CN113321648B - Synthetic method of atropine sulfate - Google Patents
Synthetic method of atropine sulfate Download PDFInfo
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- CN113321648B CN113321648B CN202110559198.7A CN202110559198A CN113321648B CN 113321648 B CN113321648 B CN 113321648B CN 202110559198 A CN202110559198 A CN 202110559198A CN 113321648 B CN113321648 B CN 113321648B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
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Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of atropine sulfate. Firstly, preparing tropine ester, then preparing atropine, then salifying to prepare atropine sulfate, and finally refining to obtain the product. In the process of preparing the tropine ester, the reaction temperature is strictly controlled to be 105-111 ℃, and the crystallization temperature is controlled to be 0-5 ℃ so as to improve the yield of the tropine ester. In the process of preparing atropine by reduction reaction, palladium-carbon is used as a catalyst, the reaction temperature is strictly controlled to be 10-15 ℃, and the product quality is effectively improved. Sulfuric acid is diluted by preparing a sulfuric acid ethanol solution, and the dropping speed of the sulfuric acid ethanol solution is controlled to ensure the stable quality of the atropine sulfate.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of atropine sulfate.
Background
Atropine is a natural compound, extracted from plants, has many medicinal values, and can dilate pupils, increase heart rate, and reduce salivary secretion and other secretions. More common uses include pre-anesthesia administration to reduce mucus secretions. Atropine is used to maintain a normal heart rate under certain conditions during anesthesia and surgery.
Atropine sulfate, chemical name of alpha-hydroxymethyl benzene acetyl tropine sulfate monohydrate, is an anticholinergic drug, has the effects of inhibiting secretion of glands and diffusing pupils, and is mainly used for treating smooth muscle spasm, gastric ulcer, duodenal ulcer, organophosphorus pesticide poisoning, infectious shock and the like.
Current processes for the synthesis of atropine sulfate suffer from a number of disadvantages which make it difficult to achieve on a commercial scale, primarily due to the low efficiency of the reactions involved.
Disclosure of Invention
The invention aims to provide a preparation method of atropine sulfate, which has the advantages of simple synthetic route, simple operation, high yield and low cost.
In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of atropine sulfate comprises the following specific process steps:
preparation of tropine ester
(1) Adding toluene, tropine and alpha-formylmethyl phenylacetate into a reaction kettle, stirring, and heating to 105-110 ℃ for reaction;
wherein the mass ratio of the tropine to the alpha-formyl methyl phenylacetate is 1: 2-3; the mass ratio of tropine to toluene is 1: 30.
(2) And cooling to 0-5 ℃ after complete reaction, crystallizing for more than 8 hours, filtering, washing a filter cake twice by using toluene until a washing liquid is clear, filtering, and drying to obtain the tropine ester.
Secondly, preparing atropine
(1) Adding methanol, trichloromethane and tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle to be below 15 ℃, adding palladium-carbon and glacial acetic acid for 3 times, finishing the addition within 1 hour, and then reacting for 5-7 hours at 10-15 ℃;
wherein the mass ratio of the trichloromethane to the methanol is 4.5-5: 1; the mass ratio of the palladium carbon to the glacial acetic acid to the tropine ester is as follows: 0.15-0.2: 0.1: 1.
(2) after the reaction is finished, emptying and filtering out palladium-carbon, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
(3) adding 2 times of acetone into the residue, cooling to 0-5 ℃, crystallizing for more than 8 hours, filtering, rinsing the filter cake with acetone, filtering, and drying to obtain atropine;
wherein the drying temperature is 55-60 ℃, and the drying time is 6-8 hours.
Thirdly, preparing atropine sulfate
(1) Sequentially adding absolute ethyl alcohol, atropine and medicinal carbon into a reaction kettle, stirring and heating to 70-80 ℃, and refluxing and decoloring for half an hour;
(2) filtering, cooling the filtrate to 20-30 ℃, dropwise adding a sulfuric acid ethanol solution, and adjusting the pH to 4-5; stirring for 0.5 hour at the temperature of 20-30 ℃ with the pH value of 4-5;
wherein, the mass ratio of sulfuric acid: ethanol is 1: 5.
(3) Adding acetone, cooling to below 10 ℃, crystallizing for more than 8 hours, performing suction filtration, and washing with acetone until a washing solution is clear; drying to obtain a crude atropine sulfate product;
wherein the drying temperature is 65-80 ℃, and the drying time is 6-8 hours.
