CN111848426B - Industrial production method of aceclofenac - Google Patents
Industrial production method of aceclofenac Download PDFInfo
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- CN111848426B CN111848426B CN202010692061.4A CN202010692061A CN111848426B CN 111848426 B CN111848426 B CN 111848426B CN 202010692061 A CN202010692061 A CN 202010692061A CN 111848426 B CN111848426 B CN 111848426B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
The invention relates to a method for industrially producing aceclofenac. The method comprises the following steps: mixing organic acid, water remover and Lewis acid, stirring fully, and adding aceclofenac tert-butyl ester for acidolysis reaction. The method has the advantages of mild reaction conditions, high reaction rate, no high temperature and high energy consumption, simple and convenient operation, environmental protection, economy, no participation or generation of major pollutants, recycling of most solvents, and reduction of the emission of waste solvents, thereby reducing the cost and protecting the environment.
Description
Technical Field
The invention belongs to the field of aceclofenac preparation, and particularly relates to a method for industrially producing aceclofenac.
Background
Many documents are reported about the synthesis of aceclofenac, and patent CN101531607A discloses that tert-butyl aceclofenac is subjected to acidolysis under the combined action of phenol and acid to obtain a product, but the method has the disadvantages of large dosage of phenol, strong toxicity and large environmental protection pressure. Patent CN103086907A discloses acidolysis of aceclofenac tert-butyl ester by using a mixed solution of hydrogen halide and a low-molecular organic acid, but the method has strong corrosion to equipment, complex operation, slow reaction rate and low conversion rate.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for industrially producing aceclofenac, so as to overcome the defects of large raw material consumption, strong toxicity, harsh reaction conditions, environmental pollution, complex operation, poor product quality and the like of the industrial preparation of aceclofenac in the prior art.
The invention relates to a method for industrially producing aceclofenac, which comprises the following steps:
mixing an organic acid, a water removing agent and Lewis acid, fully stirring, adding aceclofenac tert-butyl ester for acidolysis reaction to obtain aceclofenac, wherein the molar ratio of the aceclofenac tert-butyl ester to the Lewis acid to the organic acid to the water removing agent is 1.15-0.35.
The preparation method of the aceclofenac tert-butyl ester comprises the following steps: diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and a solvent are subjected to heat preservation reaction for 4-5h at the temperature of 60-70 ℃ according to the molar ratio of 1:1-1.5.
The solvent is ethanol; the iodide is potassium iodide.
The water remover is acetic anhydride; the organic acid is acetic acid; the Lewis acid is aluminum trichloride.
The stirring time is 5 minutes to 120 minutes.
The temperature of the acidolysis reaction is 60-65 ℃, and the time of the acidolysis reaction is 2.5-3h.
And after the acidolysis is completed, adding water to quench the reaction, cooling and crystallizing, filtering to obtain an aceclofenac crude product, dissolving the aceclofenac crude product in ethyl acetate, heating and refluxing, cooling and recrystallizing, and filtering to obtain an aceclofenac refined product, wherein the molar ratio of the aceclofenac crude product to the ethyl acetate is 1:5-6.
The weak acid solvent adopted for crystallization is acetic acid or propionic acid, and the molar ratio of the weak acid solvent to diclofenac tert-butyl ester is 9-11; the molar ratio of water to diclofenac tert-butyl ester of the quenching reaction is 13-20.
The formula for preparing aceclofenac according to the present invention is as follows:
the method uses ethanol, acetic acid and ethyl acetate as solvents, is more environment-friendly and economical, is easy to recover, saves cost, is simple and convenient to operate, and is more suitable for technological production. The method uses an environment-friendly solvent to carry out industrial production of aceclofenac, and the iodide is added to activate halogen bromine in the bromoacetic acid tert-butyl ester, so that the reaction can be carried out under a mild condition, and the reaction time is greatly shortened; removing tert-butyl from aceclofenac tert-butyl ester by acidification, controlling reaction time and temperature, tracking reaction progress, adding water after reaction to quench and remove salt. The total reaction condition is mild, high temperature and high energy consumption are avoided, the method is environment-friendly and economical, and the method has good industrial prospect.
Compared with the literature (J.Med.Industrials, 2008,39 (6): 408-409), the invention adds acetic anhydride, the function of the acetic anhydride is to react with water in a reaction system, the generation of hydrolysis impurities is reduced, and the product quality is better. The process of the invention comprises the steps of adding acetic acid, acetic anhydride and aluminum chloride, fully stirring, then adding aceclofenac tert-butyl ester for reaction, adding aceclofenac tert-butyl ester, glacial acetic acid and anhydrous aluminum trichloride into a reaction bottle in the literature (J.Med.Industry, 2008,39 (6): 408-409), and stirring for reaction, wherein the raw material adding sequence of the invention is different from that of the literature. The addition of the water removing agent and the addition sequence of the raw materials can influence the hydrolysis impurities in the aceclofenac product. Repeating the literature process to obtain a product containing about 2.6% of hydrolyzed impurities, i.e., diclofenac acid (the acid-formed product of diclofenac sodium as raw material); the product obtained by the process has hydrolysis impurities less than 0.1 percent, and the product quality far exceeds that of the literature process.
