CN111647006B - Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever - Google Patents
Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever Download PDFInfo
- Publication number
- CN111647006B CN111647006B CN202010336056.XA CN202010336056A CN111647006B CN 111647006 B CN111647006 B CN 111647006B CN 202010336056 A CN202010336056 A CN 202010336056A CN 111647006 B CN111647006 B CN 111647006B
- Authority
- CN
- China
- Prior art keywords
- cefotaxime
- reaction
- sodium
- cefotaxime sodium
- impurity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
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
- C07D501/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07D501/04—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides cefotaxime sodium, a preparation method, a cefotaxime sodium preparation and application: wherein, the mass content of the cefotaxime sodium is more than 98 percent, and the cefotaxime sodium also comprises impurities A, B and C; when in preparation, firstly, the aminothiazoly loximate reacts with an activating agent to obtain an active ester intermediate; reacting 7-ACA with an active ester intermediate under the condition of controlling the temperature, adjusting the acid, and crystallizing to obtain cefotaxime acid; carrying out salifying reaction on cefotaxime acid and a salt forming agent in a salifying solvent, and separating out cefotaxime sodium; the cefotaxime sodium has low impurity content, is favorable for long-term storage and placement, has good quality stability and better clinical curative effect and safety, and can be used for treating salmonella infection including typhoid fever and paratyphoid fever.
Description
Technical Field
The invention relates to a medicine preparation technology, in particular to a new synthesis route of cefotaxime sodium and a new indication disease of cefotaxime sodium pharmaceutical preparation for treating salmonella infection including typhoid fever and paratyphoid fever.
Background
Cefotaxime sodium is the third-generation semi-synthetic cephalosporin, has stronger effect on gram-negative bacteria than the first-generation and second-generation cephalosporins, and has very wide clinical application. The structural formula of cefotaxime sodium is as follows:
the preparation of cefotaxime sodium is mainly synthesized, and in the existing synthesis method, the problems of high production cost, low product quality and the like caused by high difficulty in controlling the activity of intermediate active ester, harsh reaction conditions and complex operation are solved, so that the product quality is not uniform, the stability of batch products is poor, and the clinical curative effect and the safety are directly influenced.
Although cefotaxime sodium has been widely used, as a cephalosporin product, the preparation method, the safety, the therapeutic effect and the stability of the product are always the key points of technical research and improvement.
Aiming at the problems, the inventor further improves the prior art and provides cefotaxime sodium with higher quality, a preparation method thereof, a cefotaxime sodium pharmaceutical preparation and a new indication.
Disclosure of Invention
In order to solve the above problems, the present inventors have conducted intensive studies and, as a result, have found that: by using the triazine active ester intermediate and strictly controlling the input amount, the condensation reaction temperature and the time, the impurity generation amount can be well reduced; in the subsequent salification and crystallization process of cefotaxime acid, the content of impurities is effectively reduced by adopting proper reaction time, reaction temperature and solution pH, thereby completing the invention.
The object of the present invention is to provide the following:
in a first aspect, the present invention provides a method for preparing cefotaxime sodium, comprising the following steps:
step 1: reacting the aminothiazoly loximate with an activating agent to obtain an active ester intermediate;
step 2: reacting 7-ACA with an active ester intermediate under the condition of controlling the temperature, adjusting the acid, and crystallizing to obtain cefotaxime acid;
and step 3: and (3) carrying out salifying reaction on cefotaxime acid and a salt forming agent in a salifying solvent, and separating out cefotaxime sodium.
Wherein, in the step 1,
the activator is selected from 2-chloro-4, 6-diphenyl triazine, dibenzothiazyl disulfide or benzothiazole, preferably 2-chloro-4, 6-diphenyl triazine;
dispersing the aminothiazoly loximate and 2-chloro-4, 6-diphenyl triazine in dimethylformamide, cooling to 0-5 ℃, adding a catalyst 1, 8-diazabicycloundec-7-ene under controlled temperature, and increasing the reaction temperature until the reaction is finished after the addition is finished;
after the reaction is finished, post-treatment is also carried out.
Wherein, in the step 2,
dispersing 7-ACA in acetonitrile, cooling to-5-0 ℃, dropwise adding a condensing agent, adding an active ester intermediate to react until the reaction is finished, adding purified water and an alcohol solvent, cooling, and adjusting the pH value of the solution to 2.3-2.5; crystallizing, filtering and drying to obtain cefotaxime acid;
the condensing agent is selected from N, O-bis (trimethylsilane) trifluoroacetamide, hexamethyl disilazane or N, O-bis trimethylsilylacetamide, preferably N, O-bis trimethylsilylacetamide is used as the condensing agent.
Wherein, in the step 3,
the salt forming agent is preferably sodium isooctanoate or sodium lactate;
the salifying solvent is one or more of water for injection, methanol, ethanol, isopropanol and acetone, and is preferably ethanol-water mixed solution or acetone-water mixed solution;
and (3) after the salt forming reaction is finished, adding dichloromethane into the reaction solution, then dropwise adding a crystallization solvent until the reaction solution is slightly turbid, adding seed crystals, growing crystals, continuously dropwise adding the crystallization solvent, and cooling and then crystallizing to obtain cefotaxime sodium.
In a second aspect, the invention provides cefotaxime sodium obtained by the method, and the mass content of the cefotaxime sodium is more than 98%.
The cefotaxime sodium also contains impurity A,
the content of the impurity A is 0.25% by mass or less, preferably 0.2% by mass or less.
Preferably, the cefotaxime sodium also contains impurity B,
the content of the impurity B is within 0.25 percent, and preferably within 0.2 percent;
furthermore, the catalyst also contains impurities C,
the content of the impurity C is within 0.25%, preferably within 0.2%.
In a third aspect, the invention also provides a cefotaxime sodium single preparation taking cefotaxime sodium obtained by the method as an active ingredient, wherein the preparation is an injection;
preferably, cefotaxime sodium is crushed to the particle size D90 of 20-100 mu m, and then aseptic subpackaging and nitrogen filling packaging are carried out.
In a fourth aspect, the invention also provides a cefotaxime sodium compound preparation, which comprises cefotaxime sodium obtained by the method and a synergist;
the synergist is tazobactam sodium, sulbactam sodium or ababactam sodium, and is preferably sulbactam sodium.
In a fifth aspect, the invention also provides the use of cefotaxime sodium, a single cefotaxime sodium preparation and a compound cefotaxime sodium preparation obtained by the method in the preparation of medicaments for treating salmonella infection including typhoid fever and paratyphoid fever.
According to the cefotaxime sodium and the preparation method and the application thereof provided by the invention, the following beneficial effects are achieved:
(1) the cefotaxime sodium provided by the invention has low impurity content, is beneficial to long-term storage and placement, and has good quality stability, better clinical curative effect and safety;
(2) the method for preparing cefotaxime sodium provided by the invention is simpler to operate, simpler in treatment steps, economic and reasonable, and more suitable for workshop production; the prepared cefotaxime sodium product has uniform particle size range, and is beneficial to the preparation and the split charging of subsequent preparations;
(3) the cefotaxime sodium and the preparation thereof provided by the invention have the application of treating salmonella infection including typhoid fever and paratyphoid fever.
