CN102477059B - High-purity tauro ursodesoxy cholic acid and preparation method thereof - Google Patents
High-purity tauro ursodesoxy cholic acid and preparation method thereof Download PDFInfo
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- CN102477059B CN102477059B CN201010552339.4A CN201010552339A CN102477059B CN 102477059 B CN102477059 B CN 102477059B CN 201010552339 A CN201010552339 A CN 201010552339A CN 102477059 B CN102477059 B CN 102477059B
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Abstract
The invention relates to high-purity tauro ursodesoxy cholic acid and a preparation method thereof. The content of taurochenodeoxycholic acid in the tauro ursodesoxy cholic acid is less than 0.7%. The tauro ursodesoxy cholic acid is safe and effective and does not have toxic and side effects in clinical application. The invention further provides a mixed anhydride reaction of ursodesoxycholic acid and ethyl chloroformate by taking acetone as a solvent. By means of control of a reaction condition and a reaction solvent, the tauro ursodesoxy cholic acid has the advantages of simple process, low cost, environmental friendlessness and industrial production; furthermore, the high-purity tauro ursodesoxy cholic acid can be obtained.
Description
Technical field
The present invention relates to a kind of medical material medicine and preparation method thereof, be specifically related to tauroursodeoxycholicacid and preparation method thereof.
technical background
Ursodeoxycholic acid (tauroursodeoxycholicacid) chemistry 2-[[(3 α by name; 5 β; 7 β)-3; 7-dihydroxyl-24-oxo cholestane-24-yl] amino] ethane sulfonic acid dihydrate; within 1902, in bear gall, find; it is main bile acide in bear gall, has the effects such as spasmolysis, anticonvulsion, anti-inflammatory and molten cholelith.Ursodeoxycholic acid can increase the secretion of bile acide, causes the variation of Bile acid, and its content in bile is increased.Ursodeoxycholic acid can also suppress the synthetic of liver cholesterol, reduces bile cholesterol and the amount of cholesteryl ester and the saturation index of cholesterol, dissolves gradually thereby be conducive to bile cholesterol.
Ursodeoxycholic acid is developed by the large pharmaceutical factory of Italian Bruschettini S.r.l. the earliest; went on the market in Italy first in 1991; within 2007, get permission to sell in China with trade(brand)name flood rood (taurolite), be clinically mainly used in treating gallbladder cholesterol calculus, primary sclerosing cholangitis, Primary biliary cirrhosis and chronic hepatitis C etc.
The research of impurity is an important content of drug research and development, and this research is through the whole process of drug research and development.The untoward reaction producing in clinical use due to medicine is except outside the Pass having with the pharmacologically active of medicine itself, sometimes with medicine in the impurity that exists also have much relations.Therefore carry out the research of impurity to specification, and within being controlled at a safety, rational limits, will be directly connected to quality and the security of listing medicine.In " the technical director's principle of chemicals impurity research " issued by State Food and Drug Administration in March, 2005, clearly specify, for the bulk drug of maximum per daily dose≤2g, the Quality Control limit of maximum single assorted amount is 0.15%, the pharmaceutical preparation that arrives 2g for maximum per daily dose at 100mg, the Quality Control limit of maximum single assorted amount is 0.2%.At present, in commercially available surging rood capsule quality standard, the assorted amount of maximum list not being limited, is only must not cross 0.5% with the total single assorted amount of other except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid in tlc restriction sheath or bow case rood.
