CN112645998A - Method for synthesizing tauroursodeoxycholic acid under catalysis of boric acid ester - Google Patents
Method for synthesizing tauroursodeoxycholic acid under catalysis of boric acid ester Download PDFInfo
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- CN112645998A CN112645998A CN202011531308.0A CN202011531308A CN112645998A CN 112645998 A CN112645998 A CN 112645998A CN 202011531308 A CN202011531308 A CN 202011531308A CN 112645998 A CN112645998 A CN 112645998A
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Abstract
The invention relates to the technical field of medicine synthesis, and discloses a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester3)2)3. According to the method, the boric acid ester is used as the catalyst to synthesize the tauroursodeoxycholic acid, the atom utilization rate is high, a product with a single structure is obtained, the application range of the substrate is wide, and the tolerance of a functional group is stronger; solves the problems of high synthesis cost and difficult industrial application in the prior art.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester.
Background
Tauroursodeoxycholic acid is an effective component of bear bile, called TUDCA for short, and has a chemical name of 3 alpha, 7 beta-dihydroxy-cholanoyl-N-taurine. Tauroursodeoxycholic acid has spasmolytic, anticonvulsive, anti-inflammatory and cholelithiasis dissolving effects, is mainly used for treating cholecystolith calculus, primary sclerosing cholangitis, primary biliary cirrhosis, chronic viral hepatitis C and the like in clinic, and is concerned by a large number of synthesizers.
Tauroursodeoxycholic acid is a conjugated bile acid formed by the shrinkage of a carboxyl group of ursodeoxycholic acid and a taurine amino group, and in recent years, research on tauroursodeoxycholic acid has been actively conducted, and chemical synthesis thereof has attracted much attention. The current chemical synthesis methods are mainly divided into three categories: a mixed acid anhydride-phenol ester method, a condensing agent method, and an activated thioester method. The condensing agent method is to form an amide directly under the action of a condensing agent. At present, when tauroursodeoxycholic acid is prepared by a condensing agent method, a reagent such as 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine salt (DMTMM) chloride is often used as the condensing agent, and the condensing agent is expensive, is not favorable for cost control, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester, and aims to solve the problems that in the prior art, when the tauroursodeoxycholic acid is chemically synthesized, the synthesis method is high in cost and is not suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme: reacting ursodeoxycholic acid and taurine under the action of boric acid ester to obtain tauroursodeoxycholic acid, wherein the structural formula of the boric acid ester is B (OCH (CF)3)2)3。
The principle and the advantages of the scheme are as follows: in the technical scheme, ursodeoxycholic acid and taurine are used as raw materials, and boric acid ester (B (OCH (CF)3)2)3) Under the condition of being used as a catalyst, the carboxyl of the ursodesoxycholic acid and the taurine amino are subjected to shrinkage to synthesize the tauroursodeoxycholic acid. Wherein, boronThe acid ester belongs to inorganic acid ester compounds, is a novel organic catalyst, and can be generally used as an efficient and environment-friendly lubricant, an antirust agent, a modified nano-material rubber filler, a surfactant and the like. The technical scheme takes the catalyst as a catalyst for synthesis reaction, so that the reaction rate is high, and the reaction yield is high; b (OCH (CF)3)2)3The functional group has strong tolerance, and hydroxyl in ursodeoxycholic acid cannot influence the reaction; in B (OCH (CF)3)2)3Under the catalysis of the catalyst, a product with a single structure can be obtained, isomerization cannot occur, and the post-treatment process is simple and easy to operate. In addition, no extra reagent is needed to be added in the reaction process to assist the reaction, the tauroursodeoxycholic acid is directly prepared by a one-pot method, no intermediate is separated, the process route is simplified, and in addition, the borate ester is relatively low in price and can be suitable for industrial batch production.
Preferably, as an improvement, ursodeoxycholic acid is dissolved by an organic solvent before reaction, and the adding ratio of the ursodeoxycholic acid to the organic solvent is 1 g: 2-10 ml.
In the technical scheme, the addition proportion range of the ursodeoxycholic acid and the organic solvent can ensure the effective dissolution of the ursodeoxycholic acid, and simultaneously waste caused by excessive organic solvent is avoided.
