CN111269120A - Environment-friendly preparation method of ozagrel impurity II - Google Patents
Environment-friendly preparation method of ozagrel impurity II Download PDFInfo
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Abstract
The invention provides ozagrel hybridsAn environment-friendly preparation method of a plasmid II belongs to the technical field of preparation of pharmaceutical impurity standards, and comprises the following preparation steps: 4-iodotoluene and ethyl propiolate in Cu2And reacting under the catalytic action of O to obtain ozagrel impurity II. The preparation method provided by the invention has the advantages of simple steps, cheap and easily-obtained raw materials, mild reaction conditions, stable process, good reproducibility, emission reduction, environmental protection and high product yield; the prepared ozagrel impurity II has high purity and good stability performance, can be used as a standard substance for identifying the impurity II generated in the synthesis of ozagrel bulk drugs, effectively detects the residual amount of the ozagrel impurity II in the ozagrel bulk drugs, is a necessary product for quality control of ozagrel, and carries out qualitative and quantitative detection and control on related substances; when the kit is used for detecting the ozagrel impurity II, the accuracy and the sensitivity of a detection result can be effectively improved, a wide linear range is shown, and the improvement of the medicine purity of the ozagrel is facilitated.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical impurity standards, and particularly relates to an environment-friendly preparation method of ozagrel impurity II.
Background
Ozagrel, named as trans-3- [4- (1H-imidazole-1-methyl) phenyl ] -2-acrylic acid in chemical formula, is a selective inhibitor of Thromboxane (TX) synthetase, can inhibit the generation of TXA2, and is mainly used for treating various acute thrombotic cerebral infarctions. Ozagrel improves the abnormal balance of TXA2 and prostaglandin PGI2 by blocking prostaglandin H2(PGH2) from generating thromboxane a2(TXA2), and by diverting platelet-derived PGH2 to endothelial cells, which synthesize PGI 2. Ozagrel has the functions of inhibiting platelet aggregation and expanding blood vessels. The ozagrel sodium for injection and the ozagrel sodium injection are preparations thereof, are mainly clinically suitable for acute thrombotic cerebral infarction and dyskinesia associated with cerebral infarction, and improve cerebral vasospasm contraction and complication cerebral ischemia symptoms after subarachnoid hemorrhage operation.
There are many kinds of synthetic processes of ozagrel, and impurities are generated in the process of synthesizing ozagrel. 12 kinds of impurities are reported in the ozagrel bulk drug. The quality of the medicine is directly related to the health and life safety of patients, is concerned with the social medical safety problem, and is the precondition guarantee of the safety, effectiveness and stability of the medicine. Impurity research is an important content of medicine quality research; the research and control of impurities are one of the key factors for ensuring the quality of medicines. In the medicine quality research guidance, many countries put forward definite technical requirements on medicine impurity research, and impurity standards are obtained during the quality research.
Therefore, the preparation and research of the impurities have important significance for the research of the ozagrel process and the quality control. At present, no relevant literature reports about a preparation method of the ozagrel impurity II, in particular to an environment-friendly preparation method of the high-purity ozagrel impurity II.
Disclosure of Invention
One of the purposes of the invention is to provide an environment-friendly preparation method of ozagrel impurity II, which has the advantages of simple steps, cheap and easily-obtained raw materials, mild reaction conditions, stable process, good reproducibility, emission reduction, environmental protection and high product yield.
The technical scheme adopted by the invention for realizing the purpose is as follows:
an environment-friendly preparation method of ozagrel impurity II comprises the following synthetic route:
the method comprises the following steps:
4-iodotoluene and ethyl propiolate in Cu2And reacting under the catalytic action of O to obtain ozagrel impurity II.
The preparation method disclosed by the invention is simple in steps, cheap and easily available in raw materials, mild in reaction conditions, stable in process, good in reproducibility, emission reduction, environment-friendly, high in product yield, high in purity of the obtained ozagrel impurity II and good in stability performance, can be used as a standard substance for identifying the impurity II generated in the synthesis of ozagrel bulk drugs, effectively detects the residual amount of the ozagrel impurity II in the ozagrel bulk drugs, is a necessary product for quality control of ozagrel, and qualitatively and quantitatively detects and controls related substances.
For the present invention, the catalytic reaction is carried out under the protection of nitrogen; the reaction temperature is 100-110 ℃, and the reaction time is 12-18 h.
For the purposes of the present invention, 4-iodotoluene, ethyl propiolate and Cu2The molar ratio of O is 1:2: 1.8-2.5.
