CN114057772A - Preparation method of ceftriaxone sodium compound - Google Patents
Preparation method of ceftriaxone sodium compound Download PDFInfo
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- CN114057772A CN114057772A CN202111372661.3A CN202111372661A CN114057772A CN 114057772 A CN114057772 A CN 114057772A CN 202111372661 A CN202111372661 A CN 202111372661A CN 114057772 A CN114057772 A CN 114057772A
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- polystyrene resin
- ceftriaxone sodium
- act
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- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- 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
-
- 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
- C07D501/12—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Discloses a preparation method of a ceftriaxone sodium compound, which comprises the following steps: stirring 7-ACT, AE active ester and tetramethylguanidine for reaction in the presence of a load phase transfer catalyst and a dichloromethane-water mixed solvent; standing and layering to obtain a water phase; adding sodium acetate aqueous solution into the water phase, and decoloring by using activated carbon; adjusting pH =2-4 at 0-10 deg.C, and keeping the temperature for 1-5 h; vacuum filtration and drying to obtain white crystal powder. In addition, the ceftriaxone sodium obtained by the method is also disclosed. The method improves the yield and color grade of the ceftriaxone sodium and reduces the impurities of the ceftriaxone polymer.
Description
Technical Field
The invention belongs to the field of chemical pharmacy; relates to a preparation method of a ceftriaxone sodium compound.
Background
The chemical name of ceftriaxone sodium is [6R [6 alpha, 7 beta (Z) ] ] -3- [ [ (1,2,5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [ (2-amino-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt triple hemihydrate, the molecular weight is 661.6, and the ceftriaxone sodium belongs to the third generation beta-lactam cephalosporin.
Ceftriaxone sodium is an antibiotic with long-acting effect, which is created by Roche, Switzerland, has long half-life, is stable to beta-lactamase, has strong tissue penetration ability, has bactericidal activity by inhibiting the synthesis of bacterial cell walls, and has bactericidal effect on a wide range of gram-negative bacteria and gram-positive bacteria. The cephalosporin injections obtained by introducing an acid group into the 3-position side chain of 7-ACA are only the same. The patent was released to the market at 21.12.1984 by FDA approval and the patent was due in 1996.
The product is white or off-white crystalline powder, odorless, soluble in water, slightly soluble in methanol, and hardly soluble in chloroform or diethyl ether. It should be preserved in dark, sealed, shady and dry place. The medicine has been loaded in British pharmacopoeia,
The United states pharmacopoeia, the Japanese Manual of antibiotic pharmaceuticals and the 2015 edition of the second part of the Chinese pharmacopoeia, page 252-253. It has the features of wide antibiotic spectrum, strong bactericidal action and low toxic side effect.
Ceftriaxone sodium can be regarded as being composed of three parts of 7-aminocephalosporanic acid (7-ACA) mother nucleus, thiotriazine heterocycle and aminothiaxime side chain acid. Therefore, ceftriaxone sodium can be regarded as being obtained by respectively condensing 7-ACA and the latter two. The first synthetic route for the industrial production of ceftriaxone sodium at home and abroad is to condense 7-ACA serving as a raw material with triazine heterocycle at C-3 position to obtain 7-aminocephalosporanic acid (7-ACT), and then carry out acylation condensation reaction with AE active ester at C-7 position.
Although the domestic production of ceftriaxone sodium has a major breakthrough in recent years, twenty raw material manufacturers and dozens of preparation manufacturers exist, the total production capacity still cannot meet the increasing market demand, and the quality of ceftriaxone sodium products and preparations thereof cannot reach the same foreign level for years, which is extremely unfavorable for the development of the antibiotic industry in China. The domestic ceftriaxone sodium crystal product not only has low ceftriaxone content, but also has obvious differences in crystal form, clarity and color of solution, content, dissolution speed, stability and the like of related substances and ceftriaxone polymers compared with foreign products, and products of a plurality of manufacturers even can not meet the requirements of pharmacopoeia and can only be sold as raw material medicaments at low cost. This indicates that the samples made in China may have certain problems in packaging, storage or production processes.
