CN113912492A - Refining method of flurbiprofen axetil - Google Patents
Refining method of flurbiprofen axetil Download PDFInfo
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Abstract
The invention discloses a refining method of flurbiprofen axetil, which comprises the steps of dispersing a crude flurbiprofen axetil into a non-hydrophilic aprotic organic solvent, adding an alkaline aqueous solution, stirring for a period of time at a certain temperature, then carrying out phase separation, water washing, saturated saline solution washing, drying and concentrating an organic phase, thereby obtaining a refined flurbiprofen axetil. The refining method has the advantages of simple operation, mild conditions and low production cost, and the flurbiprofen axetil refined by the method has high purity and high yield.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a refining method of flurbiprofen axetil.
Background
Flurbiprofen axetil (British name Flurbiprofen axetil), its chemical name is (+/-) 2- (2-fluoro-4-biphenyl) propionic acid-1-acetoxy ethyl ester, molecular formula C19H19FO4Molecular weight 330.36, density 1.169g/cm3。
The structural formula is as follows:
the flurbiprofen axetil is a nonsteroidal anti-inflammatory drug, is a prodrug of flurbiprofen, can be gathered in an operation incision and an inflammation part in a targeted mode after entering a human body, and is hydrolyzed to generate the flurbiprofen. The flurbiprofen axetil has certain targeting property, slow release property and fat solubility, and has lighter gastrointestinal side effects, stronger drug effect and longer drug effect duration than flurbiprofen. The medicament replaces flurbiprofen to be widely applied to clinical treatment of inflammatory pain, cancer pain and postoperative pain.
The flurbiprofen axetil product is oily liquid in shape, is easy to include impurities, causes low purity, and cannot be purified (or purified) by relatively simple operations such as recrystallization in production. Conventional purification methods include a reduced pressure distillation method disclosed in european patent application EP83108796.0, a molecular distillation method disclosed in chinese patent application CN201210574448.5, a silica gel column chromatography method disclosed in chinese patent applications CN201310638812.4, CN201510023365.0 and CN201810609832.1, and a silica gel adsorption method disclosed in chinese patent application CN 201110404346.4.
Reduced pressure distillation is a common method for purifying liquid products, and flurbiprofen axetil is also purified by the method at first, and a 173-175 ℃/0.8mmHg fraction is theoretically collected, and since exposure to high temperature for a long time, the flurbiprofen axetil is easily decomposed, resulting in poor product purity and yield. The reduced pressure distillation method disclosed in European patent application EP83108796.0 was repeated in Chinese patent application CN201210574448.5, and only products with yield of 73% -78% and purity of 96.5% -98.1% were obtained by multiple parallel tests. Unfortunately, vacuum levels of up to 0.8mmHg have been reached in practice, meaning that flurbiprofen axetil may have to be collected at higher temperatures in large scale production and the resulting product is difficult to use directly in pharmaceutical preparations.
In order to improve the purification method of flurbiprofen axetil, chinese patent application CN201210574448.5 discloses a molecular distillation method. Molecular distillation is a method for realizing separation by utilizing the difference of the mean free path between molecules under the condition of high vacuum, the volume and the complexity of equipment of the method are far beyond the conventional distillation equipment, and corresponding supporting equipment is more, so that the method has great difficulty in large-scale production and application, and the method has not been applied to large scale in China in fact. There are also some improvements directly based on reduced pressure distillation, such as a preparation method of flurbiprofen axetil disclosed in chinese patent application No. cn201310079429.x, which is to purify a crude flurbiprofen axetil by reduced pressure distillation, wash and decolor the crude flurbiprofen axetil to obtain a refined flurbiprofen with a purity of more than 99.7%. However, the method has complex operation and poor reproducibility, and the problems of large equipment investment, low product yield, high production cost and the like limit the popularization of the method in industrial production because the method takes reduced pressure distillation as a main purification means.