For the purposes of the present invention, the catalytic reaction is carried out in the presence of an organic solvent, which comprises one of tetrahydrofuran, dimethylformamide, dimethylacetamide and dimethylsulfoxide. Preferably, the organic solvent is dimethylformamide.
For the present invention, 2-3 vacuum/nitrogen cycles of degassing are carried out prior to the catalytic reaction.
For the invention, the method also comprises a separation and purification step after the catalytic reaction is finished, and the separation and purification step adopts thin layer chromatography.
Preferably, the developing solvent for chromatography is petroleum ether-ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 10-15: 1.
For the present invention, the yield of ozagrel impurity II is not less than 40.0%. The preparation method has the advantages of obtaining the product with high purity and high yield, simplifying the process steps, easily recovering the reagent, mild reaction conditions, low system energy consumption and achieving the purposes of emission reduction and energy conservation.
The invention also aims to provide ozagrel impurity II prepared by the environment-friendly preparation method.
For the invention, the purity of the ozagrel impurity II is not less than 99.90 percent.
The invention also aims to provide a method for detecting the impurity II in the ozagrel bulk drug, wherein the standard substance used in the method is the ozagrel impurity II. The ozagrel impurity II prepared by the method has high purity and good stability, can effectively improve the accuracy and sensitivity of a detection result when being used for detecting the ozagrel impurity II, shows a wide linear range, and is beneficial to improving the medicine purity of the ozagrel.
For the invention, the average recovery rate of the ozagrel impurity II is not less than 99.60 percent, and the RSD percent is less than or equal to 2.0 percent.
Compared with the prior art, the invention has the beneficial effects that:
1) the preparation method has the advantages of simple steps, cheap and easily-obtained raw materials, mild reaction conditions, stable process, good reproducibility, emission reduction, environmental protection and high product yield, and the obtained ozagrel impurity II can be used as a standard substance for effectively identifying the impurity II generated in the synthesis of ozagrel and qualitatively and quantitatively detecting and controlling related substances; 2) the prepared ozagrel impurity II has good stability performance and high purity, can effectively improve the accuracy and sensitivity of a detection result when used for detecting the ozagrel impurity II, shows a wide linear range, is beneficial to improving the medicine purity of ozagrel bulk drugs, and is a necessary product for quality control of ozagrel.
The invention adopts the technical scheme to provide the environment-friendly preparation method of the ozagrel impurity II, overcomes the defects of the prior art, and has reasonable design and convenient operation.
Drawings
FIG. 1 is an MS spectrum of ozagrel impurity II prepared in example 1;
FIG. 2 shows the ozagrel impurity II prepared in example 11HNMR spectrogram;
FIG. 3 is an HPLC chromatogram of ozagrel impurity II prepared in example 1.
Detailed Description
The technical solution of the present invention is further described in detail below with reference to the following detailed description and the accompanying drawings:
an environment-friendly preparation method of ozagrel impurity II comprises the following synthetic route:
the method comprises the following steps:
4-iodotoluene and ethyl propiolate in Cu2And reacting under the catalytic action of O to obtain ozagrel impurity II.
The preparation method disclosed by the invention is simple in steps, cheap and easily available in raw materials, mild in reaction conditions, stable in process, good in reproducibility, emission reduction, environment-friendly, high in product yield, high in purity of the obtained ozagrel impurity II and good in stability performance, can be used as a standard substance for identifying the impurity II generated in ozagrel synthesis, effectively detects the residual amount of the ozagrel impurity II in an ozagrel synthesis product, is a necessary product for quality control of ozagrel, and qualitatively and quantitatively detects and controls related substances.
In some embodiments of the invention, the catalytic reaction is carried out under nitrogen protection; the reaction temperature is 100-110 ℃, and the reaction time is 12-18 h.
In some embodiments of the invention, 4-iodotoluene, ethyl propiolate and Cu2The molar ratio of O is 1:2: 1.8-2.5.
In some embodiments of the invention, the catalytic reaction is carried out in the presence of an organic solvent comprising one of tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. Preferably, the organic solvent is dimethylformamide.
In some embodiments of the invention, the steps of the catalytic reaction are as follows: adding 10-13 times of dry dimethylformamide into ethyl propiolate, adding 4-iodotoluene, mixing, and adding Cu2And O, performing vacuum/nitrogen circulation degassing operation on the system for 2-3 times, and then stirring the system to react for 12-18h at the temperature of 100-110 ℃ in the nitrogen protection environment.
