CN114394964B - Preparation method of high-yield berberine - Google Patents
Preparation method of high-yield berberine Download PDFInfo
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- CN114394964B CN114394964B CN202210121569.8A CN202210121569A CN114394964B CN 114394964 B CN114394964 B CN 114394964B CN 202210121569 A CN202210121569 A CN 202210121569A CN 114394964 B CN114394964 B CN 114394964B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention belongs to the technical field of medicine preparation, and particularly discloses a preparation method of high-yield berberine. The method takes piperonylethylamine and the vanillin mixed with alkali liquor as raw materials, reacts under vacuum condition, and then adds a catalyst under protective atmosphere to continue the reaction to obtain an intermediate product; then mixing the intermediate product with glyoxal and a catalyst, and performing cyclization reaction to prepare berberine; then adding hydrochloric acid, oxidant, ammonia water, active carbon and other substances to refine the berberine, and then adding hydrochloric acid to obtain refined berberine. The method disclosed by the invention improves the yield of the berberine and reduces the preparation cost of the berberine.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of high-yield berberine.
Background
Berberine (Berberrubine) is also known as 9-demethyl berberine, etc., and is named for its red color. The results of research and clinical application show that the protoberberine compound has wide pharmacological activities of resisting tumor, reducing blood sugar, resisting inflammation, reducing blood fat, resisting pathogenic microorganism, resisting Alzheimer's disease, resisting arrhythmia and the like.
The berberine demethylation can be used for preparing berberine, but the berberine is also an anti-inflammatory antibacterial effective drug, and the method limits the yield of the berberine and is not beneficial to the expanded use of the berberine drug.
The method takes the ortho-vanillin as the raw material, the raw material is easy to obtain, the one-pot condensation hydrogenation is adopted, the solvent is recycled in the process, the time and the energy are saved, the cost is reduced, and the industrial production of the berberine is realized. However, in the reaction process of the ortho-vanillin and the piperonylethylamine, the existence of hydroxyl in the ortho-vanillin influences the condensation yield, and sometimes even the berberine product cannot be obtained, so that the yield is low, and the preparation cost of the berberine is high.
Therefore, how to provide a preparation method of high-yield berberine, and how to improve the yield of berberine is a difficult problem to be solved in the field.
Disclosure of Invention
In view of the above, the invention provides a preparation method of high-yield berberine, which solves the problem of low yield of chemically synthesized berberine by taking ortho-vanillin as a raw material.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a preparation method of high-yield berberine comprises the following steps:
1) Mixing piperonylethylamine with alkali liquor, and then adding ortho-vanillin for reaction;
2) Adding a catalyst to continue the reaction, and obtaining an intermediate product 1 after the reaction is finished;
3) Adding hydrochloric acid into the intermediate product 1, and crystallizing to obtain a crystallized product;
4) Mixing the crystallized product, glyoxal and catalyst, and reacting to obtain berberine.
Preferably, the alkali liquor in the step 1) comprises one or more of sodium carbonate solution, sodium hydroxide solution and sodium bicarbonate solution.
Preferably, the pH value of the reaction system in the step 1) is 9-10.
Preferably, the reaction condition in the step 1) is a vacuum environment, the vacuum pressure is less than or equal to 0.05Pa, the reaction temperature is 80-90 ℃, and the reaction time is 28-32 min.
Preferably, the catalyst in the step 2) is a nickel-based catalyst.
Preferably, the reaction environment in the step 2) is a mixture of shielding gas and hydrogen, the reaction pressure is 3.8-4.2 MPa, the hydrogen pressure is 2.8-3.2 MPa, the reaction temperature is 100-120 ℃, and the reaction time is 45-60 min.
Preferably, the catalyst in the step 4) is a copper-based catalyst; the reaction in the step 4) is carried out in acetic acid-acetic anhydride solution, the reaction temperature is 100-120 ℃, and the reaction time is 1.8-2.2 h.
Preferably, the molar ratio of the piperonylethylamine to the ortho-vanillin in the step 1) is 0.8-1.2:0.8-1.2;
the addition amount of the catalyst in the step 2) is 1-3% of the total mass of the reaction system in the step 1);
the molar ratio of the addition amount of the hydrochloric acid to the ortho-vanillin in the step 3) is 1.1-1.3: 1, a step of;
the mass ratio of the crystallization product to glyoxal to the catalyst in the step 4) is 10: 1-2:0.01-0.03.
Preferably, the method further comprises the following steps:
5) Adding hydrochloric acid and an oxidant into berberine obtained in the step 4) to obtain an intermediate product 2;
6) Mixing the intermediate product 2, ammonia water and active carbon for refining reaction, and adding hydrochloric acid to obtain refined berberine.
