CN110845374A - Bicalutamide impurity compound and preparation method, detection method and application thereof - Google Patents
Bicalutamide impurity compound and preparation method, detection method and application thereof Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a bicalutamide impurity compound and a preparation method, a detection method and application thereof. The structural formula of the bicalutamide impurity compound is shown as the formula (I):
the obtained impurity compound can further meet the research requirement of the quality of bicalutamide, and ensure the safety of clinical medication, etc.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a bicalutamide impurity compound and a preparation method, a detection method and application thereof.
Background
Bicalutamide (Bicalutamide) was developed by eastern astrazen, first marketed in united kingdom in 2 months 1995, approved by the FDA in the us in 9 months 1995, and approved for import and marketing in china in 1999 under the trade name of kanji. Currently, it is sold in more than 70 countries and markets. The medicine is a novel nonsteroidal antiandrogen, and can block the action of androgen produced by adrenal gland, inhibit the binding or absorption of androgen at nuclear receptor site, and cause atrophy of prostate tumor. Can be clinically used for treating advanced prostate cancer and can avoid adverse reactions caused by androgen treatment. The bicalutamide medicine has the advantages of strong specificity, good tolerance, longer half-life period, convenient administration and the like, and is widely applied to the treatment process of the prostatic cancer.
The chemical name of the bicalutamide is N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3- [ (4-fluorophenyl) sulfonyl ] -2-hydroxy-2-methylpropanamide, and the structure of the bicalutamide is shown as a formula (II):
with the continuous and deep research on the synthesis process of the bicalutamide, the research on the impurities related to the synthesis of the raw material medicines, particularly the research on the degradation impurities, is beneficial to improving the quality standard of the bicalutamide raw material medicines and preparations and the clinical medication safety.
In the preparation of bicalutamide, oxidation conditions are mostly used to oxidize the thioether to the sulfone. The hydrogen peroxide is used as a green oxidizing reagent and is applied to the production of bicalutamide bulk drugs. Combined pharmacopeia standards and literature reports, of which 12 known impurities are reported in the european pharmacopeia (version 9.0), but no report is made on oxidative degradation of impurities; or part of impurities can not be effectively detected or ignored under the detection conditions of the existing pharmacopoeia.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the invention is to provide a bicalutamide impurity compound which can be used as an impurity reference substance in the quality research of bicalutamide.
The second purpose of the invention is to provide the preparation method of the bicalutamide impurity compound, the preparation method is simple to operate, the conditions are mild, and the purity of the prepared impurity compound is high.
The third purpose of the invention is to provide the method for detecting the bicalutamide impurity compound, and the response value is improved.
The fourth purpose of the invention is to provide the application of the bicalutamide impurity compound as a standard substance or a reference substance in quality control of bicalutamide and/or preparations thereof.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the structural formula of the bicalutamide impurity compound is shown as the formula (I):
due to the low response of the bicalutamide impurity compound, the correction factor at 270nm wavelength of the detection method of the usp standard is 2.8, which is very easy to ignore and difficult to detect.
According to the invention, through research on bicalutamide degradation impurities, bicalutamide impurity 4- (3- ((4-fluorophenyl) sulfonyl) -2-hydroxy-2-methylpropionamide) -2- (trifluoromethyl) benzamide is obtained in the reaction process under the conditions of acid, alkali, oxidative damage and the like. For example, the present inventors have found that the impurity compound is generated when bicalutamide is oxidatively destroyed with hydrogen peroxide. This further illustrates that the impurity compound may be generated in the case of prolonged storage of bicalutamide. Because the bicalutamide impurity may exist in the long-term stability test of the bicalutamide, if the bicalutamide impurity is detected in the long-term stability test process of the bicalutamide, the reliability of the stability data can be further improved.
However, according to the conventional detection method, the impurity compound cannot be detected because the correction factor of the compound is 2.8, or the amount of the impurity compound is neglected by researchers because the amount of the impurity compound is small, so that the compound is not used as an impurity compound of bicalutamide and the quality of the bicalutamide is not evaluated.
The impurities can further meet the research requirement of the quality of the bicalutamide, the quality standards of the bicalutamide raw material medicines and preparations are improved, and the safety of clinical medication of the bicalutamide is ensured.