Of course, there are many documents reporting that silica gel column chromatography or silica gel adsorption can improve the purity of flurbiprofen axetil, but those skilled in the art know that the use of silica gel in the final purification process increases the risk of safety of medication and pollutes the environment due to the waste of silica gel and the recovery of solvent. When the refined product prepared by the method provided by the inventor according to the Chinese patent ZL201110404346.4 is subjected to an accelerated stability test (25 +/-2 ℃ and 60 +/-5%), the content of monoflurbiprofen reaches 1.77% in 2 months, the standard limit is exceeded (less than or equal to 0.5%), and the HPLC result is shown in figure 1; the content of monoflurbiprofen in the product prepared by the method provided by the Chinese patent ZL201310638812.4 is 0.64 percent already at 3 months, the standard limit is exceeded (less than or equal to 0.5 percent), and the HPLC result is shown in figure 2.
Therefore, the existing methods for refining (or purifying and purifying) flurbiprofen axetil have obvious disadvantages, and the methods can be used for laboratory research, but have the problems of poor reproducibility, huge equipment, complex operation, environmental pollution and high cost if being used for industrial mass production. Under the urgent need of environmental protection and the narrowing trend of drug profits, the current flurbiprofen axetil manufacturers need to find a more efficient, more environment-friendly and more economical refining method in order to obtain the pure flurbiprofen axetil with high purity, high yield and low cost.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the present application.
The invention provides a refining method of flurbiprofen axetil, which has the advantages of simple operation, mild conditions and low production cost, and the flurbiprofen axetil refined by the method has high purity and high yield.
The invention provides a refining method of flurbiprofen axetil, which comprises the following steps:
(1) dispersing the crude flurbiprofen axetil in a non-hydrophilic aprotic organic solvent, completely dissolving, adding an alkaline aqueous solution to form a mixed solution, and stirring the mixed solution at a temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent for at least 10 hours;
(2) and (2) standing the mixed solution obtained in the step (1), separating the solution, washing the obtained organic phase with water until the pH value is 6.0-8.5, washing with saturated saline water, drying, filtering and concentrating the obtained organic phase to obtain the refined flurbiprofen axetil.
In the above embodiment of the invention, the ratio of the non-hydrophilic aprotic organic solvent to the crude flurbiprofen axetil in step (1) is 1ml/g to 10ml/g, alternatively 1.5ml/g to 10ml/g, 1.5ml/g to 5ml/g, or 3ml/g to 10 ml/g.
In the above embodiment of the present invention, the volume ratio of the non-hydrophilic aprotic organic solvent to the basic aqueous solution in step (1) is 1 to 8, preferably, 3 to 5.
In the above embodiment of the present invention, the temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent in step (1) is 15 to 49 ℃, preferably 20 to 45 ℃.
In the above embodiment of the present invention, the rotation speed of the stirring in the step (1) is 200rpm to 600rpm, preferably 300rpm to 600 rpm.
In the above embodiment of the present invention, the stirring time in step (1) is 10 hours to 40 hours, preferably 12 hours to 36 hours, more preferably 16 hours to 24 hours.
In the above embodiment of the present invention, the drying time in the step (2) is not less than 1 hour, preferably not less than 3 hours.
In the above embodiment of the present invention, the temperature of the concentration in step (2) is not more than 60 ℃, preferably, not more than 50 ℃.
In the above embodiment of the present invention, the time of the standing in step (2) may be 5 minutes to 60 minutes, alternatively 5 minutes to 40 minutes, 5 minutes to 30 minutes, or 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.
In the above embodiment of the present invention, the alkaline aqueous solution is ammonia water, a sodium hydroxide solution, a sodium carbonate solution, a sodium bicarbonate solution, a sodium phosphate solution, a disodium hydrogen phosphate solution, a sodium sulfite solution, a sodium oxalate solution, a sodium fumarate solution, a sodium citrate solution, a potassium hydroxide solution, a potassium carbonate solution, a potassium hydrogen carbonate solution, a potassium phosphate solution, a dipotassium hydrogen phosphate solution, a potassium sulfite solution, a potassium oxalate solution, a potassium fumarate solution, a potassium citrate solution, a lithium hydroxide solution, or a lithium carbonate solution, or a combination thereof.
In some embodiments, the basic aqueous solution is saturated aqueous ammonia.
In some embodiments, the aqueous alkaline solution is 0.01% to 0.4% by weight sodium hydroxide solution.