Detailed Description
The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention, as illustrated in the accompanying drawings.
The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
The present invention is described in detail below.
The invention provides a preparation method of cefotaxime sodium, which comprises the following steps:
step 1: and reacting the aminothiazoly loximate with an activating agent to obtain an active ester intermediate.
Wherein the activator is selected from 2-chloro-4, 6-diphenyl triazine, dibenzothiazyl disulfide or benzothiazole. Considering that the dibenzothiazole disulfide or benzothiazole is difficult to remove and is difficult to clean in the subsequent reaction process, 2-chloro-4, 6-diphenyl triazine which has simple post-treatment and milder reaction activity is preferably used as an activating agent.
In a preferred embodiment, the reaction of the reactive ester intermediate is as follows:
the triazine active ester prepared by the reaction of the aminothiazoly loximate and the 2-chloro-4, 6-diphenyl triazine has the structure that benzene rings influence the density of electron cloud, so that the prepared triazine active ester has mild activity, and the generation of process impurities is reduced.
In preparing the active ester intermediate, it is preferable to disperse the aminothiazoly loximate and 2-chloro-4, 6-diphenyltriazine in Dimethylformamide (DMF) for reaction.
The amount of DMF as a reaction solvent is not likely to be too much or too little, and too much or too little may result in a decrease in the yield of the product. Wherein the mass ratio of the aminothiazoly loximate to the DMF is 1.0: 1.0-1.0: 8.0; the preferable ratio is 1.0: 3.0-1.0: 5.0, so that the reaction is sufficient, and the yield of the active ester intermediate product is not excessively reduced in subsequent treatment.
In order to ensure sufficient reaction of the aminothiazoly loximate with 2-chloro-4, 6-diphenyltriazine and to improve the yield of the conversion of the aminothiazoly loximate into the active ester intermediate, it is preferable to use a slightly larger amount of 2-chloro-4, 6-diphenyltriazine.
The molar ratio of the aminothiazoly loximate to the 2-chloro-4, 6-diphenyltriazine is 1.0: 1.0-1.0: 1.3, preferably 1.0: 1.0-1.0: 1.1, for example 1.0: 1.05.
Cooling the reaction solution to 0-5 ℃, adding a catalyst 1, 8-diazabicycloundecen-7-ene (DBU) at a controlled temperature, and increasing the reaction temperature after the addition is finished.
Preferably, DBU is added into the reaction solution and stirred for 0.5-1 h, so that the DBU is fully contacted with the reaction substance, and the difficulty in the reaction of the ainothiazoly loximate and 2-chloro-4, 6-diphenyl triazine is reduced. When the addition amount of DBU is too low, the catalytic reaction capability is insufficient, and when the addition amount is too high, the subsequent treatment difficulty is increased.
The molar ratio of the aminothiazoly loximate to DBU is 1.0: 1.0-1.0: 1.5, preferably 1.0: 1.0-1.0: 1.2; more preferably 1.0:1.0 to 1.0: 1.15.
During the reaction, the reaction temperature of the solution is increased to increase the contact rate of the reaction substances, thereby improving the reaction rate and the product yield. However, too high a temperature increases the reactivity of the non-target group, resulting in a decrease in the target reaction.
Preferably, the reaction temperature is increased to 20 to 30 ℃, preferably 20 to 25 ℃.
The reaction is preferably carried out for 1 to 3 hours, most preferably for 1.5 to 2.5 hours, for example, for 2 hours.
After the reaction is finished, the step 1 further comprises post-treatment. The post-treatment comprises adding an extraction solvent to extract the active ester intermediate and adding an aqueous solution to wash and separate the organic solution from it.
The extraction solvent is an organic solvent that is miscible with DMF. Preferably, the extraction solvent is selected from one or more of acetonitrile, ethyl acetate, ethanol, acetone, methanol and tetrahydrofuran, and ethyl acetate with good solubility, low boiling point and low toxicity is preferably used as the extraction solvent.
The ethyl acetate is used for extracting the active ester intermediate, and the dosage of the ethyl acetate can directly influence the extraction rate of the active ester intermediate and can also influence the residual quantity of DMF.
The mass ratio of the ethyl acetate to the aminothiazoly loximate is 1.0: 5.0-1.0: 15.0, preferably 1.0: 5.0-1.0: 10.0, and most preferably 1.0: 7.0-1.0: 9.0.
Adding an extraction solvent into the reaction solution, and uniformly mixing to obtain an organic solution to be cleaned; and adding an aqueous solution to clean impurities and DMF in the organic solution, so as to realize the separation of the extraction solvent and the DMF and improve the purity of the active ester intermediate.
Preferably, the organic solution is washed with water and then with saturated saline solution, and then dried to remove the solvent, thereby obtaining the active ester intermediate.
The organic solution and the aqueous solution are mixed and washed by the same extraction operation, and DMF is mutually soluble with water, but water and ethyl acetate are not mutually soluble, so that DMF in ethyl acetate can be gradually removed through multiple washing, and water-soluble impurities can be further removed; reduce the solvent residue of the active ester intermediate and improve the purity of the active ester intermediate.
In a more preferred embodiment, the organic solution is washed with water, then with acid, alkali, and then with brine.
Among them, the acid washing is preferably an aqueous solution of an inorganic acid, and may be selected from any one or a combination of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
Preferably, the solution during acid cleaning is hydrochloric acid solution, preferably 0.7-1.5 mol/L hydrochloric acid solution, more preferably 0.8-1.2 mol/L hydrochloric acid solution, and DBU and other alkaline substances in the organic solution can be removed without affecting the stability of ester bonds in the active ester intermediate.
The alkali washing is preferably an inorganic alkali aqueous solution, and may be any or a combination of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium hydroxide.
Preferably, the solution in the alkaline washing is Na2CO3Or K2CO3The aqueous solution has relatively mild alkalinity, and does not cause the breakage of ester bonds or other easily-hydrolyzed chemical bonds in the product. Said K2CO3Or Na2The mass concentration of CO3 in the alkaline cleaning solution is 8-15%, preferably 9-11%, for example 10%. The alkaline washing organic solution can remove acidic substances or substances with acidic groups, such as residual inorganic acid during acid washing, residual aminothiazoly loximate during reaction, and the like.
After the alkali washing is finished, washing the organic solution with saturated salt water to remove residual water-soluble substances, further reducing impurities and DMF residues, and preliminarily dehydrating the organic solution; after the saturated salt solution is used for washing, the emulsification phenomenon which is easy to occur during layering can be avoided, and the loss of products is reduced.
When the aqueous solution is used for cleaning, the amount of the aqueous solution is 0.5 to 1.5 times, preferably 0.8 to 1.2 times, and more preferably 0.9 to 1.1 times the amount of the added extraction solvent.
