CN114890962B - Synthetic method of 1,2, 4-triazine ring of coccidian-resistant veterinary drug - Google Patents
Synthetic method of 1,2, 4-triazine ring of coccidian-resistant veterinary drug Download PDFInfo
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to the technical field of veterinary drugs, in particular to a synthetic method of an anti-coccidiosis veterinary drug 1,2, 4-triazine ring, which comprises the following steps: (1) malonic acid and ethyl carbamate are taken as reaction raw materials, acetic anhydride is added, heating is carried out, heat preservation reaction and separation are carried out, and malonic acid monoamido ethyl formate (structural formula I) is obtained; (2) adding aniline compound (structural formula II) and malonic acid monoamido ethyl formate (structural formula I) into acetic acid, and performing diazo coupling by using sodium nitrite to obtain reaction liquid containing a diazo coupling product (structural formula III); (3) taking reaction liquid containing diazo coupling product (structural formula III), adding a cyclization agent into the reaction liquid, heating, refluxing and distilling to obtain 2- [ phenyl ] -1,2, 4-triazine-3, 5(2H,4H) -diketone compound (structural formula IV). The method shortens the whole reaction steps, improves the economic benefit and reduces the discharge amount of three wastes.
Description
Technical Field
The invention relates to the technical field of veterinary medicines, and in particular relates to a synthetic method of an anti-coccidiosis veterinary medicine 1,2, 4-triazine ring.
Background
Triazine ring veterinary drugs cimetiril and diclazuril are high-efficiency low-toxicity broad-spectrum anticoccidial drugs. Can be clinically used for preventing and treating avian coccidiosis. The existing anticoccidial drugs such as toltrazuril, diclazuril, climbazole and the like generally have better anticoccidial performance, the diclazuril has lower dosage, and the climbazole has lower drug resistance, so that the anticoccidial drugs are widely used for preventing and treating avian coccidia. The existing processes for synthesizing diclazuril and cimetiril triazine ring are six-step reaction including diazotization, heat preservation, coupling, heating, cyclization, hydrolysis, final separation, decarboxylation and preparation of a cyclization agent, wherein the cyclization agent diethoxycarbonyl malonamide used in the conventional synthesis process of 1,2,4 triazine ring of diclazuril and cimetiril is very easy to hydrolyze and has a low preparation yield of only 50%, so that the unit consumption of raw materials is high, a large amount of intermediates are generated in the diazotization, coupling and cyclization processes under the conventional conditions, the purity and yield of the product are low, the yield of the existing technical means in the triazine ring synthesis process is only 40%, and the qualified product can be obtained by complex refining means, so that the method is not suitable for industrial production. Therefore, aiming at the problems, a synthetic method of the 1,2, 4-triazine ring of the coccidian-resistant veterinary drug is established.
Disclosure of Invention
The invention aims to: aiming at the defects in the prior art, the synthetic method of the coccidian-resistant veterinary drug 1,2, 4-triazine ring is provided, the method is utilized to shorten the whole reaction step, improve the economic benefit and reduce the discharge amount of three wastes.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing 1,2, 4-triazine ring of an anti-coccidiosis veterinary drug, which comprises the following steps:
(1) malonic acid and ethyl carbamate are taken as reaction raw materials, acetic anhydride is added, heating is carried out, heat preservation reaction and separation are carried out, thus obtaining malonic acid monoamide ethyl formate (structural formula I),
(2) adding aniline compound (structural formula II) and ethyl malonamic acid monoamide (structural formula I) into acetic acid, diazo-coupling with sodium nitrite to obtain reaction solution containing diazo-coupled product,
(3) taking reaction liquid containing diazo coupling product (structural formula III), adding a cyclization agent into the reaction liquid, heating, refluxing and distilling to obtain 2- [ phenyl ] -1,2, 4-triazine-3, 5(2H,4H) -diketone compound (structural formula IV),
As an improved technical scheme, the molar ratio of the malonic acid to the ethyl carbamate in the step (1) is 1: 1.1-1.3.
As an improved technical scheme, the mass ratio of the acetic anhydride to the malonic acid in the step (1) is 3-5: 1.
