CN110117291B - Synthesis method of cefotaxime acid - Google Patents
Synthesis method of cefotaxime acid Download PDFInfo
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- CN110117291B CN110117291B CN201910550210.0A CN201910550210A CN110117291B CN 110117291 B CN110117291 B CN 110117291B CN 201910550210 A CN201910550210 A CN 201910550210A CN 110117291 B CN110117291 B CN 110117291B
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- acid
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- cefotaxime
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- dichloromethane
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- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 title claims abstract description 40
- 238000001308 synthesis method Methods 0.000 title description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 16
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 239000006184 cosolvent Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008213 purified water Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims abstract description 8
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 230000035484 reaction time Effects 0.000 claims abstract description 4
- 238000000605 extraction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical group CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- 238000011084 recovery Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GPRBEKHLDVQUJE-QMTHXVAHSA-N (6R,7R)-3-(acetyloxymethyl)-7-[[2-(2-amino-4-thiazolyl)-2-methoxyimino-1-oxoethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-QMTHXVAHSA-N 0.000 description 1
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000007313 Reproductive Tract Infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960002727 cefotaxime sodium Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthetic method of cefotaxime acid, which comprises the following steps: (a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution; (b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution; (c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid. The invention provides a method for synthesizing cefotaxime acid by adding a certain amount of water into aqueous dichloromethane (the water content is 0.1-0.2%), which reduces the recovery difficulty of dichloromethane by applying the aqueous dichloromethane (the water content is 0.1-0.2%), achieves the purpose of energy saving, and simultaneously obtains the high-purity cefotaxime acid.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic method of cefotaxime acid.
Background
The chemical name of cefotaxime acid is (6R, 7R) -3- [ (acetoxyl) methyl ] -7- [ (2-amino-4-thiazolyl) - (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, which is the third generation cephalosporin, is the main raw material of cephalosporin-cefotaxime sodium for injection, and is applicable to pneumonia and other lower respiratory tract infections, urinary tract infections, meningitis, septicemia, abdominal cavity infections, pelvic cavity infections, skin soft tissues, genital tract infections, bone and joint infections and the like caused by sensitive bacteria.
At present, the synthesis method is mainly an AE active ester method, and WO9620198 reports that an AE-active ester (MEAM) is obtained by reacting bis (2-benzothiazole) Disulfide (DM) with aminothiazoly loximate, and then the AE-active ester (MEAM) is condensed with 7-ACA to obtain cefotaxime acid and obtain a byproduct 2-thio benzothiazole (M). The report uses acetone as a solvent, triethylamine is added under stirring, and after the reaction is finished, acid is added for crystallization to prepare the cefotaxime acid, which is the current method for industrially producing the cefotaxime acid.
Some improvements on the above basis have been subsequently reported, such as: CN 101560217A reports that dichloromethane or trichloromethane is used as a solvent, and after the reaction is finished, acidifying agent is directly added for acidification and then crystallization is carried out to prepare cefotaxime acid; CN101550149A reports that cefotaxime acid is prepared by taking 2-methyltetrahydrofuran as a solvent, adding an organic base, and adding acid for crystallization after the reaction is finished. CN 101613360A reports that dichloromethane is used as solvent, triethylamine is added under stirring, after the reaction is finished, water is used for extracting condensed reaction liquid, and the water extract is decolored and crystallized to prepare cefotaxime acid.
In the method using dichloromethane as a solvent, anhydrous dichloromethane is not needed for the acylation reaction of cefotaxime acid, however, in practical application, the recycled dichloromethane contains part of water, the processing difficulty of recycling dichloromethane is high, and the cost is high, so that how to research a preparation method more suitable for industrial production while ensuring the high purity of the product has important practical significance.
Disclosure of Invention
The invention aims to provide a synthetic method of cefotaxime acid, and aims to solve the problems of high difficulty and high cost in the recovery of dichloromethane in the conventional method.
The purpose of the invention is realized by the following technical scheme: a synthetic method of cefotaxime acid comprises the following steps:
(a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution;
(b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution;
(c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid. The synthesis reaction of cefotaxime acid is shown in figure 1.
The mass ratio of the 7-aminocephalosporanic acid to the benzothiazole active ester is 1: 1.3, and the addition amount of the purified water is 0.5-3%, preferably 2% of the mass of the 7-aminocephalosporanic acid.
The water content of the dichloromethane with water is 0.1-0.2%.
The cosolvent is an alcohol cosolvent or an amide cosolvent, and the adding amount of the cosolvent is 20-200% of the weight of 7-ACA, and is preferably 100%.
The alcohol cosolvent is methanol, ethanol or isopropanol. Ethanol and isopropanol are preferred.
The amide cosolvent is methyl formamide, methyl acetamide, N-dimethyl formamide or dimethyl acetamide. N, N-Dimethylformamide (DMF), Dimethylacetamide (DMAC) are preferred.