After the washing of the aqueous solution for many times, only ethyl acetate is basically left in the organic solution, and DMF residue is little, so that the precipitation treatment of the active ester intermediate is very simple.
Before the precipitation treatment, the organic solution after the washing is dried, preferably by anhydrous sodium sulfate to remove water, and then concentrated and dried under reduced pressure to obtain an off-white solid, namely, an active ester intermediate.
Because the active ester intermediate is stable in water, the reaction does not need to be carried out in an anhydrous solvent, so that the reaction conditions are milder and the production difficulty is lower.
Further, the air conditioner is provided with a fan,
step 2: and (3) reacting the 7-ACA with the active ester intermediate prepared in the step (1) under the condition of controlling the temperature, adjusting the acid, and crystallizing to obtain the cefotaxime acid.
In step 2, 7-ACA is reacted with an active ester intermediate in acetonitrile. In order to fully react the 7-ACA with the active ester intermediate, the mass ratio of the 7-ACA to the acetonitrile is 1.0: 3.0-1.0: 10.0, preferably 1.0: 3.0-1.0: 8.0, and more preferably 1.0: 3.0-1.0: 5.0.
During reaction, dispersing 7-ACA in acetonitrile, cooling to-5-0 ℃, dropwise adding a condensing agent, and adding an active ester intermediate for reaction.
The condensing agent can be N, O-bis (trimethylsilane) trifluoroacetamide, hexamethyldisilazane or N, O-bis trimethylsilylacetamide, N, O-bis trimethylsilylacetamide is preferably used as the condensing agent, and the N, O-bis trimethylsilylacetamide has the advantages of mild reaction conditions, thorough reaction and high yield.
Preferably, the molar ratio of the 7-ACA to the N, O-bis (trimethylsilyl) acetamide is 1.0: 2.0-1.0: 2.5; preferably 1.0:2.0 to 1.0: 2.2.
The condensing agent will generate heat after being added into the reaction system, which causes the local temperature in the reaction system to be too high and the temperature of the reaction system to rise, thus being not favorable for the stability of the 7-ACA.
It was found that in step 2, the ester bond in 7-ACA, when the temperature is too high, may be cleaved to form impurity B due to degradation reaction caused by introduction or remaining of a small amount of water into the reaction system and solvent, as shown in the following figure:
preferably, the condensing agent is dropwise added into the reaction system, and the reaction system is controlled to be stably maintained at-5-0 ℃ in the adding process, so that the thermal degradation of the 7-ACA is reduced, and the generation of impurities B is reduced.
Further, an active ester intermediate was added to the reaction system to react with 7-ACA. With the progress of the reaction, more and more cefotaxime acid is generated, which also contains active amino groups and can react with the active ester intermediate when the reaction temperature is too high or the reaction time is too long or the content of the active ester intermediate is high.
Thus, in step 2, the active ester intermediate and cefotaxime acid may also undergo a side reaction to form impurity a, which is shown below:
preferably, the reaction system is stably maintained at-5-0 ℃, the active ester intermediate prepared in the step 1 is added in batches under the temperature control condition, and the stirring reaction is carried out after the addition is finished.
The reaction temperature is controlled to be-10 ℃, preferably-5-0 ℃, the low-temperature reaction can reduce the damage of groups, further weaken the reaction activity of the active ester intermediate, reduce the generation of non-target products or side reactions, and preferably reduce the generation of impurities A.
In order to ensure the reaction to be fully carried out, the reaction is preferably carried out for 1 to 3 hours, and preferably for 1 to 2 hours.
The addition amount of 7-ACA and the active ester intermediate has an important influence on the control of the generation of the impurity a, and the molar ratio of 7-ACA to the active ester intermediate is preferably 1.0:1.0 to 1.0:1.3, more preferably 1.0:1.0 to 1.0:1.2, even more preferably 1.0:1.0 to 1.0:1.1, for example 1.0: 1.05.
The generation amount of the impurity A can be reduced by controlling the reaction temperature, the using amount of the active ester intermediate and the adding mode; through the post-treatment, the mass content of the impurity A in the cefotaxime sodium product can be not more than 0.25%, and preferably within 0.2%.
In addition, it was found that the ester bond in 7-ACA was easily hydrolyzed by the residual moisture after the addition of the active ester intermediate. The content of impurity B in mass% may be not more than 0.25%, preferably within 0.2%, by strict control of the reaction conditions, and post-treatment.
After the reaction is completed, purified water and an alcohol solvent are added to stop the reaction. The alcohol solvent is one or more of methanol, ethanol, isopropanol and n-propanol, preferably methanol or ethanol, and more preferably ethanol with low toxicity.
Wherein the addition amount of the alcohol solvent is 5-25%, preferably 10-20% of the mass of the 7-ACA. The addition of the alcohol solvent can improve the lipid solubility of the reaction solution and fully dissolve the impurity A, thereby removing the impurity A in the subsequent precipitation treatment.
The precipitation yield of cefotaxime acid can be improved by adding purified water, and the mass ratio of the 7-ACA to the added purified water is 1.0: 10.0-1.0: 16.0; preferably 1.0:11.0 to 1.0: 13.0.
The purified water and alcohol solvent usage in the above range takes into account the influence on product yield, impurities and effective utilization rate of the solvent; if the dosage ratio is lower than the minimum critical value, the influence of the addition of the solvent on the yield of the cefotaxime acid and the removal of impurities is not obvious; if the dosage ratio is higher than the maximum critical value, although the impurity removal effect is effectively improved, the yield of the cefotaxime acid and the effective utilization rate of the solvent are low, and the method is not suitable for large-scale production.
Adding purified water and an alcohol solvent, cooling to 0-10 ℃ under stirring, preferably 0-5 ℃, and adjusting the pH of the solution to acidity.
In the process of adjusting the solution to be acidic, the tetracyclic structure of cefotaxime acid is easily hydrolyzed and broken due to the large amount of water contained in the solution, and impurity C is formed.
In order to avoid the degradation of the tetracyclic structure or reduce the generation of impurity C, the inventors found that adjusting the pH of the solution to 2-2.5 is more favorable for the precipitation of cefotaxime acid, but when adjusting the pH of the solution to 2.3-2.5, especially 2.4-2.5, the generation of impurity C is significantly reduced.
Preferably, hydrochloric acid is dripped to adjust the pH value to 2.4-2.5, the temperature of the solution is controlled not to exceed 10 ℃ in the process of dripping hydrochloric acid, and hydrolysis of products is avoided.
And (3) after the adjustment is finished, performing heat preservation and crystallization at 0-10 ℃ and preferably 0-5 ℃, preferably for 2-3 h, filtering and drying to obtain a white solid, namely cefotaxime acid.
The preparation method of cefotaxime sodium provided by the invention also comprises the following steps,
and step 3: and (3) carrying out salt forming reaction on the cefotaxime acid prepared in the step (2) and a salt forming agent in a salt forming solvent, and separating out to obtain cefotaxime sodium.