Chinese patent application CN1167112A discloses a process for the preparation of the cephalosporin antibiotic ceftriaxone sodium which comprises acylating a 7-amino-3-cephem-4-carboxylic acid derivative with 2-mercapto-5-methyl-1, 3, 4-thiadiazolyl- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetate having the following structural formula. However, the triethylamine used in this process is highly toxic and N, N-dimethylacetamide makes it cumbersome and difficult to handle.
Chinese patent application CN103539803A discloses a novel, green, low-cost method for synthesizing ceftriaxone sodium: firstly, dimethyl carbonate is used as a reaction solvent in the process of synthesizing 7-ACT, boron trifluoride-dimethyl carbonate is used as a catalyst, and the use of acetonitrile with high cost and large toxicity is replaced; secondly, in the process of synthesizing the ceftriaxone sodium, a reaction system of ethanol and water is adopted for the synthesis, and the ceftriaxone sodium with high yield and high quality is obtained. However, this method has a high reaction temperature and a long reaction time, so that the purity and yield of the product are seriously affected.
Chinese patent CN104130273B discloses a synthesis method of ceftriaxone sodium, which comprises the steps of firstly using dimethyl carbonate and organic acid as mixed solvents, using boron trifluoride dimethyl carbonate as a catalyst to condense 7-ACA and triazine ring to generate 7-ACT, using tetramethylguanidine as a cosolvent to react the 7-ACT and AE active ester to generate ceftriaxone, and finally adding sodium acetate to form sodium salt. Tetramethyl guanidine is used as a cosolvent, so that the reaction time is shortened to 2.5-4 h; the reaction can be carried out without nitrogen protection, thereby reducing the complexity of operation and increasing the feasibility of industrial production; the purity of the finally obtained sodium triamcinolone product is more than 99.7 percent, the molar yield is more than 92 percent, and the yield and the quality of the product are improved.
Liu Xiaoping et al use PEG-800 as a phase transfer catalyst and dichloromethane-water as a reaction solvent to perform condensation of active ester and 7-ACT, and have mild reaction conditions and high product purity. The molar yield of the condensation process was 93.5%; however, the color grade of the unrefined PEG product is lower than that of yellow 7 grade, which indicates that the crude product of ceftriaxone sodium still has more impurities or byproducts.
Therefore, there is an urgent need to develop a method for preparing ceftriaxone sodium compound capable of improving ceftriaxone sodium yield and color grade and reducing ceftriaxone polymer impurities on the basis of the existing method.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of a ceftriaxone sodium compound for improving the yield and the color grade of ceftriaxone sodium and reducing impurities of a ceftriaxone polymer.
In order to achieve the above object, in one aspect, the present invention provides a method for preparing ceftriaxone sodium, comprising the steps of:
stirring 7-ACT, AE active ester and tetramethylguanidine for reaction in the presence of a load phase transfer catalyst and a dichloromethane-water mixed solvent;
filtering after the reaction is finished, washing by using a dichloromethane-water mixed solvent, and combining washing liquid with the filtrate;
adding dilute hydrochloric acid solution, standing and layering to obtain a water phase;
adding sodium acetate aqueous solution into the water phase, and decoloring by using activated carbon;
adjusting pH =2-4 at 0-10 deg.C, and keeping the temperature for 1-5 h;
vacuum filtering and drying to obtain white crystal powder;
characterized in that the supported phase transfer catalyst is selected from a phase transfer catalyst supported by chloromethylated polystyrene resin.
The preparation method of the invention comprises the following steps: swelling the pretreated chloromethylated polystyrene resin by using toluene, and carrying out reflux reaction on the swelled polystyrene resin, polyoxyethylene and sodium hydroxide at the temperature of 70-90 ℃ for 6-24 hours; and (5) carrying out suction filtration, washing until no chloride ion exists, and carrying out vacuum drying.
The preparation method of the invention, wherein the weight ratio of the pretreated chloromethylated polystyrene resin to the polyoxyethylene to the sodium hydroxide is 1: (2.5-3.5): (1.5-2.5).