In some embodiments of the present invention, the method further comprises a separation and purification step after the catalytic reaction is finished, wherein the separation and purification step adopts thin layer chromatography.
In some preferred embodiments of the invention, the chromatographic developing solvent is petroleum ether-ethyl acetate in a ratio of 10-15:1 petroleum ether to ethyl acetate.
In some specific embodiments of the present invention, the separation and purification steps are as follows: cooling the mixture system after the reaction to room temperature, then vacuumizing to remove the solvent, then adding saturated NaCl solution for washing, extracting by adopting dichloromethane, and carrying out Na-treatment on the obtained organic matter2SO4Drying, filtering and vacuum concentrating to obtain a crude product, and purifying the crude product by thin-layer chromatography to obtain a yellow liquid product, namely ozagrel impurity II.
In some embodiments of the invention, the yield of ozagrel impurity ii is not less than 40.0%. The preparation method has the advantages of obtaining the product with high purity and high yield, simplifying the process steps, easily recovering the reagent, mild reaction conditions, low system energy consumption and achieving the purposes of emission reduction and energy conservation.
In some embodiments of the present invention, there is also provided ozagrel impurity II prepared by the above-described environment-friendly preparation method. Specifically, the purity of the ozagrel impurity II is not lower than 99.90%.
In some embodiments of the present invention, a method for detecting an impurity ii in an ozagrel bulk drug is also provided, and the standard substance used in the method is the ozagrel impurity ii. The ozagrel impurity II prepared by the method has high purity and good stability, can effectively improve the accuracy and sensitivity of a detection result when being used for detecting the ozagrel impurity II, shows a wide linear range, and is beneficial to improving the medicine purity of the ozagrel.
In some embodiments of the invention, the average recovery rate of the ozagrel impurity II is not less than 99.60 percent, and the RSD percent is less than or equal to 2.0 percent.
In some specific embodiments of the present invention, the method for detecting impurity ii in ozagrel bulk drug adopts an HPLC method, and specifically comprises the following steps:
(1) preparing a test solution: precisely weighing a proper amount of synthetic products of ozagrel, adding a 50% acetonitrile solution, shaking uniformly, and quantitatively diluting to prepare a solution containing 1mg of ozagrel per 1mL as a test solution;
(2) preparation of a reference solution: precisely weighing a proper amount of the ozagrel impurity II prepared by the invention, adding a 50% acetonitrile solution, shaking uniformly, and quantitatively diluting to prepare a solution containing 1 mu g of the ozagrel impurity II per 1mL as a reference solution;
(3) impurity detection: precisely measuring 20 μ l of each of the test solution and the reference solution, and respectively injecting into a liquid chromatograph under the following chromatographic conditions: a chromatographic column: inert sustatin C184.6X 250mm, 5 μm; column temperature: 35 ℃; mobile phase: a: 95% acetonitrile, B: water, and a: B ═ 80: 20; feeding amount: 0.3 mu L; flow rate: 1.2 mL/min; time: 18 min; detection wavelength: 254 nm; and recording the chromatogram.
The present invention and the conventional techniques in the embodiments are known to those skilled in the art and will not be described in detail herein.
It is to be understood that the foregoing description is to be considered illustrative or exemplary and not restrictive, and that changes and modifications may be made by those skilled in the art within the scope and spirit of the appended claims. In particular, the present invention covers other embodiments having any combination of features from the different embodiments described above and below, without the scope of the invention being limited to the specific examples below.
Example 1:
an environment-friendly preparation method of ozagrel impurity II comprises the following steps:
(1) 2.00mL of ethyl propiolate was added to 25mL of dry dimethylformamide, 2.18g of 4-iodotoluene was further added thereto and mixed well, and Cu was then added2O2.86 g, carrying out vacuum/nitrogen circulating degassing operation on the system for 3 times, and then stirring the system to react for 16 hours at the temperature of 100 ℃ in a nitrogen protection environment;
(2) cooling the reacted mixture system to room temperature, then removing the solvent by vacuum pumping, then adding 30ml of saturated NaCl solution for washing, extracting by adopting 50ml of dichloromethane, and carrying out Na-treatment on the obtained organic matter2SO4Drying, filtering and vacuum concentrating to obtain a crude product, and purifying the crude product by thin-layer chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1 to obtain 760.00mg of a yellow liquid product, namely ozagrel impurity II, wherein the yield of the product is 40.4%.