In step 3, an antioxidant is preferably added during the reaction of cefotaxime acid and a salt forming agent, so that the problems of the product appearance and quality influenced by the darkening of the solution color, the yellowing of the product, the increase of impurities and the like caused by the oxidation of cefotaxime acid are avoided.
The antioxidant is selected from sodium sulfite, sodium pyrosulfite or vitamin C, preferably sodium sulfite is used. The dosage of the antioxidant is 0.5-2.5% of the mass of the cefotaxime acid, and preferably 1.0-2%.
Preferably, the antioxidant is added into a salifying solvent to be dissolved, the temperature is reduced to 5-10 ℃, and the cefotaxime acid prepared in the step 2 is added.
The salt-forming solvent is one or more of water for injection, methanol, ethanol, isopropanol and acetone, preferably ethanol-water mixed solution or acetone-water mixed solution, and more preferably acetone-water mixed solution.
Preferably, the volume ratio of water to acetone in the salt forming solvent is 2-5: 1, and preferably 3-4: 1. By adding acetone, impurity A in cefotaxime acid can be further removed. Meanwhile, the impurity B has better solubility in a salt forming solvent, and the impurity B can be further eliminated in the salt forming process.
The mass ratio of the cefotaxime acid to the salifying solvent is 1.0: 0.7-1.0: 2.0, and preferably 1.0: 0.9-1.0: 1.4.
Controlling the temperature of the solution at 5-10 ℃, and adding the aqueous solution of the salt forming agent.
The salt forming agent is preferably sodium isooctanoate or sodium lactate, and sodium isooctanoate with better salt forming property is preferably used. The salt forming agent is preferably added after being dissolved, which is beneficial to fully carrying out the salt forming reaction and shortening the reaction time.
Preferably, the salt-forming agent is dissolved in water for injection, and the salt-forming agent may be dissolved in a saturated solution to participate in the salt-forming reaction, or may be present in a concentration set to the salt-forming agent. Preferably, the concentration of the salt forming agent is 0.6-0.9 g/ml, preferably 0.7-0.9 g/ml, for example 0.8g/ml, which allows to reduce the volume of the salt forming agent solution added and thus to reduce the subsequent amount of crystallization solvent.
In the salt-forming reaction, when the pH value of the solution is higher or the temperature of the solution is higher, the tetracyclic amide in the cephalosporanic hydroxamic acid is easy to be hydrolyzed and broken to generate an impurity C.
When the concentration of the salt forming agent is too high, the local concentration of the salt forming agent in the reaction solution is easily too high when the salt forming agent is added, so that the local environment is alkaline or overheated, and the ring-opening reaction is carried out to improve the content of the impurity C; if the concentration of the salt forming agent is too low, the product yield is easily reduced, and the loss in the solution is excessive.
The dosage of the salt forming agent is generally equal to the molar equivalent of cefotaxime acid, and preferably 1-1.2 times of the molar equivalent of cefotaxime acid.
And (3) dropwise adding a salifying agent solution into the salifying solution added with the cefotaxime acid, and continuously stirring and reacting for 0.5-1 h after dropwise adding to fully perform salifying reaction.
In a preferred embodiment, activated carbon is added to the reaction solution for decolorization, preferably activated carbon for medical needles for adsorption, not only to decolorize but also to help remove allergens such as pyrogens that may be present in the solution.
After filtration, dichloromethane is added to reduce the polarity of a reaction solution system, which is beneficial to improving the solubility of impurities A and C and reducing the solubility of cefotaxime sodium, thereby realizing the further purification of cefotaxime sodium.
The adding amount of the dichloromethane is 20-40% of the mass of the cefotaxime acid; preferably 25 to 35%.
And (3) dropwise adding a crystallization solvent into the reaction solution until the reaction solution is slightly turbid, adding seed crystals, growing crystals, continuously dropwise adding the crystallization solvent, and cooling to crystallize.
The crystallization solvent is one or more of methanol, ethanol, isopropanol and acetone, preferably acetone and ethanol, and more preferably acetone.
When the crystallization solvent is added to the reaction solution to be slightly turbid, the product is most easily separated out, particularly after being induced by the seed crystal. The quality of the seed crystals should meet the quality requirements of the target product.
Preferably growing the crystals for 1-2 h; stirring is continuously carried out in the crystal growing process, and the stirring speed is 50-80 revolutions per minute, preferably 60-80 revolutions per minute.
And continuously dropwise adding a crystallization solvent to change the property of the reaction solution, cooling to 5-10 ℃ after dropwise adding, and then carrying out heat preservation crystallization, preferably carrying out crystallization for 2-4 h, and more preferably carrying out crystallization for 2-3 h. After the temperature is reduced, the precipitation amount of the product can be improved, and the hydrolysis of the product can be reduced. Preferably, the volume of the crystallization solvent which is continuously dripped is 2.5-4 times of the volume of the crystallization solvent which is added for the first time.
Stirring is continuously carried out in the crystallization process, and the stirring speed is 50-120 revolutions per minute, preferably 70-100 revolutions per minute.
Filtering and drying to obtain a white solid, namely the cefotaxime sodium. In particular, vacuum drying is performed to ensure that the moisture content in the cefotaxime sodium is not higher than 1.0 percent so as to improve the stability of the cefotaxime sodium in storage.
In a preferred embodiment, the preparation method of cefotaxime sodium provided by the invention is carried out as follows:
in the preparation method of cefotaxime sodium, the impurity A is generated in the condensation process of cefotaxime acid, and the generation amount of the impurity A can be well reduced by strictly controlling the input amount, the condensation reaction temperature and the time of a triazine active ester intermediate; the addition of an alcohol solvent in the subsequent treatment process can effectively remove the impurity A. And the content of the impurity A can be well reduced in the salifying and crystallizing process of cefotaxime acid.
Impurity B is generated during the condensation of cefotaxime acid and the preparation of cefotaxime sodium. By adopting proper reaction time and reaction temperature, the residual amount of the 7-ACA is reduced, and the possibility of hydrolysis of the 7-ACA is reduced; meanwhile, the impurity B has better dissolubility in the salt forming solution and is further eliminated in the salt forming reaction process.
For impurity C, the acidification pH value of cefotaxime acid is strictly controlled in the post-treatment process, and the appropriate crystallization temperature and solvent are adopted, so that the generation amount of impurity C is effectively reduced.
The preparation method of cefotaxime sodium provided by the invention is feasible in industry and low in preparation difficulty, and the prepared cefotaxime sodium is low in impurity content, high in purity, white in color and good in stability, and is beneficial to reducing the difficulty of a preparation process.
Meanwhile, the preparation method of cefotaxime sodium provided by the invention has the advantages of simple synthesis steps and low processing difficulty in the operation process, and is very suitable for workshop production.
The invention also provides cefotaxime sodium obtained by the preparation method, which has high content, good purity and uniform particle size distribution.
In the cefotaxime sodium, the mass content of the cefotaxime sodium is more than 98 percent or the purity of the cefotaxime sodium is more than 99.2 percent calculated by anhydrous substances.
