CN101987860B - Preparation method of ursodesoxycholic acid - Google Patents
Preparation method of ursodesoxycholic acid Download PDFInfo
- Publication number
- CN101987860B CN101987860B CN2009100418168A CN200910041816A CN101987860B CN 101987860 B CN101987860 B CN 101987860B CN 2009100418168 A CN2009100418168 A CN 2009100418168A CN 200910041816 A CN200910041816 A CN 200910041816A CN 101987860 B CN101987860 B CN 101987860B
- Authority
- CN
- China
- Prior art keywords
- acid
- organic solvent
- ursodesoxycholic
- alcohol
- organic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 C[C@@]1(C2CCC1CCCO)ICC1C2C(*)*C(CCCC2)=C2CC1 Chemical compound C[C@@]1(C2CCC1CCCO)ICC1C2C(*)*C(CCCC2)=C2CC1 0.000 description 3
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of ursodesoxycholic acid, which comprises the flowing steps of: a. carrying out 3-bit esterification on chenodeoxycholic acid to obtain 3-esterification protected chenodeoxycholic acid; b. carrying out 7-bit oxidation reaction on 3-bit ester to obtain 3-estergroup-7-oxocompounds; c. carrying out hydrolysis reaction or reduction reaction on the 3-estergroup-7-oxocompounds; d, carrying out 7-bit reduction reaction on 3a-hydroxy-7-oxo-5 beta-cholic acid or hydrolysis reaction on 3a-estergroup-7 beta- hydroxyl-5 beta-cholic acid to obtain crude products of the ursodesoxycholic acid; e. forming salt through the crude products of the ursodesoxycholic acid and organic base; and f. carrying out steps such as water adding dissolution, acid adding crystallization and the like on ursodesoxycholate to obtain pure ursodesoxycholic acid products with the purity higher than 99.0 percent. The invention aims at overcoming the defects in the prior art to provide a novel method for preparing the ursodesoxycholic acid, and the ursodesoxycholic acid prepared by the method has high yield and high purity.
Description
Technical field
The present invention relates to a kind of preparation method of ursodesoxycholic acid.
Background technology
Bear gall is traditional simply rare medicinal herbs, and ursodesoxycholic acid has effects such as extremely strong promotion fat and lipid acid hydrolysis as the contained main effective constituent of bear gall, is mainly used in various liver and gall diseases of treatment and digestive tract diseases clinically; The chemical name of ursodesoxycholic acid is 3 α, and 7 beta-dihydroxyies-5 β-cholic acid, its English name are Ursodeoxycholic acid, and its structural formula is:
Synthetic route, the preparation method of relevant ursodesoxycholic acid are more in present all kinds of patent and the document, and the preparation method of ursodesoxycholic acid generally has following several:
1, extraction separation obtained after bear gall was got in work on one's body from bear;
2, be the synthetic method of raw material with animal cholic acid class (comprising: cholic acid, Chenodiol, Iocholic acid, Hyodeoxycholic Acid etc.);
3, with the rotex be the synthetic method of raw material;
4, complete synthesis method.
In above several method, because the requirement that saves the wild animals, the 1st kind of method is impossible substantially, and the 3rd, the cost of 4 kind of method is very high, do not have industrial production to be worth so far, thereby use the most general with the 2nd kind of method.
All there is a shortcoming in the 2nd kind of synthetic method that present document has been reported; that is: other hydroxyls beyond the 7-position are not protected and promptly carried out oxidizing reaction; even thereby under comparatively gentle oxygenant effect; still can produce a certain amount of by product; although these by products can be removed after refining, the finished product yield is still lower.
Summary of the invention
The objective of the invention is in order to overcome weak point of the prior art, a kind of new method for preparing ursodesoxycholic acid is provided, can realize the preparation of high yield, high purity ursodesoxycholic acid.
In order to achieve the above object, the ursodesoxycholic acid preparation method that the present invention adopts, it may further comprise the steps:
The 3-of a, Chenodiol is bit esterified
Chenodiol is placed in the organic solvent and reacted 1-24 hour at the 20-80 degree with acid anhydrides, organic bases; Wherein optimal reaction temperature is the 20-50 degree, and optimum reacting time 4-12 hour, its 3 hydroxyls will be esterified fully; After reaction finishes, organic solvent distillation is removed,, the bit esterified thing crystallization of the 3-of Chenodiol can be separated out by adding alcoholic solvent and controlling water and alcohol compound ratio, solution temperature, solution PH etc.
