CN110372726B - Preparation method of cefixime sodium crystal - Google Patents
Preparation method of cefixime sodium crystal Download PDFInfo
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- CN110372726B CN110372726B CN201910514759.4A CN201910514759A CN110372726B CN 110372726 B CN110372726 B CN 110372726B CN 201910514759 A CN201910514759 A CN 201910514759A CN 110372726 B CN110372726 B CN 110372726B
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- 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
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- 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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- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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Abstract
The invention belongs to the field of medicinal chemistry, and relates to a preparation method of a cefixime sodium crystal with high purity and good stability. The preparation method comprises the following steps: the cefhydroxamic acid and a salt forming agent sodium acetate react through an emulsion interface to form salt, and then, an antisolvent is added to crystallize and separate out the cefhydroxamic sodium. The cefixime sodium crystal prepared by the invention has high purity and good stability, so that the safety is better, the cefixime sodium crystal has antibacterial action on gram-positive bacteria and gram-negative bacteria, and the cefixime sodium crystal can be possibly used for infection of respiratory tracts, urinary tracts, skins, soft tissues and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a broad-spectrum antibacterial compound 3-hydroxymethyl-7- [ 2-amino-4-thiazolyl- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt (hereinafter referred to as cefixime sodium) crystal.
Background
Cephalosporin antibiotics are widely used antibiotics at present. The cephalosporin molecules have beta-lactam rings, have an antibacterial effect by acting on cell walls of bacteria, have small toxic and side effects, are bactericides in a propagation period, have time dependence of the antibacterial effect, have good tissue permeability and are suitable for various tissue infections caused by sensitive bacteria.
In 1948, cephalosporins were first extracted from the acremonium separated from the drainage sludge soil of sardinia (Sardegna) by the italian scientist Giuseppe Brotzu. Further isolation of cephalosporin and confirmation of the chemical structure of cephalosporin in the university of oxford in 1962, successful extraction of β -lactamase stable cephalosporin C, followed by structural modification to form a variety of cephalosporin antibiotics for use in humans against bacterial infections.
With the increasing expansion of cephalosporins, bacterial resistance is gradually appearing, and further development of new cephalosporin varieties is needed. In addition, cephalosporin is unstable in chemical structure and is susceptible to factors such as temperature, humidity and pH value, and various byproducts and degradation products are likely to be generated in the storage process. If the preparation conditions of the cephalosporin are inappropriate, the prepared sample has poor stability, and the sample is easy to have the phenomena of content reduction, impurity increase, color deepening and the like in the storage process, so that the antibacterial activity is reduced, and anaphylactic reaction can also occur. The inventor carries out continuous research and development, prepares the cefixime sodium crystal with high purity and good stability by adopting emulsion interface reaction on the basis of a series of experimental researches, and enhances the antibacterial action on gram-negative bacteria while keeping stronger activity on gram-positive bacteria such as staphylococcus aureus, streptococcus (except enterococcus) and the like.
Disclosure of Invention
Based on the research and development, the invention aims to provide a preparation method of cefixime sodium crystal with high purity and good stability.
The cefixime sodium crystal is a 3-hydroxymethyl-7- [ 2-amino-4-thiazolyl- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-sodium formate crystal, and the structural formula of the compound is as follows:
according to the invention, the preparation method of the cefixime sodium crystal comprises the following steps:
adding caprylic capric acid glyceride to enable the mixed solution of water and ethyl acetate to form emulsion; then adding 15-25 wt% of sodium acetate aqueous solution and 3-hydroxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino ] -acetamido-3-cephem-4-carboxylic acid (hereinafter referred to as cefhydroxamic acid) into the emulsion in batches at the same time, and keeping the pH value between 6 and 8 to perform salt forming reaction to generate cefhydroxamic acid sodium; after the reaction is finished, demulsifying, standing for layering, separating out an ethyl acetate layer, decoloring an obtained water layer with activated carbon, adding an antisolvent, and crystallizing and separating out cefixime sodium.
The process for the preparation of the crystalline cefixime sodium is described in more detail below.
In the preparation method of the cefixime sodium crystal, the molar ratio of the added cefixime acid to the added sodium acetate is 1: 1-1.2.