Preparing at present the starting raw material that ursodeoxycholic acid uses is ursodesoxycholic acid, generally obtains by two kinds of approach: the one, in animal body, extract, and be mainly that Fel Ursi extracts, this method is because of source restriction, and the very high and complicated component of cost, generally adopts less.Another kind method is chemosynthesis, and mainly with animal courage acid, such as Hyodeoxycholic Acid, Chenodiol is that raw material synthesizes.Wherein, taking Chenodiol as raw material, synthetic ursodesoxycholic acid is the main source of the ursodesoxycholic acid that purity is higher in the market.But; the ursodesoxycholic acid of preparing by such approach inevitably contains a certain amount of Chenodiol; same in the preparation process of ursodeoxycholic acid; can produce a certain amount of Taurochenodeoxycholic Acid, and Taurochenodeoxycholic Acid can be replied as sequestered Chenodiol in small intestine in partial hydrolysis.Although Chenodiol and Taurochenodeoxycholic Acid also have certain pharmacological action; but also there is certain toxicity simultaneously; can make glutamyl transferase (ALT) in human body raise; cause apoptosis and cause serious liver tissue injury, finally develop into liver cirrhosis (Zheng Xing " comparative study of ursodesoxycholic acid and Chenodiol ").Further proof of external test, the toxic action of bile acide depends on their hydrophobicity, in general, hydrophobicity is stronger, larger to hepatocellular toxicity.Taurochenodeoxycholic Acid hydrophobicity index HI is 0.46, and ursodeoxycholic acid is hydrophilic, and HI is-0.4, is nontoxic (He Xiuling etc. " Taurochenodeoxycholic Acid progress ").Therefore, strictly controlling the content of Taurochenodeoxycholic Acid in ursodeoxycholic acid, avoid hepatotoxic appearance, is very important.
The report relevant with ursodeoxycholic acid chemical synthesising technology and generally adopted the method for the synthesis of ursodeoxycholic acid mainly to comprise in prior art:
US5565587 reported to react under the reaction conditions of making solvent with ursodesoxycholic acid with pivaloyl chloride at dioxane and formed mixed acid anhydride, then reacts with taurine under alkaline condition, and the crude product obtaining makes ursodeoxycholic acid through ion-exchange column purification.But this method is used dioxane as solvent, and dioxane claims again dioxan, and toxicity is larger, has carinogenicity, and can put aside in vivo.Meanwhile, this law adopts ion-exchange column purification, complicated operation, and cost is high, is unfavorable for suitability for industrialized production.(" Chinese Journal of Pharmaceuticals " 2009 such as Wang Hailong, 40) reported improving one's methods of this method, with ursodesoxycholic acid and 2,2 '-phenyl disulfide thiazole reaction make ursodesoxycholic acid-2-[4-morpholinodithio thioesters, obtain sterling through acetone-water (12: 1) recrystallization again, without ion-exchange column purification.But yield is low after this method scale-up, cause energy consumption very high, its cost is that suitability for industrialized production can not be born.
(the Bioorg Med Chem such as Dayal B; 1996; 4) reported ursodesoxycholic acid and taurine under alkaline condition in N-ethoxycarbonyl-2-oxyethyl group-1, the lower direct polycondensation of 2-dihydroquinoline (EEDQ) effect obtains ursodeoxycholic acid, but this method reagent high price is expensive.
US5362891 has reported that ursodesoxycholic acid and Vinyl chloroformate form after mixed acid anhydride, with ethyl-para-hydroxyphenyl ketone condensation, obtain the active phenolic ester of ursodesoxycholic acid, then react and make ursodeoxycholic acid with taurine, but this method reactions steps is more, and total recovery is low.
And ursodeoxycholic acid synthetic method of the prior art, all can not effectively remove the Taurochenodeoxycholic Acid of bringing in raw material, for the use of ursodeoxycholic acid has brought certain potential safety hazard.
summary of the invention
One of object of the present invention is to obtain the extremely low ursodeoxycholic acid of a kind of Taurochenodeoxycholic Acid content.
Another object of the present invention is under the prerequisite that Taurochenodeoxycholic Acid content is extremely low in guarantee ursodeoxycholic acid, controls other the maximum single assorted content except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid.
A further object of the present invention is to provide the preparation method of tauroursodeoxycholicacid.
Another object of the present invention is to provide a kind of pharmaceutical composition using high purity ursodeoxycholic acid as activeconstituents.
To achieve these goals, the invention provides a kind of highly purified ursodeoxycholic acid, it is characterized in that the contained Taurochenodeoxycholic Acid of this ursodeoxycholic acid is not more than 0.7% with liquid phase chromatogram condition and method mensuration; Preferably contained Taurochenodeoxycholic Acid is measured and is not more than 0.5% with liquid phase chromatogram condition and method, and more preferably in aforementioned ursodeoxycholic acid, the maximum list except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid is assorted measures and be less than 0.15% with liquid phase chromatogram condition and method; Most preferably be in aforementioned ursodeoxycholic acid that the maximum list except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid is assorted to be measured and be less than 0.1% with liquid phase chromatogram condition and method.