Preferably, the molar ratio of berberine to hydrochloric acid to oxidant in the step 5) is 10:2-3:2-3 in sequence;
the molar ratio of the intermediate product 2 to the ammonia water to the hydrochloric acid in the step 6) is 1:1.1-1.3:1.1-1.3 in sequence; the addition amount of the activated carbon is 1-2% of the mass of the intermediate product 2;
the temperature of the refining reaction in the step 6) is 80-85 ℃, and the time of the refining reaction is 30-50 min.
Compared with the prior art, the invention has the following beneficial effects:
in the condensation process of piperonylethylamine and ortho-vanillin, the theoretical requirement is that amino groups are condensed with aldehyde groups to generate C-N links, but due to the existence of a hydroxyl group in the ortho-vanillin, the hydroxyl group and the amino groups also have an effect, so that the condensation selectivity and the yield are influenced. The invention protects hydroxyl by adding alkali liquor and adjusting pH value, enhances the combination opportunity of amino and aldehyde, improves the stability of reaction, correspondingly improves the yield, and the final yield is up to 45%.
Detailed Description
The invention provides a preparation method of high-yield berberine, which comprises the following steps:
1) Mixing piperonylethylamine with alkali liquor, and then adding ortho-vanillin for reaction;
2) Adding a catalyst to continue the reaction, and obtaining an intermediate product 1 after the reaction is finished;
3) Adding hydrochloric acid into the intermediate product 1, and crystallizing to obtain a crystallized product;
4) Mixing the crystallized product, glyoxal and catalyst, and reacting to obtain berberine.
In the invention, the alkali liquor in the step 1) comprises one or more of sodium carbonate solution, sodium hydroxide solution and sodium bicarbonate solution.
In the present invention, the pH of the reaction system in the step 1) is 9 to 10, preferably 10.
In the present invention, the reaction condition in the step 1) is a vacuum environment, and the reaction temperature is 80 to 90 ℃, preferably 84 to 87 ℃, and more preferably 86 ℃; the reaction time is 28 to 32 minutes, preferably 29 to 31 minutes, and more preferably 30 minutes.
In the invention, the vacuum pressure is less than or equal to 0.05Pa; preferably 0.1Pa.
In the present invention, the catalyst in the step 2) is a nickel-based catalyst, preferably nickel acetate.
In the invention, the reaction environment in the step 2) is a mixture of a shielding gas and hydrogen, and the shielding gas is preferably nitrogen; the reaction pressure is 3.8 to 4.2MPa, preferably 3.9 to 4.1MPa, and more preferably 4MPa; the hydrogen pressure is 2.8 to 3.2MPa, preferably 2.9 to 3.1MPa, and more preferably 3MPa; the reaction temperature is 100-120 ℃, preferably 112-116 ℃, and more preferably 114 ℃; the reaction time is 45 to 60min, preferably 52min.
In the present invention, the catalyst in the step 4) is a copper-based catalyst, preferably copper chloride; the reaction in the step 4) is carried out in an acetic acid-acetic anhydride solution, wherein the reaction temperature is 100-120 ℃, preferably 110-120 ℃, and further preferably 115 ℃; the reaction time is 1.8 to 2.2 hours, preferably 1.9 to 2.1 hours, and more preferably 2 hours.
In the invention, the acetic acid-acetic anhydride solution is prepared by mixing glacial acetic acid and acetic anhydride according to the proportion of 1:0.5-1.5, and the preferable proportion is 1:1.
In the present invention, the mass concentration of the crystalline product of the step 4) is 10 to 30g/L, preferably 20g/L.
In the present invention, the molar ratio of piperonylethylamine to orthovanillin in the step 1) is 0.8-1.2:0.8-1.2, preferably 1-1.
In the present invention, the catalyst is added in the step 2) in an amount of 1 to 3%, preferably 2% of the total mass of the reaction system in the step 1).
In the invention, the molar ratio of the addition amount of the hydrochloric acid to the ortho-vanillin in the step 3) is 1.1-1.3: 1, preferably 1.2:1.
in the invention, the mass ratio of the crystallization product to glyoxal and the catalyst in the step 4) is 10: 1-2: 0.01 to 0.03, preferably 10:2:0.02.
in the invention, the preparation method of the berberine also comprises the following steps:
5) Adding hydrochloric acid and an oxidant into berberine obtained in the step 4) to obtain an intermediate product 2;
6) Mixing the intermediate product 2, ammonia water and active carbon for refining reaction, and adding hydrochloric acid to obtain refined berberine.
In the invention, the molar ratio of the berberine in the step 5) to the hydrochloric acid to the oxidant is 10:2-3:2-3 in sequence, preferably 10:3:2.
In the present invention, the oxidizing agent is preferably hydrogen peroxide.