In the preparation method of the cefixime sodium crystal, in an emulsion of water and ethyl acetate, the volume ratio of water to ethyl acetate is 0.5-1: 1; the formation of an emulsion from a mixture of water and ethyl acetate by the addition of caprylic capric acid glyceride may be formed as follows: adding caprylic capric acid glyceride into ethyl acetate, stirring uniformly, adding water under stirring, and controlling the stirring speed at 50-100 revolutions per minute to form uniform emulsion; wherein the using amount of the caprylic/capric glyceride is 1-5% of the volume of the ethyl acetate.
In the preparation method of the cefixime sodium crystal, the dosage of ethyl acetate is 1.5-3 ml of ethyl acetate per gram of cefixime acid relative to cefixime acid.
In the preparation method of the cefixime sodium crystal, the salt forming reaction is carried out at 5-30 ℃, and preferably at 10-20 ℃.
In the preparation method of the cefixime sodium crystal, after the reaction is finished, emulsion is demulsified by centrifugation, standing and layering are carried out, and an ethyl acetate layer is separated, so that unreacted cefixime acid and impurities dissolved in ethyl acetate can be further removed, and a product with high purity can be obtained; wherein, the centrifugal demulsification is carried out at the rotating speed of the centrifugal machine of 10000-25000 r/min.
In the preparation method of the cefixime sodium crystal, when the obtained water layer is decolorized by activated carbon, the dosage of the activated carbon is 0.1-0.5 g of activated carbon per g of cefixime acid relative to the cefixime acid.
In the preparation method of the cefixime sodium crystal, the anti-solvent is isopropanol or acetone, and the volume ratio of the water layer decolorized by the activated carbon to the anti-solvent is 1: 10-20.
Advantageous effects
The invention has the advantages that:
(1) the cefixime sodium crystal has high purity and good stability.
The preparation of sodium salt is generally carried out by water method, adding acid and salt forming agent into water or water-water miscible solvent (such as ethanol and acetone) to react to obtain sodium salt, wherein the acid can not be dissolved in reaction liquid, the reaction is solid-liquid reaction, the relative reaction rate is slow, the reaction is insufficient, and solid acid can be wrapped in the product. The invention adopts the method of salifying in the state of emulsion, the organic phase is ethyl acetate which can dissolve cefixime acid, the aqueous phase can dissolve salt forming agent sodium acetate and salified product cefixime sodium, the mixed solution of water and ethyl acetate is added with emulsifier caprylic capric glyceride to form emulsion, and the contact area of acid and salt forming agent on the interface of the emulsion is large, thus the reaction is rapid and sufficient. After the reaction, emulsion is demulsified by centrifugation, and the emulsion is kept stand to separate an ethyl acetate layer, so that unreacted cefhydroxamic acid and impurities dissolved in an organic phase can be further removed, and a product with high purity can be obtained.
(2) The emulsifier adopts caprylic capric glyceride which is colorless transparent liquid, is tasteless or nearly tasteless, has LD50 more than 36mL/kg (rat and oral), LD50 more than 24mL/kg (intraperitoneal injection), and is negative in intramuscular injection, skin and eye irritation test, two-generation reproduction test and teratogenesis test. Due to its high safety, the Food and Drug Administration (FDA) has classified caprylic capric glyceride into GRAS, i.e., food as safe drug. The caprylic capric glyceride is listed in GB2760-80 hygienic Standard for food additive use in China, and is approved by the Ministry of health in 1996 to be used for various foods, and the using amount is not limited. The caprylic capric glyceride is soluble in oil, oxidant, vitamins and various organic solvents (such as ethyl acetate, acetone, isopropanol, etc.), and insoluble in water. Because the caprylic/capric glyceride is colorless, tasteless and transparent, has no additional negative influence on salt formation when being added into a salt formation reaction, is dissolved in an organic phase and is insoluble in water, the caprylic/capric glyceride can be basically removed from a water layer by separating an ethyl acetate layer, a larger amount of acetone or isopropanol can be added into the water layer subsequently, and if residues exist, the caprylic/capric glyceride and a product can be separated by secondary dissolution, so that the emulsifying effect can be achieved, and the product cannot be brought into the caprylic/capric glyceride.