The present invention also provides a kind of preparation method of high-content ursodeoxycholic acid, to make mixed acid anhydride by ursodesoxycholic acid and Vinyl chloroformate, react to obtain again ursodeoxycholic acid crude product with taurine, crude product carries out recrystallization again and obtains, and it is characterized in that whole technique is only used acetone, two kinds of solvents of water; Wherein the preparation method of mixed acid anhydride is preferably: in reactor, add ursodesoxycholic acid and acetone, under stirring, add triethylamine, open refrigeration, be cooled to-10--5 DEG C, stream adds Vinyl chloroformate, controls and adds speed to make reacting liquid temperature be no more than 5 DEG C, about 15-30 minute adds, and continues insulated and stirred 20-40 minute; Wherein recrystallizing technology is preferably
(1) ursodeoxycholic acid crude product is dropped in reactor, add acetone and water, heated and stirred is to all dissolving;
(2) be cooled to-5-5 DEG C under stirring, crystallization 30-48 hour;
(3) be discharged to suction filtration in strainer, drain rear frozen water (5-5 DEG C) the drip washing filter cake of using, again drain.
Wherein, the volume/weight ratio of acetone and water is 1: 7～1: 12, is preferably 1: 10.
The present invention also provides a kind of pharmaceutical composition, and it contains high purity ursodeoxycholic acid and pharmaceutically acceptable carrier or vehicle.Wherein carrier or vehicle can be lactose, Microcrystalline Cellulose, starch, Magnesium Stearate, PVP, sodium starch glycolate, polyvinylpolypyrrolidone, hydroxypropylcellulose, silicon-dioxide and ethanol, and this pharmaceutical composition can be for oral capsule; Be preferably and in every 1000, contain following component: high purity ursodeoxycholic acid 250g, lactose 36g, Microcrystalline Cellulose 20g, starch 10g, Magnesium Stearate 4g and appropriate PVP K30 and 95% ethanol.
The present invention compared with prior art it is advantageous that:
1, ursodeoxycholic acid purity of the present invention is high, and contained Taurochenodeoxycholic Acid and maximum single assorted amount are few, therefore, in clinical use security higher, almost without any toxic side effects.
2, the preparation technology of high purity ursodeoxycholic acid is simple, cost is low, environmental friendliness, is more suitable for suitability for industrialized production.
Contriver learns by a large amount of experimental studies in the process of the mixed acid anhydride forming at ursodesoxycholic acid and Vinyl chloroformate, if stream adds initial reaction temperature before Vinyl chloroformate below-10 DEG C, to make reaction be difficult to carry out, in the time that starting temperature is greater than-5 DEG C, will make reaction occur more byproduct of reaction and impurity.In the time that stream adds Vinyl chloroformate, reaction can discharge amount of heat, if flow into Vinyl chloroformate excessive velocities, make reacting liquid temperature exceed 5 DEG C, or stream to add the speed of Vinyl chloroformate excessively slow, the reaction times exceedes 70 minutes, all can cause reaction to occur more by product and impurity.
In ursodeoxycholic acid refining, because ursodeoxycholic acid all has certain solvability in water and acetone, prior art generally all adopts ion-exchange column purification or adopts taking acetone as main solvent system recrystallization ursodeoxycholic acid and obtains sterling.But contriver learns through large quantity research; in ursodeoxycholic acid refining; if adopted taking water as main solvent system; in the time that acetone add-on is certain proportion; can make ursodeoxycholic acid separate out in a large number with good crystalline form; and required time of crystallization is shorter; only need recrystallization one can effectively remove impurity to secondary; improve purity; remove inorganic salt; greatly save the required industrial raw material acetone of refining purifying and purifying time and purification step, made indudstrialized refining become easier, feasible.
Contriver learns by a large amount of experimental studies; in the ratio of acetone higher than 1: 7 or lower than 1: 12 o'clock; ursodeoxycholic acid can be difficult to separate out; and very tiny (the yield < 50% of crystal; the crystallization time is greater than 50 hours), be unfavorable for very much industrialized production.But; in acetone/water=1: 7～1: between 12; preferably 1: 10 time; ursodeoxycholic acid can separate out with good crystal habit, and also quite high (>=80%) of yield, simultaneously; only need recrystallization one to secondary; can obtain the ursodeoxycholic acid end product that purity is greater than 99.0%, greatly save industrial raw material acetone, simplify the treatment process to ursodeoxycholic acid crude product refining.