In some embodiments, the aqueous alkaline solution is 10% to saturated sodium carbonate solution by mass.
In some embodiments, the basic aqueous solution is a saturated sodium bicarbonate solution.
In some embodiments, the aqueous alkaline solution is 0.01% to 0.4% by weight potassium hydroxide solution.
In some embodiments, the aqueous alkaline solution is 10% to 20% by mass potassium carbonate solution.
In one embodiment, the alkaline aqueous solution is a 10% to 20% by weight potassium bicarbonate solution.
In the above embodiment of the present invention, the non-hydrophilic aprotic organic solvent is one of diethyl ether, isopropyl ether, petroleum ether, n-hexane, cyclohexane, n-heptane, isoheptane, octane, ethyl acetate, ethyl formate, isopropyl acetate, methylethyl ether, methyl t-butyl ether, dichloromethane, dichloroethane, and chloroform, or a mixed solvent of two or more thereof.
In some embodiments, the non-hydrophilic aprotic organic solvent is one of n-heptane, isoheptane, ethyl acetate, methyl ethyl ether, and methyl tert-butyl ether, or a mixed solvent of two or more thereof.
In the above embodiment of the present invention, the purity of the refined flurbiprofen axetil product is not less than 99.9%.
In the above embodiment of the present invention, the yield of the refined flurbiprofen axetil product is not less than 95%.
In the above embodiment of the present invention, the crude flurbiprofen axetil is prepared from flurbiprofen and bromoethyl acetate. The Chinese patent medicine can also refer to Chinese patent ZL201110404346.4, CN201310079429.X, CN201810609832.1 and the like.
The invention has the beneficial effects that:
the refining method of flurbiprofen axetil provided by the invention has simple process and is easy to operate, for example, the finished product can be obtained only by stirring at room temperature, washing and concentrating. The purity of the obtained finished product reaches more than 99.9 percent, the yield reaches more than 95 percent, the quality detection meets the standard through the accelerated 9-month and long-term 2-year examination, the product stability is good, only general reaction equipment is needed in the production process, and the reproducibility is good; compared with a reduced pressure distillation mode, the yield is improved by 10% -25%, a high-temperature reduced pressure distillation mode is avoided, the energy consumption is greatly reduced, the cost is greatly reduced, expensive high-precision high-temperature reduced pressure distillation equipment is avoided being used on the equipment, the method can be widely applied to industrial mass production, the use of silica gel is avoided, the potential safety hazard of medication is reduced, and the problems of poor product stability and long production period are solved.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.
Drawings
The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.
FIG. 1 is an accelerated month 2 HPLC chromatogram of a finished flurbiprofen axetil product obtained by a ZL201110404346.4 method (retention time 8.83min is a flurbiprofen peak, retention time 29.85 min and retention time 31.76min are flurbiprofen axetil peaks, and other peaks are unknown impurity peaks);
FIG. 2 is an accelerated monthly HPLC chromatogram of a finished flurbiprofen axetil product obtained by ZL201310638812.4 method (retention time 8.84min is a flurbiprofen peak, retention time 29.97 min and retention time 31.88min are flurbiprofen axetil peaks, and others are unknown impurity peaks);
FIG. 3 is an HPLC chromatogram of the finished flurbiprofen axetil in example 1 (retention time 8.77min is the flurbiprofen peak, 15.5min is the peak of unknown impurities, 29.63 and 31.49min are the peaks of flurbiprofen axetil);
FIG. 4 is an HPLC chromatogram of the finished flurbiprofen axetil in example 2 (retention times 32.43min and 34.56min are flurbiprofen axetil peaks, others are unknown impurity peaks);
fig. 5 is an HPLC chromatogram of the finished flurbiprofen axetil in example 3 (retention times 34.06min and 36.34min are flurbiprofen axetil peaks, others are unknown impurity peaks);
FIG. 6 is an HPLC chromatogram of the finished flurbiprofen axetil in example 4 (retention times of 34.08min and 36.35min are flurbiprofen axetil peaks, and others are unknown impurity peaks);
FIG. 7 is an HPLC chromatogram of the finished flurbiprofen axetil in example 5 (retention times 29.42min and 31.27min are flurbiprofen axetil peaks).
