CN112629990A - Azithromycin reference substance and preparation method thereof - Google Patents
Azithromycin reference substance and preparation method thereof Download PDFInfo
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- CN112629990A CN112629990A CN202110092376.XA CN202110092376A CN112629990A CN 112629990 A CN112629990 A CN 112629990A CN 202110092376 A CN202110092376 A CN 202110092376A CN 112629990 A CN112629990 A CN 112629990A
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Abstract
The invention relates to the technical field of test medicaments, in particular to an azithromycin reference substance and a preparation method thereof, which comprises the following raw materials in parts by weight: 50-100 parts of azithromycin, 10-15 parts of acetone, 10-15 parts of acetic acid, 8-10 parts of acetaldehyde, 2-5 parts of metal ions, 2-4 parts of a catalyst, 10-15 parts of a cosolvent and 20-25 parts of a stabilizer. The invention forms the compound acid salt which is easy to dissolve in water by the azithromycin and the cosolvent acid in the water solution, solves the problem of poor water solubility of the azithromycin, provides possibility for further preparing the preparation for injection, ensures that the azithromycin can be dissolved by the cosolvent, has small quantity which is not enough to completely dissolve the azithromycin, brings unnecessary impurities when excessive quantity is added, and prevents the influence on the product quality by adding a proper quantity; the stabilizer can further improve the quality of the product.
Description
Technical Field
The invention relates to the technical field of test medicaments, in particular to an azithromycin reference substance and a preparation method thereof.
Background
Azithromycin is macrolide antibiotic, has wide antibacterial spectrum, has high bactericidal activity on gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, staphylococcus aureus and pneumococcus, and has strong effect on chlamydia, mycoplasma pneumoniae and legionella pneumonia. Because of the strong antibacterial action and the obviously reduced incidence rate of adverse reactions compared with the erythromycin, the azithromycin becomes one of the clinical common antibiotics. Due to the fact that the azithromycin has a great effect, the azithromycin needs to be researched, a comparison sample needs to be used for comparison and reference in experiments, so that more accurate test data can be obtained, the types of the azithromycin contrast products at present are few, and the azithromycin has low solubility in water and cannot be scientifically researched.
Disclosure of Invention
The invention aims to provide an azithromycin reference substance and a preparation method thereof, which aim to solve the problem of low solubility of the azithromycin reference substance in water in the background art.
In order to achieve the purpose, the invention provides the following technical scheme:
an azithromycin contrast product comprises the following raw materials in parts by weight: 50-100 parts of azithromycin, 10-15 parts of acetone, 10-15 parts of acetic acid, 8-10 parts of acetaldehyde, 2-5 parts of metal ions, 2-4 parts of a catalyst, 10-15 parts of a cosolvent and 20-25 parts of a stabilizer.
Preferably, the feed comprises the following raw materials in parts by weight: 70 parts of azithromycin, 12 parts of acetone, 13 parts of acetic acid, 9 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 13 parts of a cosolvent and 22 parts of a stabilizer.
Preferably, the feed comprises the following raw materials in parts by weight: 60 parts of azithromycin, 12 parts of acetone, 11 parts of acetic acid, 8 parts of acetaldehyde, 3 parts of metal ions, 3 parts of a catalyst, 13 parts of a cosolvent and 21 parts of a stabilizer.
Preferably, the feed comprises the following raw materials in parts by weight: 100 parts of azithromycin, 15 parts of acetone, 15 parts of acetic acid, 10 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 15 parts of a cosolvent and 25 parts of a stabilizer.
Preferably, the azithromycin adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at the temperature of 30-60 ℃ for 10-36h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 3-4h at the temperature of 3-5 ℃ and the pH value of 9.7-10.5, and centrifuging.
Preferably, the metal ion is Ca2+、Cu2+、Fe3+Any one of the above.
Preferably, the catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon specifically comprises the following steps: taking 70-80g of platinum carbon with 5 percent of platinum content, adding 600-700ml of water, stirring uniformly, adding 1.0-1.5g of calcium chloride, pulping for 30-40min, and filtering to obtain the treated platinum carbon catalyst.
Preferably, the cosolvent is one of hydrochloric acid, lactobionic acid or citric acid, and if the cosolvent is hydrochloric acid, the concentration of the solution is 1-5%, if the cosolvent is lactobionic acid, the concentration is 15-20%, and if the cosolvent is citric acid, the concentration is 20-25%.