Brief description of the drawings
Fig. 1 measures the HPLC color atlas that commercially available surging rood and lot number are related substance in 100801,100901,100902 the capsule that contains ursodeoxycholic acid.
Fig. 2 measures the HPLC color atlas that lot number is related substance in 100702 ursodeoxycholic acid bulk drug.
Fig. 3 measures the HPLC color atlas that lot number is related substance in 100801 ursodeoxycholic acid bulk drug.
Fig. 4 measures the HPLC color atlas that lot number is related substance in 100802 ursodeoxycholic acid bulk drug.
Reference example
Under identical test conditions, detect respectively a collection of commercially available surging rood capsule and taking the ursodeoxycholic acid of lot number 100801 as the prepared capsule of bulk drug: lot number 100801; Taking lot number 100702 as the prepared capsule of bulk drug: lot number 100901; Taking lot number 100802 as the prepared capsule of bulk drug: lot number 100902 (preparation method of three batches of capsules is all prepared by embodiment seven).
Three batches from the ursodeoxycholic acid bulk drug (lot number: 100702,100801,100802), its HPLC spectrogram is shown in Fig. 2, Fig. 3, Fig. 4 grinding.
Measuring method is:
Sample thief (contains the about 25mg of ursodeoxycholic acid) in right amount, accurately weighed, adds acetonitrile-water (1: 1) and dissolves and quantitatively dilute and make the solution that approximately contains ursodeoxycholic acid 5mg in every 1ml, as need testing solution; Get this solution 20 μ l, injection liquid chromatography, records 3.5 times to principal constituent peak retention time of color atlas; In need testing solution color atlas, if any impurity peaks, press and long-pending normalization method calculating.(note: ursodeoxycholic acid peak retention time is about 21min.)
Measuring chromatographic condition used is:
Instrument: Shimadzu LC-10A high performance liquid chromatograph;
Workstation title: LC-Solutio;
Chromatographic column: Dikrma C18 (4.6 × 150mm, 5 μ are m);
Moving phase: 0.05mol/l SODIUM PHOSPHATE, MONOBASIC-acetonitrile (67:33) (with phosphorus acid for adjusting pH value to 4.4);
Detect wavelength: 202nm;
Flow velocity is 1.0ml/min;
Calculation formula is as follows:
In formula, A
ifor single impurity peak area;
∑ A
ifor impurity peak area sum;
Determination of related substances result in table 1 bulk drug
| Sample lot number | Sample weighting amount | Total impurities content % | Taurochenodeoxycholic Acid content % | Other single largest impurity % |
| 100702 | 25.2mg | 0.603 | 0.361 | 0.087 |
| 100801 | 25.2mg | 0.714 | 0.431 | 0.132 |
| 100802 | 25.8mg | 0.418 | 0.251 | 0.056 |
Determination of related substances result in table 2 capsule
| Sample lot number | Sample weighting amount | Total impurities content % | Taurochenodeoxycholic Acid content % | Other single largest impurity % |
| Commercially available surging rood | 32.1mg | 1.460 | 0.931 | 0.253 |
| 100801 | 32.3mg | 0.760 | 0.456 | 0.136 |
| 100901 | 33.9mg | 0.655 | 0.386 | 0.096 |
[0053]
| 100902 | 34.2mg | 0.467 | 0.265 | 0.061 |
These results suggest that, total assorted content, Taurochenodeoxycholic Acid content and other the maximum single assorted content except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid in the present invention in the bulk drug of ursodeoxycholic acid and preparation are all significantly less than the content of above-mentioned substance in commercially available surging rood.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.But these embodiment only limit to illustrate the present invention instead of the further restriction to protection scope of the present invention.Unreceipted experiment condition in the following example, according to normal condition.
Embodiment mono-
This experiment is studied the liver toxicity of the ursodeoxycholic acid sample containing different Taurochenodeoxycholic Acid impurity levels.