In the invention, the molar ratio of the intermediate 2, the ammonia water and the hydrochloric acid in the step 6) is sequentially 1:1.1-1.3:1.1-1.3, preferably 1:1.2:1.2; the amount of activated carbon added is 1 to 2% by mass, preferably 1.6% by mass, of intermediate 2.
In the present invention, the temperature of the refining reaction in the step 6) is 80 to 85 ℃, preferably 81 to 83 ℃, and more preferably 82 ℃; the refining reaction time is 30 to 50 minutes, preferably 40 minutes.
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Weighing 0.1mol of piperonylethylamine, placing the piperonylethylamine and 0.1mol of orthovanillin into a sodium carbonate solution, placing the solution into an autoclave (ensuring the pH value to be 9), uniformly stirring, heating to 82 ℃ under vacuum condition (the vacuum pressure is 0.04 Pa), and reacting for 30min;
after the reaction is finished, nickel acetate accounting for 2 percent of the total system mass is added into an autoclave, nitrogen is introduced to empty air, hydrogen is introduced to ensure that the hydrogen pressure is 3MPa, the total pressure is 4MPa, and the reaction is carried out for 50 minutes at the temperature of 114 ℃;
adding 0.12mol of hydrochloric acid, and cooling to 4 ℃ to obtain a crystallized product; mixing the crystallization product with glyoxal and copper chloride (the mass ratio is 10:2:0.02 in sequence), and carrying out cyclization reaction for 2 hours at 116 ℃ in acetic acid-acetic anhydride solution to obtain berberine;
adding hydrochloric acid and hydrogen peroxide into the obtained berberine according to the molar ratio of 10:3:2, and reacting for 10min; washing the obtained product, adding ammonia water and active carbon with the mass of 1.5% of the product into the product according to the molar ratio of 1:1.2, carrying out a refining reaction at 82 ℃ for 40min, and adding hydrochloric acid with the same molar ratio as the ammonia water to obtain refined berberine, wherein the final yield of the berberine is 45.5%.
Example 2
Weighing 0.1mol of piperonylethylamine, placing the piperonylethylamine and 0.12mol of orthovanillin in a sodium bicarbonate solution, placing the solution in an autoclave (ensuring the pH value to be 10), stirring uniformly, heating to 80 ℃ under vacuum condition (the vacuum pressure is 0.03 Pa), and reacting for 32min;
after the reaction is finished, nickel acetate accounting for 3 percent of the total system mass is added into an autoclave, nitrogen is introduced to empty air, hydrogen is introduced to ensure that the hydrogen pressure is 3.2MPa, the total pressure is 4.2MPa, and the reaction is carried out for 45min at 120 ℃;
adding 0.14mol of hydrochloric acid, and cooling to 4 ℃ to obtain a crystallized product; mixing the crystallization product with glyoxal and copper chloride (the mass ratio is 10:1:0.01 in sequence), and carrying out cyclization reaction for 2.2 hours at 100 ℃ in acetic acid-acetic anhydride solution to obtain berberine;
adding hydrochloric acid and hydrogen peroxide into the obtained berberine according to the molar ratio of 10:2:2, and reacting for 10min; washing the obtained product, adding ammonia water and active carbon with the mass of 1% of the product into the product according to the molar ratio of 1:1.1, carrying out refining reaction at 81 ℃ for 50min, and adding hydrochloric acid with the same molar ratio as the ammonia water to obtain refined berberine, wherein the final yield of the berberine is 43%.
Example 3
Weighing 0.12mol of piperonylethylamine, placing the piperonylethylamine and 0.1mol of orthovanillin into a sodium carbonate solution, placing the solution into an autoclave (ensuring the pH value to be 9), uniformly stirring, heating to 90 ℃ under vacuum condition (the vacuum pressure is 0.01 Pa), and reacting for 28min;
after the reaction is finished, nickel acetate accounting for 1 percent of the total system mass is added into the autoclave, nitrogen is introduced to empty air, hydrogen is introduced to ensure that the hydrogen pressure is 2.8MPa, the total pressure is 3.8MPa, and the reaction is carried out for 60 minutes at the temperature of 100 ℃;
adding 0.13mol of hydrochloric acid, and cooling to 4 ℃ to obtain a crystallized product; mixing the crystallization product with glyoxal and copper chloride (the mass ratio is 10:1:0.01 in sequence), and carrying out cyclization reaction for 1.8 hours at 120 ℃ in acetic acid-acetic anhydride solution to obtain berberine;
adding hydrochloric acid and hydrogen peroxide into the obtained berberine according to the molar ratio of 10:2:3, and reacting for 10min; washing the obtained product, adding ammonia water and active carbon with the mass of 2% of the product into the product according to the molar ratio of 1:1.3, carrying out refining reaction for 30min at 84 ℃, and adding hydrochloric acid with the same molar ratio as the ammonia water to obtain refined berberine, wherein the final yield of the berberine is 43.8%.