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In an embodiment of the present invention, the present invention provides a method for refining flurbiprofen axetil, including the following steps:
(1) dispersing the crude flurbiprofen axetil in a non-hydrophilic aprotic organic solvent, completely dissolving, adding an alkaline aqueous solution to form a mixed solution, and stirring the mixed solution at a temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent for at least 10 hours;
(2) standing the mixed solution obtained in the step (1), separating the solution, washing the obtained organic phase with water until the pH value is 6.0-8.5, washing with saturated saline water, drying, filtering and concentrating the obtained organic phase to obtain a refined flurbiprofen axetil product;
optionally, the ratio of the non-hydrophilic aprotic organic solvent to the crude flurbiprofen axetil in step (1) is 1ml/g to 10ml/g, optionally 1.5ml/g to 10ml/g, 1.5ml/g to 5ml/g, or 3ml/g to 10 ml/g; and/or
The volume ratio of the non-hydrophilic aprotic organic solvent to the basic aqueous solution in the step (1) is 1-8, preferably 3-5; and/or
The temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent in the step (1) is 15-49 ℃, preferably 20-45 ℃; and/or
The rotation speed of the stirring in the step (1) is 200rpm-600rpm, preferably 300rpm-600 rpm; and/or
The stirring time in the step (1) is 10 hours to 40 hours, preferably 12 hours to 36 hours, more preferably 16 hours to 24 hours;
the alkaline aqueous solution in the step (1) is saturated ammonia water, a sodium hydroxide solution with the mass percent of 0.01-0.4%, a sodium carbonate solution with the mass percent of 10-saturated, a saturated sodium bicarbonate solution, a potassium carbonate solution with the mass percent of 10-20%, or a potassium bicarbonate solution with the mass percent of 10-20%;
alternatively, the time of said standing in step (2) may be 5 minutes to 60 minutes, alternatively 5 minutes to 40 minutes, 5 minutes to 30 minutes, or 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes;
the drying time in the step (2) is not less than 1 hour, preferably not less than 3 hours; and/or
The temperature of the concentration in step (2) is not more than 60 ℃, preferably, not more than 50 ℃.
In the present invention, the conditions for purity detection by HPLC are as follows:
a chromatographic column: octadecylsilane chemically bonded silica (column model: XBridge @ C184.6X 250mm5um)
Column temperature: 35 deg.C
Wavelength: 254nm
Flow rate: 1mL/min
Mobile phase: acetonitrile and water 500:500
Sampling quantity: 20 μ L
The detection method comprises the following steps: precisely measuring an appropriate amount of the product, dissolving with mobile phase, and diluting to obtain a solution containing 0.5mg per mL as a test solution; 1mL was measured precisely, placed in a 100mL measuring flask, diluted to the scale with the mobile phase, and shaken up to serve as a control solution. Separately, flurbiprofen axetil was dissolved in a mobile phase to prepare a solution containing 0.5mg of flurbiprofen axetil and 5. mu.g of each impurity per mL, and the solution was used as a system suitability test solution. According to the chromatographic conditions under the content determination item, 20 mu L of the system adaptive solution is taken and injected into the liquid chromatograph, and 20 mu L of the control solution is taken and injected into the liquid chromatograph, and the detection sensitivity is adjusted to ensure that the peak height of the main component chromatographic peak is about 20 percent of the full scale. Precisely measuring 20 μ L of each of the sample solution and the control solution, and injecting into a liquid chromatograph.
The crude flurbiprofen axetil is prepared from flurbiprofen and bromoethyl acetate, and can also be prepared by methods such as ZL201110404346.4, CN201310079429.X, CN201810609832.1 and the like.