Wherein, the cefotaxime sodium contains impurity A,
the mass content of the impurity A is within 0.25%, preferably within 0.2%, more preferably within 0.1%;
and also contains the impurity B, and the impurity B,
the mass content of the impurity B is within 0.25%, preferably within 0.2%, more preferably within 0.1%;
furthermore, the catalyst also contains impurities C,
the content of impurity C is 0.25% by mass or less, preferably 0.2% by mass or less, and more preferably 0.1% by mass or less.
The cefotaxime sodium has good quality stability, and after the cefotaxime sodium is placed under long-term test conditions (25 +/-2 ℃/60% RH +/-10% RH) for 24 months, the impurity A is preferably within 0.25%, and more preferably within 0.2%. The content of impurity B is preferably 0.25% or less, more preferably 0.2% or less. The content of impurity C is preferably 0.25% or less, more preferably 0.2% or less, for example 0.19%.
In the cefotaxime sodium, the residual quantity of organic solvents, particularly the residual quantities of DMF, ethyl acetate, acetonitrile, ethanol, dichloromethane and acetone are very low, and the safety is good.
The invention also provides a cefotaxime sodium single preparation, which takes cefotaxime sodium prepared by the method as an active ingredient, and preferably is an injection.
In a preferred embodiment, the single preparation of cefotaxime sodium is prepared by aseptic packaging process, wherein cefotaxime sodium is pulverized, packaged, and encapsulated with nitrogen.
In the preparation, cefotaxime sodium is subjected to crushing treatment and then sterile subpackaging, preferably crushed to have the particle size D90 of 20-100 microns, more preferably 30-80 microns, and the dissolving speed is high in use.
The invention also provides a cefotaxime sodium compound preparation which comprises an active ingredient cefotaxime sodium and a synergist.
The synergist is tazobactam sodium, sulbactam sodium or ababactam sodium, and is preferably sulbactam sodium.
The weight ratio of cefotaxime sodium (calculated as cefotaxime) to sulbactam sodium (calculated as sulbactam) is 2-8: 1, and preferably 2-4: 1.
In a more preferred embodiment, the weight ratio of cefotaxime sodium (calculated as cefotaxime) to sulbactam sodium (calculated as sulbactam) is 2: 1.
The sulbactam sodium is inhibited by beta lactamase, and when the sulbactam sodium is used together with cefotaxime sodium, the cefotaxime sodium is more stable to the beta lactamase, so that the antibacterial effect of the cefotaxime sodium is further improved.
The cefotaxime sodium compound preparation can be prepared by uniformly mixing active ingredients and then performing aseptic subpackaging, and can also be prepared by freeze drying.
Preferably, in the cefotaxime sodium compound preparation, active ingredients are crushed, or the particle size of the active ingredients in the prepared compound preparation is very small, so that the active ingredients can be quickly dissolved, and the clinical use requirement is met.
Because cefotaxime sodium is unstable to oxygen, nitrogen, particularly high-purity nitrogen (more than 99.999 percent) is preferably used for protection during preparation sub-packaging, the stability under long-term storage is improved by removing the oxygen in a sub-packaging bottle, the generation of oxidative degradation impurities is reduced, and the clinical curative effect and the use safety are improved.
The invention also provides the use of the cefotaxime sodium, the cefotaxime sodium single preparation and the cefotaxime sodium compound preparation in preparing the medicines for treating salmonella infection including typhoid fever and paratyphoid fever.
The typhoid fever is a systemic acute infectious disease caused by salmonella typhi through intestinal tracts, mainly attacks the lower end of ileum, has clinical symptoms of persistent fever, systemic poisoning symptoms, diarrhea, abdominal pain and other digestive tract symptoms, and can also see roseola, hepatosplenomegaly, leukopenia, neuropsychiatric system symptoms and the like. The onset is common in summer and autumn, and is mostly in developing countries with poor living conditions and sanitary conditions, and is mainly transmitted through water sources and food.
The paratyphoid fever is an acute digestive tract infectious disease caused by salmonella paratyphi, and is similar to salmonella belonging to the same genus of typhoid bacillus in clinical expression, but the paratyphoid fever is lighter in disease condition and shorter in disease course. The acute gastroenteritis such as abdominal pain, diarrhea and emesis are often caused.
The cefotaxime sodium, the single preparation of the cefotaxime sodium and the compound preparation of the cefotaxime sodium provided by the invention are used for treating typhoid fever or paratyphoid fever, and are also suitable for children, pregnant women and lactating women.
Examples
Example 1
Preparation of an active ester intermediate:
dispersing 500.0g of aminothiazoly loximate and 700.0g of 2-chloro-4, 6-diphenyl triazine in 2.0kg of DMF, cooling to 2-5 ℃, adding 380.0g of DBU at a controlled temperature, stirring for 0.5h after the addition is finished, heating to 20-25 ℃, and carrying out heat preservation reaction for 2 h. After the reaction, 4.0kg of ethyl acetate was added, and the organic phase was washed with an equal amount of purified water, 1mol/L hydrochloric acid solution and 10% K2CO3Washing with an aqueous solution, washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure at 50 ℃ to obtain 988.5g of an active ester intermediate in a yield of 92.0%.
Preparation of cefotaxime acid:
adding 500.0g of 7-ACA and 2.0kg of acetonitrile into a reaction bottle, cooling a reaction system to-5-0 ℃ under stirring, controlling the temperature to-5-0 ℃, dropwise adding 784.0g N, O-bis (trimethylsilyl) acetamide, controlling the temperature to-5-0 ℃, gradually adding 834.0g of active ester intermediates in batches, and after the addition is finished, carrying out heat preservation reaction for 1 h. After the reaction is finished, adding 6.0kg of purified water and 100.0g of ethanol, cooling to 0-5 ℃, dropwise adding hydrochloric acid to adjust the pH value to 2.5, carrying out heat preservation and crystallization for 2 hours, filtering, and drying to obtain a white solid, namely 778.4g of cefotaxime acid, wherein the yield is as follows: 93.1 percent.
Preparation of cefotaxime sodium:
adding 700g of mixed solvent of water for injection and acetone (water: acetone is 3:1) into a reaction bottle, adding 7g of sodium sulfite, stirring and dissolving, cooling to 5-10 ℃, adding 700g of cefotaxime acid, stirring to dissolve clearly, dropwise adding 350ml of sodium isooctanoate aqueous solution (containing 281.0g of sodium isooctanoate) at controlled temperature, and reacting for 30min after dropwise adding; adding 10g of medicinal activated carbon for needle decolorization for 1 hour, filtering with a 0.2-micron microporous filter membrane to remove the activated carbon, heating to 10-15 ℃, adding 200g of dichloromethane, dropwise adding about 1000g of acetone until the reaction solution is slightly turbid, adding 0.1g of seed crystal, growing the crystals at 70 r/min for 1 hour, continuously dropwise adding 3000g of crystallization solvent acetone, cooling to 5-10 ℃, preserving heat and crystallizing for 2 hours, wherein the stirring speed is 100 r/min. Filtering and drying to obtain a white solid, namely 697.3g of cefotaxime sodium, and obtaining the yield: 95.0 percent.