Preferably, the weight ratio of the pretreated chloromethylated polystyrene resin to the polyoxyethylene to the sodium hydroxide is 1: (2.8-3.2): (1.8-2.2).
In a specific embodiment, the weight ratio of the pretreated chloromethylated polystyrene resin, polyoxyethylene and sodium hydroxide is 1: 3: 2.
the preparation method of the invention is characterized in that the polyoxyethylene is selected from PEG-400.
According to the preparation method, the preprocessed chloromethylated polystyrene resin is obtained by washing chloromethylated polystyrene resin until the smell of chloromethylated methyl ether is eliminated, then washing until no chloride ion exists, then leaching with ethanol, and drying in vacuum.
According to the preparation method, the DVB crosslinking degree of the chloromethylated polystyrene resin is 2%, the chlorine content is 22.2%, and the particle size is 100-200 meshes.
The preparation method provided by the invention is characterized in that the molar ratio of the 7-ACT to the AE active ester is 1: (1-1.1); and/or, the weight ratio of 7-ACT to tetramethylguanidine is 1: (0.5-0.8).
Preferably, the molar ratio of 7-ACT to AE active ester is 1: (1-1.05); and/or, the weight ratio of 7-ACT to tetramethylguanidine is 1: (0.6-0.7).
In one specific embodiment, the molar ratio of 7-ACT to AE active ester is 1: 1; and/or, the weight ratio of 7-ACT to tetramethylguanidine is 1: 0.67.
the preparation method of the invention is characterized in that the weight ratio of the 7-ACT to the supported phase transfer catalyst is 1: (0.7-1).
Preferably, the weight ratio of 7-ACT to supported phase transfer catalyst is 1: (0.8-0.9).
In one embodiment, the weight ratio of 7-ACT to supported phase transfer catalyst is 1: 0.86.
on the other hand, the invention also provides ceftriaxone sodium obtained by the preparation method.
In another aspect, the present invention further provides a method for refining ceftriaxone sodium, comprising the following steps: dissolving ceftriaxone sodium in an acetone-water mixed solvent, and adjusting the pH = 7; dripping isopropanol at 10-20 deg.C; dripping 60-120min, and adding seed crystal; growing the crystal for 10-60 min; then continuously dropwise adding isopropanol for 90-150 min; after the elution and crystallization are finished, vacuum filtration and drying are carried out to obtain white crystal powder.
According to the refining method of the invention, the seed crystal is added in an amount of 0.5-1.5% of the ceftriaxone sodium.
Preferably, the seed crystal is added in an amount of 0.8-1.2% of the ceftriaxone sodium.
In a specific embodiment, the seed crystals are added in an amount of 1% of the ceftriaxone sodium.
According to the refining method of the invention, the dropping speed of the isopropanol before the seed crystal is added is 0.02-0.2 ml/min; and/or the dropping speed of the isopropanol after the seed crystal is added is 0.1-0.3 ml/min.
Preferably, the dropping speed of the isopropanol in the seed crystal is 0.05-0.15 ml/min; and/or the dropping speed of the isopropanol after the seed crystal is added is 0.15-0.25 ml/min.
In a specific embodiment, the dropping speed of the isopropanol in the seed crystal is 0.1 ml/min; and/or the dropping speed of the isopropanol after the seed crystal is added is 0.2 ml/min.
According to the refining method of the invention, the filter cake is washed 1-3 times with acetone after vacuum filtration.
Without wishing to be bound by any theory, the aforementioned preparation method of the present invention effectively improves the yield and color grade of the ceftriaxone sodium; on the basis, the method for further refining further improves the color grade of the ceftriaxone sodium and reduces the polymer impurities of the ceftriaxone sodium.
Detailed Description
It should be understood that the detailed description of the invention is merely illustrative of the spirit and principles of the invention and is not intended to limit the scope of the invention. Furthermore, it should be understood that various changes, substitutions, deletions, modifications or adjustments may be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents are also within the scope of the invention as defined in the appended claims.