Preferably, the stabilizer is polyethylene glycol 400.
A preparation method of an azithromycin reference substance comprises the azithromycin reference substance, and specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to be 20-25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 4-5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.0-1.2MPa, keeping the reaction temperature at 55-60 ℃ during the heat preservation reaction, and controlling the reaction time to be 8-12 h;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 5-6, preserving the temperature, and carrying out N methylation reaction at the temperature of 40-50 ℃ for 20-25 h;
s5: after the reaction is finished, adjusting the pH value to 10-11, standing for layering, taking an organic layer, heating to 40-45 ℃, slowly dripping water until crystals are separated out, cooling to 30-35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Compared with the prior art, the invention has the beneficial effects that:
1. in the azithromycin reference substance and the preparation method thereof, the azithromycin and the cosolvent acid form a complex acid salt which is easy to dissolve in water in aqueous solution, so that the problem of poor water solubility of the azithromycin is solved, the possibility is provided for further preparation of injection preparations, the cosolvent can ensure that the azithromycin is dissolved, the quantity is small and is not enough to completely dissolve the azithromycin, unnecessary impurities are brought in if the quantity is excessive, and the addition of a proper amount prevents the influence on the product quality.
2. According to the azithromycin reference substance and the preparation method thereof, after the platinum carbon is treated by the metal ions, the activity is reduced to some extent, the carbon-nitrogen double bond is not reduced, the double bond is subjected to imine hydrolysis under an acidic condition, and the formed amino is provided with two methyl groups under the action of formic acid and formaldehyde; the stabilizer can further improve the quality of the product, if the product is not added with the stabilizer and is placed at room temperature for half a year, the content of the main azithromycin is reduced by about 5 percent, the content of the azithromycin reference substance is increased from 1 percent to more than 2 percent, and the indexes are basically unchanged when the product is placed under the same condition with the stabilizer added sample.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides the following technical scheme:
example 1
An azithromycin contrast product comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: 70 parts of azithromycin, 12 parts of acetone, 13 parts of acetic acid, 9 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 13 parts of a cosolvent and 22 parts of a stabilizer.
Specifically, the azithromycin in the embodiment adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at 60 ℃ for 24h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in acetone-water system at a mass ratio of acetone to water of 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting at pH of 9.8 and temperature of 5 deg.C for 3.5h, and centrifuging.
It is worth mentioning that the metal ion is specifically Fe3+The catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 650ml of water, stirring uniformly, adding 1g of calcium chloride, pulping for 30min, and filtering to obtain the treated platinum carbon catalyst.
Further, the cosolvent is specifically hydrochloric acid, and the concentration of the hydrochloric acid solution is 3%.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 4.5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.2MPa, keeping the reaction temperature at 55 ℃ during the reaction, and controlling the reaction time to be 10 hours;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 6, preserving the temperature, and carrying out N methylation reaction at the temperature of 40 ℃ for 25 hours;
s5: after the reaction is finished, adjusting the pH value to 11, standing for layering, taking an organic layer, heating to 45 ℃, slowly dripping water until crystals are separated out, cooling to 35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 2
An azithromycin contrast product comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: 60 parts of azithromycin, 12 parts of acetone, 11 parts of acetic acid, 8 parts of acetaldehyde, 3 parts of metal ions, 3 parts of a catalyst, 13 parts of a cosolvent and 21 parts of a stabilizer.
Specifically, in this embodiment, the azithromycin adopts erythromycin 6, 9-imino ether, and the specific synthesis of erythromycin 6, 9-imino ether includes the following steps: rhodomyces rhodaniReacting the erythromycin with hydroxylamine at 60 ℃ for 15h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 4h at the pH of 9.8 and the temperature of 5 ℃, and centrifuging. The metal ion is Ca2+。
Further, the catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 650ml of water, stirring uniformly, adding 1.5g of calcium chloride, pulping for 40min, and filtering to obtain the treated platinum carbon catalyst.