1. materials and methods
1.1 tested medicines: containing the ursodeoxycholic acid (lot number: 100810), white powder, makes by oneself of Taurochenodeoxycholic Acid impurity level 2%; Containing the ursodeoxycholic acid (lot number: 100811), white powder, makes by oneself of Taurochenodeoxycholic Acid impurity level 1%; Containing the ursodeoxycholic acid (lot number: 100812), white powder, makes by oneself of Taurochenodeoxycholic Acid impurity level 0.7%; Containing the ursodeoxycholic acid (lot number: 100813), white powder, makes by oneself of Taurochenodeoxycholic Acid impurity level 0.5%; Above sample is all water insoluble.
1.2 detection reagent: liver function correlation detection test kit is bought from Sichuan Michelson's thing Science and Technology Ltd., mainly comprises: gpt (ALT), glutamic-oxal(o)acetic transaminase (AST).
1.3 detecting instruments: full wavelength fluorescent, point optical detector (MD company of the U.S.)
1.4 method
Adopt 60 of normal SD rats, be divided at random 5 groups, be respectively the ursodeoxycholic acid group (2% group) containing Taurochenodeoxycholic Acid impurity level 2%, containing the ursodeoxycholic acid group (1% group) of Taurochenodeoxycholic Acid impurity level 1%, containing the ursodeoxycholic acid group (0.7% group) of Taurochenodeoxycholic Acid impurity level 0.7%, containing the ursodeoxycholic acid group (0.5% group) of Taurochenodeoxycholic Acid impurity level 0.5%, placebo group (giving the physiological saline of same volume), according to dosage 50mg/kg gastric infusion of each medicine group, once a day, continuous 20 days (above-mentioned dosage is that conversion obtains according to quantity).Duration of test detects rat liver function related biochemical indicator gpt (ALT), glutamic-oxal(o)acetic transaminase (AST) respectively at administration for the 5th, 10,20 days, and the method that detection method reference reagent box provides is carried out.
2. result
Observed gastric infusion and respectively organized rat ALT and AST level in 5,10,20 days, result shows, the not obviously change (table 3) of rat ALT and AST level is respectively organized in administration 5 days.But when administration 10 days, be increased significantly trend containing the ursodeoxycholic acid group (2% group) of Taurochenodeoxycholic Acid impurity level 2% with containing ALT and the AST mean value of ursodeoxycholic acid group (1% group) rat of Taurochenodeoxycholic Acid impurity level 1%, relatively have significant difference (P < 0.05) with placebo; All the other each medicine groups and placebo group are relatively without significant difference (be shown in table 4).When successive administration to 20 day, the ALT or the AST mean value that contain ursodeoxycholic acid group (2% group) rat of Taurochenodeoxycholic Acid impurity level 2% still maintain higher level, relatively there is significant difference (P < 0.05) with placebo, but have a declining tendency; The ALT and the AST mean value level that contain ursodeoxycholic acid group (1% group) rat of Taurochenodeoxycholic Acid impurity level 1% recover normal substantially, with relatively no difference of science of statistics (P > 0.05) of placebo; Simultaneously containing Taurochenodeoxycholic Acid impurity level 0.7% and normal containing ALT and the AST mean value level of ursodeoxycholic acid group (0.7% group and the 0.5% group) rat of Taurochenodeoxycholic Acid impurity level 0.5%, with placebo group relatively without significant difference (in table 5).
The impact of table 3 administration each reagent in 5 days on rat liver function related biochemical indicator
The impact of table 4 administration each reagent in 10 days on rat liver function related biochemical indicator
* with the comparison of placebo rat, P < 0.05
The impact of table 5 administration each reagent in 20 days on rat liver function related biochemical indicator
* with the comparison of placebo rat, P < 0.05
3. conclusion and discussion
Cause that Liver Function index ALT and AST mean value raise from administration the 10th day containing the ursodeoxycholic acid group of Taurochenodeoxycholic Acid impurity level 2%, and continue to the 20th day.Ursodeoxycholic acid group containing Taurochenodeoxycholic Acid impurity level 1% only causes on the 10th day that in administration rat ALT and AST level raise, and in the time of the 20th day, recovers normal.Containing the ursodeoxycholic acid group of Taurochenodeoxycholic Acid impurity level 0.7%, all keep normal level containing the ursodeoxycholic acid group of Taurochenodeoxycholic Acid impurity level 0.5% ALT or AST mean value in 20 days.The above results explanation Taurochenodeoxycholic Acid foreign matter content height can cause Liver Function infringement, and this hepatic disorder effect exists dose-dependence.Therefore control Taurochenodeoxycholic Acid impurity level in ursodeoxycholic acid and can effectively avoid the infringement of liver function.