Example 1: preparation of supported phase transfer catalysts
Pre-treating chloromethylated polystyrene resin: washing with tap water until chloromethylated polystyrene resin (DVB crosslinking degree is 2%, chlorine content is 22.2%, particle size is 100-200 meshes) has no chlorine methyl ether smell, washing with deionized water until no chlorine ions exist, leaching with ethanol, and vacuum drying at 40 ℃ for later use.
The supported phase transfer catalyst was prepared as follows: taking 20g of pretreated chloromethylated polystyrene resin, firstly swelling with 50mL of toluene for 24h, then adding 100m of 1 toluene, 60g of PEG-400 and 80g of 50wt% sodium hydroxide solution, carrying out reflux reaction at 80 ℃ for 12h, cooling, carrying out suction filtration, sequentially washing with ethanol, tap water and deionized water respectively until no chloride ion exists, then carrying out leaching with ethanol, and carrying out vacuum drying at 40 ℃.
Example 2:
to a dry four-necked flask equipped with an electric stirrer, 100mL of a solution of 3: 2 dichloromethane-water mixed solvent, 32g of the above-mentioned supported phase transfer catalyst, 37g (0.1mol) of 7-ACT, 35g (0.1mol) of AE active ester and 25g of tetramethylguanidine, and reacted for 3 hours under stirring. After the reaction is finished, filtering to remove the loaded phase transfer catalyst, and reserving filtrate; and using a volume ratio of 3: washing with 2-dichloromethane-water mixed solvent for 3 times, and combining the washing solution with the filtrate. Adding 20mL of 1mol/L hydrochloric acid solution, stirring for 15min, standing for layering to obtain a water phase.
Dropwise adding 50mL of 0.3g/mL sodium acetate aqueous solution into the water phase, and stirring to uniformly mix the sodium acetate aqueous solution and the water phase; then 5g of activated carbon is added for decolorization for 30 min. And slowly dropwise adding 1mol/L hydrochloric acid to adjust the pH =3 of the solution at the temperature of 5 ℃. Stirring at 200rpm for 3h under heat preservation. Vacuum filtering, washing the filter cake with acetone for 2 times, and vacuum drying to obtain white crystal powder.
The product yield was 94.1% calculated according to 7-ACT; the color grade of the product is 3 grades.
Example 3:
20g of the white crystalline powder was dissolved in 60mL of a solvent having a volume ratio of 2: 1 acetone-water mixed solvent, dilute NaOH solution was added dropwise to pH =7 and added to a constant temperature ice machine. Starting a constant temperature ice machine, and dropwise adding isopropanol when the temperature of the solution reaches 15 ℃, wherein the dropwise adding speed is 0.1 ml/min; adding seed crystal 0.2g (Lizhu pharmaceutical group Co., Ltd., injection grade ceftriaxone sodium) after 90 min; growing the grains for 30 min; then the dropping speed of the isopropanol is adjusted to be 2ml/min, and the dropping is continued for 120 min. The stirring speed was controlled at 200rpm throughout the crystallization. And after the elution crystallization is finished, carrying out vacuum filtration, washing the filter cake for 2 times by using acetone, and carrying out vacuum drying to obtain white crystal powder. The product has a color grade of 1 grade, a ceftriaxone polymer content of 0.13 percent and a pH value of 6.78.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A preparation method of ceftriaxone sodium comprises the following steps:
stirring 7-ACT, AE active ester and tetramethylguanidine for reaction in the presence of a load phase transfer catalyst and a dichloromethane-water mixed solvent;
filtering after the reaction is finished, washing by using a dichloromethane-water mixed solvent, and combining washing liquid with the filtrate;
adding dilute hydrochloric acid solution, standing and layering to obtain a water phase;
adding sodium acetate aqueous solution into the water phase, and decoloring by using activated carbon;
adjusting the pH =2-4 at the temperature of 0-10 ℃, and reacting for 1-5h under the condition of heat preservation;
vacuum filtering and drying to obtain white crystal powder;
characterized in that the supported phase transfer catalyst is selected from a phase transfer catalyst supported by chloromethylated polystyrene resin.