Preferably, as a modification, the organic solvent is one or more of dichloromethane, acetonitrile, methanol, ethanol, tetrahydrofuran, and N, N-dimethylformamide.
In the technical scheme, the addition type of the organic solvent is optimized, and the organic solvent can ensure the dissolution of ursodeoxycholic acid and is beneficial to the later amidation reaction.
Preferably, as a modification, the organic solvent is a mixture of acetonitrile and tetrahydrofuran, and the volume ratio of the acetonitrile to the tetrahydrofuran is 5: 1.
In the technical scheme, through the optimization of the organic solvent and experimental verification, the acetonitrile: under the condition that tetrahydrofuran is 5:1, ursodeoxycholic acid can be fully dissolved, and the yield of the tauroursodeoxycholic acid can be ensured to be about 90% by combining the proportion of reaction raw materials and the optimization of reaction conditions.
Preferably, as an improvement, in S2, the molar ratio of ursodeoxycholic acid, taurine and boric acid ester is 1: 1-3: 1-5.
In the technical scheme, the addition amount of the catalyst is optimized, the waste of resources can be avoided on the basis of ensuring the full catalysis, and the proportion is the optimal proportion range verified by tests.
Preferably, as an improvement, in S2, the molar ratio of ursodeoxycholic acid, taurine and boric acid ester is 1: 1-2: 1-3.
In the technical scheme, in the synthetic process of tauroursodeoxycholic acid, insufficient reaction can be caused due to too little catalyst, side reaction is increased due to excessive catalyst, the yield of the tauroursodeoxycholic acid is reduced, the waste of resources can be avoided on the basis of ensuring sufficient catalysis through optimizing the addition amount of the catalyst, and the proportion is the optimal proportion range verified by experiments.
Preferably, as an improvement, the reaction condition of the ursodeoxycholic acid and the taurine is that the temperature is raised to 20-80 ℃ for 6-10 hours.
In the technical scheme, ursodeoxycholic acid and taurine react under the reaction conditions, so that the yield of tauroursodeoxycholic acid can be ensured, and the reaction can be completed after 6-10 hours.
Preferably, as an improvement, the tauroursodeoxycholic acid is obtained and then subjected to purification treatment, wherein the purification treatment comprises extraction, washing, acidification, filtration and concentration.
According to the technical scheme, after the tauroursodeoxycholic acid is preliminarily prepared through condensation reaction, the impurities in the product can be effectively removed through the operations of extraction, washing, acidification, filtration, concentration and the like, the purity of the finished product is improved, and the pure product of the tauroursodeoxycholic acid is obtained.
Preferably, as an improvement, in the extraction step, the extractant is dichloromethane, and the addition ratio of the tauroursodeoxycholic acid to the extractant is 1 g: 3-10 ml, stirring for 10-30 min during extraction, and standing for 20-40 min.
In the technical scheme, when the adding proportion of the extracting agent is determined, a tauroursodeoxycholic acid crude product prepared by reacting ursodesoxycholic acid and taurine is taken as a reference, the extraction condition is the most suitable extraction condition verified by experiments, and the tauroursodeoxycholic acid can be effectively purified by utilizing dichloromethane.
Preferably, as an improvement, in the washing step, the detergent is a saturated sodium carbonate solution, and the addition ratio of the tauroursodeoxycholic acid to the detergent is 1 g: 4-6 ml, stirring for 10-30 min during washing, and standing for 20-40 min.
In the technical scheme, when the addition proportion of the detergent is determined, a tauroursodeoxycholic acid crude product prepared by reacting ursodesoxycholic acid and taurine is taken as a reference, the washing condition is the optimum extraction condition verified by tests, and the saturated sodium carbonate can be used for effectively extracting and purifying the tauroursodeoxycholic acid.
Drawings
FIG. 1 is a liquid phase diagram of a sample of example 14.
FIG. 2 is a liquid phase diagram of the standard of example 14.
Detailed Description
The following is further detailed by way of specific embodiments:
example 1
Ursodeoxycholic acid (cas: 128-13-2), taurine (cas: 07-35-7), tauroursodeoxycholic acid (cas: 14605-22-2) are respectively shown as formula (I) -formula (III), and the formula of the boric acid ester is as follows: b (OCH (CF)3)2)3The synthetic process of tauroursodeoxycholic acid in this example is shown as formula (IV).