The preparation of embodiment bis-highly purified ursodeoxycholic acids
A) preparation of ursodeoxycholic acid crude product, carry out according to the following steps:
In reactor, add 4.0KG ursodesoxycholic acid, add 19KG acetone, under stirring, add triethylamine 1650ml, open chuck refrigeration, the temperature of mixed solution is down to-10 DEG C.Stream adds Vinyl chloroformate 1120ml; control the speed that adds of Vinyl chloroformate; make between maintain-5-0 of reacting liquid temperature DEG C; 30 minutes time, add; continue holding temperature stirring reaction 40 minutes; make the mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate; use nitrogen press filtration to 4.2KG purified water is housed by strainer above-mentioned mixed anhydride reaction liquid; 1.4KG taurine; in 50 liters of reactors of 0.4KG sodium hydroxide; fully stirring reaction 3 hours, further makes ursodeoxycholic acid crude product 4.0KG.
B) ursodeoxycholic acid crude product is refining, carries out according to the following steps:
(1) 4.0KG ursodeoxycholic acid is dropped in 50L reactor, adds 4KG water and 580ml acetone,, heated and stirred is to all dissolving;
(2) be cooled to-5-0 DEG C under stirring, crystallization 30 hours;
(3) be discharged to suction filtration in strainer; drain rear with frozen water (3-0 DEG C) drip washing filter cake; again drain; obtain ursodeoxycholic acid 3.3KG (purity 99.6%; HPLC); wherein the content of Taurochenodeoxycholic Acid is 0.3%, other maximum single assorted content 0.05% (liquid chromatogram measuring)
The preparation method of embodiment tri-highly purified ursodeoxycholic acids
A) preparation of ursodeoxycholic acid crude product, carry out according to the following steps:
In reactor, add 40.0KG ursodesoxycholic acid, add 190KG acetone, under stirring, add triethylamine 16.5L, open chuck refrigeration, the temperature of mixed solution is down to-5 DEG C.Stream adds Vinyl chloroformate 11.2L; control the speed that adds of Vinyl chloroformate; reacting liquid temperature is maintained between 3-5 DEG C; 30 minutes time, add; continue holding temperature stirring reaction 30 minutes; make the mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate; use nitrogen press filtration to 42KG purified water is housed by strainer above-mentioned mixed anhydride reaction liquid; 14KG taurine; in 500 liters of reactors of 4KG sodium hydroxide; fully stirring reaction 3 hours, further makes ursodeoxycholic acid crude product 39.8KG.
B) ursodeoxycholic acid crude product is refining, carries out according to the following steps:
(1) 39.8KG ursodeoxycholic acid is dropped in 500L reactor, adds 40KG water and 3334ml acetone,, heated and stirred is to all dissolving;
(2) under stirring, be cooled to 3-5 DEG C, crystallization 48 hours;
(3) be discharged to suction filtration in strainer; drain rear with frozen water (0-3 DEG C) drip washing filter cake; again drain; obtain ursodeoxycholic acid 32.8KG (purity 99.2%; HPLC); wherein the content of Taurochenodeoxycholic Acid is 0.6%, other maximum single assorted content 0.12% (liquid phase look is dived and measured)
The preparation method of embodiment tetra-highly purified ursodeoxycholic acids
A) preparation of ursodeoxycholic acid crude product, carry out according to the following steps:
In reactor, add 30.0KG ursodesoxycholic acid, add 142.5KG acetone, under stirring, add triethylamine 12.38L, open chuck refrigeration, the temperature of mixed solution is down to 0 DEG C.Stream adds Vinyl chloroformate 8.4L; control the speed that adds of Vinyl chloroformate; reacting liquid temperature is maintained between 0-5 DEG C; 20 minutes time, add; continue holding temperature stirring reaction 35 minutes; make the mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate; use nitrogen press filtration to 31.5KG purified water is housed by strainer above-mentioned mixed anhydride reaction liquid; 10.5KG taurine; in 500 liters of reactors of 3KG sodium hydroxide; fully stirring reaction 3 hours, further makes ursodeoxycholic acid crude product 28.9KG.
