CN101948446B - Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride - Google Patents
Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride Download PDFInfo
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- CN101948446B CN101948446B CN 201010273615 CN201010273615A CN101948446B CN 101948446 B CN101948446 B CN 101948446B CN 201010273615 CN201010273615 CN 201010273615 CN 201010273615 A CN201010273615 A CN 201010273615A CN 101948446 B CN101948446 B CN 101948446B
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- CN
- China
- Prior art keywords
- chemical formula
- aminothiazol
- acid hydrochloride
- formula
- thiourea
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- ZEWJJZKVQOMYKJ-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)acetic acid;hydrochloride Chemical compound Cl.NC1=NC(CC(O)=O)=CS1 ZEWJJZKVQOMYKJ-UHFFFAOYSA-N 0.000 title claims abstract description 13
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000126 substance Substances 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 5
- UCTNTYHJFWMUBD-UHFFFAOYSA-N 4-chloro-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CCl UCTNTYHJFWMUBD-UHFFFAOYSA-N 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 229930186147 Cephalosporin Natural products 0.000 abstract description 5
- 229940124587 cephalosporin Drugs 0.000 abstract description 5
- 150000001780 cephalosporins Chemical class 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- DYCLHZPOADTVKK-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-4-yl)acetate Chemical compound NC1=NC(CC(O)=O)=CS1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 2
- 150000004729 acetoacetic acid derivatives Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- PYBFUAILVOXGRT-UHFFFAOYSA-N (2-amino-1,3-thiazol-4-yl) acetate Chemical compound CC(=O)OC1=CSC(N)=N1 PYBFUAILVOXGRT-UHFFFAOYSA-N 0.000 description 1
- SVSFIELZISOJDT-XRZFDKQNSA-N (6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl]tetrazol-5-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrochloride Chemical compound Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 SVSFIELZISOJDT-XRZFDKQNSA-N 0.000 description 1
- -1 2-aminothiazol-4-yl Chemical group 0.000 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 229960004700 cefotiam hydrochloride Drugs 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention provides a method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride represented by a chemical formula 1. In the method, thiourea and alpha-halo ethyl acetoacetate are used as raw materials to undergo stepwise reaction under an organic solvent condition. The method is characterized by comprising two steps: a first step of reacting 4-chloro ethyl acetoacetate represented by achemical formula 2 with the thiourea represented by a chemical formula 3 in a water phase; and a second step of suspending and reacting white crystals obtained by the first step in cold concentrated hydrochloric acid. The reaction is performed under a more mild condition, and the 2-aminothiazol-4-ylacetic acid hydrochloride, which is a core intermediate of cephalosporin is prepared with high purity and high yield. Meanwhile, the 4-chloro ethyl acetoacetate serving as a starting material can be processed easily at low cost, the solvent used in reaction is water and therefore is safe to the environment. The production cost is thus reduced considerably, which is favorable for industrial development.
Description
Technical Field
The invention relates to a method for preparing a medical intermediate, in particular to a method for preparing an intermediate 2-aminothiazole-4-yl acetic acid hydrochloride used in the preparation of cephalosporin antibiotics.
Background
7- [2- (2-aminothiazol-4-yl) acetamido- [3- [ [ [ (N, N) -dimethyl-amino-ethyl-tetrazol-1-yl ] thio ] methyl ] -8 oxo-5-thia-1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid ] dihydrochloride (cefotiam hydrochloride), represented by chemical formula 5, is a compound originally disclosed in U.S. Pat. No. 4755598, which is a cephalosporin antibiotic showing good antibacterial effects against gram-negative and gram-positive bacteria, and its manufacturing method has been disclosed in Korean patent publication Nos. 80-1672, 83-1415, etc.
[ chemical formula 5 ]
In the process of manufacturing the compound of chemical formula 5, the manufacture of 2-aminothiazol-4-ylacetic acid hydrochloride represented by chemical formula 1 is an important link in the process of manufacturing the compound of chemical formula 5, and is a key in relation to the production cost thereof.
[ chemical formula 1 ]
At present, no specific report on the manufacturing method of chemical formula 1 is reported in domestic and foreign documents. According to the synthesis experience of thiazole compounds, the synthesis method is generally a three-step method: thiourea and gamma-halogenated acetoacetate are taken as raw materials, the first step is directly closed to form 2-aminothiazole-4-acetate, then the second step is saponified by alkaline solution to obtain 2-aminothiazole-4-sodium acetate, and the target product is obtained by acidification in the third step. The reaction process is as follows:
the process is carried out in an organic solvent, and the corresponding product can be obtained through repeated acid-base treatment for many times, the method has the defects of complex post-treatment and great environmental pollution, and the post-treatment for obtaining the target 2-aminothiazole-4-acetic acid usually adopts a capillary electrophoresis method, so the method is complex, is only limited to be carried out in a laboratory and is not suitable for industrialization. The existing manufacturing method is complex, pollutes the environment, has low product yield and high product cost, greatly influences the purity of the product, and the manufacturing process is in urgent need of improvement.