The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester comprises the following steps:
s1: adding 1mol of ursodeoxycholic acid into an organic solvent, placing the mixture on a magnetic stirrer, and uniformly stirring the mixture at the rotating speed of 180rpm, wherein the organic solvent in the embodiment is dichloromethane, and the adding ratio of the ursodeoxycholic acid to the organic solvent is 1 g: 4 ml;
s2: adding 1mol of taurine and 1.5mol of boric acid ester into the dissolved reaction system, and reacting for 6 hours under a heating reflux state after the addition of the taurine and the boric acid ester is finished to obtain tauroursodeoxycholic acid;
s3: after the reaction is finished, extracting, washing, acidifying, filtering and concentrating to obtain a pure tauroursodeoxycholic acid product; in the extraction step, the extractant is dichloromethane, and the addition ratio of the dichloromethane to the tauroursodeoxycholic acid is 1 g: 4ml, stirring for 20min during extraction, and standing for 30 min; in the washing step, the detergent is a saturated sodium carbonate solution, and the addition ratio of the saturated sodium carbonate solution to the tauroursodeoxycholic acid is 1 g: 4ml, stirring for 20min while washing, and standing for 30 min. Collecting solid tauroursodeoxycholic acid (sampling to be detected, sample for short), and calculating the yield of the tauroursodeoxycholic acid to be 10%.
Examples 1 to 17 and comparative examples 1 to 9, wherein the default amount of ursodeoxycholic acid added is 1mol and the amount of solvent is 1 g: 4ml means that the addition ratio of ursodeoxycholic acid to organic solvent was 1g ursodeoxycholic acid dissolved in 4ml organic solvent, and the results are expressed as an average number for each treatment group in three replicates.
TABLE 1
Note: in the above table, B (OCH (CF)3)2)3Representing a borate catalyst, DCM representing dichloromethane, CH3CN represents acetonitrile, CH3OH for methanol, EtOH for ethanol, THF for tetrahydrofuran, DMF for N, N-dimethylformamide, TUDCA for tauroursodeoxycholic acid.
As can be seen from Table 1, the types of organic solvents in examples 2-10 were adjusted, and the results show that the type of solvent has a large influence on the yield of TUDCA with a constant amount of solvent, wherein DCM and CH3CN、CH3When OH, EtOH, THF and DMF are independently used as solvents, the yield of TUDCA is obviously lower than that of the compound use of organic solvents, wherein CH3When CN and THF are mixed and used in a volume ratio of 5:1, the yield of TUDCA after the later-stage synthesis reaction is optimal.
Examples 11 to 13 and comparative examples 1 to 2, in which the amount of taurine added was adjusted, showed that the yield of TUDCA was not greatly affected by the addition of 1 to 2mol of taurine and the excessive addition of taurine, but the synthesis reaction was affected by the insufficient amount of taurine, and the yield of TUDCA decreased accordingly.
The results of examples 14 to 17 and comparative examples 5 to 6, in which the amount of the catalyst added was adjusted, show that the amount of the catalyst added has a great influence on the yield of TUDCA, and when the amount of the catalyst added is too low, the progress of the synthesis reaction is affected, so that the reaction is insufficient, and the yield of TUDCA is reduced; when the amount of the catalyst is too large, the side reaction is high, which also results in a decrease in the yield of TUDCA.
The comparative examples 3 to 4 adjust the types of the catalysts, and the yield of the TUDCA is obviously reduced and is less than 30% of that of the TUDCA in the technical scheme on the premise of not changing other reaction conditions. Comparative examples 7-9, in which the reaction temperature was adjusted, show that the chemical synthesis of tauroursodeoxycholic acid was also possible at normal temperature and relatively low temperature, but the yield of TUDCA was relatively low, and also at high temperature, but the yield of TUDCA was also decreased.