TABLE I accelerated stability test of patent samples (ZL201310638812.4) (25 ℃ C. + -. 2 ℃ C., 60%. + -. 5%)
TABLE II accelerated stability test of patent samples (ZL201110404346.4) (25 ℃ C. + -. 2 ℃ C., 60%. + -. 5%)
The table is prepared according to patent ZL201310638812.4 example 1; table two was prepared according to example 4 of patent ZL 201110404346.4. Preparation of a crude flurbiprofen axetil: referring to ZL201110404346.4, the preparation process of example 4 is as follows, weighing 600g of flurbiprofen, adding into a reaction kettle, adding 6L of acetone, stirring for dissolving, weighing 350g of anhydrous potassium carbonate and 550g of 1-bromoethyl acetate, refluxing for 2 hours at 50-60 ℃, filtering, washing with 1L of acetone, and concentrating to dryness to obtain a crude product.
Example 1
200g of crude flurbiprofen axetil is taken and dissolved in 600mL of ethyl acetate, 1200mL of saturated sodium carbonate solution is added, the temperature is raised to 35 ℃, and the mixture is stirred for 28 hours at 400 rpm.
Standing for 5 minutes for liquid separation, washing an organic phase with water until the pH of the water phase is 7.1, washing with saturated saline water, collecting the organic phase, adding anhydrous sodium sulfate, drying for 3 hours, filtering, and concentrating under reduced pressure at 50 ℃ until the solvent residue is qualified (ethyl acetate is less than or equal to 0.5 percent), thus obtaining the finished product. The yield of the final product was 193g, 96.5% and 99.99% purity by HPLC, as shown in FIG. 3.
After the obtained flurbiprofen axetil is detected to be qualified, placing the flurbiprofen axetil for 3 months, 6 months and 9 months under the acceleration condition (25 ℃ plus or minus 2 ℃, 60 percent plus or minus 5 percent); long term stability studies were conducted at (6 ℃. + -. 2 ℃) for samples taken at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. The properties, correlations, contents and colors were examined.
The results of the measurements are shown in tables 1 and 2:
TABLE 1 sample (25 ℃ C. + -. 2 ℃, 60%. + -. 5%) of example 1 accelerated stability testing
TABLE 2 example 1 Long term stability test of samples (6 ℃. + -. 2 ℃)
As can be seen from tables 1 and 2, the product quality of the finished product synthesized by the invention hardly changes after being accelerated for 9 months (25 ℃ +/-2 ℃ and 60% +/-5%) and being accelerated for 24 months (6 ℃ +/-2 ℃), which indicates that the product stability is good.
Example 2
200g of crude flurbiprofen axetil is dissolved in 600mL of n-heptane, 1200mL of 20% potassium carbonate solution is added, the temperature is raised to 30 ℃, and the mixture is stirred for 24 hours at 400 r.
Standing for 10 minutes for liquid separation, washing an organic phase with water until the pH of the aqueous phase is 7.3, washing with saturated saline solution, collecting the organic phase, adding anhydrous magnesium sulfate, drying for 4 hours, filtering, and concentrating under reduced pressure at 45 ℃ until the solvent residue is qualified (n-heptane is less than or equal to 0.5 percent), thus obtaining the finished product. 192g of finished product are obtained, the yield is 96 percent, and the HPLC purity is 99.95 percent.
After the obtained flurbiprofen axetil is detected to be qualified, placing the flurbiprofen axetil for 3 months, 6 months and 9 months under the acceleration condition (25 ℃ plus or minus 2 ℃, 60 percent plus or minus 5 percent); long term stability studies were conducted at (6 ℃. + -. 2 ℃) for samples taken at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. The properties, correlations, contents and colors were examined.
The results of the measurements are shown in tables 3 and 4:
TABLE 3 sample of example 2 (25 ℃ C. + -. 2 ℃, 60%. + -. 5%) accelerated stability test
TABLE 4 example 2 Long-term stability test of samples (6 ℃. + -. 2 ℃)
As can be seen from tables 3 and 4, the product quality of the finished product synthesized by the invention hardly changes after being accelerated for 9 months (25 ℃ +/-2 ℃ and 60% +/-5%) and being accelerated for 24 months (6 ℃ +/-2 ℃), which indicates that the product stability is good.
Example 3
200g of crude flurbiprofen axetil is dissolved in 600mL of n-heptane, 1200mL of saturated aqueous ammonia is added, the temperature is raised to 30 ℃, and the mixture is stirred at 600rpm for 24 hours.