Example 2
Preparation of an active ester intermediate:
dispersing 500.0g of aminothiazoly loximate and 700.0g of 2-chloro-4, 6-diphenyl triazine in 1.5kg of DMF, cooling to 0-5 ℃, adding 395g of DBU at a controlled temperature, stirring for 0.75h after the addition is finished, heating to 20-23 ℃, and carrying out heat preservation reaction for 2 h. After the reaction, 3.5kg of ethyl acetate was added, and the organic phase was washed with 3.8kg of purified water, 1mol/L hydrochloric acid solution and 10% K2CO3Washing with an aqueous solution, washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating at 50 deg.C under reduced pressure to obtain 979.1g of an active ester intermediate as a white-like solid with a yield of 91.1%.
Preparation of cefotaxime acid:
adding 500.0g of 7-ACA and 1.75kg of acetonitrile into a reaction bottle, cooling the reaction system to-5-2 ℃ under stirring, dropwise adding 750g N of O-bis (trimethylsilyl) acetamide under controlled temperature, continuously adding 795g of active ester intermediate in batches under controlled temperature, and keeping the temperature for reaction for 2 hours after the addition is finished. After the reaction is finished, adding 5.5kg of purified water and 100.0g of ethanol, cooling to 0-5 ℃, dropwise adding hydrochloric acid to adjust the pH value to 2.4, carrying out heat preservation and crystallization for 2 hours, filtering, and drying to obtain a white solid, namely 774.2g of cefotaxime acid, wherein the yield is as follows: 92.6 percent.
Preparation of cefotaxime sodium:
adding 700g of mixed solvent of water for injection and acetone (water: acetone is 3.5:1) into a reaction bottle, adding 7g of sodium sulfite, stirring and dissolving, cooling to 5-10 ℃, adding 700g of cefotaxime acid, stirring to clear, controlling the temperature to 5-10 ℃, dropwise adding 350ml of sodium isooctanoate aqueous solution (containing 281.0g of sodium isooctanoate), reacting for 30min after dropwise adding, then adding 10g of medicinal activated carbon for needle decolorization for 1h, filtering with a 0.2 mu m microporous filter membrane to remove the activated carbon, heating to 10-15 ℃, adding 245g of dichloromethane, dropwise adding about 1300g of crystallization solvent acetone until the reaction solution is slightly turbid, adding 0.1g of seed crystal, performing crystallization for 1h at 60 r/min, continuously dropwise adding 3300g of crystallization solvent acetone, after dropwise adding, cooling to 10 ℃, maintaining the temperature and crystallizing for 2h, stirring at a rate of 90 r/min, filtering, drying to obtain white solid, namely 682.7g of cefotaxime sodium, and the yield is as follows: 93.0 percent.
Example 3
Preparation of an active ester intermediate:
dispersing 500.0g of aminothiazoly loximate and 700.0g of 2-chloro-4, 6-diphenyl triazine in 2.5kg of DMF, cooling to 0-5 ℃, adding 390g of DBU under the temperature control, stirring for 0.5h after the addition is finished, heating to 20-25 ℃, and carrying out heat preservation reaction for 2 h. After the reaction, 4.5kg of ethyl acetate was added, and the organic phase was washed with 4.9kg of purified water, 1mol/L of hydrochloric acid solution, 10% of K2CO3 aqueous solution, saturated brine, dried over anhydrous sodium sulfate and concentrated at 50 ℃ under reduced pressure to obtain a white-like solid, i.e., 980.3g of an active ester intermediate, with a yield of 91.2%.
Preparation of cefotaxime acid:
adding 500.0g of 7-ACA and 2.0kg of acetonitrile into a reaction bottle, starting stirring, cooling the reaction system to-5-3 ℃, dropwise adding 810g of N, O-bis (trimethylsilyl) acetamide under controlled temperature, continuously controlling the temperature, adding 870g of active ester intermediate in batches, and keeping the temperature for reaction for 2 hours after the addition. After the reaction is finished, adding 6.5kg of purified water and 100.0g of ethanol, cooling to 0-5 ℃, dropwise adding hydrochloric acid to adjust the pH value to 2.5, carrying out heat preservation and crystallization for 2 hours, filtering, and drying to obtain a white solid, namely 775.9g of cefotaxime acid, wherein the yield is as follows: 92.8 percent.
Preparation of cefotaxime sodium:
adding 700g of mixed solvent of water for injection and acetone (water: acetone is 3.2:1) into a reaction bottle, adding 7g of sodium sulfite, stirring and dissolving, cooling to 5-10 ℃, adding 700g of cefotaxime acid, stirring to clear, controlling the temperature to 5-10 ℃, dropwise adding 350ml of sodium isooctanoate aqueous solution (containing 281.0g of sodium isooctanoate), reacting for 30min after dropwise adding, then adding 10g of medicinal activated carbon for needle decolorization for 1h, filtering with a 0.2 mu m microporous filter membrane to remove the activated carbon, heating to 10-15 ℃, adding 180g of dichloromethane, dropwise adding about 1200g of crystallization solvent acetone until the reaction solution is slightly turbid, adding 0.1g of seed crystal, performing crystallization for 1h at 80 revolutions per minute, continuously dropwise adding 3500g of crystallization solvent acetone, cooling to 10 ℃, performing crystallization for 2h at a heat preservation temperature, stirring at a speed of 80 revolutions per minute, filtering, drying to obtain a white solid, namely 692.5g of cefotaxime sodium, and the yield is as follows: 94.3 percent.
Example 4
The cefotaxime sodium prepared in examples 1-3 was pulverized by a ball mill to obtain cefotaxime sodium powders having D90 of 53.46 μm, 59.93 μm and 57.21. mu.m, respectively.
Taking the cefotaxime sodium powder, measuring the loading by 1.0g of cefotaxime, sealing and packaging to respectively obtain cefotaxime sodium preparations A, B and C.
Example 5
The cefotaxime sodium prepared in example 1 was pulverized using a ball mill to obtain cefotaxime sodium powder with D90 of 50.36 μm.
The D90 of the commercially available medicinal sulbactam sodium powder is 45.33 μm.
Taking cefotaxime sodium powder and sulbactam sodium powder, and mixing the components according to the weight ratio of 2:1, 1.0g of cefotaxime, sealing and packaging to obtain a cefotaxime sodium preparation D.
Examples of the experiments
Experimental example 1
The related substances, contents and residual solvents of cefotaxime sodium obtained in examples 1-3 were tested according to the method of cefotaxime sodium item of "Chinese pharmacopoeia" 2015 edition, and the results are shown in Table 1 below:
TABLE 1
As can be seen from the detection results, the products prepared in examples 1-3 have low impurity content, complete removal of DMF, little organic solvent residue and high quality.