Disclosure of Invention
To overcome the disadvantages of the prior art, the present inventors have made extensive studies to solve the problems of the prior art, and as a result, the present invention provides a novel process for producing 2-aminothiazol-4-ylacetic acid hydrochloride as an intermediate for cephalosporin production with high purity and high yield while minimizing the production of impurities under more environmentally friendly conditions.
The technical scheme for solving the problems is as follows: a method for preparing 2-aminothiazole-4-yl acetic acid hydrochloride takes thiourea and gamma-halogenated acetoacetate as raw materials to carry out stepwise reaction in the presence of a solvent, and is characterized in that: the method comprises the following steps of reacting 4-chloroacetoacetic ester shown in chemical formula 2 and thiourea shown in chemical formula 3 in an aqueous phase in the first step; in the second step, the white crystals obtained in the first step are suspended in cold concentrated hydrochloric acid for reaction.
Wherein,
[ chemical formula 1 ]
[ chemical formula 2 ]
[ chemical formula 3 ]
[ chemical formula 4 ]
The invention is represented by the following reaction formula:
[ REACTION TYPE ]
The solvent used may be methanol, ethanol, water or a mixture thereof, and water is most preferable.
Wherein the chemical formula 2 can be methyl ester, ethyl ester, tert-butyl ester, etc., preferably ethyl ester.
The molar ratio of 4-chloroacetoacetate to thiourea is in the range of 1: 1 to 1: 1.5.
The invention has the advantages that the reaction is carried out under milder conditions, and the 2-aminothiazole-4-yl acetic acid hydrochloride serving as the core intermediate of the cephalosporin is prepared with high purity and high yield; meanwhile, 4-chloroacetoacetic ester used as a starting material is easy to treat and low in price, and particularly, the solvent used in the reaction is water, so that the method is favorable for improving the environment, greatly reduces the production cost and is favorable for industrial development.
Detailed Description
In the first step, thiourea (chemical formula 3) is suspended in a solvent and cooled to-5 ℃ to 3 ℃, more preferably to O-3 ℃, and then stirred for 15 to 30 minutes, more preferably for 20 to 30 minutes. In this case, methanol, ethanol, water or a mixed solvent thereof may be used as the solvent, but water is most preferable; then, 4-chloroacetoacetate (chemical formula 2), which may be methyl ester, ethyl ester, tert-butyl ester, etc., but is preferably ethyl ester, is slowly added to the above-prepared thiourea solution over 2 to 3 hours while maintaining O to 5 ℃, more preferably O to 3 ℃, and stirred at the same temperature for 2 to 3 hours, the molar ratio of 4-chloroacetoacetate to thiourea is controlled in the range of 1: 1 to 1: 1.5, ammonia is slowly added to the mixture while maintaining O to 5 ℃, more preferably 5 ℃ or lower to adjust the pH to 7 to 10, and stirred at O to 5 ℃ for O.5 to 1 hour to obtain white crystals. The white crystals were filtered under reduced pressure and washed with tap water to obtain 2-aminothiazol-4-yl acetate, an intermediate compound represented by chemical formula 4.
And secondly, cooling concentrated hydrochloric acid to the temperature of-5-3 ℃, preferably to the temperature of O-3 ℃, suspending the intermediate compound in the previous step in prepared cold hydrochloric acid at the temperature, stirring for 30-60 minutes, preferably for 60 minutes, then heating to the temperature of 50-100 ℃, preferably for 50-60 ℃, preserving heat, hydrolyzing for 3-6 hours, preferably for 6 hours, cooling to the temperature of-5-0 ℃ after heat preservation, and filtering to obtain the target product, namely the chemical formula 1.
Example 1
40g of thiourea was suspended in 100ml of water and stirred for 20 minutes to dissolve it, the temperature was lowered to 0 ℃ and kept at O-3 ℃ and 68.5ml of 4-ethyl chloroacetoacetate was added dropwise over 2 hours and stirred at the same temperature for 3 hours. After the incubation, the PH was adjusted to 7 with ammonia, white crystals precipitated and filtered to obtain the intermediate compound of formula 4.
After 100ml of concentrated hydrochloric acid is cooled to O-3 ℃, the intermediate compound obtained in the previous step is suspended in prepared cold concentrated hydrochloric acid at the temperature, stirred for 60 minutes, then heated to 60 ℃, kept warm and hydrolyzed for 6 hours, cooled to-5-0 ℃ after the heat preservation is finished, and filtered to obtain 90g of a target product (chemical formula 1), the yield is 92%, and the purity (HPLC) is 99.5%.