2. The method according to claim 1, wherein the chloromethylated polystyrene resin-supported phase transfer catalyst is prepared by the following method: swelling the pretreated chloromethylated polystyrene resin by using toluene, and carrying out reflux reaction on the swelled polystyrene resin, polyoxyethylene and sodium hydroxide at the temperature of 70-90 ℃ for 6-24 hours; and (5) carrying out suction filtration, washing until no chloride ion exists, and carrying out vacuum drying.
3. The method according to claim 2, wherein the weight ratio of the pretreated chloromethylated polystyrene resin to the polyoxyethylene to the sodium hydroxide is 1: (2.5-3.5): (1.5-2.5).
4. The method according to claim 2, wherein the polyoxyethylene is PEG-400.
5. The method according to claim 2, wherein the pre-treated chloromethylated polystyrene resin is prepared by washing chloromethylated polystyrene resin until no chlorine methyl ether smell exists, then washing until no chloride ion exists, then leaching with ethanol, and vacuum drying.
6. The method according to claim 2, wherein the chloromethylated polystyrene resin has a DVB crosslinking degree of 2%, a chlorine content of 22.2%, and a particle size of 100-200 mesh.
7. The method of claim 2, wherein the molar ratio of 7-ACT to AE active ester is 1: (1-1.1); and/or, the weight ratio of 7-ACT to tetramethylguanidine is 1: (0.5-0.8).
8. The method of claim 2, wherein the weight ratio of 7-ACT to supported phase transfer catalyst is 1: (0.7-1).
9. Ceftriaxone sodium, characterized in that it is obtained by the preparation process according to any one of claims 1 to 8.
10. A process for the purification of ceftriaxone sodium as claimed in claim 9, comprising the steps of: dissolving ceftriaxone sodium in an acetone-water mixed solvent, and adjusting the pH = 7; dripping isopropanol at 10-20 deg.C; dripping 60-120min, and adding seed crystal; growing the crystal for 10-60 min; then continuously dropwise adding isopropanol for 90-150 min; after the elution and crystallization are finished, vacuum filtration and drying are carried out to obtain white crystal powder.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4132789A (en) * | 1975-08-25 | 1979-01-02 | Takeda Chemical Industries, Ltd. | 7-[2-(2-Imino-4-thiazolin-4-yl)-2-sulfoacetamido]cephalosporins and antibacterial compositions containing them |
| CA2045143A1 (en) * | 1989-11-13 | 1991-05-14 | Susumu Nakagawa | Cephalosporin derivatives |
| CN101747346A (en) * | 2009-12-22 | 2010-06-23 | 山东鑫泉医药中间体有限公司 | Method for synthesizing coarse salt of ceftriaxone sodium by phase transfer catalysis method |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN106562971A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Ceftriaxone sodium powder-needle preparation production method |
| CN107793432A (en) * | 2017-12-12 | 2018-03-13 | 淄博鑫泉医药技术服务有限公司 | The process for purification of coarse salt of ceftriaxone sodium |
-
2021
- 2021-11-19 CN CN202111372661.3A patent/CN114057772A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4132789A (en) * | 1975-08-25 | 1979-01-02 | Takeda Chemical Industries, Ltd. | 7-[2-(2-Imino-4-thiazolin-4-yl)-2-sulfoacetamido]cephalosporins and antibacterial compositions containing them |
| CA2045143A1 (en) * | 1989-11-13 | 1991-05-14 | Susumu Nakagawa | Cephalosporin derivatives |
| CN101747346A (en) * | 2009-12-22 | 2010-06-23 | 山东鑫泉医药中间体有限公司 | Method for synthesizing coarse salt of ceftriaxone sodium by phase transfer catalysis method |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN106562971A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Ceftriaxone sodium powder-needle preparation production method |
| CN107793432A (en) * | 2017-12-12 | 2018-03-13 | 淄博鑫泉医药技术服务有限公司 | The process for purification of coarse salt of ceftriaxone sodium |
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| 俞善信 等: "聚苯乙烯固载聚乙二醇的合成及表征", 《高分子学报》 * |
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