CN112592380A - Method for synthesizing tauroursodeoxycholic acid under promotion of trichloroisocyanuric acid - Google Patents
Method for synthesizing tauroursodeoxycholic acid under promotion of trichloroisocyanuric acid Download PDFInfo
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- CN112592380A CN112592380A CN202011527274.8A CN202011527274A CN112592380A CN 112592380 A CN112592380 A CN 112592380A CN 202011527274 A CN202011527274 A CN 202011527274A CN 112592380 A CN112592380 A CN 112592380A
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Abstract
The invention relates to the technical field of drug synthesis, in particular to a method for promoting synthesis of tauroursodeoxycholic acid by trichloroisocyanuric acid, which comprises the following steps in sequence: and (3) synthesizing an intermediate product: reacting taurine under the action of trichloroisocyanuric acid to obtain a system I; the synthesis of tauroursodeoxycholic acid comprises the following steps: adding tauroursodeoxycholic acid and alkali into the system I, and reacting to obtain a system II. The synthesis method has the advantages of economy and environmental protection, is simple in operation process, is suitable for industrial expansion, and can be applied to the production practice of tauroursodeoxycholic acid.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing tauroursodeoxycholic acid under the promotion of trichloroisocyanuric acid.
Background
Tauroursodeoxycholic acid is an effective component of bear bile, called TUDCA for short, and has the chemical name of 3 alpha, 7 beta-dihydroxy-cholanoyl-N-taurine, has the effects of spasmolysis, anticonvulsant, anti-inflammatory, cholelithiasis dissolving and the like, is mainly used for treating cholecystolith calculi, primary sclerosing cholangitis, primary biliary cirrhosis, chronic viral hepatitis C and the like in clinic, and is concerned by a great number of synthesizers. Tauroursodeoxycholic acid is a conjugated bile acid formed by the shrinkage between the carboxyl group of ursodesoxycholic acid and the amino group of taurine. The current chemical synthesis methods are mainly divided into three categories: firstly, mixed acid anhydride, active phenolic ester and the like of an active intermediate are formed and then react with taurine; secondly, amide is directly formed under the action of a condensing agent; thirdly, forming acyl sulfide by cystamine substances and then oxidizing the acyl sulfide to obtain the target product. The first method often uses a reagent with stronger toxicity, and the yield of the synthesized target product is limited; the second method often uses a reagent such as 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine salt (DMTMM) as a condensing agent, which is expensive and not cost-effective to control; the third method is generally not well suited for industrial scale-up. Therefore, there is a need to develop a new synthetic method of tauroursodeoxycholic acid, which makes the synthetic process more environment-friendly, economical and suitable for industrial production.
Disclosure of Invention
The invention aims to provide a synthetic method of tauroursodeoxycholic acid under the promotion of trichloroisocyanuric acid, so as to solve the technical problem that the synthetic method of the tauroursodeoxycholic acid is not environment-friendly and economical.
In order to achieve the purpose, the invention adopts the following technical scheme:
the method for promoting the synthesis of tauroursodeoxycholic acid by trichloroisocyanuric acid comprises the following steps of:
and (3) synthesizing an intermediate product: reacting taurine under the action of trichloroisocyanuric acid to obtain a system I;
the synthesis of tauroursodeoxycholic acid comprises the following steps: adding tauroursodeoxycholic acid and alkali into the system I, and reacting to obtain a system II.
The principle and the advantages of the scheme are as follows: trichloroisocyanuric acid (TCCA) is a better oxidant and chlorinating agent, in the scheme, the TCCA is used for treating taurine, under a certain condition, an N-Cl bond can be quickly formed by the amino group of the taurine, and the N-Cl bond is unstable under an alkaline condition and can be subsequently reacted with ursodeoxycholic acid to form tauroursodeoxycholic acid. Ursodeoxycholic acid and alkali form a salt, then N-Cl bonds are broken under the action of the alkali, and C-O bonds of carboxylate are broken at the same time, so that tauroursodeoxycholic acid is formed.