B, the bit esterified thing of above-mentioned 3-is carried out 7-position oxidizing reaction
With the bit esterified thing of above-mentioned 3-with organic solvent dissolution after, add oxygenant and carry out oxidizing reaction, obtain 3-esterification-7-oxo thing;
C, with above-mentioned 3-esterification-7-oxo thing be hydrolyzed the reaction or reduction reaction
3-esterification-7-oxo thing adds strong base solution after dissolving fully in organic solvent or alkaline aqueous solution, make the blocking group hydrolysis of 3-position, removes organic solvent through vacuum distilling, the crystallizable 3a-hydroxyl-7-oxo-5 β-cholic acid of separating out; Perhaps, 3-esterification-7-oxo thing reacts with reductive agent in the presence of organic solvent, obtains 3a-ester group-7 beta-hydroxy-5 β-cholic acid;
The reaction that is hydrolyzed of d, above-mentioned 3a-hydroxyl-7-oxo-5 β-cholic acid 7-position reduction reaction or 3a-ester group-7 beta-hydroxy-5 β-cholic acid
3a-hydroxyl-7-oxo-5 β-cholic acid with reductive agent reaction, and after vacuum distilling removes organic solvent, can obtain the ursodeoxycholic acid crude in the presence of organic solvent; After perhaps 3a-ester group-7 beta-hydroxy-5 β-cholic acid dissolves fully, add strong base solution in organic solvent or alkaline aqueous solution, make the blocking group hydrolysis of 3-position, remove organic solvent through vacuum distilling, the crystallizable ursodeoxycholic acid crude of separating out.In the ursodeoxycholic acid crude of two kinds of order preparations, all contain a certain proportion of Chenodiol, under the best synthesis condition, the ratio of ursodesoxycholic acid can reach more than 90%;
E, ursodeoxycholic acid crude and organic bases salify
Ursodeoxycholic acid crude organic solvent dissolution combines with organic bases, forms organic alkali salt of ursodesoxycholic acid.
F, the pure product preparation of ursodesoxycholic acid
With the dissolving of the mixture of the organic alkali salt water of above-mentioned ursodesoxycholic acid or water and organic solvent, regulate PH1-3 by adding mineral acid or organic acid, wherein preferred PH2 can obtain the pure product crystallization of ursodesoxycholic acid (content more than 99.0%, HPLC method).
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein organic solvent comprises furans solvent, ketones solvent described in the step a; Described acid anhydrides comprises the acid anhydrides that dewaters two molecule monoprotic acid the dehydration of formed acid anhydrides and a part diprotic acid forms; Described organic bases comprises aminated compounds, pyridine and derivative thereof, aniline and derivative thereof, morphine quinoline and derivative thereof, guanidine compound, dicyclo amidine compound.Described crystallization comprises the lower alcohol of 1-3 carbon with alcoholic solvent.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein said furans organic solvent is a kind of or two or more mixtures in furans, tetrahydrofuran (THF), 2-methyl furan, 3-methyl furan, the 2-methyltetrahydrofuran; Described organic solvent of ketone is one or both in acetone, the butanone; The described two molecule monoprotic acid formed acid anhydrides that dewaters is one or more a mixture in diacetyl oxide, propionic anhydride, butyryl oxide, the phthalic anhydride; Described a part diprotic acid formed acid anhydrides that dewaters is one or more a mixture in MALEIC ANHYDRIDE, Succinic anhydried, Pyroglutaric acid, the phthalic acid; Described aminated compounds is one or more mixtures in methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, Isopropylamine, the tripropyl amine; Described pyridine and derivative thereof are pyridine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, N, the mixture of one or more in the N-Dimethylamino pyridine; Described aniline and derivative thereof are aniline, N, accelerine, N, the mixture of one or more in the N-Diethyl Aniline; Described morphine quinoline and derivative thereof are one or more the mixture in morphine quinoline, N-methylmorpholine, the N-Ethylmorphine quinoline; Described guanidine compound is a tetramethyl guanidine; Described dicyclo amidine compound is a diazabicylo; Described crystallization alcoholic solvent is one or more the mixture in methyl alcohol, ethanol, the Virahol.