(4) Refining atropine sulfate
(1) Putting the atropine sulfate crude product and absolute ethyl alcohol into a reaction kettle, stirring and heating to 70-80 ℃, and refluxing for 0.5 hour; filtering, adding acetone into the filtrate, slowly cooling to below 10 ℃, and crystallizing for more than 8 hours;
(2) performing suction filtration, rinsing with acetone until the filtrate is clear, and filtering to dryness to obtain atropine sulfate wet product; discharging, drying, pulverizing, and sieving with 80 mesh sieve.
Wherein the drying temperature is 65-80 ℃, the vacuum degree is less than or equal to-0.08 MPa, and the drying time is 6-8 hours.
The invention has the beneficial effects that:
(1) in the process of preparing the tropine ester, the reaction temperature is strictly controlled at 105-110 ℃, the crystallization temperature is controlled at 0-5 ℃, and the yield of the tropine ester reaches more than 90 percent.
(2) In the process of preparing atropine by reduction reaction, palladium-carbon is selected as a catalyst, the reaction temperature is strictly controlled to be 10-15 ℃, and the product yield can be effectively improved.
(3) And in the process of forming the sulfate, sulfuric acid is diluted by preparing a sulfuric acid ethanol solution, and the dropping speed is controlled to ensure stable and qualified quality.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
Preparation of tropine ester
(1) Adding 31kg of toluene, 1kg of tropine and 2.6kg of alpha-formyl methyl phenylacetate into a reaction kettle, stirring, and heating to 110 ℃ for reaction;
(2) after reacting for 3h, cooling to 2 ℃, crystallizing for 8h, filtering, washing a filter cake twice by toluene until a washing liquid is clear, filtering to dryness, and drying at 58 ℃ for 7h to obtain the tropine ester with the yield of 96%.
Secondly, preparing atropine
(1) Adding 2.8kg of methanol, 13.65kg of trichloromethane and 1kg of tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle below 15 ℃, adding 188g of palladium-carbon and 100g of glacial acetic acid for 3 times, completing the addition within 1 hour, and then reacting for 7 hours at 12 ℃;
(2) after the reaction is finished, emptying and filtering out palladium-carbon, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
(3) adding 2 times of acetone into the residue, cooling to 2 ℃, crystallizing for more than 8 hours, filtering, rinsing the filter cake with acetone, filtering, drying at 58 ℃ for 7 hours to obtain atropine with the yield of 92%.
Thirdly, preparing atropine sulfate
(1) Putting 4kg of absolute ethyl alcohol, 1kg of atropine and 0.05kg of medicinal carbon into a reaction kettle in sequence, stirring and heating to 75 ℃, and refluxing and decoloring for half an hour;
(2) filtering, cooling the filtrate to 25 ℃, dropwise adding a sulfuric acid ethanol solution (wherein, 0.18kg of sulfuric acid and 0.94kg of ethanol), and adjusting the pH to 4-5; stirring for 0.5 hour at the temperature of 25 ℃ with the pH value of 4-5;
(3) adding acetone, cooling to below 10 ℃, crystallizing for more than 8 hours, performing suction filtration, and washing with acetone until a washing solution is clear; drying at 78 deg.C for 7h to obtain atropine sulfate crude product; the yield thereof was found to be 90%.
(4) Refining atropine sulfate
(1) Putting 1kg of atropine sulfate crude product and 4kg of absolute ethyl alcohol into a reaction kettle, stirring and heating to 75 ℃, and refluxing for 0.5 hour; filtering, adding 10kg acetone into the filtrate, slowly cooling to below 10 deg.C, and crystallizing for more than 8 hr;
(2) performing suction filtration, rinsing with acetone until the filtrate is clear, and filtering to dryness to obtain atropine sulfate wet product; discharging at 75 deg.C under vacuum degree of less than or equal to-0.08 MPa, drying for 7 hr, pulverizing, and sieving with 80 mesh sieve. The yield thereof was found to be 92%.
Example 2
Preparation of tropine ester
(1) Adding 31kg of toluene, 1kg of tropine and 2.6kg of alpha-formyl methyl phenylacetate into a reaction kettle, stirring, and heating to 105 ℃ for reaction;
(2) after 4h of reaction, cooling to 0 ℃ for crystallization for 8h, filtering, washing a filter cake twice with toluene until a washing solution is clear, filtering to dryness, and drying at 58 ℃ for 7h to obtain the tropine ester with the yield of 95.6%.