Standing for 15 minutes for liquid separation, washing an organic phase with water until the pH of the aqueous phase is 7.5, washing with saturated saline, collecting the organic phase, adding anhydrous magnesium sulfate, drying for 4 hours, filtering, and concentrating under reduced pressure at 45 ℃ until the solvent residue is qualified (n-heptane is less than or equal to 0.5%) to obtain the finished product. 195g of finished product was obtained in 97.5% yield with an HPLC purity of 99.97%.
After the obtained flurbiprofen axetil is detected to be qualified, placing the flurbiprofen axetil for 3 months, 6 months and 9 months under the acceleration condition (25 ℃ plus or minus 2 ℃, 60 percent plus or minus 5 percent); long term stability studies were conducted at (6 ℃. + -. 2 ℃) for samples taken at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. The properties, correlations, contents and colors were examined.
The results of the measurements are shown in tables 5 and 6:
TABLE 5 sample of example 3 (25 ℃. + -. 2 ℃, 60%. + -. 5%) accelerated stability test
TABLE 6 example 3 Long term stability test of samples (6 ℃. + -. 2 ℃)
As can be seen from tables 5 and 6, the product quality of the finished product synthesized by the invention hardly changes after being accelerated for 9 months (25 ℃ +/-2 ℃ and 60% +/-5%) and being accelerated for 24 months (6 ℃ +/-2 ℃), which indicates that the product stability is good.
Example 4
200g of crude flurbiprofen axetil is dissolved in 600mL of methyl tert-butyl ether, 1200mL of saturated sodium bicarbonate solution is added, the temperature is raised to 45 ℃, and the mixture is stirred at 600rpm for 36 hours.
Standing for 20 minutes for liquid separation, washing an organic phase with water until the pH of the aqueous phase is 7.0, washing with saturated saline solution, collecting the organic phase, adding anhydrous magnesium sulfate, drying for 4 hours, filtering, and concentrating under reduced pressure at 45 ℃ until the solvent residue is qualified (the methyl tert-butyl ether is less than or equal to 0.5 percent), thus obtaining the finished product. 196g of finished product is obtained, the yield is 98%, and the HPLC purity is 99.95%.
After the obtained flurbiprofen axetil is detected to be qualified, placing the flurbiprofen axetil for 3 months, 6 months and 9 months under the acceleration condition (25 ℃ plus or minus 2 ℃, 60 percent plus or minus 5 percent); long term stability studies were conducted at (6 ℃. + -. 2 ℃) for samples taken at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. The properties, correlations, contents and colors were examined.
The results of the measurements are shown in tables 7 and 8:
TABLE 7 sample of example 4 (25 ℃ C. + -. 2 ℃, 60%. + -. 5%) accelerated stability test
TABLE 8 example 4 Long term stability test of samples (6 ℃. + -. 2 ℃)
As can be seen from tables 7 and 8, the product quality of the finished product synthesized by the invention hardly changes after being accelerated for 9 months (25 ℃ +/-2 ℃ and 60% +/-5%) and being accelerated for 24 months (6 ℃ +/-2 ℃), which indicates that the product stability is good.
Example 5
200g of crude flurbiprofen axetil is dissolved in 600mL of methyl tert-butyl ether, 900mL of 10% sodium carbonate solution is added, the temperature is raised to 40 ℃, and the mixture is stirred at 600rpm for 28 hours.
Standing for 25 minutes for liquid separation, washing an organic phase with water until the pH of the aqueous phase is 7.2, washing with saturated saline solution, collecting the organic phase, adding anhydrous magnesium sulfate, drying for 3 hours, filtering, and concentrating under reduced pressure at 45 ℃ until the solvent residue is qualified (the methyl tert-butyl ether is less than or equal to 0.5 percent), thus obtaining the finished product. 192g of finished product are obtained, the yield is 96 percent, and the HPLC purity is 99.97 percent.
After the obtained flurbiprofen axetil is detected to be qualified, placing the flurbiprofen axetil for 3 months, 6 months and 9 months under the acceleration condition (25 ℃ plus or minus 2 ℃, 60 percent plus or minus 5 percent); long term stability studies were conducted at (6 ℃. + -. 2 ℃) for samples taken at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. The properties, correlations, contents and colors were examined.