(3) As cefhydroxamic acid is easy to generate impurities under the condition of partial acid or partial alkali, the pH of a reaction solution is kept between 6 and 8 by adding the cefhydroxamic acid and a sodium acetate aqueous solvent in batches and simultaneously in the reaction process, the pH of the reaction solution is kept neutral, and the reaction conditions are mild, so that the cefhydroxamic acid and the cefhydroxamic sodium are prevented from being in the environment of partial acid or partial alkali, and the generation of impurities is reduced. The method has mild and controllable conditions, and the prepared cefixime sodium product has high purity, good stability and stable and uniform crystal form.
(4) The cefixime sodium has an antibacterial effect on gram-positive bacteria and gram-negative bacteria, and is a potential antibacterial medicament.
Detailed Description
The present invention is described more specifically by the following examples, but the scope of the present invention is not limited to the following examples.
Example 1
Adding 3.6 g of sodium acetate trihydrate into 14.4ml of water, stirring and dissolving to prepare about 20 wt% of sodium acetate aqueous solution;
adding 20ml of ethyl acetate and 0.2ml of caprylic-capric glyceride into a reaction vessel at 15-20 ℃, uniformly stirring, adding 10ml of water under stirring, and controlling the stirring speed at 60-70 r/min to form uniform emulsion; then adding 10g of cefhydroxamic acid and the sodium acetate aqueous solution with the weight percent of about 20% into the emulsion in batches at the same time, keeping the pH value between 6 and 8, carrying out salt forming reaction, and stirring for 30 minutes after the addition is finished;
after the salt-forming reaction, transferring the mixture into a centrifuge, centrifuging at the centrifugal speed of 15000-;
and dropwise adding acetone into the water layer at 15-20 ℃ under stirring until the solution is turbid, stirring until more solid is separated out, continuously adding acetone into the solution until the total volume is 400ml, then cooling to 5-10 ℃, continuously stirring for 1 hour, filtering, washing the solid with acetone, and drying to obtain 9.2g of cefixime sodium crystal.
Comparative example 1
Adding 3.6 g of sodium acetate trihydrate into 20ml of water, stirring and dissolving to prepare a sodium acetate aqueous solution with the weight percent of about 15, wherein the pH value is about 9; adding 10g of cefhydroxamic acid into a sodium acetate aqueous solution at 15-20 ℃, and stirring for reaction for about 40-50 minutes;
then adding 1g of activated carbon, stirring for 10 minutes, filtering, washing the activated carbon layer with 5ml of water, and combining water layers;
and dropwise adding acetone into the water layer at 15-20 ℃ under stirring until the solution is turbid, stirring until more solid is separated out, continuously adding acetone into the solution until the total volume is 400ml, then cooling to 5-10 ℃, continuously stirring for 1 hour, filtering, washing the solid with acetone, and drying to obtain 8.7g of cefixime sodium crystal.
Test example 1
The antibacterial activity of cefixime sodium on various strains is determined by adopting the cefixime sodium crystal prepared in example 1 and a standard agar double dilution method, and the result is as follows:
test example 2
Comparing the cefixime sodium crystal prepared in example 1 with the cefixime sodium crystal prepared in comparative example 1, placing the two samples in a small aluminum bottle, sealing, placing at 35-40 ℃ and 50-70% of relative humidity, and sampling for detection at 0 month and 6 months respectively, wherein the test items comprise appearance, purity, color and clarity.
Example 2
Adding 3.3 g of sodium acetate trihydrate into 10ml of water, stirring and dissolving to prepare about 25 wt% of sodium acetate aqueous solution;
adding 15ml of ethyl acetate and 0.3ml of caprylic-capric glyceride into a reaction vessel at 25-30 ℃, uniformly stirring, adding 10ml of water under stirring, and controlling the stirring speed at 90-100 revolutions per minute to form uniform emulsion; then adding 10g of cefhydroxamic acid and the sodium acetate aqueous solution with the weight percent of about 25% into the emulsion in batches at the same time, keeping the pH value between 6 and 8, carrying out salt forming reaction, and stirring for 25 minutes after the addition is finished;
after the salt-forming reaction, transferring the mixture into a centrifuge, centrifuging at the centrifugation speed of 20000-25000r/min for demulsification, standing for layering, removing an ethyl acetate layer, adding 2g of activated carbon into the obtained water layer, stirring for 10 minutes, filtering, washing the activated carbon layer with 5ml of water, and combining the water layers;
dropwise adding isopropanol into the water layer at 15-20 ℃ under stirring until the solution is turbid, stirring until more solids are separated out, continuously adding isopropanol, wherein the total volume is 250ml, then cooling to 5-10 ℃, continuously stirring for 1 hour, filtering, washing the solids with isopropanol, and drying to obtain 9.0g of cefixime sodium crystals.