TCCA has the advantages of low price, safety, high efficiency and environmental protection, and can be used for disinfection and sterilization of drinking water, industrial circulating water, swimming pools, restaurants, hotels, public places, families, hospitals, poultry eggs, fish diseases prevention and treatment and the like in life. The inventor applies TCCA to the synthesis of tauroursodeoxycholic acid for the first time, and finds that under the action of TCCA, the whole reaction process is relatively mild and the reaction efficiency is high. According to the scheme, N-Cl with poor alkali stability is formed by chlorination of TCCA, then the N-Cl reacts with carboxyl of ursodesoxycholic acid, and finally an amido bond is formed, so that the target product tauroursodeoxycholic acid is obtained. After the reaction is finished, the isocyanuric acid formed by TCCA is separated out in the form of precipitate, so that the impurities can be conveniently removed. The inventors have tried to use other chlorinating agents (e.g., N-chlorosuccinimide, NCS), but when NCS and TCCA are identical in chlorine equivalent and under optimal reaction conditions, the yield of tauroursodeoxycholic acid is much higher than the yield of the desired product using NCS using TCCA. This demonstrates that TCCA has a specific promoting effect on the synthesis of tauroursodeoxycholic acid from taurine and ursodeoxycholic acid.
Further, in the step of synthesizing tauroursodeoxycholic acid, ursodesoxycholic acid, alkali and a second solvent are added into the system I, and the system II is obtained through reaction under the condition of heating and refluxing at the temperature of 25-65 ℃.
By adopting the technical scheme, under the alkaline condition, the N-Cl bond and the C-O bond can be promoted to be broken by heating and refluxing at 25-65 ℃, so that an amido bond is formed, and the synthesis of a target product is promoted. Too low a temperature will result in low yield of the desired product, and too high a temperature will also affect the stability of the desired product.
Further, the second solvent is methanol.
By adopting the technical scheme, a large number of experiments prove that the yield of the product can be improved by using methanol as a solvent for the second step reaction (the synthesis step of tauroursodeoxycholic acid). The reason why the phenomenon is analyzed by the inventor is that in a methanol environment, the activity of each molecular reaction site is high, and the forward progress of the reaction is promoted, so that the yield of the target product is ensured to meet the requirement.
Further, the alkali is sodium hydroxide; the molar ratio of the ursodeoxycholic acid to the sodium hydroxide is 1: 2-5.
By adopting the technical scheme, the sodium hydroxide is common strong alkali and is easy to obtain. When the molar ratio of ursodesoxycholic acid to sodium hydroxide is 1: 2-5, enough alkali can be ensured to promote the breakage of N-Cl bonds and C-O bonds, so that the synthesis of tauroursodeoxycholic acid is promoted. The excessive use amount of the sodium hydroxide can cause the pH value of a reaction system to be too high, and a target product cannot be generated; the use amount of the sodium hydroxide is too low, so that the alkalinity of the system is insufficient, and N-Cl bonds and C-O bonds can not be effectively broken.
Further, in the step of synthesizing the intermediate product, the molar ratio of taurine to trichloroisocyanuric acid is 1.2: 0.33-4.
By adopting the technical scheme, the molar ratio of the taurine to the trichloroisocyanuric acid can ensure that an N-H bond on the taurine is replaced by an N-Cl bond. The dosage of trichloroisocyanuric acid is too small, and the generated N-Cl bonds are few; the excessive consumption of trichloroisocyanuric acid no longer has the promotion effect on the reaction, and is a waste of trichloroisocyanuric acid which is a material.
Further, the first solvent is dichloromethane.
With the above technical solution, a lot of experiments verify that dichloromethane is the best solvent for the first reaction (the synthesis step of the intermediate product). Compared with other reaction solvents, the method has the advantage that the yield of the target product can be improved by using dichloromethane as the reaction solvent.
Further, after the step of synthesizing tauroursodeoxycholic acid, the method also comprises the step of purifying: concentrating the system II, and sequentially extracting, acidifying and filtering to obtain pure tauroursodeoxycholic acid.