In addition, the cosolvent is citric acid, the solution concentration is 20%, and the stabilizer is polyethylene glycol 400.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.2MPa, keeping the reaction temperature at 55 ℃ during the reaction, and controlling the reaction time to be 10 hours;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 5.5, preserving the temperature, and carrying out N methylation reaction at the reaction temperature of 50 ℃ for 25 hours;
s5: after the reaction is finished, adjusting the pH value to 11, standing for layering, taking an organic layer, heating to 45 ℃, slowly dripping water until crystals are separated out, cooling to 30 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 3
An azithromycin contrast product comprises the following raw materials in parts by weight: 100 parts of azithromycin, 15 parts of acetone, 15 parts of acetic acid, 10 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 15 parts of a cosolvent and 25 parts of a stabilizer.
The azithromycin in the embodiment adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at 30 ℃ for 10-36h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1: and 3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 4 hours at the pH of 9.8 and the temperature of 5 ℃, centrifuging and centrifuging.
Specifically, the metal ion is Cu2+The catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 700ml of water, stirring uniformly, adding 1.5g of calcium chloride, pulping for 40min, and filtering to obtain the treated platinum carbon catalyst.
The cosolvent is lactobionic acid, the concentration of the solution is 15%, and the stabilizing agent is polyethylene glycol 400.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 20 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.1MPa, keeping the reaction temperature at 55-60 ℃ during the heat preservation reaction, and controlling the reaction time to be 8-12 h;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 6, preserving the temperature, and carrying out N methylation reaction at the reaction temperature of 50 ℃ for 24 hours;
s5: after the reaction is finished, adjusting the pH value to 10, standing for layering, taking an organic layer, heating to 40 ℃, slowly dripping water until crystals are separated out, cooling to 35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 4
An azithromycin contrast product comprises the following raw materials in parts by weight: 80 parts of azithromycin, 5 parts of acetone, 15 parts of acetic acid, 10 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 15 parts of a cosolvent and 25 parts of a stabilizer.
The azithromycin in the embodiment adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at 30 ℃ for 10-36h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1: and 3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 4 hours at the pH of 9.8 and the temperature of 5 ℃, centrifuging and centrifuging.
Specifically, the metal ion is Cu2+The catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 700ml of water, stirring uniformly, adding 1.5g of calcium chloride, pulping for 40min, and filtering to obtain the treated platinum carbon catalyst.
The cosolvent is lactobionic acid, the concentration of the solution is 15%, and the stabilizing agent is polyethylene glycol 400.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 20 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.5MPa, keeping the reaction temperature at 55-60 ℃ during the heat preservation reaction, and controlling the reaction time to be 8-12 h;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 6, preserving the temperature, and carrying out N methylation reaction at the reaction temperature of 50 ℃ for 24 hours;
s5: after the reaction is finished, adjusting the pH value to 10, standing for layering, taking an organic layer, heating to 40 ℃, slowly dripping water until crystals are separated out, cooling to 35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 5
An azithromycin contrast product comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: 60 parts of azithromycin, 12 parts of acetone, 11 parts of acetic acid, 8 parts of acetaldehyde, 3 parts of metal ions, 3 parts of a catalyst, 13 parts of a cosolvent and 21 parts of a stabilizer.
Specifically, in this embodiment, the azithromycin adopts erythromycin 6, 9-imino ether, and the specific synthesis of erythromycin 6, 9-imino ether includes the following steps: reacting erythromycin thiocyanate with hydroxylamine at 60 ℃ for 15h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 4h at the pH of 9.8 and the temperature of 5 ℃, and centrifuging. The metal ion is Ca2+。
Further, the catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 650ml of water, stirring uniformly, adding 1.5g of calcium chloride, pulping for 60min, and filtering to obtain the treated platinum carbon catalyst.
In addition, the cosolvent is citric acid, the solution concentration is 20%, and the stabilizer is polyethylene glycol 400.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.2MPa, keeping the reaction temperature at 55 ℃ during the reaction, and controlling the reaction time to be 10 hours;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 5.5, preserving the temperature, and carrying out N methylation reaction at the reaction temperature of 50 ℃ for 25 hours;
s5: after the reaction is finished, adjusting the pH value to 11, standing for layering, taking an organic layer, heating to 45 ℃, slowly dripping water until crystals are separated out, cooling to 30 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 6
An azithromycin contrast product comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: 70 parts of azithromycin, 12 parts of acetone, 13 parts of acetic acid, 9 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 13 parts of a cosolvent and 22 parts of a stabilizer.
Specifically, the azithromycin in the embodiment adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at 60 ℃ for 24h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in acetone-water system at a mass ratio of acetone to water of 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting at pH of 9.8 and temperature of 5 deg.C for 3.5h, and centrifuging.