Experimental example 2
The mass contents of cefotaxime sodium prepared in examples 1-3, impurities A, B and C after 6, 12 and 24 months of standing under long-term test conditions (25 ℃. + -. 2 ℃, 60% RH. + -. 10% RH) were determined according to the method of Experimental example 1.
The results are as follows:
it can be seen that after long-term testing, the content of cefotaxime sodium in examples 1-3 is still stable, indicating that it has higher stability and safety.
Experimental example 3
The content and related substances of the cefotaxime sodium preparation obtained in example 4 were tested according to the method described in the item of cefotaxime sodium in the 'Chinese pharmacopoeia' 2015 edition, and the results are shown in the following table 2:
TABLE 2
As can be seen from the table, formulations A, B and C were of good quality.
Experimental example 4
The content of cefotaxime sodium (the relative value of the measured amount to the indicated amount), related substances, in the cefotaxime sodium preparation obtained in example 4 was measured according to the method in experimental example 3. The test samples were placed under long-term test conditions (25 ℃. + -. 2 ℃/60% RH. + -. 10% RH) for 6, 12, 24 months, respectively. The results are as follows:
therefore, after long-term test, the content of cefotaxime sodium in the preparations A-C is stable, and only a small amount of cefotaxime sodium is degraded; the preparation has good long-term stability and long shelf life.
Experimental example 5
100 healthy mice (4 weeks old, 18-20g in weight) were taken and randomly divided into placebo and observation groups, each of which had 50 mice each and half of males and females. Inoculating Salmonella typhi 1 x 10 respectively8Model mice with typhoid fever were obtained.
Taking cefotaxime sodium preparation A in example 4, administering 110mg/kg (calculated as cefotaxime sodium) of tail vein injection for the observation group at the administration frequency of 24h, and simultaneously administering tail vein injection (normal saline) for the placebo group at the administration frequency of 24 h; after 5 days of treatment, clinical symptoms were recorded, mice sacrificed, dissected, and spleen and liver pathology were observed.
Wherein, the judgment standards of healing, improvement, obvious effect and ineffectiveness of the typhoid are as follows:
and (3) healing: normal body temperature, normal liver and spleen, and normal liver function:
improvement: the body temperature is basically normal, the liver and spleen are obviously reduced, and the liver function is normal:
the effect is shown: the body temperature is lowered, the liver and spleen are obviously reduced, and the liver function is normal;
and (4) invalidation: fever, hepatosplenomegaly and obvious abnormality of liver function
Wherein the treatment results of the typhoid mice are as follows:
observation group: 37 patients are cured, 6 patients are improved, 3 patients are obviously effective, and 4 patients are ineffective.
Placebo group: 4 patients are cured, 7 patients are improved, 9 patients are obviously effective, and 30 patients are ineffective.
Therefore, the therapeutic effect of the observation group on the rat typhoid is obviously better than that of the placebo group.
Experimental example 6
Taking healthy mice (4 weeks old, weight 18-2)0g)100, randomly divided into placebo and observation groups, 50 each, and hermaphrodite halves. Inoculating salmonella paratyphi 1 x 10 respectively8Model mice with paratyphoid were obtained.
Taking cefotaxime sodium preparation A in example 4, administering 110mg/kg (calculated as cefotaxime sodium) of tail vein injection for the observation group at the administration frequency of 24h, and simultaneously administering tail vein injection (normal saline) for the placebo group at the administration frequency of 24 h; after 3 days of treatment, clinical symptoms were recorded.
Wherein, the judgment standard of the paratyphoid fever recovery, improvement, obvious effect and ineffectiveness is as follows:
and (3) healing: normal body temperature without obvious fluctuation;
improvement: the body temperature is basically normal and has partial fluctuation;
the effect is shown: the body temperature is reduced and the fluctuation is obvious;
and (4) invalidation: generate heat
Wherein the treatment result of the paratyphoid mice is as follows:
observation group: 39 patients are cured, 7 patients are improved, 2 patients are obviously effective, and 2 patients are ineffective.
Placebo group: 5 patients are cured, 6 patients are improved, 10 patients are obviously effective, and 29 patients are ineffective.
Therefore, the treatment effect of the observation group on the paratyphoid of the rat is obviously better than that of the placebo group.
The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made in the technical solution of the present invention and the embodiments thereof without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is to be determined by the appended claims.
Claims (3)
1. A preparation method of cefotaxime sodium is characterized in that,
the cefotaxime sodium contains impurity A,
the mass content of the impurity A is within 0.2 percent;
the impurity B is a nitrogen-containing impurity,
the mass content of the impurity B is within 0.2 percent;
the impurity C is the impurity C which is the impurity,
the mass content of the impurity C is within 0.2 percent;
in the cefotaxime sodium, the mass content of the cefotaxime sodium is more than 98 percent calculated by anhydrous substances;
the preparation method comprises the following steps:
step 1: reacting the aminothiazoly loximate with an activating agent to obtain an active ester intermediate;
step 2: reacting 7-ACA with an active ester intermediate under the condition of controlling the temperature, adjusting the acid, and crystallizing to obtain cefotaxime acid;
and step 3: carrying out salifying reaction on cefotaxime acid and a salt forming agent in a salifying solvent, and separating out cefotaxime sodium;
in the step 1, the method comprises the following steps of,
the activator is 2-chloro-4, 6-diphenyl triazine;
dispersing the aminothiazoly loximate and 2-chloro-4, 6-diphenyl triazine in dimethylformamide, cooling to 0-5 ℃, adding a catalyst 1, 8-diazabicycloundec-7-ene at a controlled temperature, and increasing the reaction temperature until the reaction is finished after the addition is finished;
wherein the mass ratio of the aminothiazoly loximate to the 2-chloro-4, 6-diphenyl triazine is 1.0: 3.0-1.0: 5.0;
after the reaction is finished, post-treatment is also carried out;
the post-treatment comprises adding an extraction solvent to extract an active ester intermediate and adding an aqueous solution to clean the organic solution and stratify with the organic solution;
in the step 2, the step of the method is carried out,
dispersing 7-ACA in acetonitrile, cooling to-5-0 ℃, dropwise adding a condensing agent, adding an active ester intermediate to react until the reaction is finished, adding purified water and an alcohol solvent, cooling, and adjusting the pH value of the solution to 2.3-2.5; crystallizing, filtering and drying to obtain cefotaxime acid;
the condensing agent is selected from N, O-bis (trimethylsilane) trifluoroacetamide, hexamethyl disilazane or N, O-bis trimethylsilylacetamide;
in the step 3, the step of the method is that,
the salt forming agent is sodium isooctanoate or sodium lactate;
the salifying solvent is one or more of water for injection, methanol, ethanol, isopropanol and acetone;
and (3) after the salt forming reaction is finished, adding dichloromethane into the reaction solution, then dropwise adding a crystallization solvent until the reaction solution is slightly turbid, adding seed crystals, growing crystals, continuously dropwise adding the crystallization solvent, and cooling and then crystallizing to obtain cefotaxime sodium.