Secondly, preparing atropine
(1) Adding 2.8kg of methanol, 13.65kg of trichloromethane and 1kg of tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle below 15 ℃, adding 188g of palladium-carbon and 100g of glacial acetic acid for 3 times, completing the addition within 1 hour, and then reacting at 10 ℃ for 8 hours;
(2) after the reaction is finished, emptying and filtering out palladium-carbon, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
(3) adding 2 times of acetone into the residue, cooling to 2 ℃, crystallizing for more than 8 hours, filtering, rinsing the filter cake with acetone, filtering, drying at 58 ℃ for 7 hours to obtain atropine, wherein the yield is 91.8%.
Preparation and purification of atropine sulfate were the same as in example 1.
Example 3
Preparation of tropine ester
(1) Adding 31kg of toluene, 1kg of tropine and 2.6kg of alpha-formyl methyl phenylacetate into a reaction kettle, stirring, and heating to 110 ℃ for reaction;
(2) after reacting for 3h, cooling to 5 ℃, crystallizing for 8h, filtering, washing a filter cake twice by toluene until a washing liquid is clear, filtering to dryness, and drying at 58 ℃ for 7h to obtain the tropine ester with the yield of 95.8%.
Secondly, preparing atropine
(1) Adding 2.8kg of methanol, 13.65kg of trichloromethane and 1kg of tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle below 15 ℃, adding 188g of palladium-carbon and 100g of glacial acetic acid for 3 times, completing the addition within 1 hour, and then reacting for 6 hours at 15 ℃;
(2) after the reaction is finished, emptying and filtering out palladium-carbon, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
(3) adding 2 times of acetone into the residue, cooling to 2 deg.C, crystallizing for more than 8 hr, filtering, rinsing the filter cake with acetone, filtering, and drying at 58 deg.C for 7 hr to obtain atropine with yield of 89.6%.
Preparation and purification of atropine sulfate were the same as in example 1.
Comparative example 1
The first, tropine ester, second, atropine were prepared as in example 1.
Thirdly, preparing atropine sulfate
(1) Putting 4kg of absolute ethyl alcohol, 1kg of atropine and 0.05kg of medicinal carbon into a reaction kettle in sequence, stirring and heating to 75 ℃, and refluxing and decoloring for half an hour;
(2) filtering, cooling the filtrate to 25 ℃, and dropwise adding dilute sulfuric acid to adjust the pH to 4-5; stirring for 0.5 hour at the temperature of 25 ℃ with the pH value of 4-5;
(3) adding acetone, cooling to below 10 ℃, crystallizing for more than 8 hours, performing suction filtration, and washing with acetone until a washing solution is clear; drying at 78 deg.C for 7h to obtain atropine sulfate crude product; the yield thereof was found to be 89.5%.
(4) Atropine sulfate was purified as in example 1.
Comparative example 2
Preparation of tropine ester
(1) Adding 31kg of toluene, 1kg of tropine and 2.6kg of alpha-formyl methyl phenylacetate into a reaction kettle, stirring, and heating to 100 ℃ for reaction;
(2) after reacting for 3h, cooling to 2 ℃, crystallizing for 8h, filtering, washing a filter cake twice by toluene until a washing liquid is clear, filtering to dryness, and drying at 58 ℃ for 7h to obtain the tropine ester with the yield of 86%.
Comparative example 3
First, the preparation of tropyl ester is the same as in example 1.
Secondly, preparing atropine
(1) Adding 2.8kg of methanol, 13.65kg of trichloromethane and 1kg of tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle below 15 ℃, adding 188g of potassium borohydride for 3 times, completing the addition within 1 hour, and then reacting for 7 hours at 12 ℃;
(2) after the reaction is finished, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
(3) adding 2 times of acetone into the residue, cooling to 2 ℃, crystallizing for more than 8 hours, filtering, rinsing the filter cake with acetone, filtering, drying at 58 ℃ for 7 hours to obtain atropine with the yield of 79%.
Preparation and purification of atropine sulfate were the same as in example 1.