It is worth mentioning that the metal ion is specifically Fe3+The catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 650ml of water, stirring uniformly, adding 1g of calcium chloride, pulping for 30min, and filtering to obtain the treated platinum carbon catalyst.
Further, the cosolvent is specifically acetic acid, and the concentration of the acetic acid solution is 3%.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 4.5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.2MPa, keeping the reaction temperature at 55 ℃ during the reaction, and controlling the reaction time to be 10 hours;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 6, preserving the temperature, and carrying out N methylation reaction at the temperature of 40 ℃ for 25 hours;
s5: after the reaction is finished, adjusting the pH value to 11, standing for layering, taking an organic layer, heating to 45 ℃, slowly dripping water until crystals are separated out, cooling to 35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Example 7
An azithromycin contrast product comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: 70 parts of azithromycin, 12 parts of acetone, 13 parts of acetic acid, 9 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 13 parts of a cosolvent and 22 parts of a stabilizer.
Specifically, the azithromycin in the embodiment adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at 60 ℃ for 24h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in acetone-water system at a mass ratio of acetone to water of 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting at pH of 9.8 and temperature of 5 deg.C for 3.5h, and centrifuging.
It is worth mentioning that the metal ion is specifically Mg2+The catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70g of platinum carbon with platinum content of 5%, adding 650ml of water, stirring uniformly, adding 1g of calcium chloride, pulping for 30min, and filtering to obtain the treated platinum carbon catalyst.
Further, the cosolvent is specifically hydrochloric acid, and the concentration of the hydrochloric acid solution is 3%.
The preparation method of the azithromycin reference substance in the embodiment specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to 25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 4.5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.2MPa, keeping the reaction temperature at 55 ℃ during the reaction, and controlling the reaction time to be 10 hours;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 6, preserving the temperature, and carrying out N methylation reaction at the temperature of 40 ℃ for 25 hours;
s5: after the reaction is finished, adjusting the pH value to 11, standing for layering, taking an organic layer, heating to 45 ℃, slowly dripping water until crystals are separated out, cooling to 35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
Comparative example 1:
the only difference from example 1, provided that the other conditions were not changed, was that the solubilizing acid was replaced with a 70% strength ethanol solution.
After being left for 14 months, the contents of the azithromycin reference substances and azithromycin of the above examples 1 to 7 and comparative example 1 were measured, and the results of the measurements are shown in the following table. (+, -represents increase and decrease)
| Amount of change in azithromycin (%) | Control Change (%) | |
| Example 1 | -0.39 | +0.03 |
| Example 2 | -0.21 | +0.02 |
| Example 3 | -0.29 | +0.03 |
| Example 4 | -1.36 | +0.08 |
| Example 5 | -1.28 | +0.06 |
| Example 6 | -1.39 | +0.06 |
| Example 7 | -1.42 | +0.05 |
| Comparative example 1 | -5.69 | +1.36 |
As can be seen from the above experiments, the content changes of the azithromycin control and the azithromycin after being left for more than one year in the examples 1 to 7, particularly in the examples 1 to 3, are small, and the effect is self-evident as compared with the effect of the comparative example 1.
According to the azithromycin reference substance and the preparation method thereof, the azithromycin and the cosolvent acid form the compound acid salt which is easy to dissolve in water in the aqueous solution, so that the problem of poor water solubility of the azithromycin is solved, the possibility is provided for further preparation of the preparation for injection, the cosolvent ensures that the azithromycin can be dissolved, the quantity is small and is not enough to completely dissolve the azithromycin, and unnecessary impurities are brought in if the quantity is excessive, so that the product quality is influenced; because the activity of the platinum carbon is reduced after the platinum carbon is treated by metal ions, the platinum carbon does not play a role in reducing carbon-nitrogen double bonds, the double bonds are subjected to imine hydrolysis under an acidic condition, and the formed amino groups are two methyl groups under the action of formic acid formaldehyde; the quality of the product can be further improved by the stabilizer, if the product is not added with the stabilizer and is placed at room temperature for half a year, the content of the main azithromycin is reduced by about 5 percent, the content of the azithromycin reference substance is increased from 1 percent to more than 2 percent, and the indexes are basically unchanged when the product is placed under the same condition by adding the stabilizer.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and the preferred embodiments of the present invention are described in the above embodiments and the description, and are not intended to limit the present invention. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. An azithromycin control, characterized in that: the feed comprises the following raw materials in parts by weight: 50-100 parts of azithromycin, 10-15 parts of acetone, 10-15 parts of acetic acid, 8-10 parts of acetaldehyde, 2-5 parts of metal ions, 2-4 parts of a catalyst, 10-15 parts of a cosolvent and 20-25 parts of a stabilizer.