The invention defines the charging sequence of acidolysis, firstly mixing organic acid, water removing agent and Lewis acid, stirring for 5-120 minutes, then adding aceclofenac tert-butyl ester for acidolysis reaction, and the hydrolysis impurity of the obtained product is less than 0.1%. If organic acid, water removing agent and aceclofenac tert-butyl ester are mixed firstly and Lewis acid is added for acidolysis, the hydrolysis impurity of the obtained product can be up to 0.5 percent.
Advantageous effects
The method adopts dehalogenation esterification and acetic acid and Lewis acid tert-butyl removal reaction, has mild reaction conditions, high reaction rate, good product quality, high yield, low energy consumption, environmental protection, economy and simple and convenient operation, can recycle most of the solvents, and reduces the discharge of waste solvents, thereby reducing the cost and protecting the environment.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
(1) 120g of ethanol was added to a 500ml reaction vessel, and the mixture was stirred and heated, 112.5g of diclofenac sodium, 89.7g (1.3 eq) of t-butyl bromoacetate, 4.11g (0.07 eq) of potassium iodide as a catalyst were added, and 30g of ethanol was added to wash the material tube. Heating to 60-70 deg.C, holding the temperature for 3 hr, sampling, and detecting to obtain a liquid phase containing diclofenac sodium 2%, and finishing the reaction. After the heating is stopped, the temperature is not required to be reduced too fast so as to prevent the materials from being separated out quickly to cause agglomeration. Cooling to 10 deg.C, filtering, adding 100g water to drip wash the material, and washing off salts. After drying, 136.5g of aceclofenac tert-butyl ester, 99.20% purity and 94.1% yield were obtained.
(2) To a 500ml reaction vessel, 200g of acetic acid and 4.0g (0.12 eq) of acetic anhydride were added, and stirring was started, and 8.8g (0.2 eq) of aluminum trichloride was added and stirring was continued for 1 hour. Adding 136.5g of aceclofenac tert-butyl ester in the step (1), adding 40g of acetic acid to rinse the material pipe, and heating to 60-65 ℃ for heat preservation. Reacting for 2.5 hours, sampling and detecting, stopping the reaction when the liquid phase intermediate ester is less than 1%. Cooling to the temperature of the feed liquid less than or equal to 15 ℃, and adding 85g of water to quench the reaction. After quenching, a large amount of solid is separated out, the mixture is kept at the temperature of 10-20 ℃ and stirred for 1 hour, the mixture is filtered, a small amount of drinking water is added into the mixture for leaching, and the crude aceclofenac product is dried to obtain 105.6g, the purity is 99.22%, the hydrolysis impurities are 0.07%, and the yield is 89.6%.
(3) Adding 104.6g of crude aceclofenac into a reaction bottle, adding 130g of ethyl acetate, heating and stirring, heating to 80 ℃, and keeping the temperature and stirring until the crude aceclofenac is dissolved. Cooling for recrystallization, filtering at 10 ℃ to obtain refined aceclofenac product 100.1g, purity 99.83% and total yield 80.7%.
Example 2
(1) 2.5kg of ethanol was added to a 10L reactor, and the mixture was stirred and heated, 2.25kg of diclofenac sodium, 1.8kg (1.3 eq) of t-butyl bromoacetate and 0.082kg (0.07 eq) of potassium iodide as a catalyst were added, and 0.6kg of ethanol was further added to wash the material tube. Heating to 61-65 deg.C, holding the temperature for 3 hr, sampling, and detecting to obtain a liquid phase containing diclofenac sodium 2%, and finishing the reaction. After the heating is stopped, the temperature is reduced to 10 ℃, then the filtration is carried out, 2kg of water is added to drip wash the materials, and the salts are washed away. After drying, 2.74kg of aceclofenac tert-butyl ester was obtained with a purity of 99.28% and a yield of 94.45%.