Comparative example 1
In the first step, no alkali liquor is added, and the addition and the process of the other materials are the same as those of the example 1, so that the final yield of the berberine is 13.5%.
Comparative example 2
The material addition and the process are the same as those of comparative example 1, and the final yield of berberine is 20.8%.
Comparative example 3
The material addition and the process are the same as those of comparative example 1, and the final yield of berberine is 5.6%.
It can be seen from examples 1 to 3 and comparative examples 1 to 3 that the yield of berberine is remarkably improved after alkali liquor is added, and meanwhile, the analysis can also obtain that the yield of berberine is extremely unstable in the comparative example without alkali liquor, which is that hydroxyl and amino in piperonylethylamine and ortho-vanillin have an effect to influence the selectivity of condensation, thereby leading to unstable yield, protecting the hydroxyl after alkali liquor is added, and improving the stability of the yield of berberine.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. The preparation method of the berberine is characterized by comprising the following steps:
1) Mixing piperonylethylamine with alkali liquor, and then adding ortho-vanillin for reaction;
2) Adding a catalyst to continue the reaction, and obtaining an intermediate product 1 after the reaction is finished;
3) Adding hydrochloric acid into the intermediate product 1, and crystallizing to obtain a crystallized product;
4) Mixing the crystallization product, glyoxal and a catalyst, and reacting to obtain berberine;
the pH value of the reaction system in the step 1) is 9-10.
2. The method for preparing berberine according to claim 1, wherein the alkaline solution in the step 1) comprises one or more of sodium carbonate solution, sodium hydroxide solution and sodium bicarbonate solution.
3. The method for preparing berberine according to any one of claims 1-2, wherein the reaction condition in the step 1) is vacuum environment, the vacuum pressure is less than or equal to 0.05Pa, the reaction temperature is 80-90 ℃, and the reaction time is 28-32 min.
4. The method for preparing berberine according to claim 3, wherein the catalyst in the step 2) is a nickel-based catalyst.
5. The method for preparing berberine according to claim 4, wherein the reaction environment in the step 2) is a mixture of a shielding gas and hydrogen, the reaction pressure is 3.8-4.2 mpa, the hydrogen pressure is 2.8-3.2 mpa, the reaction temperature is 100-120 ℃, and the reaction time is 45-60 min.
6. The method for preparing berberine according to claim 5, wherein the catalyst in the step 4) is a copper-based catalyst; the reaction in the step 4) is carried out in acetic acid-acetic anhydride solution, the reaction temperature is 100-120 ℃, and the reaction time is 1.8-2.2 hours.
7. The method for preparing berberine according to any one of claims 1-2 and 4-6, wherein the molar ratio of piperonylethylamine to orthovanillin in the step 1) is 0.8-1.2:0.8-1.2;
the addition amount of the catalyst in the step 2) is 1-3% of the total mass of the reaction system in the step 1);
the molar ratio of the addition amount of the hydrochloric acid to the ortho-vanillin in the step 3) is 1.1-1.3: 1, a step of;
the mass ratio of the crystallization product to glyoxal to the catalyst in the step 4) is 10: 1-2:0.01-0.03.
8. The method for preparing berberine according to claim 7, further comprising the steps of:
5) Adding hydrochloric acid and an oxidant into berberine obtained in the step 4) to obtain an intermediate product 2;
6) Mixing the intermediate product 2, ammonia water and active carbon for refining reaction, and adding hydrochloric acid to obtain refined berberine.
9. The method for preparing berberine according to claim 8, wherein the molar ratio of berberine to hydrochloric acid and oxidant in the step 5) is 10:2-3:2-3 in sequence;
the molar ratio of the intermediate product 2 to the ammonia water to the hydrochloric acid in the step 6) is 1:1.1-1.3:1.1-1.3 in sequence; the addition amount of the activated carbon is 1-2% of the mass of the intermediate product 2;
the temperature of the refining reaction in the step 6) is 80-85 ℃, and the time of the refining reaction is 30-50 min.
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| CN104910196A (en) * | 2015-05-25 | 2015-09-16 | 暨南大学 | Chiral tetranuclear copper-based organic metal framework, and preparation method and applications thereof |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104910196A (en) * | 2015-05-25 | 2015-09-16 | 暨南大学 | Chiral tetranuclear copper-based organic metal framework, and preparation method and applications thereof |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
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| Palladium-Catalyzed Allylic Alkylation of Aldimine Esters with Vinyl-Cyclopropanes to Yield α,α-Disubstituted α-Amino Acid Derivatives;Jiahua Wang等;《advanced synthesis & catalysis》;20190917;第361卷(第22期);第5105-5111页 * |
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