2. The azithromycin control of claim 1, wherein: the feed comprises the following raw materials in parts by weight: 70 parts of azithromycin, 12 parts of acetone, 13 parts of acetic acid, 9 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 13 parts of a cosolvent and 22 parts of a stabilizer.
3. The azithromycin control of claim 1, wherein: the feed comprises the following raw materials in parts by weight: 60 parts of azithromycin, 12 parts of acetone, 11 parts of acetic acid, 8 parts of acetaldehyde, 3 parts of metal ions, 3 parts of a catalyst, 13 parts of a cosolvent and 21 parts of a stabilizer.
4. The azithromycin control of claim 1, wherein: the feed comprises the following raw materials in parts by weight: 100 parts of azithromycin, 15 parts of acetone, 15 parts of acetic acid, 10 parts of acetaldehyde, 5 parts of metal ions, 4 parts of a catalyst, 15 parts of a cosolvent and 25 parts of a stabilizer.
5. The azithromycin control according to any of claims 1-4, wherein: the azithromycin adopts erythromycin 6, 9-imino ether, and the specific synthesis of the erythromycin 6, 9-imino ether comprises the following steps: reacting erythromycin thiocyanate with hydroxylamine at the temperature of 30-60 ℃ for 10-36h, and neutralizing with alkali to obtain erythromycin oxime; dissolving the obtained erythromycin oxime in an acetone-water system, wherein the mass ratio of acetone to water is 1:3, adding methanesulfonyl chloride and sodium hydroxide, reacting for 3-4h at the pH of 9.7-10.5 and the temperature of 3-5 ℃, and centrifuging.
6. The azithromycin control according to any of claims 1-4, wherein: the metal ion is Ca2+、Cu2+、Fe3+Any one of the above.
7. The azithromycin control according to any of claims 1-4, wherein: the catalyst is specifically platinum carbon, and the pretreatment of the platinum carbon comprises the following specific steps: taking 70-80g of platinum carbon with 5 percent of platinum content, adding 600-700ml of water, stirring uniformly, adding 1.0-1.5g of calcium chloride, pulping for 30-40min, and filtering to obtain the treated platinum carbon catalyst.
8. The azithromycin control according to any of claims 1-4, wherein: the cosolvent is hydrochloric acid, lactobionic acid or citric acid, and if the cosolvent is hydrochloric acid, the concentration of the solution is 1-5%, if the cosolvent is lactobionic acid, the concentration is 15-20%, and if the cosolvent is citric acid, the concentration is 20-25%.
9. The azithromycin control according to any of claims 1-4, wherein: the stabilizer is specifically polyethylene glycol 400.
10. A method of making an azithromycin control, comprising an azithromycin control of any of claims 1-9, characterized in that: the method specifically comprises the following steps:
s1: weighing the raw materials in parts by weight;
s2: preparing a cosolvent into an aqueous solution, adding azithromycin into a reaction kettle, controlling the temperature to be 20-25 ℃, adding the cosolvent aqueous solution under the stirring condition, adjusting the ph to 4-5, adding a stabilizer in the dissolving process, and uniformly stirring;
s3: adding a catalyst and metal ions, controlling the pressure in the reaction kettle to be 1.0-1.2MPa, keeping the reaction temperature at 55-60 ℃ during the heat preservation reaction, and controlling the reaction time to be 8-12 h;
s4: filtering the catalyst, recovering the feed liquid, adding acetone, stirring, adding acetic acid and acetaldehyde, controlling the pH to be 5-6, preserving the temperature, and carrying out N methylation reaction at the temperature of 40-50 ℃ for 20-25 h;
s5: after the reaction is finished, adjusting the pH value to 10-11, standing for layering, taking an organic layer, heating to 40-45 ℃, slowly dripping water until crystals are separated out, cooling to 30-35 ℃, continuously dripping water until the crystals are completely separated out, filtering and drying to obtain a crude product;
s6: and purifying the crude product by a silica gel column method to obtain a finished product.
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