By adopting the technical scheme, impurities are removed by extraction, and the tauroursodeoxycholic acid is precipitated and separated out by acidification, so that a pure product of the tauroursodeoxycholic acid is obtained.
Further, the molar ratio of taurine to ursodeoxycholic acid is 0.5-3: 1.
By adopting the technical scheme, the taurine and the ursodeoxycholic acid in the proportion are used for reaction, so that the yield of the target product can be ensured, and the waste of raw materials is reduced.
Further, in the purification step, the concentration system II is concentrated to obtain a concentrate; extracting the concentrate with ethyl acetate and water to obtain an aqueous phase I; extracting the water phase I by using ethyl acetate to obtain a water phase II; and adjusting the pH value of the water phase II to 1-3, and collecting the precipitate.
By adopting the technical scheme, impurities are fully removed through multiple times of extraction, and finally the pH value of the water phase II is adjusted to 1-3, and a large amount of tauroursodeoxycholic acid is separated out.
Drawings
FIG. 1 is a liquid phase diagram of a sample of example 1.
FIG. 2 is a liquid phase diagram of the standard of example 1.
Detailed Description
The following is further detailed by way of specific embodiments:
example 1:
taurine (cas: 07-35-7), N-chlorotaurine (cas: 51036-13-6, an intermediate product thereof), ursodeoxycholic acid (cas: 128-13-2), tauroursodeoxycholic acid (cas: 14605-22-2) and trichloroisocyanuric acid (cas: 87-90-1) have structural formulas shown as formula (I) -formula (V) respectively, and the synthetic process of the tauroursodeoxycholic acid is shown as formula (VI).
The specific synthetic process is as follows:
and (3) synthesizing an intermediate product: dissolving 1.2mol of taurine in dichloromethane (a first solvent), wherein the volume mass ratio of the dichloromethane to the taurine is 5 (namely 5V/m, 1g of taurine corresponds to every 5ml of dichloromethane), then cooling the dichloromethane solution of the taurine to 5 ℃ (the TCCA feeding temperature, the selectable temperature range is 0-30), then adding 0.6mol of trichloroisocyanuric acid, putting into a magnetic stirrer, putting the magnetic stirrer at the rotating speed of 150rpm, and reacting for 2h at the temperature of 25 ℃ (usually reacting for 1-10h fully). After the reaction is finished, a system I is obtained.
The synthesis of tauroursodeoxycholic acid comprises the following steps: in the step, 1mol of ursodeoxycholic acid and 4mol of sodium hydroxide are used, firstly, 4mol of sodium hydroxide is dissolved in water to prepare a 30% sodium hydroxide solution, and then, the ursodeoxycholic acid is dissolved in the sodium hydroxide solution to obtain an ursodeoxycholic acid-base solution. Dissolving all ursodeoxycholic acid alkali solution in the system I, adding methanol (a second solvent) into the system I, and heating and refluxing at 60 ℃ for 10 hours (generally, the reaction can be fully carried out for 8-16 hours). And (3) after the reaction of the methanol and the ursodesoxycholic acid with the volume-mass ratio of 5 (namely 5V/m, 1g of ursodesoxycholic acid is corresponding to every 5ml of methanol), obtaining a system II, wherein the system II contains the tauroursodeoxycholic acid. In the process of synthesizing tauroursodeoxycholic acid, the molar ratio of taurine to ursodesoxycholic acid can be 0.5-3: 1, and the reaction can be smoothly carried out.
A purification step: concentrating the system II to remove the organic solvent to obtain a concentrate, and extracting the concentrate with ethyl acetate and water. The amount of ethyl acetate was 3V/m (1 g ursodeoxycholic acid per 3ml ethyl acetate), the amount of water was 2V/m (1 g ursodeoxycholic acid per 2ml water), standing for liquid separation and taking the aqueous phase (aqueous phase I), the aqueous phase I was extracted once more with 2V/m ethyl acetate (1 g ursodeoxycholic acid per 2ml ethyl acetate), standing for liquid separation and taking the aqueous phase (aqueous phase II). And adjusting the pH of the water phase II to 2 (adjusting the pH to 1-3) by using acid, separating out solids, filtering and drying to obtain tauroursodeoxycholic acid. The solid tauroursodeoxycholic acid (sample to be tested, sample for short) is collected, and the yield is calculated to be 85%.