Example 2
60g of thiourea is suspended in 160 ml of water, stirred for 20 minutes to be dissolved, the temperature is reduced to 0 ℃, the temperature is kept at 1-3 ℃, 132.5ml of 4-ethyl chloroacetoacetate is dripped in about 2 hours, and the mixture is stirred for 3 hours at the same temperature after the dripping is finished. After the completion of the heat preservation, the PH was adjusted to 7 with ammonia water, white crystals were precipitated, and the intermediate compound represented by formula 4 was obtained by filtration.
After 150ml of concentrated hydrochloric acid is cooled to 1-3 ℃, the intermediate compound obtained in the previous step is suspended in prepared cold concentrated hydrochloric acid at the temperature, the mixture is stirred for 60 minutes, then the liver is heated to 60 ℃, the mixture is subjected to heat preservation and hydrolysis for 6 hours, the mixture is cooled to-3-0 ℃ after the heat preservation, and the target product (chemical formula 1)135.1g is obtained through filtration, wherein the yield is 92%, and the purity (HPLC) is 99.6%.
Example 3
100g of thiourea was suspended in 250ml of water, stirred for 20 minutes to dissolve it, the temperature was lowered to 0 ℃ and kept at O-2 ℃, 171.5ml of 4-ethyl chloroacetoacetate was added dropwise over 2 hours, and stirred at the same temperature for 3 hours after the addition. After the incubation, the PH was adjusted to 7 with ammonia, white crystals precipitated and filtered to obtain the intermediate compound of formula 4.
After 250ml of concentrated hydrochloric acid is cooled to 1-2 ℃, the intermediate compound obtained in the previous step is suspended in prepared cold concentrated hydrochloric acid at the temperature, stirred for 60 minutes, then heated to 60 ℃, kept warm and hydrolyzed for 6 hours, cooled to-5 to-2 ℃ after the heat preservation is finished, and filtered to obtain 228g of a target product (chemical formula 1), the yield is 92%, and the purity (HPLC) is 99.4%.
Claims (4)
1. Using chemical formula 1A process for producing 2-aminothiazole-4-ylacetic acid hydrochloride, which comprises reacting thiourea and a gamma-haloacetoacetate in the presence of a solvent in a stepwise manner, characterized in that: is carried out in two steps, the first step is to make chemical formula 2
4-chloroacetyl group shownAcetate and chemical formula 3
The thiourea is reacted in a water phase; in the second step, the white crystals obtained in the first step are suspended in cold concentrated hydrochloric acid for reaction.
2. A catalyst of the formula 1 according to claim 1
A process for producing 2-aminothiazol-4-ylacetic acid hydrochloride represented by the following formula: the solvent may be methanol, ethanol, water or a mixed solvent thereof.
3. A catalyst of the formula 1 according to claim 1
A process for producing 2-aminothiazol-4-ylacetic acid hydrochloride represented by the following formula: wherein chemical formula 2
Can be methyl ester, ethyl ester and tert-butyl ester.
4. A catalyst of the formula 1 according to claim 1A process for producing 2-aminothiazol-4-ylacetic acid hydrochloride represented by the following formula: the molar ratio of 4-chloroacetoacetate to thiourea is in the range of 1: 1 to 1: 1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010273615 CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010273615 CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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| Publication Number | Publication Date |
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| CN101948446A CN101948446A (en) | 2011-01-19 |
| CN101948446B true CN101948446B (en) | 2013-05-15 |
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| CN 201010273615 Expired - Fee Related CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827099A (en) * | 2012-08-20 | 2012-12-19 | 哈尔滨恒运科技开发有限公司 | Method for synthesis of 2-(2-aminothiazol-4-yl)acetic acid hydrochloride |
| CN111533710B (en) * | 2020-06-02 | 2022-04-22 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260607A (en) * | 1976-08-10 | 1981-04-07 | Takeda Chemical Industries, Ltd. | Cephalosporin esters |
| US4391979A (en) * | 1980-02-18 | 1983-07-05 | Lonza Ltd. | Process for the preparation of (2-amino-thiazol-4yl)-acetic acid hydrochloride |
| US4725592A (en) * | 1983-08-10 | 1988-02-16 | Takeda Chemical Industries, Ltd. | 1-Acyloxyalkyl esters of cephalosporin |
-
2010
- 2010-08-30 CN CN 201010273615 patent/CN101948446B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260607A (en) * | 1976-08-10 | 1981-04-07 | Takeda Chemical Industries, Ltd. | Cephalosporin esters |
| US4391979A (en) * | 1980-02-18 | 1983-07-05 | Lonza Ltd. | Process for the preparation of (2-amino-thiazol-4yl)-acetic acid hydrochloride |
| US4725592A (en) * | 1983-08-10 | 1988-02-16 | Takeda Chemical Industries, Ltd. | 1-Acyloxyalkyl esters of cephalosporin |
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| CN101948446A (en) | 2011-01-19 |
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