As an improved technical scheme, the reaction temperature in the step (1) is 50-140 ℃.
As an improved technical scheme, in the step (2), the molar ratio of the aniline compound to the ethyl malonamic acid monoamide is 1:1.1-1.5, the amount of the sodium nitrite is 1.05 equivalent, and the concentration is 20 wt%.
As an improved technical scheme, the temperature of the diazo coupling reaction in the step (2) is 10-20 ℃.
As an improved technical scheme, the equivalent ratio of the cyclizing agent in the step (3) to the aniline compound in the step (2) is 0.2-1.1:1, and the cyclizing agent is sodium salt or potassium salt of carboxylic acid.
As a preferable technical scheme, the cyclotomic agent in the step (3) is sodium acetate or potassium acetate.
As an improved technical scheme, R in the structural formula IV in the step (3) 1 Represents p-acetamidophenoxy, R 2 Represents hydrogen, R 3 Represents methyl or R 1 Represents 2- (4-chlorophenyl) acetonitrile, R 2 Represents chlorine, R 3 Represents chlorine.
By adopting the technical scheme, compared with the prior art, the invention has the following advantages:
the anti-coccidian veterinary drug containing 1,2, 4-triazine ring can be prepared by adopting the process method of the invention, compared with the existing preparation process, the whole reaction step is shortened, the economic benefit is improved, and the discharge amount of three wastes is reduced.
Detailed Description
The present invention will be described in further detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Examples 1-9 are synthetic processes for the anticoccidial veterinary drug cimetiril, the specific synthetic process route is as follows:
example 1
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 50 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 162.74g of malonic acid monoamino ethyl formate, wherein the purity is 81.03%, and the purity yield is 65.29%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 46.38g of ethyl malonamic acid monoacid into a 1000ml four-neck flask, adding 200g of acetic acid, controlling the reaction temperature to be 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, keeping the temperature for 1h, finishing the reaction, adding 17.6g of 1.1 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing the liquid phase tracking reaction, recovering the solvent, filtering, washing with water, and separating to obtain 62.74g of cimetidine, the purity is 99.30%, and the purification yield is 90.64%;
example 2
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 70 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 185.79g of malonic acid monoamido ethyl formate, wherein the purity is 93.12%, and the purification yield is 85.66%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 43.42g of 1.25 equivalents of ethyl malonamic acid monoacid into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalents of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, keeping the temperature for 1h, finishing the reaction, adding 17.6g of 1.1 equivalents of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing the liquid phase tracking reaction, recovering the solvent, filtering, washing with water, and separating to obtain 63.31g of cimetidine, the purity is 99.12%, and the purity yield is 91.30%;
example 3
Adding 480g of acetic anhydride into a 1000ml four-mouth bottle, then adding 120g of malonic acid, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding 0.5h, keeping the temperature at 90 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 201.95g of malonic acid monoamido ethyl formate, wherein the purity is 98.36%, and the purity-reduced yield is 98.35%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 51.65g of 1.5 equivalent of ethyl malonamic acid into a 1000ml four-necked bottle, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 17.6g of 1.1 equivalent of sodium acetate into the four-necked bottle, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 63.26g of cimetidine, the purity is 99.64%, and the purity yield is 91.70%;
example 4
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 110 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 187.54g of malonic acid monoamino ethyl formate, wherein the purity is 99.23%, and the purity yield is 92.14%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 40.36g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 15-20 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 17.6g of 1.1 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 56.66g of cimetidine, the purity is 98.5%, and the purity yield is 81.20%;
example 5
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 140 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 179.80g of malonic acid monoamino ethyl formate, wherein the purity is 99.02%, and the purity yield is 88.15%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 37.95g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after 1h of heat preservation, adding 22.95g of 1.1 equivalent of potassium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 63.83g of climbazole, the purity is 99.50%, and the purification yield is 92.40%;
example 6
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 128.42g of 1.25 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 85 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 205.87g of malonic acid monoamino ethyl formate, wherein the purity is 96.31 percent, and the yield is 98.17 percent;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 39.02g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 14.4g of 0.9 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 60.28g of climbazole, the purity is 95.23%, and the purity yield is 83.51%;