(2) 4.25kg of acetic acid was added to a 10L reactor, 80.3g (0.12 eq) of acetic anhydride was added thereto, and stirring was started, and 176.6g (0.2 eq) of aluminum trichloride was added thereto and stirred for 1 hour. Adding 2.74kg of aceclofenac tert-butyl ester in the step (1), adding 0.55kg of acetic acid to rinse the material pipe, heating to 60-65 ℃, keeping the temperature and reacting for 2.5 hours, sampling and detecting, stopping the reaction when the liquid-phase intermediate ester is lower than 1%. Cooling to the temperature of the feed liquid less than or equal to 15 ℃, and adding 1.8kg of water to quench the reaction. After quenching, a large amount of solid is separated out, the mixture is kept at the temperature of 10-20 ℃ and stirred for 1 hour, the mixture is filtered, a small amount of drinking water is added into the mixture for leaching, and the crude aceclofenac product is dried to obtain 2.15kg, the purity is 99.38%, the yield is 90.2%, the hydrolysis impurities are 0.08%, and the total yield is 85.8%.
(3) 2.15kg of the crude aceclofenac was added with 2.6kg of ethyl acetate, heated and stirred, the temperature was raised to 80 ℃, and the mixture was stirred while being kept warm until it was dissolved. Cooling and recrystallizing, filtering at 10 deg.C to obtain refined aceclofenac product 2.08kg, with purity of 99.88% and total yield of 83.0%.
Comparative example 1
(1) 20.0g (62.8 mmol) of diclofenac sodium, DMF (80 ml) and 11.3g (75.0 mmol) of chloroacetic acid tert-butyl ester are added into a reaction bottle, the mixture is stirred and heated to reflux for 2 hours, TLC shows that the raw material diclofenac sodium completely reacts, and DMF and excess chloroacetic acid tert-butyl ester are evaporated under reduced pressure after normal pressure. The residue was poured into 100ml of cold water and stirred to give a pink cake precipitate. And (3) carrying out suction filtration, washing a filter cake with water, and drying under an infrared lamp to obtain 25.5g of pink powdery solid (namely intermediate aceclofenac tert-butyl ester) which is directly used for subsequent reaction.
(2) Adding 25.5g of aceclofenac tert-butyl ester, 70ml of glacial acetic acid and 1.63g of anhydrous aluminum chloride (12.2 mmol) into a reaction bottle, stirring at 60 ℃ for reacting for 2 hours, cooling to room temperature, adding 200ml of water to precipitate a large amount of white crystals, cooling in an ice water bath, standing, performing suction filtration after complete crystallization, washing a filter cake with water, drying under an infrared lamp, and recrystallizing with toluene to obtain 17.6g of white needle crystals with the purity of 96.86%, 2.6% of crude hydrolysis impurities and the yield of two steps of 79.0%.
Comparative example 2
(1) 120g of ethanol was added to a 500ml reaction vessel, and the mixture was stirred and heated, 112.5g of diclofenac sodium, 89.7g (1.3 eq) of t-butyl bromoacetate, 4.11g (0.07 eq) of potassium iodide as a catalyst were added, and 30g of ethanol was added to wash the material tube. Heating to 60-70 deg.C, holding the temperature for 3 hr, sampling, and detecting to obtain a liquid phase containing diclofenac sodium 2%, and finishing the reaction. After the heating is stopped, the temperature is not required to be reduced too fast so as to prevent the materials from being separated out quickly to cause agglomeration. Cooling to 10 deg.C, filtering, adding 100g water to drip wash the material, and washing off salts. After drying, 136.5g of aceclofenac tert-butyl ester, 99.20% purity and 94.1% yield were obtained.
(2) Adding 200g of acetic acid into a 500ml reaction kettle, adding 4.0g (0.12 eq) of acetic anhydride, adding 136.5g of aceclofenac tert-butyl ester in the step (1), adding 40g of acetic acid to rinse a material pipe, starting stirring, and stirring for 1 hour. Adding 8.8g (0.2 eq) of aluminum trichloride, heating to 60-65 ℃ and preserving heat. Reacting for 2.5 hours, sampling and detecting, stopping the reaction when the liquid phase intermediate ester is less than 1%. Cooling to the temperature of the feed liquid less than or equal to 15 ℃, and adding 85g of water to quench the reaction. After quenching, a large amount of solid is separated out, the mixture is stirred for 1 hour at the temperature of 10-20 ℃, filtered, rinsed by adding a small amount of drinking water into the mixture, and dried to obtain 103.6g of crude aceclofenac with the purity of 98.62 percent, 0.5 percent of hydrolyzed impurities and the yield of 87.9 percent.
(3) Adding 102.6g of crude aceclofenac into a reaction bottle, adding 130g of ethyl acetate, heating and stirring, heating to 80 ℃, and keeping the temperature and stirring until the crude aceclofenac is dissolved. Cooling and recrystallizing, filtering at 10 ℃ to obtain refined aceclofenac product 98.1g, with purity of 99.83% and total yield of 79.8%.