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 is shown in figure 1, the liquid chromatogram of the standard is shown in figure 2, comparing figure 1 with figure 2 (the abscissa in the figures represents the retention time min), the retention time of the tauroursodeoxycholic acid peak is consistent, and the scheme is proved to successfully synthesize the tauroursodeoxycholic acid. Further, the sample is identified as tauroursodeoxycholic acid through nuclear magnetic resonance detection and identification.
Examples 2 to 7 and comparative examples 1 to 15 are basically the same as example 1 except for the parameter settings shown in table 1.
Table 1: parameter setting of the Synthesis step of the intermediate products
In Table 1, TCCA represents trichloroisocyanuric acid, DCM represents dichloromethane, THF represents tetrahydrofuran, NCS represents N-chlorosuccinimide, UDCA represents ursodeoxycholic acid, and TUDCA represents tauroursodeoxycholic acid.
According to the experimental data in table 1, it can be known that the amount of TCCA used in examples 2 and 3 is adjusted, and that too low amount of TCCA may affect the yield of TUDA to some extent; the yield is not greatly improved due to the over-high consumption of TCCA. Comparative example 6 the yield of TUDCA decreased with the first solvent being changed to acetonitrile, indicating that too low an amount of TCCA affects the product yield, but that the use of a suitable reaction solvent also promotes the reaction to some extent in the forward direction. Comparative example 10, in which too much TCCA was used, the reaction efficiency was increased, indicating that too much TCCA was used to cause waste of raw materials.
Examples 4 and 5, the amount of sodium hydroxide used in the synthesis step of tauroursodeoxycholic acid was adjusted, and both of them obtained yields with a molar ratio of ursodeoxycholic acid to sodium hydroxide of 1:2 to 5. However, if the ratio exceeds the above range, the yield of the objective product is drastically reduced as shown in comparative examples 7 and 8.
Examples 6 and 7 the reaction temperature in the synthesis step of tauroursodeoxycholic acid was adjusted, and the reaction proceeded smoothly in the temperature range of 25 to 65 degrees. Comparative example 9 methanol was replaced with DCM and it was found that after solvent replacement the reaction efficiency decreased, again illustrating the importance of solvent selection. The reaction temperature of the synthesis step of tauroursodeoxycholic acid of comparative example 15 was too low, resulting in too low yield of TUDCA.
Comparative examples 1 to 4, in which acetonitrile, methanol, ethanol and tetrahydrofuran were used as solvents in the synthesis steps of the intermediate products, respectively, the yield of the objective product was significantly lower than that of example 1, indicating that the selection of dichloromethane as a reaction solvent is very important for the synthesis of the objective product.
Comparative example 5 was carried out using NCS as a chlorinating agent, reacting in methanol, which is an optimum solvent for NCS, and reacting with taurine using the same equivalent amounts of NCS and TCCA. The low yield of TUDCA of comparative example 5 relative to example 1 indicates that TCCA, the chlorinating agent, is more efficient for the synthesis of TUDCA than other chlorinating agents.
Comparative examples 11-14 the use of non-methanol as the reaction solvent in the tauroursodeoxycholic acid synthesis step, the yield of TUDCA is much lower than in example 1, which illustrates the importance of the choice of solvent for the reaction. In particular, at this step, if DCM is used, the yield will be very low. The inventors analyzed that the reason for this phenomenon is that DCM reacts in this reaction system to a certain extent, resulting in a decrease in the yield of the desired product. DCM is the best solvent for the previous step, and in order to remove its influence, the prior art usually removes it by rotary evaporation or the like. However, the inventor finds in the research that the technical problem caused by using DCM in the previous step can be solved by adding a certain amount of methanol solution, and the complicated step of removing the organic solvent is not needed, so that the operation process is accelerated, and the time is saved. Therefore, the methanol is added as an optimal reaction solvent, and the defects brought by DCM can be overcome, thereby achieving two purposes.