The invention has the following technical progress and beneficial effects:
the invention provides a method for synthesizing cefotaxime acid by adding a certain amount of water into aqueous dichloromethane (the water content is 0.1-0.2%), which reduces the recovery difficulty of dichloromethane by applying the aqueous dichloromethane (the water content is 0.1-0.2%), achieves the purpose of energy saving, and simultaneously obtains the high-purity cefotaxime acid.
According to the invention, the reaction time is shortened, the product conversion rate is improved, crystallization and filtration are carried out after HPLC detection reaction is completed, the purity of the obtained cefotaxime acid product is more than or equal to 98%, the quality is ensured within the product validity period, the yield reaches more than 98.5%, and the method is suitable for industrial popularization and application.
Drawings
FIG. 1 shows the reaction scheme for the synthesis of cefotaxime acid. Wherein 1 is cefotaxime acid, 2 is 7-ACA, and 3 is AE-active ester.
Detailed Description
Example 1
Mixing 20.0g of 7-ACA and 26.0g of AE-active ester in a mixed solvent of 100mL of aqueous dichloromethane (water content: 0.17%) and 20mL of ethanol, adding 4mL of purified water and 17mL of triethylamine, reacting for 60min, extracting an organic phase twice with water, decoloring, adjusting pH to 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.38 g of cefotaxime acid, and detecting that the purity of the cefotaxime acid is 99.5% and the water content is 0.6%, wherein the water content is specifically shown in Table 1.
Comparative example 1
Mixing 20.0g of 7-ACA and 26.0g of AE-active ester in a mixed solution of 100mL of anhydrous dichloromethane (water content: 0.05%), 20mL of anhydrous ethanol and 17mL of triethylamine, reacting for 180min, extracting an organic phase with water twice, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 35g of cefotaxime acid wet powder, drying to obtain 31.34 g of cefotaxime acid, and detecting that the purity of the cefotaxime acid is 98.1% and the water content is 0.6%, wherein the water content is shown in Table 1.
Example 2
Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 20mL of ethanol, adding 4mL of purified water and 17mL of triethylamine, reacting for 50min, extracting an organic phase twice with water, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.66 g of cefotaxime acid, wherein the purity is 99.4% and the water content is 0.6%, and the content is shown in Table 1.
Example 3
Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 20mL of DMF, adding 3mL of purified water and 17mL of triethylamine, reacting for 80min, extracting an organic phase twice with water, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.17 g of cefotaxime acid, wherein the purity is 99.3% and the water content is 0.7%, and the specific formula is shown in Table 1.
Example 4
Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 15mL of DMA, adding 3mL of purified water and 17mL of triethylamine, reacting for 70min, extracting an organic phase twice with water respectively, decoloring, adjusting the pH value to be 2.5-3.0 by hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.24g of cefotaxime acid, wherein the purity is 99.0% and the water content is 0.7%, and the specific formula is shown in Table 1.
Table 1:
example 5
Examples of industrial applications:
mixing 100Kg of 7-ACA and 130Kg of AE-active ester in a mixed solvent consisting of 500L of aqueous dichloromethane (water content: 0.17%) and 75L of LDMA, adding 15L of purified water and 85L of triethylamine, reacting for 70min, extracting an organic phase with water twice, decoloring, adjusting pH to 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 186Kg of cefotaxime acid wet powder, and drying to obtain 116.5Kg of cefotaxime acid, wherein the purity is 99.4% and the water content is 0.6%.
Claims (1)
1. A synthetic method of cefotaxime acid is characterized by comprising the following steps:
(a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution;
the mass ratio of the 7-aminocephalosporanic acid to the benzothiazole active ester is 1: 1.3;
the water content of the dichloromethane with water is 0.1-0.2%;
the cosolvent is an alcohol cosolvent or an amide cosolvent, the alcohol cosolvent is methanol, ethanol or isopropanol, and the amide cosolvent is methyl formamide, methyl acetamide, N-dimethyl formamide or dimethyl acetamide;
(b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution;
the adding amount of the purified water is 0.5-3% of the mass of the 7-aminocephalosporanic acid;
(c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid.
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CN116655559B (en) * | 2023-04-19 | 2024-04-09 | 济宁市食品药品检验检测研究院(济宁市药品不良反应监测中心) | Process and device for recovering 2-mercaptobenzothiazole from cefotaxime acid mother liquor |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101613360A (en) * | 2009-08-07 | 2009-12-30 | 哈药集团制药总厂 | A kind of preparation method of cefotaxime |
CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
CN105646535A (en) * | 2016-01-24 | 2016-06-08 | 哈尔滨合佳制药有限公司 | Synthesis method of cefotaxime sodium |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN101613360A (en) * | 2009-08-07 | 2009-12-30 | 哈药集团制药总厂 | A kind of preparation method of cefotaxime |
CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
CN105646535A (en) * | 2016-01-24 | 2016-06-08 | 哈尔滨合佳制药有限公司 | Synthesis method of cefotaxime sodium |
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