And (3) structural verification of the compound:
the condition of the synthesized product (sample) was checked by liquid chromatography, and tauroursodeoxycholic acid having a purity of 99% was used as a standard. The liquid chromatogram of the sample prepared in example 14 is shown in fig. 1, with the abscissa being time, unit: and in minutes, the liquid chromatogram of the standard substance is shown in figure 2, and by comparing the figure 1 with the figure 2, the retention time of the tauroursodeoxycholic acid peak is consistent, which indicates that the scheme successfully synthesizes the tauroursodeoxycholic acid. Further, the sample is identified as tauroursodeoxycholic acid through nuclear magnetic resonance detection and identification. In addition, the spectrum shows that the tauroursodeoxycholic acid prepared by the technical scheme has few miscellaneous peaks and the product is relatively single.
The foregoing is merely an example of the present invention and common general knowledge in the art of designing and/or characterizing particular aspects and/or features is not described in any greater detail herein. It should be noted that, for those skilled in the art, without departing from the technical solution of the present invention, several variations and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (10)
1. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester is characterized by comprising the following steps: reacting ursodeoxycholic acid and taurine under the action of boric acid ester to obtain tauroursodeoxycholic acid, wherein the molecular formula of the boric acid ester is B (OCH (CF)3)2)3。
2. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 1, characterized in that: dissolving ursodeoxycholic acid in an organic solvent before reaction, wherein the addition ratio of the ursodeoxycholic acid to the organic solvent is 1 g: 2-10 ml.
3. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 2, characterized in that: the organic solvent is one or more of dichloromethane, acetonitrile, methanol, ethanol, tetrahydrofuran and N, N-dimethylformamide.
4. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 3, characterized in that: the organic solvent is a mixture of acetonitrile and tetrahydrofuran, and the volume ratio of the acetonitrile to the tetrahydrofuran is 5: 1.
5. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 4, characterized in that: the mole ratio of the ursodeoxycholic acid, the taurine and the boric acid ester is 1: 1-3: 1-5.
6. The borate ester catalyzed method for synthesizing tauroursodeoxycholic acid according to claim 5, characterized in that: in S2, the molar ratio of ursodeoxycholic acid, taurine and boric acid ester is 1: 1-2: 1-3.
7. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 6, characterized in that: the reaction condition of the ursodeoxycholic acid and the taurine is that the temperature is raised to 20-80 ℃ for reaction for 6-10 hours.
8. The borate ester catalyzed method for synthesizing tauroursodeoxycholic acid according to claim 7, characterized in that: and purifying the obtained tauroursodeoxycholic acid, wherein the purification treatment comprises extraction, washing, acidification, filtration and concentration.
9. The borate ester catalyzed method for synthesizing tauroursodeoxycholic acid according to claim 8, characterized in that: in the extraction step, the extractant is dichloromethane, and the addition ratio of the tauroursodeoxycholic acid to the extractant is 1 g: 3-10 ml, stirring for 10-30 min during extraction, and standing for 20-40 min.
10. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 9, characterized in that: in the washing step, the detergent is a saturated sodium carbonate solution, and the addition ratio of the tauroursodeoxycholic acid to the detergent is 1 g: 4-6 ml, stirring for 10-30 min during washing, and standing for 20-40 min.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112588319A (en) * | 2020-12-22 | 2021-04-02 | 重庆极泽生物科技有限公司 | Application of silane and synthesis of tauroursodeoxycholic acid under catalysis of silane |
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| CN103183716A (en) * | 2011-12-31 | 2013-07-03 | 山东天绿制药有限公司 | Preparation method of tauro ursodesoxy cholic acid |
| CN111825737A (en) * | 2019-04-16 | 2020-10-27 | 迪法玛弗朗西斯有限公司 | Purification of cholanic acid conjugates |
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Patent Citations (3)
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| CN101307088A (en) * | 2008-07-08 | 2008-11-19 | 四川大学 | Method for preparing cholic acid conjugates |
| CN103183716A (en) * | 2011-12-31 | 2013-07-03 | 山东天绿制药有限公司 | Preparation method of tauro ursodesoxy cholic acid |
| CN111825737A (en) * | 2019-04-16 | 2020-10-27 | 迪法玛弗朗西斯有限公司 | Purification of cholanic acid conjugates |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112588319A (en) * | 2020-12-22 | 2021-04-02 | 重庆极泽生物科技有限公司 | Application of silane and synthesis of tauroursodeoxycholic acid under catalysis of silane |
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