The results of the measurements are shown in tables 9 and 10:
TABLE 9 sample of example 5 (25 ℃ C. + -. 2 ℃, 60%. + -. 5%) accelerated stability testing
TABLE 10 Long term stability test of samples (6 ℃. + -. 2 ℃) of example 5
As can be seen from tables 9 and 19, the final product synthesized by the present invention has almost no significant change in product quality after accelerated at 25 ℃. + -. 2 ℃ and 60%. + -. 5% for 9 months and after accelerated at 6 ℃. + -. 2 ℃ for 24 months, indicating that the product stability is very good.
The present application describes embodiments, but the description is illustrative rather than limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein.
Claims (10)
1. A refining method of flurbiprofen axetil, which comprises the following steps:
(1) dispersing the crude flurbiprofen axetil in a non-hydrophilic aprotic organic solvent, completely dissolving, adding an alkaline aqueous solution to form a mixed solution, and stirring the mixed solution at a temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent for at least 10 hours;
(2) and (2) standing the mixed solution obtained in the step (1), separating the solution, washing the obtained organic phase with water until the pH value is 6.0-8.5, washing with saturated saline water, drying, filtering and concentrating the obtained organic phase to obtain the refined flurbiprofen axetil.
2. The purification process as claimed in claim 1, wherein the ratio of the non-hydrophilic aprotic organic solvent to the crude flurbiprofen axetil in step (1) is 1ml/g to 10ml/g, optionally 1.5ml/g to 10ml/g, 1.5ml/g to 5ml/g, or 3ml/g to 10 ml/g.
3. The purification process according to claim 1, wherein the volume ratio of the non-hydrophilic aprotic organic solvent to the basic aqueous solution in step (1) is (1-8):1, preferably (3-5): 1.
4. The refining process according to claim 1, wherein the temperature lower than the boiling point of the non-hydrophilic aprotic organic solvent in step (1) is 15 to 49 ℃, preferably 20 to 45 ℃.
5. Refining process according to claim 1, wherein the rotation speed of the stirring in step (1) is between 200rpm and 600rpm, preferably between 300rpm and 600 rpm.
6. The refining process of claim 1, wherein the stirring time in step (1) is 10 hours to 40 hours, preferably 12 hours to 36 hours, more preferably 16 hours to 24 hours.
7. The purification process according to claim 1, wherein the non-hydrophilic aprotic organic solvent is one of diethyl ether, isopropyl ether, petroleum ether, n-hexane, cyclohexane, n-heptane, isoheptane, octane, ethyl acetate, ethyl formate, isopropyl acetate, methyl ethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, and chloroform, or a mixed solvent of two or more thereof;
optionally, the non-hydrophilic aprotic organic solvent is one of n-heptane, iso-heptane, ethyl acetate, methyl ethyl ether, and methyl tert-butyl ether, or a mixed solvent of two or more thereof.
8. The refining method of any one of claims 1 to 7, wherein the drying time in step (2) is not less than 1 hour, preferably not less than 3 hours.
9. Refining process according to any one of claims 1 to 7, wherein the temperature of the concentration in step (2) does not exceed 60 ℃, preferably does not exceed 50 ℃.
10. The purification method according to any one of claims 1 to 7, wherein the purity of the refined flurbiprofen axetil product is not less than 99.9%.
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| CN102381970A (en) * | 2011-12-08 | 2012-03-21 | 南京优科生物医药有限公司 | Method for preparing flurbiprofen axetil compound |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
| CN103254075A (en) * | 2013-03-13 | 2013-08-21 | 武汉大安制药有限公司 | Preparation method of flurbiprofen axetil |
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| CN102381970A (en) * | 2011-12-08 | 2012-03-21 | 南京优科生物医药有限公司 | Method for preparing flurbiprofen axetil compound |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
| CN103254075A (en) * | 2013-03-13 | 2013-08-21 | 武汉大安制药有限公司 | Preparation method of flurbiprofen axetil |
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| CN115932135A (en) * | 2022-01-22 | 2023-04-07 | 湖南九典制药股份有限公司 | Method for analyzing related substances in flurbiprofen sodium gel |
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