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 promoting the synthesis of tauroursodeoxycholic acid by trichloroisocyanuric acid is characterized by comprising the following steps of:
and (3) synthesizing an intermediate product: reacting taurine under the action of trichloroisocyanuric acid to obtain a system I;
the synthesis of tauroursodeoxycholic acid comprises the following steps: adding tauroursodeoxycholic acid and alkali into the system I, and reacting to obtain a system II.
2. The method for synthesizing tauroursodeoxycholic acid under the acceleration of trichloroisocyanuric acid according to claim 1, wherein in the step of synthesizing the tauroursodeoxycholic acid, ursodesoxycholic acid, alkali and a second solvent are added into the system I, and the system II is obtained through reaction under the condition of heating and refluxing at 25-65 ℃.
3. The method of claim 2, wherein the second solvent is methanol.
4. The trichloroisocyanuric acid-promoted tauroursodeoxycholic acid synthesis method according to claim 3, wherein the base is sodium hydroxide; the molar ratio of the ursodeoxycholic acid to the sodium hydroxide is 1: 2-5.
5. The method for promoting the synthesis of tauroursodeoxycholic acid by trichloroisocyanuric acid according to claim 1, wherein in the step of synthesizing the intermediate product, the molar ratio of taurine to trichloroisocyanuric acid is 1.2: 0.33-4.
6. The method for promoting the synthesis of tauroursodeoxycholic acid according to claim 5, wherein the system I is obtained by reacting taurine in a first solvent at a reaction temperature of 0-30 ℃ under the action of trichloroisocyanuric acid.
7. The method of claim 6, wherein the first solvent is dichloromethane.
8. The method for promoting the synthesis of tauroursodeoxycholic acid according to any one of claims 1-7, wherein the method further comprises a purification step after the synthesis step of tauroursodeoxycholic acid: concentrating the system II, and sequentially extracting, acidifying and filtering to obtain pure tauroursodeoxycholic acid.
9. The method for promoting the synthesis of tauroursodeoxycholic acid according to claim 8, wherein the molar ratio of taurine to ursodesoxycholic acid is 0.5-3: 1.
10. The method for promoting the synthesis of tauroursodeoxycholic acid according to claim 9, wherein in the purification step, the concentration system II is concentrated to obtain a concentrate; extracting the concentrate with ethyl acetate and water to obtain an aqueous phase I; extracting the water phase I by using ethyl acetate to obtain a water phase II; and adjusting the pH value of the water phase II to 1-3, and collecting the precipitate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100015633A (en) * | 2007-04-23 | 2010-02-12 | 프로도티케미시에엘리멘타리에스피에이 | Process for the preparation of tauroursodeoxycholic acid |
| CN102718829A (en) * | 2012-05-23 | 2012-10-10 | 杭州宝积生物科技有限公司 | Method for preparing sodium tauroursodeoxycholate |
| CN108299540A (en) * | 2017-12-28 | 2018-07-20 | 广州市盈宇医药科技有限公司 | A kind of synthetic method of Tauro ursodesoxy cholic acid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100015633A (en) * | 2007-04-23 | 2010-02-12 | 프로도티케미시에엘리멘타리에스피에이 | Process for the preparation of tauroursodeoxycholic acid |
| CN102718829A (en) * | 2012-05-23 | 2012-10-10 | 杭州宝积生物科技有限公司 | Method for preparing sodium tauroursodeoxycholate |
| CN108299540A (en) * | 2017-12-28 | 2018-07-20 | 广州市盈宇医药科技有限公司 | A kind of synthetic method of Tauro ursodesoxy cholic acid |
Non-Patent Citations (2)
| Title |
|---|
| TIMOTHY P. SHIAU: "Stieglitz rearrangement of N,N-dichloro-b,b-disubstituted taurines under mild aqueous conditions", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 王鹏等: "牛磺熊去氧胆酸的合成进展", 《氨基酸和生物资源》 * |
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