2. The method according to claim 1, wherein the condensing agent is N, O-bistrimethylsilyl acetamide.
3. The production method according to claim 1,
the salifying solvent is ethanol-water mixed liquor or acetone-water mixed liquor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010336056.XA CN111647006B (en) | 2020-04-25 | 2020-04-25 | Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010336056.XA CN111647006B (en) | 2020-04-25 | 2020-04-25 | Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111647006A CN111647006A (en) | 2020-09-11 |
| CN111647006B true CN111647006B (en) | 2021-06-08 |
Family
ID=72340904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010336056.XA Active CN111647006B (en) | 2020-04-25 | 2020-04-25 | Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111647006B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989194B (en) * | 2022-06-07 | 2023-09-26 | 艾美科健（中国）生物医药有限公司 | Method for reducing polymer in cefotaxime sodium |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL163670B1 (en) * | 1988-09-06 | 1994-04-29 | Inst Chemii Organicznej Pan | Method of obtaining aminothiasolyl derivatives of cephalosporine as well as their sodium or potassium salts |
| CN1171110A (en) * | 1994-12-23 | 1998-01-21 | 生化企业 | Production of cefotaxime and new sodium salts |
| CN1425376A (en) * | 2002-08-14 | 2003-06-25 | 海南国瑞堂制药有限公司 | Sodium cefetaxime and sodium tazotactam compound preparation for injection |
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| CN109575048A (en) * | 2018-12-26 | 2019-04-05 | 辽宁美亚制药有限公司 | A kind of preparation method of Cefotaxime Sodium |
| CN110393721A (en) * | 2018-12-03 | 2019-11-01 | 金华铂典医药科技合伙企业(有限合伙) | Cefotaxime Sodium pharmaceutical preparation is through the preoperative prevention infection application such as abdomen or vagina uterine excision, gastrointestinal tract and genital tract |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0053276A3 (en) * | 1980-12-02 | 1983-08-03 | Dr. Karl Thomae GmbH | Cephalosporins, process for their preparation and pharmaceutical compositions containing them |
| KR920021559A (en) * | 1991-05-06 | 1992-12-18 | 이정훈 | Novel cefem derivatives and preparation method |
| US20050119244A1 (en) * | 2003-12-02 | 2005-06-02 | Acs Dobfar S.P.A. | Process for preparing cephalosporins with salified intermediate |
| CN100361995C (en) * | 2004-10-27 | 2008-01-16 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic cefotaxime sodium for injection |
| CN102219794A (en) * | 2011-08-03 | 2011-10-19 | 天津华药医药有限公司 | Preparation method of ceftizoxime sodium |
| CN105418641B (en) * | 2015-12-30 | 2018-08-10 | 广东金城金素制药有限公司 | It is a kind of former to develop quality Ceftriaxone Sodium and its pharmaceutical preparation |
-
2020
- 2020-04-25 CN CN202010336056.XA patent/CN111647006B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL163670B1 (en) * | 1988-09-06 | 1994-04-29 | Inst Chemii Organicznej Pan | Method of obtaining aminothiasolyl derivatives of cephalosporine as well as their sodium or potassium salts |
| CN1171110A (en) * | 1994-12-23 | 1998-01-21 | 生化企业 | Production of cefotaxime and new sodium salts |
| CN1425376A (en) * | 2002-08-14 | 2003-06-25 | 海南国瑞堂制药有限公司 | Sodium cefetaxime and sodium tazotactam compound preparation for injection |
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| CN110393721A (en) * | 2018-12-03 | 2019-11-01 | 金华铂典医药科技合伙企业(有限合伙) | Cefotaxime Sodium pharmaceutical preparation is through the preoperative prevention infection application such as abdomen or vagina uterine excision, gastrointestinal tract and genital tract |
| CN109575048A (en) * | 2018-12-26 | 2019-04-05 | 辽宁美亚制药有限公司 | A kind of preparation method of Cefotaxime Sodium |
Non-Patent Citations (2)
| Title |
|---|
| 2-CHLORO-4,6-DIMETHOXY-1,3,5-TRIAZINE: A NEW EFFECTIVE AND CONVENIENT COUPLING REAGENT FOR CEPHALOSPORIN DERIVATIVES;Hong-Woo Lee等;《SYNTHETIC COMMUNICATIONS》;20060822;第28卷(第8期);第1339-1349页 * |
| 头孢噻肟钠杂质谱分析与控制;崔雪君;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20190415(第4期);第B016-442页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111647006A (en) | 2020-09-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102603684B (en) | Sterile andrographolide and preparation method thereof | |
| CN102766148B (en) | Cefamandole nafate compound and composite thereof | |
| CN111647006B (en) | Cefotaxime sodium pharmaceutical preparation and treatment of salmonella infection indications including typhoid fever and paratyphoid fever | |
| CN103102357B (en) | A kind of synthetic method of Cefuroxime sodium | |
| CN110393721B (en) | Preparation method of cefotaxime sodium | |
| JP2006291028A (en) | Low-molecular heparin or salt thereof, and manufacturing method thereof | |
| CN111718299B (en) | Levosimendan sodium crystal form B and preparation method thereof | |
| CN110393719B (en) | Cefoperazone sodium and sulbactam sodium composition pharmaceutical preparation and new indications for treating infectious endocarditis | |
| CN103232477B (en) | Cefotiam hydrochloride compound, and preparation method and pharmaceutical composition thereof | |
| CN102643255A (en) | Andrographolide compound | |
| CN104644572B (en) | A kind of high-purity clindamycin phosphate powder and its preparation technology | |
| CN110393720B (en) | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating infection of patients with low immune function | |
| CN108066338B (en) | Antibiotic composition and preparation method thereof | |
| CN103159817A (en) | Preparation method for methylprednisolone succinate | |
| CN114767829A (en) | Oxytocin composition without preservative and preparation method and application thereof | |
| CN110396102B (en) | Cefoxitin sodium compound pharmaceutical preparation and application thereof in prevention of infection before vaginal hysterectomy, abdominal hysterectomy and cesarean section (uterine) | |
| CN110396104B (en) | New indication of Taistin ceftazidime medicinal preparation for treating gynecological infection | |
| CN110396101B (en) | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating bacterial endometritis | |
| CN112535725A (en) | Reduced glutathione for injection and preparation method thereof | |
| US3839317A (en) | Digoxin complexes | |
| KR20120101462A (en) | Process for the preparation of gadobenate dimeglumine complex in a solid form | |
| CN110684038B (en) | Pharmaceutical preparation of compound of trissofene ceftriaxone sodium and new indication for treating pelvic inflammation | |
| CN111499658B (en) | Cefoperazone compound medicinal preparation and new indication for treating endometritis and other gynecological genital tract infection | |
| CN110396103B (en) | Cefazolin sodium or composition thereof, preparation method and preparation thereof, and new indications of reproductive system infection | |
| CN111560028A (en) | New indication of cefepime hydrochloride medicinal preparation for treating otitis media |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |