CN112645998B - Method for synthesizing tauroursodeoxycholic acid under catalysis of borate - Google Patents
Method for synthesizing tauroursodeoxycholic acid under catalysis of borate Download PDFInfo
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- CN112645998B CN112645998B CN202011531308.0A CN202011531308A CN112645998B CN 112645998 B CN112645998 B CN 112645998B CN 202011531308 A CN202011531308 A CN 202011531308A CN 112645998 B CN112645998 B CN 112645998B
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Abstract
The application relates to the technical field of medicine synthesis, and discloses a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester, wherein ursodeoxycholic acid and taurine react under the action of boric acid ester to obtain tauroursodeoxycholic acid, and the molecular formula of the boric acid ester is B (OCH (CF) 3 ) 2 ) 3 . The method adopts the borate as the catalyst to synthesize the tauroursodeoxycholic acid, has high atom utilization rate in the method, obtains a product with a single structure, has wide application range to a substrate and has stronger tolerance to functional groups; solves the problems of high synthesis cost and difficult industrial application in the prior art.
Description
Technical Field
The application relates to the technical field of medicine synthesis, in particular to a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester.
Background
Tauroursodeoxycholic acid is an active ingredient of bear bile, and is called TUDCA for short, and the chemical name is 3 alpha, 7 beta-dihydroxyl-cholanoyl-N-taurine. Tauroursodeoxycholic acid has the functions of spasmolysis, anticonvulsant, anti-inflammatory, cholelithiasis dissolving and the like, is mainly used for treating cholecystolithiasis, primary sclerosing cholangitis, primary biliary cirrhosis, chronic viral hepatitis C and the like clinically, and is focused by vast synthesizer workers.
Tauroursodeoxycholic acid is a conjugated bile acid formed by shrinking between carboxyl groups of ursodeoxycholic acid and taurine amino groups, and research on tauroursodeoxycholic acid has been very active in recent years, and chemical synthesis thereof has been attracting attention. At present, the chemical synthesis methods are mainly divided into three types: the mixed anhydride-phenolic ester method, the condensing agent method and the active thioester method. The condensing agent method refers to the method that amide is directly formed under the action of 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) is frequently used as the condensing agent, and the reagent is high in price, unfavorable for controlling the cost and not suitable for industrial production.
Disclosure of Invention
The application aims to provide a method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester, which aims to solve the problems that the synthesis method has high cost and is not suitable for industrial production when the tauroursodeoxycholic acid is chemically synthesized in the prior art.
In order to achieve the above purpose, the application adopts the following technical scheme: ursodeoxycholic acid and taurine are reacted 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 proposal, ursodeoxycholic acid and taurine are used as raw materials, and the raw materials are mixed with boric acid ester (B (OCH (CF) 3 ) 2 ) 3 ) Under the condition of serving as a catalyst, the carboxyl of ursodeoxycholic acid and taurine amino are glycided to synthesize tauroursodeoxycholic acid. Wherein, the borate 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, and has the advantages of high reaction rate and high reaction yield; b (OCH (CF) 3 ) 2 ) 3 The functional group has strong tolerance, and the hydroxyl in ursodeoxycholic acid can not influence the reaction; in B (OCH (CF) 3 ) 2 ) 3 Under the catalysis of the catalyst, a product with a single structure can be obtained, isomerization does not occur, and the post-treatment process is simple and easy to operate. In addition, no additional reagent is needed to assist in the reaction process, tauroursodeoxycholic acid is directly prepared by a one-pot method, the separation of intermediates is not needed, the process route is simplified, and in addition, the cost of the borate is relatively low, so that the method is suitable for industrialized mass production.
Preferably, as a modification, ursodeoxycholic acid is dissolved by an organic solvent before the reaction, and the addition ratio of ursodeoxycholic acid to the organic solvent is 1g: 2-10 ml.
In the technical scheme, the adding proportion range of the ursodeoxycholic acid and the organic solvent can ensure the effective dissolution of the ursodeoxycholic acid, and meanwhile, the 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 adding type of the organic solvent is optimized, and the organic solvent can ensure the dissolution of ursodeoxycholic acid and is beneficial to the implementation of the later amidation reaction.
Preferably, as a modification, the organic solvent is a mixture of acetonitrile and tetrahydrofuran, and the volume ratio of acetonitrile to tetrahydrofuran is 5:1.
In the technical scheme, through optimizing an organic solvent, experiments prove that acetonitrile: under the condition of tetrahydrofuran=5:1, ursodeoxycholic acid can be fully dissolved, and the yield of tauroursodeoxycholic acid can be ensured to be about 90 percent by combining the optimization of the proportion of reaction raw materials and the reaction conditions.
Preferably, as a modification, in S2, the molar ratio of ursodeoxycholic acid, taurine and boric acid ester is 1:1-3:1-5.