The invention also provides a preparation method of the bicalutamide impurity compound, which comprises the following steps:
under the action of alkali, bicalutamide and an oxidant are mixed and reacted.
The bicalutamide is used as a starting material, and the material is easy to obtain. The method is simple to operate and mild in condition.
In a particular embodiment of the invention, the base is selected from inorganic bases.
Alternatively, the inorganic base may include at least one of potassium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium phosphate.
Optionally, the molar ratio of the inorganic base to the bicalutamide is 1: 1-10.
As in the different embodiments, the molar ratios of inorganic base to bicalutamide can be 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 10, etc.
Optionally, the molar ratio of the inorganic base to the bicalutamide is 1: 2 to 8, and further 1: 5.
In a specific embodiment of the present invention, the system of the mixed reaction further comprises an organic solvent. Preferably, the organic solvent comprises an aprotic organic solvent.
Optionally, the aprotic organic solvent is at least one selected from the group consisting of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, and acetone.
Optionally, the ratio of the bicalutamide to the organic solvent is 1 g/1-30 mL.
In various embodiments, the organic solvent is added at a ratio of the mass of the bicalutamide to the volume of the organic solvent of 1 g: 1mL, 1 g: 2mL, 1 g: 3mL, 1: 4mL, 1: 5mL, 1: 6mL, 1: 7mL, 1: 8mL, 1: 9mL, 1: 10mL, 1: 11mL, 1: 12mL, 1: 13mL, 1: 14mL, 1: 15mL, 1: 16mL, 1: 17mL, 1: 18mL, 1: 19mL, 1: 20mL, 1: 21mL, 1: 22mL, 1: 23mL, 1: 24mL, 1: 25mL, 1: 26mL, 1: 27mL, or 1: 14 mL.
Optionally, the ratio of bicalutamide to the organic solvent is 1 g/10-25 mL, and further 1 g/20 mL.
In a specific embodiment of the present invention, the oxidizing agent is at least one selected from the group consisting of hydrogen peroxide and sodium hypochlorite.
Optionally, the molar ratio of the oxidant to the bicalutamide is 1: 1 to 50.
In different embodiments, the molar ratios of oxidant to carinamide can be 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 11, 1: 12, 1: 13, 1: 14, 1: 15, 1: 16, 1: 17, 1: 18, 1: 19, 1: 20, 1: 21, 1: 22, 1: 23, 1: 24, 1: 25, 1: 26, 1: 27, 1: 28, 1: 29, 1: 30, 1: 31, 1: 32, 1: 33, 1: 36, 1: 45, 1: 48, 1: 11, 1: 24, 1: 25, 1: 49, 1: 27, 1: 45, 1: 31, 1: 32, 1: 40: 45, 1: 40: 11, 1: 8, 1: 11, 1: 6, 1: 11, 1: 6, 1: 11, 1: 18, 1: 11, and the like.
Optionally, the molar ratio of the oxidant to the bicalutamide is 1: 2 to 20, further 1: 5 to 15, and further 1: 10.
Optionally, the reaction temperature of the mixing reaction may be 20 to 40 ℃. The reaction temperature may be appropriately increased or decreased for the purpose of controlling the reaction rate and the like. Further, the reaction temperature of the mixing reaction may be 25 ℃.
Optionally, the reaction time of the mixing reaction is 1-8 hours, and further 3-5 hours. The reaction time can be adjusted according to the actual reaction condition, and the reaction time can increase the yield and the purity of the product within the range.
In a specific embodiment of the invention, the oxidant can be added at a low temperature to avoid side reactions and the like caused by violent reaction. If the temperature is 0-20 ℃, adding an oxidant, and then stirring and reacting at room temperature. Specifically, the oxidizing agent may be added under an ice bath condition, and after the oxidizing agent is added, the temperature is raised to the reaction temperature for a mixing reaction.
Optionally, the method further includes a post-processing step, and the post-processing step includes: stirring and crystallizing in a water system, and separating to obtain a coarse bicalutamide impurity compound. In one embodiment of the invention, the separation is carried out by means of filtration.
Optionally, the stirring and crystallizing in the water system includes: adding water into the mixed reacted system, stirring and crystallizing, or adding the mixed reacted system into water, stirring and crystallizing.
Optionally, the addition amount of the water is 2-60 times of the mass of the bicalutamide.