B) ursodeoxycholic acid crude product is refining, carries out according to the following steps:
(1) 28.9KG ursodeoxycholic acid is dropped in 500L reactor, add 30KG water and 3000ml acetone, heated and stirred is to all dissolving;
(2) under stirring, be cooled to 0 DEG C, crystallization 35 hours;
(3) be discharged to suction filtration in strainer; drain rear with frozen water (0-3 DEG C) drip washing filter cake; again drain; obtain ursodeoxycholic acid 23.5KG (purity 99.3%; HPLC); wherein the content of Taurochenodeoxycholic Acid is 0.4%, other maximum single assorted content 0.09% (liquid chromatogram measuring)
The preparation method of embodiment five highly purified ursodeoxycholic acids
A) preparation of ursodeoxycholic acid crude product, carry out according to the following steps:
In reactor, add 20.0KG ursodesoxycholic acid, add 95KG acetone, under stirring, add triethylamine 8.25L, open chuck refrigeration, the temperature of mixed solution is down to-6 DEG C.Stream adds Vinyl chloroformate 5.6L; control the speed that adds of Vinyl chloroformate; reacting liquid temperature is maintained between 0-3 DEG C; 15 minutes time, add; continue holding temperature stirring reaction 40 minutes; make the mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate; use nitrogen press filtration to 21KG purified water is housed by strainer above-mentioned mixed anhydride reaction liquid; 7KG taurine; in 500 liters of reactors of 2KG sodium hydroxide; fully stirring reaction 3 hours, further makes ursodeoxycholic acid crude product 18.9KG.
B) ursodeoxycholic acid crude product is refining, carries out according to the following steps:
(1) 18.9KG ursodeoxycholic acid is dropped in 500L reactor, add 20KG water and 2230ml acetone, heated and stirred is to all dissolving;
(2) be cooled to-2-1 DEG C under stirring, crystallization 35 hours;
(3) be discharged to suction filtration in strainer; drain rear with frozen water (0-3 DEG C) drip washing filter cake; again drain; obtain ursodeoxycholic acid 15.55KG (purity 99.4%; HPLC); wherein the content of Taurochenodeoxycholic Acid is 0.38%, other maximum single assorted content 0.09% (liquid chromatogram measuring)
The preparation method of embodiment six highly purified ursodeoxycholic acids
A) preparation of ursodeoxycholic acid crude product, carry out according to the following steps:
In reactor, add 2.0KG ursodesoxycholic acid, add 9.5KG acetone, under stirring, add triethylamine 825ml, open chuck refrigeration, the temperature of mixed solution is down to-6 DEG C.Stream adds Vinyl chloroformate 0.56L; control the speed that adds of Vinyl chloroformate; reacting liquid temperature is maintained between 0-3 DEG C; 30 minutes time, add; continue holding temperature stirring reaction 20 minutes; make the mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate; use nitrogen press filtration to 2.1KG purified water is housed by strainer above-mentioned mixed anhydride reaction liquid; 0.7KG taurine; in 50 liters of reactors of 0.2KG sodium hydroxide; fully stirring reaction 3 hours, further makes ursodeoxycholic acid crude product 2.2KG.
B) ursodeoxycholic acid crude product is refining, carries out according to the following steps:
(1) 2KG ursodeoxycholic acid is dropped in 50L reactor, add 2KG water and 200ml acetone, heated and stirred is to all dissolving;
(2) be cooled to-3-0 DEG C under stirring, crystallization 40 hours;
(3) be discharged to suction filtration in strainer; drain rear with frozen water (0-3 DEG C) drip washing filter cake; again drain; obtain ursodeoxycholic acid 1.61KG (purity 99.5%; HPLC); wherein the content of Taurochenodeoxycholic Acid is 0.3%, other maximum single assorted content 0.08% (liquid chromatogram measuring)
Embodiment seven is containing the pharmaceutical composition of high purity ursodeoxycholic acid
In every 1000 ursodeoxycholic acid pharmaceutical compositions, contain:
Ursodeoxycholic acid 250g prepared by embodiment 2
Lactose 36g
Microcrystalline Cellulose 20g
Starch 10g
Magnesium Stearate 4g
PVP K30 is appropriate
95% appropriate amount of ethanol
Note: tamanori is 95% ethanol of 5% PVP K30
Highly purified ursodeoxycholic acid, lactose, Microcrystalline Cellulose, starch, Magnesium Stearate prepared by embodiment 2 are crossed respectively 80 mesh sieves.Again 250g ursodeoxycholic acid is mixed with 36g lactose, 20g Microcrystalline Cellulose, 10g starch; mix the 95% ethanolic soln processed softwood (every 64 gram approximately need 7ml slurr) of rear use containing 5%PVP; then cross 20 mesh sieves and make wet grain, the grain that will wet is positioned over 50-60 DEG C and is dried.The grain that will wet is dry, adds the Magnesium Stearate of 4g to mix dry granular after the whole grain of 40 mesh sieves, packs No. 0 capsule (compacting) into.