Example 2:
an environment-friendly preparation method of ozagrel impurity II, which is different from the embodiment 1 only in that:
in the step (1): cu2Adding 3.00g of O, performing vacuum/nitrogen circulating degassing operation on the system for 2 times, and then stirring the system to react for 15 hours at the temperature of 105 ℃ in a nitrogen protection environment;
in the step (2): the crude product was purified by thin layer chromatography using a developing solvent of petroleum ether and ethyl acetate at a ratio of 12:1 to give 769.41mg of a yellow liquid product, ozagrel impurity ii, in a yield of 40.9%.
Example 3:
an environment-friendly preparation method of ozagrel impurity II, which is different from the embodiment 1 only in that:
in the step (1): 2.00mL of ethyl propiolate was added to 25mL of dry dimethylformamide, 2.18g of 4-iodotoluene was further added thereto and mixed well, and Cu was then added2O2.86 g, and performing vacuum/nitrogen cyclic degassing operation on the system for 3 times, and then stirring the system in a nitrogen protective environment and reacting for 16 hours at the temperature of 100 ℃, wherein the dimethyl formamide contains 0.225mM of monoisopinocampheylborane and 0.445mM of diisopinocampheylborane; finally, 878.51mg of the product ozagrel impurity II is obtained after purification, and the yield of the product is 46.7%.
The yield of the target product ozagrel impurity II obtained in the embodiment is obviously improved compared with that of the embodiments 1 and 2, probably because the introduction of borane enhances the activity of an electron group of propiolic acid ester, inhibits the self-oxidative coupling reaction of the propiolic acid ester, effectively improves the selectivity of the reaction, and reduces the generation of side reactions and the yield of byproducts, thereby improving the yield of the target product, being beneficial to reducing the difficulty of purifying and refining the product, being beneficial to reducing the energy consumption of separation and purification, and having the effects of energy conservation and emission reduction.
Example 4:
a method for detecting an impurity II in an ozagrel bulk drug specifically comprises the following steps:
(1) preparing a test solution: precisely weighing a proper amount of the ozagrel bulk drug, adding a 50% acetonitrile solution, shaking uniformly, and quantitatively diluting to prepare a solution containing 1mg of ozagrel per 1mL as a test solution;
(2) preparation of a reference solution: precisely weighing a proper amount of the ozagrel impurity II prepared in the example 1, adding a 50% acetonitrile solution, shaking uniformly, and quantitatively diluting to prepare a solution containing 1 mu g of the ozagrel impurity II in 1mL, wherein the solution is used as a reference solution;
(3) impurity detection: precisely measuring 20 μ l of each of the test solution and the reference solution, and respectively injecting into a liquid chromatograph under the following chromatographic conditions: a chromatographic column: inert sustatin C184.6X 250mm, 5 μm; column temperature: 35 ℃; mobile phase: a: 95% acetonitrile, B: water, and a: B ═ 80: 20; feeding amount: 0.3 mu L; flow rate: 1.2 mL/min; time: 18 min; detection wavelength: 254 nm; and recording the chromatogram.
Example 5:
the method for detecting the impurity II in the ozagrel bulk drug is different from the method in the embodiment 4 only in that:
preparing a reference substance solution in the step (2): ozagrel impurity II from example 2 was used.
Example 6:
the method for detecting the impurity II in the ozagrel bulk drug is different from the method in the embodiment 4 only in that:
preparing a reference substance solution in the step (2): ozagrel impurity II from example 3 was used.
Test example 1:
determination of ozagrel impurity II
The molecular structural formula of the ozagrel impurity II prepared in the invention is as follows:
1) Mass spectrometry analysis: the ozagrel impurity II prepared in example 1 was analyzed by a mass spectrometer, and the MS spectrum thereof is shown in FIG. 1.
FIG. 1 is an MS spectrum of ozagrel impurity II prepared in example 1. As can be seen from the figure, the peak with m/z of 189.2 is an ion peak of the ozagrel impurity ii, and is almost consistent with the molecular weight of the ozagrel impurity ii, and the main component peak and the related substances can be completely separated.
2) Hydrogen spectrum analysis: after taking ozagrel impurity II prepared in example 1 and analyzing the hydrogen spectrum by using nuclear magnetic resonance apparatus, the ozagrel impurity II was obtained1The HNMR spectrum is shown in FIG. 2.