In the technical scheme, the catalyst addition amount is optimized, so that the waste of resources can be avoided on the basis of ensuring sufficient catalysis, and the proportion is the optimal proportion range verified by the test.
Preferably, as a modification, 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 synthesis process of tauroursodeoxycholic acid, the catalyst is too small to cause insufficient reaction, and the catalyst is excessive to cause side reaction to increase, so that the yield of tauroursodeoxycholic acid is reduced, and the waste of resources can be avoided on the basis of ensuring sufficient catalysis by optimizing the addition amount of the catalyst, so that the ratio is the optimal ratio range verified by experiments.
Preferably, as a modification, the reaction condition of ursodeoxycholic acid and taurine is that the temperature is raised to 20-80 ℃ for reaction for 6-10 h.
In the technical scheme, ursodeoxycholic acid and taurine react under the reaction conditions, so that the yield of the tauroursodeoxycholic acid can be ensured, and the tauroursodeoxycholic acid can completely react after 6-10 hours.
Preferably, as a modification, the tauroursodeoxycholic acid is obtained and then subjected to a purification treatment including extraction, washing, acidification, filtration and concentration.
In the technical scheme, after the tauroursodeoxycholic acid is preliminarily prepared through condensation reaction, impurities in the product can be effectively removed through operations such as extraction, washing, acidification, filtration, concentration and the like, the purity of the product is improved, and the pure tauroursodeoxycholic acid product is obtained.
Preferably, as a modification, in the extraction step, the extractant is methylene dichloride, and the addition ratio of tauroursodeoxycholic acid to the extractant is 1g: 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 extractant is determined, crude tauroursodeoxycholic acid prepared by the reaction of ursodeoxycholic acid and taurine is taken as a reference, the extraction conditions are the optimal extraction conditions verified by experiments, and the tauroursodeoxycholic acid can be effectively purified by using dichloromethane.
Preferably, as a modification, in the washing step, the detergent is saturated sodium carbonate solution, and the addition ratio of tauroursodeoxycholic acid to the detergent is 1g: 4-6 ml, stirring for 10-30 min during washing, and standing for 20-40 min.
In the technical scheme, when the adding proportion of the detergent is determined, the crude tauroursodeoxycholic acid prepared by the reaction of ursodeoxycholic acid and taurine is taken as a reference, the washing condition is the optimal extraction condition verified by a test, and saturated sodium carbonate can be used for effectively extracting and purifying tauroursodeoxycholic acid.
Drawings
FIG. 1 is a sample liquid phase diagram of example 14.
FIG. 2 is a liquid phase diagram of the standard of example 14.
Detailed Description
The following is a further detailed description of the embodiments:
example 1
Ursodeoxycholic acid (cas: 128-13-2), taurine (cas: 07-35-7) and tauroursodeoxycholic acid (cas: 14605-22-2) are respectively shown in the formulas (I) - (III), and the molecular formula of the boric acid ester is as follows: b (OCH (CF) 3 ) 2 ) 3 The synthesis process of tauroursodeoxycholic acid in this example is shown in formula (IV).
The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester comprises the following steps:
s1: 1mol of ursodeoxycholic acid is added into an organic solvent, and the organic solvent is placed on a magnetic stirrer and stirred uniformly at a rotating speed of 180rpm, wherein the organic solvent in the embodiment is methylene dichloride, and the addition ratio of the ursodeoxycholic acid to the organic solvent is 1g:4ml;
s2: adding 1mol of taurine and 1.5mol of boric acid ester into the dissolved reaction system, and reacting for 6 hours in a heating reflux state after the addition is finished to obtain tauroursodeoxycholic acid;
s3: extracting, washing, acidifying, filtering and concentrating after the reaction is finished to obtain pure tauroursodeoxycholic acid; in the extraction step, the extractant is dichloromethane, and the addition ratio of the dichloromethane to the tauroursodeoxycholic acid is 1g:4ml, stirring for 20min during extraction, and standing for 30min; in the washing step, the detergent is saturated sodium carbonate solution, and the adding ratio of the saturated sodium carbonate solution to tauroursodeoxycholic acid is 1g:4ml, stirring for 20min during washing, and standing for 30min. The solid tauroursodeoxycholic acid (sample to be detected, short for sample) was collected, and the yield of tauroursodeoxycholic acid was calculated to be 10%.
Examples 1-17, comparative examples 1-9 the settings of the parameters in the synthesis method are shown in the following table, wherein the default ursodeoxycholic acid addition amount is 1mol, 1g in solvent amount: 4ml means that ursodeoxycholic acid was dissolved in 4ml of organic solvent at an addition ratio of 1g ursodeoxycholic acid to organic solvent, and three repeated experiments were performed for each treatment group, and the results are expressed as an average.