Claims (2)
1. a preparation method for highly purified ursodeoxycholic acid, it is to be made up after mixed acid anhydride of ursodesoxycholic acid and Vinyl chloroformate, then recrystallization and obtaining after reacting completely with taurine, only uses acetone, two kinds of solvents of water in whole technological process;
Wherein mixed acid anhydride is prepared by following methods: in reactor, add ursodesoxycholic acid and acetone, under stirring, add triethylamine, open refrigeration, be cooled to-10～-5 DEG C, stream adds Vinyl chloroformate, controls and adds speed to make reacting liquid temperature be no more than 5 DEG C, within 15-30 minute, add, continue insulated and stirred 20-40 minute;
Described recrystallizing technology is as follows:
(1) ursodeoxycholic acid crude product is dropped in reactor, add acetone and purified water, wherein the volume of acetone and the weight ratio of water are 1: 7～1: 12, and heated and stirred is to all dissolving;
(2) under stirring, be cooled to-5～5 DEG C, crystallization 30-48 hour;
(3) be discharged to suction filtration in strainer, drain the frozen water drip washing filter cake of rear use-5～5 DEG C, again drain;
The ursodeoxycholic acid preparing is measured with liquid phase chromatogram condition and method, and the amount of Taurochenodeoxycholic Acid is wherein less than 0.7%, and the assorted amount of maximum list except taurine, ursodesoxycholic acid, Taurochenodeoxycholic Acid is less than 0.15%.
2. the preparation method of high purity ursodeoxycholic acid according to claim 1, is characterized in that the volume of acetone and the weight ratio of water are 1: 10.
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| CN104367561B (en) * | 2014-11-14 | 2017-10-13 | 成都新恒创药业有限公司 | A kind of preparation method of Tauro ursodesoxy cholic acid preparation |
| CN105784854B (en) * | 2014-12-23 | 2020-06-16 | 重庆药友制药有限责任公司 | Method for detecting related substances in tauroursodeoxycholic acid |
| CN104434874B (en) * | 2015-01-04 | 2017-05-17 | 扬子江药业集团四川海蓉药业有限公司 | Tauroursodeoxycholic acid capsule and preparation method thereof |
| CN105601705B (en) * | 2015-12-23 | 2020-04-14 | 国药一心制药有限公司 | Preparation method of bortezomib |
| CN110183506A (en) * | 2019-06-27 | 2019-08-30 | 浙江天顺药业有限公司 | A kind of cow-bezoar ursodesoxycholic acid and preparation method thereof |
| CN110376301A (en) * | 2019-07-01 | 2019-10-25 | 四川利民中药饮片有限责任公司 | The detection method of Tauro ursodesoxy cholic acid and its salt in bear gall juice dried frozen aquatic products |
| CN111135153A (en) * | 2020-01-21 | 2020-05-12 | 安士制药（中山）有限公司 | Ursodeoxycholic acid capsule and preparation method thereof |
| CN113583076A (en) * | 2021-08-07 | 2021-11-02 | 浙江天顺药业有限公司 | Anthragma bear deoxycholic acid and preparation method thereof |
| CN114539342B (en) * | 2022-02-28 | 2023-07-04 | 成都百途医药科技有限公司 | Preparation method of mixed anhydride and industrialized preparation method of tauroursodeoxycholic acid dihydrate |
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| US5508453A (en) * | 1993-05-20 | 1996-04-16 | Sanofi | Intermediate for use in the preparation of taurocholanic acids |
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