FIG. 2 shows the ozagrel impurity II prepared in example 11HNMR spectrogram. As can be seen from the figures, the,1HNMR(400MHz,CDCl3):δ7.47-7.49(q,2H,Ar-H),7.16-7.26(m,2H,Ar-H),4.27-4.32(m,2H,CH2),2.38(s,3H,CH3),1.34-1.37(t,3H,CH3)。
3) purity analysis: the ozagrel impurity II prepared in example 1 is taken and detected by an HPLC method, and the chromatographic conditions are as follows: a chromatographic column: inert sustatin C184.6X 250mm, 5 μm; column temperature: 35 ℃; mobile phase: a: 95% acetonitrile, B: water, and a: B ═ 80: 20; feeding amount: 0.3 mu L; flow rate: 1.2 mL/min; gradient elution procedure was performed as in table 1, time: 18 min; detection wavelength: 254 nm; and recording the chromatogram. The HPLC spectrum obtained is shown in FIG. 3.
Table 1 mobile phase gradient elution procedure
| Time (Min) | A(％) | B(％) |
| 0.00 | 80 | 20 |
| 18.00 | 80 | 20 |
FIG. 3 is an HPLC chromatogram of ozagrel impurity II prepared in example 1. The peak values obtained by analyzing the peaks from the graphs are shown in Table 2.
TABLE 2 Peak Table of HPLC spectrogram
| Peak# | Ret.Time | Area | Height | Area，％ |
| 1 | 3.359 | 4001 | 681 | 0.039 |
| 2 | 3.965 | 2911 | 500 | 0.028 |
| 3 | 4.141 | 1948 | 340 | 0.019 |
| 4 | 4.728 | 10247036 | 1616460 | 99.914 |
| Total | 10255897 | 1617981 | 100.000 |
From the above figure, it can be seen that the purity of ozagrel impurity ii prepared in example 1 was 99.91%. The purity of ozagrel impurity ii prepared in examples 2 and 3 was also analyzed to obtain a product purity of 99.92% for example 2 and 99.91% for example 3. The purity of the obtained product is higher than that in the prior art, the product can be used as a standard substance to effectively improve the accuracy of identification and detection results, and the product has beneficial effects on quality detection and control of ozagrel.
Test example 2:
systematic applicability investigation of ozagrel impurity II
1) Quantitative limit, lowest detection limit and linear relation test: the test solution and the control solution prepared in examples 4, 5 and 6 were precisely measured and diluted with mobile phase to linear solutions of different concentrations. Then, the measurement was carried out in the same manner as in the step (3) in example 4, and a curve was drawn with the peak response as the y value and the solution concentration as the x value. The same test conditions were carried out using a commercially available ozagrel impurity II standard as a control group. The statistics of the linear equation, correlation coefficient, detection limit (S/N ═ 3) and quantitation limit (S/N ═ 10) are shown in table 3.
TABLE 3 Linear Range, regression equation, correlation coefficient, detection Limit and quantitation Limit measurements
As can be seen from the above table, the ozagrel impurity ii prepared in the embodiment of the present invention has superior performance compared with the control group, can be used as a standard substance to perform effective quantitative and qualitative detection on the ozagrel impurity ii in an ozagrel bulk drug, and has high sensitivity, and the ozagrel impurity ii exhibits a good linear relationship with a peak area within a concentration range of 5.00-150.00 ng/mL.
2) And (3) precision test: 20 μ L of the reference solutions prepared in examples 4, 5 and 6 were each precisely measured, injected into a liquid chromatograph, detected according to the method of step (3) in example 4, and each sample was injected in parallel 6 times to calculate the RSD value. The same test conditions were carried out using a commercially available ozagrel impurity II standard as a control group. The results obtained are shown in Table 4.
TABLE 4 results of precision test
| Example 4 | Example 5 | Example 6 | Control group | |
| Average indicated amount% | 99.63 | 99.64 | 99.71 | 99.05 |
| RSD％ | 0.23 | 0.32 | 0.26 | 1.03 |
As is clear from the above table, the detection methods in examples 4 to 6 are excellent in precision, and have RSD% of 2.0% or less, which is superior to the control group.
