in silicon urea and dialkyl group silicon acid amides.
7. the method for silyation technigue purifying ursodeoxycholic acid according to claim 6, is characterized in that, no more than 5 of carbon atom in described silylating reagent alkyl.
8. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, is characterized in that, described mineral acid is at least one in 5% sulfuric acid, 5% hydrochloric acid and 5% phosphoric acid.
9. the method for silyation technigue purifying ursodeoxycholic acid according to claim 1, is characterized in that, described ursodesoxycholic acid sterling (C) purity is higher than 99.0%.
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| CN201711277931.6A CN107915767A (en) | 2014-06-20 | 2014-06-20 | The method of silyation technigue purifying ursodeoxycholic acid |
| CN201410279478.2A CN104017043A (en) | 2014-06-20 | 2014-06-20 | Method for purifying ursodesoxycholic acid by adopting silanization technology |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104328454A (en) * | 2014-09-29 | 2015-02-04 | 华东理工大学 | Method for stereo-selectively preparing ursodesoxycholic acid |
| CN104804055A (en) * | 2015-03-18 | 2015-07-29 | 苏州天绿生物制药有限公司 | Method for purifying 7-ketolithocholic acid by adopting silylation reagent |
| 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 |
| CN114892189A (en) * | 2022-06-20 | 2022-08-12 | 华东理工大学 | Method for generating ursodeoxycholic acid by electroreduction in composite aprotic solvent |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110003302B (en) * | 2019-04-30 | 2021-05-11 | 山东省药学科学院 | Refining method of 7-ketolithocholic acid |
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- 2014-06-20 CN CN201711277931.6A patent/CN107915767A/en active Pending
- 2014-06-20 CN CN201410279478.2A patent/CN104017043A/en active Pending
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104328454A (en) * | 2014-09-29 | 2015-02-04 | 华东理工大学 | Method for stereo-selectively preparing ursodesoxycholic acid |
| CN104804055A (en) * | 2015-03-18 | 2015-07-29 | 苏州天绿生物制药有限公司 | Method for purifying 7-ketolithocholic acid by adopting silylation reagent |
| CN104804055B (en) * | 2015-03-18 | 2016-07-06 | 苏州天绿生物制药有限公司 | A kind of method adopting silylating reagent purification 7-Ketolithocholsaeure |
| 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 |
| CN114892189A (en) * | 2022-06-20 | 2022-08-12 | 华东理工大学 | Method for generating ursodeoxycholic acid by electroreduction in composite aprotic solvent |
| CN114892189B (en) * | 2022-06-20 | 2024-01-26 | 华东理工大学 | Method for generating ursodeoxycholic acid by electroreduction in composite aprotic solvent |
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Application publication date: 20140903 |