Comparative example 3
(1) 120g of ethanol was added to a 500ml reaction vessel, and the mixture was stirred and heated, 112.5g of diclofenac sodium, 89.7g (1.3 eq) of t-butyl bromoacetate, 4.11g (0.07 eq) of potassium iodide as a catalyst were added, and 30g of ethanol was added to wash the material tube. Heating to 60-70 deg.C, holding the temperature for 3 hr, sampling, and detecting to obtain a liquid phase containing diclofenac sodium 2%, and finishing the reaction. After the heating is stopped, the temperature is not required to be reduced too fast so as to prevent the materials from being separated out quickly to cause agglomeration. Cooling to 10 deg.C, filtering, adding 100g water to drip wash the material, and washing off salts. After drying, 136.8g of aceclofenac tert-butyl ester was obtained with a purity of 99.27% and a yield of 94.3%.
(2) Adding 200g of acetic acid into a 500ml reaction kettle, adding 4.0g (0.12 eq) of acetic anhydride, 8.8g (0.2 eq) of aluminum trichloride and 136.5g of aceclofenac tert-butyl ester, supplementing 40g of acetic acid to elute a material pipe, heating to 60-65 ℃ and preserving heat. Reacting for 2.5 hours, sampling and detecting, stopping the reaction when the liquid phase intermediate ester is less than 1%. Cooling to the temperature of the feed liquid less than or equal to 15 ℃, and adding 85g of water to quench the reaction. After quenching, a large amount of solid is separated out, the mixture is stirred for 1 hour at the temperature of 10-20 ℃, filtered, rinsed by adding a small amount of drinking water into the mixture, and dried to obtain 102.3g of crude aceclofenac, the purity of which is 98.24%, the hydrolysis impurity content of which is 1.1% and the yield of which is 86.3%.
(3) Adding 102g of crude aceclofenac into a reaction bottle, adding 130g of ethyl acetate, heating and stirring, heating to 80 ℃, and keeping the temperature and stirring until the crude aceclofenac is dissolved. Cooling and recrystallizing, filtering at 10 deg.C to obtain refined aceclofenac product 97.4g, with purity of 99.87% and total yield of 77.7%.
Claims (6)
1. A method for industrially producing aceclofenac, comprising:
mixing an organic acid, a water removing agent and Lewis acid, fully stirring, adding aceclofenac tert-butyl ester for acidolysis reaction to obtain aceclofenac, wherein the molar ratio of the aceclofenac tert-butyl ester to the Lewis acid to the organic acid to the water removing agent is 1.15-0.35; the water removing agent is acetic anhydride, the organic acid is acetic acid, and the Lewis acid is aluminum trichloride.
2. The method according to claim 1, wherein said preparation of tert-butyl aceclofenac comprises: diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and a solvent are subjected to heat preservation reaction for 4-5h at the temperature of 60-70 ℃ according to the molar ratio of 1:1-1.5.
3. The method of claim 2, wherein the solvent is ethanol; the iodide is potassium iodide.
4. The method of claim 1, wherein the stirring time is from 5 minutes to 120 minutes.
5. The method as claimed in claim 1, wherein the acidolysis reaction is carried out at a temperature of 60-65 ℃ for 2.5-3 hours.
6. The method as claimed in claim 1, wherein the acidolysis is completed, water is added to quench the reaction, the reaction is cooled and crystallized, the crude aceclofenac is obtained by filtration, then the crude aceclofenac is dissolved in ethyl acetate and heated for reflux, the temperature is reduced for recrystallization, and the refined aceclofenac is obtained by filtration, wherein the molar ratio of the crude aceclofenac to the ethyl acetate is 1:5-6.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
| CN108383745A (en) * | 2018-05-08 | 2018-08-10 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aceclofenac |
| CN110143891A (en) * | 2019-05-21 | 2019-08-20 | 浙江工业大学 | Preparation method of aceclofenac |
| CN110305027A (en) * | 2019-06-11 | 2019-10-08 | 宁波斯迈克制药有限公司 | A method of producing the Aceclofenac tert-butyl ester |
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- 2020-07-17 CN CN202010692061.4A patent/CN111848426B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
| CN108383745A (en) * | 2018-05-08 | 2018-08-10 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aceclofenac |
| CN110143891A (en) * | 2019-05-21 | 2019-08-20 | 浙江工业大学 | Preparation method of aceclofenac |
| CN110305027A (en) * | 2019-06-11 | 2019-10-08 | 宁波斯迈克制药有限公司 | A method of producing the Aceclofenac tert-butyl ester |
Non-Patent Citations (3)
| Title |
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| 吴修艮 等.醋氯芬酸的合成.《齐鲁药事》.2009,第28卷(第10期), * |
| 醋氯芬酸的合成;吴修艮 等;《齐鲁药事》;20091231;第28卷(第10期);620-621 * |
| 醋氯芬酸的合成;秦丙昌 等;《中国医药工业杂志》;20081231;第39卷(第6期);408-409 * |
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