As in various embodiments, the water may be added in an amount 2 times, 5 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 55 times, 60 times, etc. the mass of the bicalutamide.
Optionally, the amount of the added water is 25-55 times, further 30-50 times, and further 40 times of the mass of the bicalutamide. The addition amount of water in the above range can further ensure the precipitation amount of the product and also the purity of the precipitated crystals.
Optionally, the stirring time is 1-3 h; further, the stirring time may be 2 hours.
Optionally, recrystallizing the crude bicalutamide impurity compound.
Optionally, the solvent used for recrystallization includes ethyl acetate and n-heptane.
Optionally, the volume ratio of ethyl acetate to n-heptane is 1: 3 (3-10), and further 1: 3.
The invention also provides a detection method of the bicalutamide impurity compound, which comprises the following steps:
and detecting the test solution on a high performance liquid chromatograph, wherein the detection wavelength is 250-260 nm.
Optionally, the detection wavelength is 252-256 nm, and further may be 254 nm.
The latest relevant substance detection methods provided by the european pharmacopoeia (version 9.0), the british pharmacopoeia (version 2017) and the united states pharmacopoeia (version 40) use a detection wavelength of 210nm or 270nm, under which the bicalutamide impurity compound has a low response, requiring an increased sample size, but causing an unsatisfactory separation of the main peak from the isomer impurity (e.g., formula III below). Therefore, the related substance detection methods provided by the original european pharmacopoeia (version 9.0), the british pharmacopoeia (version 2017) and the united states pharmacopoeia (version 40) are not suitable for the detection of the impurities.
For example, under the standard detection method of the United states Pharmacopeia, the detection wavelength is 270nm, the correction factor of the bicalutamide impurity compound is 2.8, the response value is low, the overrun risk is caused (the original standard is controlled by 0.1 percent of the limit concentration), and the calibration factor is extremely easy to be ignored under the standard detection method of the original Pharmacopeia.
The invention can greatly improve the detection sensitivity of the bicalutamide impurity compound under the detection wavelength of 250-260 nm, such as 254nm, the correction factor of the bicalutamide impurity can reach 0.71, the responsiveness of the bicalutamide impurity compound is improved, and the impurity compound can be accurately quantified.
Meanwhile, in the detection method, the correction factor of the bicalutamide impurity compound is 0.71, a main component external standard method without the correction factor can be selected for detection and calculation, the same reference substance and test substance are used for detection of other impurities of the bicalutamide, and the complexity of the preparation process is avoided.
In a specific embodiment of the invention, after detecting a test solution and a bicalutamide reference solution with the same volume on a high performance liquid chromatograph respectively, calculating a bicalutamide impurity compound in the test solution by adopting an external standard method;
the calculation formula of the external standard method is as follows:
wherein, impurity J: the content of the bicalutamide impurity compound in the test solution is unit percent;
Cto pair: control concentration in mg/ml;
Csample (A): the concentration of the test sample is unit mg/ml;
Ato pair: major peak area of bicalutamide control solution;
Aimpurity J: peak area of impurity J in the test sample solution.
Wherein, the content of the reference substance is the content value marked by the reference substance when the reference substance is purchased, namely the purity of the reference substance.
Optionally, the conditions for performing detection on the high performance liquid chromatograph further include: the mobile phase A is an aqueous solution of trifluoroacetic acid with the volume fraction of 0.01 percent, and the mobile phase B is an acetonitrile solution of trifluoroacetic acid with the volume fraction of 0.01 percent; gradient elution is carried out, and the volume fractions of the time/mobile phase A in the mobile phase are respectively 0 min/66% -67%, 16.5 min/66% -67%, 26.5 min/39-40%, 32.5 min/4-5%, 32.6 min/66% -67% and 35 min/66% -67%.
Optionally, the flow rate of the mobile phase is 0.8-1.2 mL/min; further, the flow rate of the mobile phase may be 1 mL/mnin.
Optionally, the concentration of the test solution is 0.8-1.2 mg/mL; further, the concentration of the sample solution may be 1 mg/mL.
Optionally, the concentration of the reference solution is 0.8-1.2 mug/mL; further, the concentration of the control solution may be 1. mu.g/mL.