3) Destructive testing: precisely measuring ozagrel impurity II prepared in examples 1, 2 and 3 respectively, placing the ozagrel impurity II into a 10mL volumetric flask, adding a mobile phase to dilute the ozagrel impurity II to a scale, accurately measuring 5mL of the ozagrel impurity II, placing the ozagrel impurity II into a 200mL volumetric flask, and adding the mobile phase to dilute the ozagrel impurity II to obtain a solution containing 0.05mg of ozagrel impurity II in each 1mL of the solution. The solution is respectively taken to carry out a high-temperature destruction test, a high-humidity destruction test and a strong light destruction test, and the experimental conditions are as follows: high-temperature test: exposing the sample in a thermostat at the temperature of 60 ℃, placing the sample in the thermostat for 10 days, sampling and detecting; high humidity test: exposing the sample in an environment with the temperature of 25 ℃ and the relative humidity of 92.5%, placing for 10 days, sampling and detecting; strong light test: and (3) exposing the sample in an illumination box with illumination intensity of 4500Lx for 10d, sampling and detecting. The same test conditions were carried out using a commercially available ozagrel impurity II standard as a control group. The above detection method was the method of step (3) in example 4, and RSD of the peak area was calculated. The results are shown in Table 5 below.
TABLE 5 destructive test results
The results show that the ozagrel impurity II prepared by the method has no obvious change under the conditions of room temperature, high humidity and strong light, has stable property and is more excellent than a control group.
4) Recovery rate test: the ozagrel impurities ii prepared in examples 1, 2 and 3 were precisely measured, and sample-adding solutions having concentrations of 50%, 100% and 120% were precisely measured and prepared by sample-adding recovery test. The detection was carried out by the method of step (3) in example 4, and the RSD value was calculated. The results are shown in Table 6 below.
TABLE 6 recovery test results
| Example 1 | Example 2 | Example 3 | Control group | |
| Average recovery rate% | 99.78 | 99.73 | 99.88 | 99.17 |
| RSD％(n＝9) | 0.68 | 0.69 | 0.61 | 1.92 |
The result shows that the average recovery rate of the ozagrel impurity II prepared by the method is not less than 99.60 percent, the RSD percent is not more than 2.0 percent, the accuracy of the detection result can be effectively improved, and the method is favorable for improving the medicine purity of the ozagrel.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (10)
1. An environment-friendly preparation method of ozagrel impurity II comprises the following synthetic route:
the method comprises the following steps:
4-iodotoluene and ethyl propiolate in Cu2And reacting under the catalytic action of O to obtain ozagrel impurity II.
2. The environment-friendly preparation method of ozagrel impurity II according to claim 1, which is characterized in that: the catalytic reaction is carried out under the protection of nitrogen; the reaction temperature is 100-110 ℃, and the reaction time is 12-18 h.
3. The environment-friendly preparation method of ozagrel impurity II according to claim 1, which is characterized in that: the 4-iodotoluene, the ethyl propiolate and the Cu2The molar ratio of O is 1:2: 1.8-2.5.
4. The environment-friendly preparation method of ozagrel impurity II according to claim 1, which is characterized in that: and after the catalytic reaction is finished, the method also comprises a separation and purification step, wherein the separation and purification step adopts thin layer chromatography.
5. The environment-friendly preparation method of ozagrel impurity II according to claim 4, which is characterized in that: the developing solvent for chromatography is petroleum ether-ethyl acetate, and preferably, the ratio of the petroleum ether to the ethyl acetate is 10-15: 1.
6. The environment-friendly preparation method of ozagrel impurity II according to claim 1, which is characterized in that: the yield of the ozagrel impurity II is not lower than 40.0%.
7. Ozagrel impurity II prepared by the environment-friendly preparation method as defined in any one of claims 1 to 6.
8. The ozagrel impurity II according to claim 7, characterized in that: the purity of the ozagrel impurity II is not lower than 99.90%.
9. A method for detecting an impurity II in an ozagrel bulk drug is characterized by comprising the following steps: the ozagrel impurity II used in the method is the ozagrel impurity II in any one of claims 7 to 8.
10. The method for detecting the impurity II in the ozagrel bulk drug according to claim 9, which is characterized in that: the average recovery rate of the ozagrel impurity II is not less than 99.60 percent, and the RSD percent is less than or equal to 2.0 percent.
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| CN106065012A (en) * | 2015-04-24 | 2016-11-02 | 广东众生药业股份有限公司 | Glyoxaline compound |
Non-Patent Citations (2)
| Title |
|---|
| ALISSA C. GOTZINGER等: "3-Phenothiazinyl propiolates-Fluorescent electrophores by Sonogashira coupling of ethyl propiolate", 《DYES AND PIGMENTS》 * |
| 于明等: "奥扎格雷钠氯化钠注射液中特定杂质的研究", 《中国药师》 * |
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