TABLE 1
Note that: in the above table, B (OCH (CF) 3 ) 2 ) 3 Represents a borate catalyst, DCM represents dichloromethane, CH 3 CN represents acetonitrile, CH 3 OH represents methanol, etOH represents ethanol, THF represents tetrahydrofuran, DMF represents N, N-dimethylformamide, TUDCA represents tauroursodeoxycholic acid.
As is clear from Table 1, examples 2 to 10, in which the types of the organic solvents were respectively adjusted, showed that the types of the solvents had a large effect on TUDCA yield on the premise of a constant solvent addition amount, in which DCM and CH 3 CN、CH 3 OH, etOH, THF and DMF are used as solvents independently, the TUDCA yield is obviously lower than that of the organic solvent compounded use, wherein CH 3 When CN and THF are mixed in the volume ratio of 5:1, the TUDCA yield after the post-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 addition of 1 to 2mol of taurine did not greatly affect the TUDCA yield when the amount of taurine added was excessive, but the progress of the synthesis reaction was affected when the amount of taurine added was insufficient, and the TUDCA yield was decreased accordingly.
The catalyst addition amounts of examples 14 to 17 and comparative examples 5 to 6 were adjusted, and the results show that the catalyst addition amount has a large influence on the TUDCA yield, and when the catalyst addition amount is too low, the synthesis reaction is affected, the reaction is insufficient, and the TUDCA yield is reduced; and excessive addition of the catalyst leads to high side reactions and also to a decrease in TUDCA yield.
Comparative example 3-comparative example 4 the type of catalyst was adjusted, and the TUDCA yield was significantly reduced, not more than 30% of the TUDCA yield of the present technical scheme, without changing other reaction conditions. Comparative example 7-comparative example 9 the reaction temperature was adjusted, and the results show that chemical synthesis of tauroursodeoxycholic acid was also possible at normal temperature and relatively low temperature, but the TUDCA yield was relatively low, and also possible at high temperature, but the TUDCA yield was also decreased.
And (3) structural verification of the compound:
the condition of the synthesized product (sample) was detected using liquid chromatography, and tauroursodeoxycholic acid having a purity of 99% was used as a standard. Liquid chromatogram of the sample prepared in example 14 referring to fig. 1, the abscissa is time in units: in minutes, the liquid chromatogram of the standard substance is shown in fig. 2, and the retention time of tauroursodeoxycholic acid peaks is consistent in comparison between fig. 1 and fig. 2, which shows that tauroursodeoxycholic acid is successfully synthesized by the scheme. Further, the sample is identified by nuclear magnetic resonance detection to be tauroursodeoxycholic acid. In addition, according to the graph, the tauroursodeoxycholic acid prepared by the technical scheme has few impurity peaks and the product is relatively single.
The foregoing is merely exemplary of the present application, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present application, and these should also be regarded as the protection scope of the present application, which does not affect the effect of the implementation of the present application and the practical applicability of the patent. The protection scope of the present application is subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (8)
1. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester is characterized by comprising the following steps: ursodeoxycholic acid and taurine are reacted 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 The method comprises the steps of carrying out a first treatment on the surface of the Ursodeoxycholic acid is dissolved in organic solvent before reaction, wherein the organic solvent isAcetonitrile and tetrahydrofuran in the volume ratio of 5 to 1.
2. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 1, wherein the method comprises the following steps: the addition ratio of ursodeoxycholic acid to organic solvent is 1g: 2-10 ml.
3. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 2, wherein the method comprises the following steps: the mol ratio of ursodeoxycholic acid to taurine to boric acid ester is 1:1-3:1-5.
4. A method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 3, wherein: the mol ratio of ursodeoxycholic acid to taurine to boric acid ester is 1:1-2:1-3.
5. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 4, wherein the method comprises the following steps: the reaction condition of ursodeoxycholic acid and taurine is that the temperature is raised to 20-80 ℃ for reaction for 6-10 h.
6. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 5, wherein the method comprises the following steps: after obtaining tauroursodeoxycholic acid, carrying out purification treatment, wherein the purification treatment comprises extraction, washing, acidification, filtration and concentration.
7. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 6, wherein the method comprises the following steps: in the extraction step, the extractant is methylene dichloride, and the adding ratio of the tauroursodeoxycholic acid to the extractant is 1g: 3-10 ml, stirring for 10-30 min during extraction, and standing for 20-40 min.
8. The method for synthesizing tauroursodeoxycholic acid under the catalysis of boric acid ester according to claim 7, wherein the method comprises the following steps: in the washing step, the detergent is saturated sodium carbonate solution, and the adding ratio of the tauroursodeoxycholic acid to the detergent is 1g: 4-6 ml, stirring for 10-30 min during washing, and standing for 20-40 min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| Borate esters: Simple catalysts for the sustainable synthesis of complex amides;Marco T. Sabatini 等;《SCIENCE ADVANCES》;20170922;第3卷;第1-8页 * |
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