example 7
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 133.56g of 1.3 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 85 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 209.01g of malonic acid monoamido ethyl formate, wherein the purity is 94.41%, and the purity yield is 97.70%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 39.81g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 11.2g of 0.7 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 57.55g of cimetidine, the purity is 94.60%, and the purity yield is 79.2%;
example 8
Adding 360g of acetic anhydride into a 1000ml four-neck bottle, then adding 120g of malonic acid, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 85 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 204.22g of malonic acid monoamino ethyl formate, wherein the purity is 96.90%, and the purity yield is 97.98%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 38.78g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-necked bottle, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 8g of 0.5 equivalent of sodium acetate into the four-necked bottle, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, and separating to obtain 50.89g of climbazole, wherein the purity is 93.20%, and the purification yield is 69.00%;
example 9
Adding 600g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 85 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 205.51g of malonic acid monoamino ethyl formate, wherein the purity is 96.31%, and the purity yield is 98%;
adding 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and 39.02g of 1.1 equivalent of ethyl malonamic acid into a 1000ml four-necked bottle, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 70.66g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after heat preservation for 1h, adding 3.2g of 0.2 equivalent of sodium acetate into the four-necked bottle, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water, separating to obtain 47.53g of cimetidine, the purity is 92.70%, and the purification yield is 64.10%;
examples 10-12 are processes for preparation of diclazuril, the specific synthetic route is as follows:
example 10
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of ethyl carbamate by using a peristaltic pump, dropwise adding for 0.5h, keeping the temperature at 90 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, and separating to obtain 202.51g of malonic acid monoamido ethyl formate, wherein the purity is 97.33%, and the purification yield is 97.59%;
adding 50g of 2- (4-amino-2, 6-dichlorophenyl) -2- (4-chlorophenyl) acetonitrile and 31.76g of 1.1 equivalent of ethyl malonamic acid monoamidoformate into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 58.13g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after 1h of heat preservation, adding 14.48g of 1.1 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water and separating to obtain 60.31g of diclazuril, wherein the purity yield is 90.64%, and the purity is 98.31%;
example 11
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of malonic acid monoamido ethyl formate by using a peristaltic pump, dropwise adding 0.5h, keeping the temperature at 90 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, separating to obtain 204.96g of malonic acid monoamido ethyl formate, wherein the purity is 96.52%, and the purity yield is 97.95%;
adding 50g of 2- (4-amino-2, 6-dichlorophenyl) -2- (4-chlorophenyl) acetonitrile and 32.03g of 1.1 equivalent of ethyl malonamic acid monoamidoformate into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 15-20 ℃, dropwise adding 58.13g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after 1h of heat preservation, adding 14.48g of 1.1 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing and separating to obtain 50.45g of diclazuril, wherein the purity yield is 75.20%, and the purity is 97.50%;
example 12
Adding 480g of acetic anhydride and 120g of malonic acid into a 1000ml four-neck bottle, accurately dropwise adding 113.01g of 1.1 equivalent of malonic acid monoamido ethyl formate by using a peristaltic pump, dropwise adding 0.5h, keeping the temperature at 90 ℃, finishing the liquid phase monitoring reaction, finishing the reaction, separating to obtain 201.13g of malonic acid monoamido ethyl formate, wherein the purity is 98.76%, and the purity yield is 98.35%;
adding 50g of 2- (4-amino-2, 6-dichlorophenyl) -2- (4-chlorophenyl) acetonitrile and 42.69g of 1.5 equivalent of ethyl malonamic acid monoamidoformate into a 1000ml four-neck flask, adding 200g of acetic acid, cooling to 10-15 ℃, dropwise adding 58.13g of 1.05 equivalent of 20wt% sodium nitrite aqueous solution, finishing dropwise adding after 0.5h, finishing reaction after 1h of heat preservation, adding 14.48g of 1.1 equivalent of sodium acetate into the four-neck flask, heating to reflux for cyclization, finishing liquid phase tracking reaction, recovering solvent, filtering, washing with water and separating to obtain 61.29g of diclazuril, wherein the purity yield is 92.12%, and the purity is 98.32%;
the present patent is not limited to the above-mentioned embodiments, and those skilled in the art can make various changes without creative efforts from the above-mentioned conception, and fall within the protection scope of the present patent.