Claims (5)
1. The preparation method of atropine sulfate is characterized by comprising the following steps:
(1) the specific steps for preparing the tropine ester are as follows:
1) adding toluene, tropine and alpha-formylmethyl phenylacetate into a reaction kettle, stirring, and heating to 105-110 ℃ for reaction;
2) cooling to 0-5 ℃ after complete reaction for crystallization for more than 8 hours, filtering, washing a filter cake twice with toluene until a washing solution is clear, filtering, and drying to obtain tropine ester;
(2) preparing atropine
1) Adding methanol, trichloromethane and tropine ester into a reaction kettle, and stirring; controlling the temperature in the kettle to be below 15 ℃, adding palladium-carbon and glacial acetic acid for 3 times, finishing the addition within 1 hour, and then reacting for 5-7 hours at 10-15 ℃;
2) after the reaction is finished, emptying and filtering out palladium-carbon, adding 3 times of drinking water, stirring for 10 minutes, standing for 20 minutes, and separating an organic layer; extracting the water layer with chloroform for three times, stirring for 5 minutes each time, and standing for 10 minutes; mixing the organic layers, adding 3 times of drinking water for washing, stirring for 10 minutes, standing for 20 minutes, and decompressing the organic layers to recover the trichloromethane;
3) adding 2 times of acetone into the residue, cooling to 0-5 ℃, crystallizing for more than 8 hours, filtering, rinsing the filter cake with acetone, filtering, and drying to obtain atropine;
(3) preparation of atropine sulfate
(1) Sequentially adding absolute ethyl alcohol, atropine and medicinal carbon into a reaction kettle, stirring and heating to 70-80 ℃, and refluxing and decoloring for half an hour;
(2) filtering, cooling the filtrate to 20-30 ℃, dropwise adding a sulfuric acid ethanol solution, and adjusting the pH to 4-5; stirring for 0.5 hour at the temperature of 20-30 ℃;
(3) adding acetone, cooling to below 10 ℃, crystallizing for more than 8 hours, performing suction filtration, and washing with acetone until a washing solution is clear; drying to obtain a crude atropine sulfate product;
(4) and refining atropine sulfate.
2. The process for the preparation of atropine sulfate according to claim 1, wherein in the step (1), the mass ratio of tropine alcohol to methyl α -formylphenylacetate is 1: 2-3; the mass ratio of tropine to toluene is 1: 30.
3. The method for preparing atropine sulfate according to claim 1, wherein in the step (2), the mass ratio of trichloromethane to methanol is 4.5-5: 1; the mass ratio of the palladium carbon to the glacial acetic acid to the tropine ester is as follows: 0.15-0.2: 0.1: 1.
4. the method for preparing atropine sulfate according to claim 1, wherein in the step (3) of preparing atropine sulfate and the step 2) of preparing atropine sulfate, the mass ratio of sulfuric acid to ethanol is 1: 5.
5. The method for preparing atropine sulfate according to claim 1, wherein the refining in the step (4) comprises the following specific steps:
(1) putting the atropine sulfate crude product and absolute ethyl alcohol into a reaction kettle, stirring and heating to 70-80 ℃, and refluxing for 0.5 hour; filtering, adding acetone into the filtrate, slowly cooling to below 10 ℃, and crystallizing for more than 8 hours;
(2) performing suction filtration, rinsing with acetone until the filtrate is clear, and filtering to dryness to obtain atropine sulfate wet product; discharging, drying, pulverizing, and sieving with 80 mesh sieve.
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CA1328106C (en) * | 1986-03-17 | 1994-03-29 | Nicholas S. Bodor | Anticholinergic compounds, pharmaceutical compositions and method of treatment |
| CN101003535A (en) * | 2006-01-17 | 2007-07-25 | 上海绿健医药技术有限公司 | Alpha hydroxy - alpha phenyl phenylacetic acid 8 - aza dicyclo [3. 2. 1] - 3 heptyl ester, midbody compound, and preparation method |
| WO2014102829A1 (en) * | 2012-12-31 | 2014-07-03 | Mylan Laboratories Ltd. | Crystalline atropine sulfate |
| CN104341414B (en) * | 2014-11-11 | 2016-04-20 | 武汉武药制药有限公司 | A kind of preparation method of anticholinergic drug Tropintran |
| CN104402877B (en) * | 2014-12-07 | 2017-05-03 | 河南慧锦药业有限公司 | Preparation method of atropine sulphate |
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