Example 3
Adding 3.95 g of sodium acetate trihydrate into 19.8ml of water, and stirring to dissolve the sodium acetate to prepare an aqueous sodium acetate solution with the weight percent of about 16.6;
adding 30ml of ethyl acetate and 1.5ml of caprylic-capric glyceride into a reaction vessel at the temperature of 5-10 ℃, uniformly stirring, adding 30ml of water under stirring, and controlling the stirring speed at 50-65 r/min to form uniform emulsion; then adding 10g of cefhydroxamic acid and the sodium acetate aqueous solution with the weight percent of about 16.6 into the emulsion in batches at the same time, keeping the pH value between 6 and 8 for salt forming reaction, and stirring for 30 minutes after the salt forming reaction is finished;
after the salt-forming reaction, transferring the mixture into a centrifuge, centrifuging at the centrifugal speed of 15000-;
and dropwise adding acetone into the water layer at 15-20 ℃ under stirring until the solution is turbid, stirring until more solid is separated out, continuously adding acetone into the solution, wherein the total volume is 1100ml, then cooling to 5-10 ℃, continuously stirring for 1 hour, filtering, washing the solid with acetone, and drying to obtain 8.9g of cefixime sodium crystal.
Claims (10)
1. A process for producing a crystalline sodium 3-hydroxymethyl-7- [ 2-amino-4-thiazolyl- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, i.e., a crystalline sodium cefixime, which comprises:
adding caprylic capric acid glyceride to enable the mixed solution of water and ethyl acetate to form emulsion; then adding 15-25 wt% of sodium acetate aqueous solution and 3-hydroxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino ] -acetamido-3-cephem-4-carboxylic acid, namely cefhydroxamic acid, into the emulsion in batches at the same time, so that the pH value is kept between 6 and 8, and carrying out salt forming reaction to generate cefhydroxamic acid sodium; after the reaction is finished, demulsifying, standing for layering, separating out an ethyl acetate layer, decoloring an obtained water layer with activated carbon, adding an antisolvent, and crystallizing and separating out cefixime sodium.
2. The process according to claim 1, wherein the molar ratio of the cefhydroxamic acid to the sodium acetate is 1: 1-1.2.
3. The method according to claim 1, wherein the volume ratio of water to ethyl acetate in the emulsion of water and ethyl acetate is 0.5 to 1: 1.
4. The method according to claim 1, wherein the emulsion is formed by adding caprylic/capric glyceride to a mixture of water and ethyl acetate by the following method: adding caprylic capric acid glyceride into ethyl acetate, stirring uniformly, adding water under stirring, and controlling the stirring speed at 50-100 revolutions per minute to form uniform emulsion; wherein the using amount of the caprylic/capric glyceride is 1-5% of the volume of the ethyl acetate.
5. The method according to claim 1, wherein the amount of ethyl acetate is 1.5 to 3 mL/g of cefuroxime acid.
6. The method according to claim 1, wherein the salt-forming reaction is carried out at 5 to 30 ℃.
7. The method according to claim 6, wherein the salt-forming reaction is carried out at 10 to 20 ℃.
8. The process according to claim 1, wherein the emulsion is broken by centrifugation at a centrifuge speed of 10000 to 25000r/min after the completion of the reaction, and the emulsion is allowed to stand for separation to separate an ethyl acetate layer.
9. The method according to claim 1, wherein the aqueous layer is decolorized with activated carbon in an amount of 0.1 to 0.5g of activated carbon per gram of cefhydroxamic acid.
10. The method according to claim 1, wherein the anti-solvent is isopropanol or acetone, and the anti-solvent is used in an amount such that the volume ratio of the water layer decolorized by the activated carbon to the anti-solvent is 1:10 to 20.
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| CN100361996C (en) * | 2004-10-22 | 2008-01-16 | 浙江震元制药有限公司 | Cephalosporin analog antibiotic preparation method |
| CN103467496A (en) * | 2013-09-29 | 2013-12-25 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose |
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