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein the organic solvent described in the step b is a kind of in furans organic solvent, hydrocarbon organic solvent, the organic solvent of ketone; Described oxygenant is bromine-containing compound, chloracid compounds, contain a kind of in chromic acid compounds, the oxygenatedchemicals.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein said furans organic solvent is one or both in furans, tetrahydrofuran (THF), 2-methyl furan, 3-methyl furan, the 2-methyltetrahydrofuran; Described hydro carbons is one or more the mixture in methylene dichloride, chloroform, the normal hexane; Described ketone is an acetone; Described bromine-containing compound is one or more the mixture in bromine, N-bromosuccinimide (NBS), C5H6Br2N2O2, the bromochlorohydantoin; Described chloracid compounds is a hypochlorous acid; The described chromic acid compounds that contains is one or more a mixture in chromic acid, potassiumchromate, the Sodium chromate; Described oxygenatedchemicals is one or both in hydrogen peroxide, the Peracetic Acid.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein the organic solvent described in step c and the steps d comprises the alcohol compound of carbon to five carbon; Described reductive agent comprises the active metal or contains the mixture of active metal, hydroborate etc.Described highly basic comprises inorganic strong alkali and organic alkali, and wherein organic alkali can further be subdivided into aminated compounds, pyridine and derivative thereof, aniline and derivative thereof, morphine quinoline and derivative thereof, guanidine compound, dicyclo amidine compound etc.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein said carbon to five a carbon alcohol compound comprises methyl alcohol, ethanol, Virahol, propyl alcohol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, sec.-amyl alcohol, 3-amylalcohol, tertiary amyl alcohol etc.Described active metal or the mixture that contains the active metal comprise sodium Metal 99.5, potassium metal, sodium amalgam, potassium amalgam etc.; Described hydroborate comprises sodium borohydride, POTASSIUM BOROHYDRIDE or lithium triethylborohydride etc.Described inorganic strong alkali comprises one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide and the strong aqua etc.; Described organic alkali comprises aminated compounds such as methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, Isopropylamine, tripropyl amine; Pyridine and derivative thereof such as pyridine, 2,6-lutidine, 4-picoline; Aniline and derivative thereof such as aniline, N, accelerine, N, N-Diethyl Aniline; Morphine quinoline and derivative thereof such as morphine quinoline, N-methylmorpholine, N-Ethylmorphine quinoline; Guanidine compound such as tetramethyl guanidine; Dicyclo amidine compound diazabicylo (DBU, DBN) etc.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein the described organic solvent of step e is a kind of in alcoholic solvent, the ketones solvent; Described organic bases is one or more the mixture in aminated compounds, pyridine and derivative thereof, aniline and derivative thereof, morphine quinoline and derivative thereof, guanidine compound, the dicyclo amidine compound.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein said alcoholic solvent is one or more the mixture in methyl alcohol, ethanol, the Virahol; Described ketones solvent is an acetone; Described aminated compounds is one or both in methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, Isopropylamine, the tripropyl amine; Described pyridine and derivative thereof are pyridine, 2, the mixture of one or more in 6-lutidine, the 4-picoline; Described aniline and derivative thereof are aniline, N, accelerine, N, the mixture of one or more in the N-Diethyl Aniline; Described morphine quinoline and derivative thereof are one or more the mixture in morphine quinoline, N-methylmorpholine, the N-Ethylmorphine quinoline; Described guanidine compound is a tetramethyl guanidine; Described dicyclo amidine compound is a diazabicylo.
The preparation method of aforesaid a kind of ursodesoxycholic acid, wherein the described organic solvent of step f comprises methyl alcohol, ethanol, propyl alcohol, different third gradegrade C alcoholic solvent, ketones solvents such as acetone; Described mineral acid and organic acid comprise hydrochloric acid, phosphoric acid, sulfuric acid, acetate etc.
The structural formula of some organic compound among the present invention:
Formula I, ursodesoxycholic acid, UDCA
Formula II, Chenodiol, CDCA
Formula III, 3a-ester group-7a-hydroxyl-5 β-cholic acid, R-CDCA
Formula IV, 3a-ester group-7-oxo-5 β-cholic acid, R-KDCA
Formula V, 3a-hydroxyl-7-oxo-5 β-cholic acid, KDCA
Formula VI, 3a-ester group-7 beta-hydroxy-5 β-cholic acid, R-UDCA
In sum, beneficial effect of the present invention:
1, among the preparation method of the present invention the 3-OH of Chenodiol protected and carry out oxidizing reaction again, avoided oxidising process the shortcoming of more by product to occur;
2, among the preparation method of the present invention, the bit esterified thing of 3-makes 3-ester group 7-oxo thing through oxidizing reaction, this compound both can also can obtain containing the ursodeoxycholic acid crude of 5-10% Chenodiol and other impurity by the method for reduction posthydrolysis earlier by reducing after the first hydrolysis;
3, utilize behind ursodesoxycholic acid, Chenodiol and the organic bases salify feature of different solubility in certain solvent, reach the purpose of separating ursodesoxycholic acid, and ursodesoxycholic acid purity is very high, can be used as medicinal.
Embodiment
Below in conjunction with embodiment the present invention is described further:
Embodiment 1
In 2000 milliliters of reaction flasks, add Chenodiol 100 grams, MALEIC ANHYDRIDE 61 grams, 400 milliliters in acetone, diethylamine 43.6 grams, 2,6-lutidine 2 grams.Be warming up to 38-40 ℃, and under this temperature, keep and stirred 4-5 hour.Behind the TLC method detection reaction completeness, add 300 milliliters in water, acetone is removed in vacuum distilling, obtains a clarifying brown yellow solution, is cooled to 20-25 ℃.Drip 10% hydrochloric acid, regulate PH to 3.5-4.0, become turbid.Stream adds 300 milliliters of methyl alcohol about 20 minutes, crystallization occurs.Add 300 milliliters in water, and stirred 2-3 hour in 20-25 ℃, filter, the washing of 200 ml waters, drying obtain white to off-white color pressed powder 123.6 grams (formula III, 3a-ester group-7a-hydroxyl-5 β-cholic acid, R-CDCA).
In 2000 milliliters of reaction flasks, the product 123.6 in step gram in the adding, 700 milliliters of tetrahydrofuran (THF)s, 25-30 ℃ was stirred 20-30 minute, dissolved fully to the 3-carboxylate, obtained a yellow solution.Add bromochlorohydantoin 69.2 grams, 20-35 ℃ is continued to stir 2-3 hour, gets the off-white color suspended matter.Complete as TLC method detection reaction, add 400 milliliters of entry, tetrahydrofuran (THF) is removed in 40 ℃ of following vacuum distillings.Add 566 milliliters of methyl alcohol, be cooled to 10-15 ℃ under stirring.Stream adds 20% sodium hydroxide, 212 grams, is warming up to 40-50 ℃, and reacts 4-5 hour under this temperature.As TLC method detection reaction completeness, dripped 10% hydrochloric acid, PH is adjusted to 3.5-4.0 by original 12-13 in 25-30 minute.Reaction solution is cooled to 20-25 ℃, and keeps this temperature and stirred 2-3 hour.Filter, methanol-water mixture (methyl alcohol: 400 milliliters of washing secondaries water=1: 1), each 200 milliliters, obtain the off-white color solid, 55-65 ℃ of following vacuum-drying to moisture content less than 0.5%, product 96.1 gram (formula V, 3a-hydroxyls-7-oxo-5 β-cholic acid, KDCA, HPLC method detection level is 96.9%).
Get step product 96.1 grams, add 1000 milliliters of Pentyl alcohols, potassium metal 65 grams, reaction is 4-8 hour under reflux state, add 100 milliliters in water, after stirring, standing demix is got the tertiary amyl alcohol phase, after being distilled to small volume, add 800 milliliters in water again, continue to be distilled to till the no Pentyl alcohol outflow.Add 10% hydrochloric acid and regulate PH2-3, filter, 300 milliliters of washings of pure water, drying gets ursodeoxycholic acid crude 94.7 grams (ursodesoxycholic acid 92.8%, Chenodiol 5.5%, HPLC method).
Ursodeoxycholic acid crude 94.7 gram in last step, add 200 milliliters of dissolvings of dehydrated alcohol after, add N-methylmorpholine 25 grams, back flow reaction more than 1 hour, filter, the wet product of the organic alkali salt of ursodesoxycholic acid.In these wet product, add 1500 milliliters of purified water, after the stirring and dissolving, add 10% hydrochloric acid and regulate PH2, and be cooled to 5 ℃ and kept 1 hour, filter, vacuum-drying, ursodesoxycholic acid 86.6 restrains (purity 99.3%, HPLC method).
Embodiment 2
In 2000 milliliters of reaction flasks, add Chenodiol 100 grams, Pyroglutaric acid 59 grams, 400 milliliters of 3-methyl furans, tetramethyl guanidine 58.6 grams are warming up to 25-30 ℃, and keep under this temperature and stirred 7-9 hour.Behind the TLC method detection reaction completeness, add 300 milliliters in water, organic solvent is removed in reactant vacuum distilling, obtains brown yellow solution, is cooled to 20-25 ℃.Drip 10% hydrochloric acid, regulate PH to 3.5-4.0.Whole process temperature must maintain below 30 ℃, becomes turbid.Drip 220 milliliters of ethanol about 20 minutes, crystallization occurs.Continuation dripped 300 milliliters in water at 5-10 minute, and stirred 2-3 hour in 20-25 ℃, filter, the washing of 200 ml waters, drying obtain white to off-white color pressed powder 127.4 grams (formula III, 3a-ester group-7a-hydroxyl-5 β-cholic acid, R-CDCA).
In 2000 milliliters of reaction flasks, the product 127.4 in step gram in the adding, 600 milliliters of methylene dichloride, 25-30 ℃ was stirred 20-30 minute, dissolved fully to derivative, obtained a yellow solution.Add N-bromosuccinimide 46.5 grams, 20-35 ℃ was continued stirring reaction 10-13 hour.Complete as TLC method detection reaction, add 200 milliliters of methyl alcohol, and after being cooled to-10 ℃, stream adds 5-10 ℃ sodium borohydride solution (sodium borohydride 12 grams add 80 milliliters of dissolvings of water promptly) in 2-3 hour, keep 0 to-10 ℃ of reaction 6-8 hour, react completely up to the check of HPLC method.Be cooled to 10-15 ℃.Stream adds 20% sodium hydroxide, 212 grams in 5-10 minute, and stream adds process temperature should be less than 50 ℃.Add 300 milliliters in water again, stirred 15 minutes, standing demix, the water intaking phase is warming up to 50-60 ℃, and reacts 3-5 hour under this temperature.As TLC method detection reaction completeness, methyl alcohol is removed in vacuum distilling, is cooled to 20-25 ℃, drips 10% hydrochloric acid adjusting PH to 3.5-4.0, and keeps this temperature and stirred 2-3 hour in 25-30 minute.Filter, 400 milliliters of washings of pure water secondary uses 200 milliliters of pure water at every turn, obtains the off-white color solid, 55-65 ℃ of following vacuum-drying to moisture content less than 0.5%, ursodeoxycholic acid crude 95.2 grams (ursodesoxycholic acid 93.1%, Chenodiol 5.3%, HPLC method).
Ursodeoxycholic acid crude 95.2 grams in last step add 200 milliliters in acetone, add 4-picoline 25 grams, back flow reaction then more than 1 hour, filter, and get the wet product of the organic alkali salt of ursodesoxycholic acid.In these wet product, add 1500 milliliters of purified water, after the stirring and dissolving, filter, add 10% hydrochloric acid in the filtrate and regulate PH2, be cooled to 5 ℃ and kept 1 hour, filter, vacuum-drying, ursodesoxycholic acid 85.3 restrains (purity 99.7%, HPLC method).
Claims (5)
1. the preparation method of a ursodesoxycholic acid, it may further comprise the steps:
The 3-of a, Chenodiol is bit esterified
Chenodiol reacted 1-24 hour at the 20-80 degree with acid anhydrides, organic bases in organic solvent; After reaction finishes, organic solvent distillation is removed,, the bit esterified thing crystallization of the 3-of Chenodiol is separated out by adding alcoholic solvent and controlling the method for pH value of solution;
B, the bit esterified thing of above-mentioned 3-is carried out 7-position oxidizing reaction
With the bit esterified thing of above-mentioned 3-with organic solvent dissolution after, add oxygenant and carry out oxidizing reaction, obtain 3-esterification-7-oxo thing;
C, with above-mentioned 3-esterification-7-oxo thing be hydrolyzed the reaction or reduction reaction
3-esterification-7-oxo thing adds strong base solution after dissolving fully in organic solvent, make the blocking group hydrolysis of 3-position, removes organic solvent through vacuum distilling, and 3a-hydroxyl-7-oxo-5 β-cholic acid is separated out in crystallization; Perhaps, 3-esterification-7-oxo thing reacts with reductive agent in the presence of organic solvent, obtains 3a-ester group-7 beta-hydroxy-5 β-cholic acid;
The reaction that is hydrolyzed of reduction reaction or 3a-ester group-7 beta-hydroxy-5 β-cholic acid is carried out in d, above-mentioned 3a-hydroxyl 7-oxo-5 β-cholic acid 7-position
3a-hydroxyl-7-oxo-5 β-cholic acid with the reductive agent reaction, after organic solvent is removed in vacuum distilling, obtains the ursodeoxycholic acid crude in the presence of organic solvent; After perhaps 3a-ester group-7 beta-hydroxy-5 β-cholic acid dissolves fully, add strong base solution in organic solvent, make the blocking group hydrolysis of 3-position, remove organic solvent through vacuum distilling, the crystallizable ursodeoxycholic acid crude of separating out;
E, ursodeoxycholic acid crude and organic bases salify
Ursodeoxycholic acid crude organic solvent dissolution combines with organic bases, forms organic alkali salt of ursodesoxycholic acid;
F, the pure product preparation of ursodesoxycholic acid
With the mixture dissolving of the organic alkali salt water of above-mentioned ursodesoxycholic acid or water and organic solvent, regulate pH1-3 by adding mineral acid or organic acid, obtain the pure product crystallization of ursodesoxycholic acid;
Wherein organic solvent described in the step a is furans solvent or ketones solvent; Described acid anhydrides is the two molecule monoprotic acid acid anhydrides that the dehydration of formed acid anhydrides or a part diprotic acid forms that dewater; Described organic bases is methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, tripropyl amine, pyridine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, N, N-Dimethylamino pyridine, aniline, N, accelerine, N, N-Diethyl Aniline, morphine quinoline, N-methylmorpholine, N-Ethylmorphine quinoline, tetramethyl guanidine or diazabicylo; Described crystallization alcoholic solvent is the lower alcohol of 1-3 carbon;
Wherein the organic solvent described in the step b is a kind of in furans organic solvent, hydrocarbon organic solvent, the organic solvent of ketone; Described oxygenant is bromine, N-bromosuccinimide, C5H6Br2N2O2, bromochlorohydantoin, hypochlorous acid, chromic acid, potassiumchromate, Sodium chromate, hydrogen peroxide or Peracetic Acid;
Wherein the organic solvent described in step c and the steps d is the alcohol compound of carbon to five carbon; Described reductive agent is sodium Metal 99.5, potassium metal, sodium amalgam, potassium amalgam, sodium borohydride, POTASSIUM BOROHYDRIDE or lithium triethylborohydride;
Wherein the organic solvent described in the step e is a kind of in alcoholic solvent, the ketones solvent; Described organic bases is methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, tripropyl amine, pyridine, 2,6-lutidine, 4-picoline, aniline, N, accelerine, N, N-Diethyl Aniline, morphine quinoline, N-methylmorpholine, N-Ethylmorphine quinoline, tetramethyl guanidine or diazabicylo;
Wherein the organic solvent described in the step f is methyl alcohol, ethanol, propyl alcohol or acetone; Described mineral acid is hydrochloric acid, phosphoric acid or sulfuric acid, and described organic acid is an acetate.
2. the preparation method of a kind of ursodesoxycholic acid according to claim 1, wherein the furans organic solvent described in the step a is a kind of or two or more mixtures in furans, tetrahydrofuran (THF), 2-methyl furan, 3-methyl furan, the 2-methyltetrahydrofuran; Described organic solvent of ketone is a kind of in acetone, the butanone or two kinds; The described two molecule monoprotic acid formed acid anhydrides that dewaters is one or more a mixture in diacetyl oxide, propionic anhydride, butyryl oxide, the phthalic anhydride; Described a part diprotic acid formed acid anhydrides that dewaters is one or more a mixture in MALEIC ANHYDRIDE, Succinic anhydried, the Pyroglutaric acid; Described crystallization alcoholic solvent is one or more the mixture in methyl alcohol, ethanol, the Virahol.
3. according to the preparation method of the described a kind of ursodesoxycholic acid of claim 1, it is characterized in that the furans organic solvent described in the step b is one or both in furans, tetrahydrofuran (THF), 2-methyl furan, 3-methyl furan, the 2-methyltetrahydrofuran; Described hydro carbons is one or more the mixture in methylene dichloride, chloroform, the normal hexane; Described ketone is an acetone.
4. according to the preparation method of the described a kind of ursodesoxycholic acid of claim 1, wherein carbon to the five carbon alcohol compound described in step c and the steps d is methyl alcohol, ethanol, propyl alcohol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, sec.-amyl alcohol, 3-amylalcohol or tertiary amyl alcohol; Described highly basic is sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, strong aqua, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, tripropyl amine, pyridine, 2,6-lutidine, 4-picoline, aniline, N, accelerine, N, N-Diethyl Aniline, morphine quinoline, N-methylmorpholine, N-Ethylmorphine quinoline, tetramethyl guanidine or dicyclo amidine compound diazabicylo.
5. the preparation method of a kind of ursodesoxycholic acid according to claim 1, wherein the alcoholic solvent described in the step e is one or more the mixture in methyl alcohol, ethanol, the Virahol; Described ketones solvent is an acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100418168A CN101987860B (en) | 2009-08-06 | 2009-08-06 | Preparation method of ursodesoxycholic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100418168A CN101987860B (en) | 2009-08-06 | 2009-08-06 | Preparation method of ursodesoxycholic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101987860A CN101987860A (en) | 2011-03-23 |
| CN101987860B true CN101987860B (en) | 2011-12-14 |
Family
ID=43744671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100418168A Active CN101987860B (en) | 2009-08-06 | 2009-08-06 | Preparation method of ursodesoxycholic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101987860B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558268A (en) * | 2011-12-23 | 2012-07-11 | 中山百灵生物技术有限公司 | Process for preparing tauroursodeoxycholic acid hydrate |
| BR112017001623B1 (en) | 2014-07-29 | 2022-11-29 | Shenzhen Hightide Biopharmaceutical, Ltd | ACID-BASE ADDITION SALT IN SUBSTANTIALLY PURE FORM, PHARMACEUTICAL COMPOSITION COMPRISING AN AMOUNT OF SAID SALT AND ITS USES |
| CN104193792B (en) * | 2014-08-29 | 2015-12-02 | 哈尔滨工业大学 | A kind of technique preparing ursodesoxycholic acid |
| 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 |
| CN105418714B (en) * | 2015-12-28 | 2017-03-22 | 成都市新功生物科技有限公司 | Method for synthesizing ursodesoxycholic acid with chenodeoxycholic acid by photochemical method |
| CN106957886A (en) * | 2017-03-01 | 2017-07-18 | 南京远淑医药科技有限公司 | A kind of preparation method 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 |
| CN109154016B (en) * | 2017-12-29 | 2021-11-16 | 邦泰生物工程(深圳)有限公司 | Method for preparing ursodeoxycholic acid by chemical-enzymatic method |
| CN110669091A (en) * | 2019-10-18 | 2020-01-10 | 武汉大学 | Method for purifying ursodeoxycholic acid |
| CN110818763A (en) * | 2019-11-21 | 2020-02-21 | 安徽科宝生物工程有限公司 | Method for separating and purifying ursodeoxycholic acid mother liquor |
| CN112813128A (en) * | 2021-01-12 | 2021-05-18 | 中山百灵生物技术股份有限公司 | Synthetic method of alloursodeoxycholic acid |
| CN113480589B (en) * | 2021-07-09 | 2023-08-25 | 华东师范大学 | Purification method of ursodeoxycholic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0088637A2 (en) * | 1982-03-09 | 1983-09-14 | Kabushiki Kaisha Yakult Honsha | A method for producing ursodeoxycholic acid |
| CN1217336A (en) * | 1998-01-25 | 1999-05-26 | 云南大学 | Stereo-selective synthesizing method for ursodesoxycholic acid |
| CN101215308A (en) * | 2007-01-04 | 2008-07-09 | 苏州天绿生物制药有限公司 | Method for producing ursodeoxycholic acid by using swine bladder as raw material |
-
2009
- 2009-08-06 CN CN2009100418168A patent/CN101987860B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0088637A2 (en) * | 1982-03-09 | 1983-09-14 | Kabushiki Kaisha Yakult Honsha | A method for producing ursodeoxycholic acid |
| CN1217336A (en) * | 1998-01-25 | 1999-05-26 | 云南大学 | Stereo-selective synthesizing method for ursodesoxycholic acid |
| CN101215308A (en) * | 2007-01-04 | 2008-07-09 | 苏州天绿生物制药有限公司 | Method for producing ursodeoxycholic acid by using swine bladder as raw material |
Non-Patent Citations (1)
| Title |
|---|
| 柳湘云等.熊去氧胆酸的新合成路线和方法的研究.《哈尔滨师范大学自然科学学报》.2000,第16卷(第2期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101987860A (en) | 2011-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101987860B (en) | Preparation method of ursodesoxycholic acid | |
| CN104230803B (en) | Preparation method of hydroxychloroquine sulfate | |
| EP1960416B1 (en) | Purification process for chenodeoxycholic acid | |
| CN110256517B (en) | Method for producing high-purity chenodeoxycholic acid from pig bile or leftovers | |
| CN101830956A (en) | Preparation method for separating and purifying chenodeoxycholic acid in porcine bile paste or leftovers | |
| CN106279328A (en) | A kind of method preparing 6 alpha-alkyl chenodeoxycholic acid | |
| EP1903050B1 (en) | A process for the preparation of cholanic acids | |
| CN102911235A (en) | Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material | |
| CN101215311B (en) | Method for producing ursodesoxycholic acid from 86% of chenodeoxycholic acid | |
| CN109796461B (en) | Preparation process of tadalafil impurity I | |
| CN101302244A (en) | Production process of betulinic acid | |
| EP1966228B1 (en) | Purification process for chenodeoxycholic acid | |
| CN112062802A (en) | Chenodeoxycholic acid butyl acetate extracting solution and preparation method thereof, and chenodeoxycholic acid ammonium salt and chenodeoxycholic acid preparation method | |
| CN113135971B (en) | Carbon-loss cholesterin and preparation method and application thereof | |
| EP2545065B1 (en) | Water-soluble phytosterol derivatives for reducing cholesterol and preparation thereof | |
| CN103992263B (en) | A kind of purification process of E2020 | |
| CN109776649A (en) | A kind of refining methd of natrium taurocholicum | |
| CN113461764A (en) | Synthetic method of ursodeoxycholic acid | |
| CN112939941A (en) | Preparation method of lansoprazole | |
| CN110003302B (en) | Refining method of 7-ketolithocholic acid | |
| CN102351805B (en) | Method for preparing, separating and refining 5-amino-1H-tetrazol-1-ylacetic acid | |
| CN101735214B (en) | Method for extracting ajmaline from devilpepper waste liquor | |
| JPH0411557B2 (en) | ||
| CN106957886A (en) | A kind of preparation method of urso | |
| CN117264006A (en) | Synthetic method of chenodeoxycholic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 28, Jiuzhou Avenue, Torch Development Zone, Zhongshan City, Guangdong Province Patentee after: Zhongshan bailing Biotechnology Co.,Ltd. Address before: 528400 Zhongshan bailing Biotechnology Co., Ltd., National Health Science and technology industrial base, Torch Development Zone, Zhongshan City, Guangdong Province Patentee before: ZHONGSHAN BELLING BIOTECHNOLOGY Co.,Ltd. |