Claims (2)
1. A synthetic method of an anti-coccidiosis veterinary drug 1,2, 4-triazine ring is characterized by comprising the following steps:
(1) malonic acid and ethyl carbamate are used as reaction raw materials, acetic anhydride is added, heating is carried out to 50-140 ℃, heat preservation reaction and separation are carried out, thus obtaining the malonic acid monoamido ethyl formate as shown in the structural formula I, wherein the molar ratio of the malonic acid to the ethyl carbamate is 1:1.1-1.3, the mass ratio of the acetic anhydride to the malonic acid is 3-5:1,
(2) adding aniline compound shown as a structural formula II and malonic acid monoamino ethyl formate shown as a structural formula I into acetic acid, and carrying out diazo coupling with sodium nitrite at 10-20 ℃ to obtain reaction liquid containing diazo coupling product shown as a structural formula III, wherein the molar ratio of the aniline compound to the malonic acid monoamino ethyl formate is 1:1.1-1.5, the amount of the sodium nitrite is 1.05 equivalent, and the concentration is 20wt%,
wherein R in the structural formula II 1 Represents p-acetamidophenoxy, R 2 Represents hydrogen, R 3 Represents methyl or R 1 Represents 2- (4-chlorophenyl) acetonitrile, R 2 Represents chlorine, R 3 Represents chlorine;
(3) taking the reaction liquid containing the diazo coupling product in the step (2), adding a cyclization agent into the reaction liquid, heating, refluxing and distilling to obtain a 2- [ phenyl ] -1,2, 4-triazine-3, 5(2H,4H) -diketone compound with a structural formula of IV, wherein the equivalent ratio of the cyclization agent to the aniline compound in the step (2) is 0.2-1.1:1, and the cyclization agent is sodium salt or potassium salt of carboxylic acid,
2. The method for synthesizing 1,2, 4-triazine ring as an anti-coccidial veterinary drug according to claim 1, wherein the cyclomodifier in the step (3) is sodium acetate or potassium acetate.
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| CN101265238A (en) * | 2007-12-12 | 2008-09-17 | 重庆天极旅业有限公司 | Method for synthesizing triazine ring derivatives |
| CN104098521A (en) * | 2014-07-26 | 2014-10-15 | 威海出入境检验检疫局检验检疫技术中心 | Preparation method for diclazuril and isotope interior label D4-diclazuril |
| JP2015189808A (en) * | 2014-03-27 | 2015-11-02 | キヤノンファインテック株式会社 | Resin particulate dispersion, inkjet recording ink, inkjet recording method, ink cartridge, and inkjet recording device |
| CN110950815A (en) * | 2019-12-25 | 2020-04-03 | 山东国邦药业有限公司 | Green synthesis method of anticoccidial veterinary drug cimetiril |
| CN113248454A (en) * | 2021-07-06 | 2021-08-13 | 山东国邦药业有限公司 | Method for preparing 2- [ phenyl ] -1,2, 4-triazine-3, 5(2H,4H) -diketone compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101265238A (en) * | 2007-12-12 | 2008-09-17 | 重庆天极旅业有限公司 | Method for synthesizing triazine ring derivatives |
| JP2015189808A (en) * | 2014-03-27 | 2015-11-02 | キヤノンファインテック株式会社 | Resin particulate dispersion, inkjet recording ink, inkjet recording method, ink cartridge, and inkjet recording device |
| CN104098521A (en) * | 2014-07-26 | 2014-10-15 | 威海出入境检验检疫局检验检疫技术中心 | Preparation method for diclazuril and isotope interior label D4-diclazuril |
| CN110950815A (en) * | 2019-12-25 | 2020-04-03 | 山东国邦药业有限公司 | Green synthesis method of anticoccidial veterinary drug cimetiril |
| CN113248454A (en) * | 2021-07-06 | 2021-08-13 | 山东国邦药业有限公司 | Method for preparing 2- [ phenyl ] -1,2, 4-triazine-3, 5(2H,4H) -diketone compound |
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