The invention also provides application of the bicalutamide impurity compound as a standard substance or a reference substance in quality control of bicalutamide and/or preparations thereof.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a bicalutamide impurity compound which can be used as an impurity reference substance in bicalutamide quality research;
(2) the invention provides a preparation method of a bicalutamide impurity compound, which is simple to operate and mild in condition, and the prepared impurity compound is high in purity;
(3) the bicalutamide impurity compound can be used as a standard substance or a reference substance, and is used for quality control of bicalutamide and/or a preparation thereof so as to improve the safety of clinical medication of bicalutamide and the like;
(4) the invention also provides a detection method of the bicalutamide impurity compound, which improves the responsiveness of the bicalutamide impurity compound and can accurately quantify the impurity compound.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a mass spectrum of a bicalutamide impurity compound provided by the examples of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of a bicalutamide impurity compound provided by an embodiment of the present invention;
FIG. 3 is a UV absorption spectrum of a bicalutamide impurity compound provided by an embodiment of the present invention;
fig. 4 is a high performance liquid chromatography purity chart of bicalutamide impurity compound provided in the embodiments of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. 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 examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In a specific embodiment of the invention, the structure of the compound is characterized by a WATERS-SQD2 mass spectrometer.
In the specific implementation mode of the invention, a 400M high-resolution superconducting nuclear magnetic resonance spectrometer is adopted to characterize the structure of the compound.
In the present invention, the purity of the compound was confirmed by Waters e2695 HPLC.
Example 1
The preparation method of the bicalutamide impurity compound comprises the following steps:
adding bicalutamide (5.00g) into N, N-dimethylformamide (100mL), stirring to dissolve, adding sodium carbonate (6.16g), and then dropwise adding 30 wt% hydrogen peroxide (13.20g) under the ice bath condition. After the dripping is finished, the mixture is stirred and reacted for 3 hours at room temperature. After the reaction is finished, dropwise adding water (200mL) into the system after the reaction is finished, stirring for 2h at room temperature after the dropwise adding is finished, and filtering to obtain a white-like solid, namely a crude product of the bicalutamide impurity compound.
The crude bicalutamide impurity was recrystallized from ethyl acetate and n-heptane (volume ratio 1: 3) to yield 4.74g of white powder.
The reaction route is as follows:
example 2
The preparation method of the bicalutamide impurity compound comprises the following steps:
bicalutamide (5.00g) was added to acetone (50mL), dissolved with stirring, sodium carbonate (6.16g) was added, and then sodium hypochlorite (8.60g) was added in portions. After the sodium hypochlorite is added, the reaction is continued to be stirred for 5 hours at room temperature. After completion of the reaction, water (100mL) was added dropwise to the reacted system. After the dripping is finished, stirring for 2h at room temperature, and filtering to obtain crude bicalutamide impurity compound.
The crude bicalutamide impurity was recrystallized from ethyl acetate and n-heptane (volume ratio 1: 3) to yield a white powder, 4.42 g.
Example 3
The preparation method of the bicalutamide impurity compound comprises the following steps:
adding bicalutamide (5.00g) into dimethyl sulfoxide (100mL), stirring to dissolve, adding sodium carbonate (6.16g), and then dropwise adding 30 wt% hydrogen peroxide (13.20g) under an ice bath condition. After the dripping is finished, the mixture is stirred and reacted for 3 hours at room temperature. After completion of the reaction, water (200mL) was added dropwise to the reacted system. After the dripping is finished, stirring for 2h at room temperature, and filtering to obtain a white-like solid, namely a crude product of the bicalutamide impurity compound.
The crude bicalutamide impurity was recrystallized from ethyl acetate and n-heptane (volume ratio 1: 3) to yield 4.70g of white powder.
Example 4
The preparation method of the bicalutamide impurity compound comprises the following steps:
adding bicalutamide (5.00g) into dimethyl sulfoxide (100mL), stirring to dissolve, adding sodium bicarbonate (4.88g), and then dropwise adding 30 wt% hydrogen peroxide (13.20g) under ice bath conditions. After the dripping is finished, the mixture is stirred and reacted for 3 hours at room temperature. After completion of the reaction, water (200mL) was added dropwise to the reacted system. After the dripping is finished, stirring for 2h at room temperature, and filtering to obtain a white-like solid, namely a crude product of the bicalutamide impurity compound.
The crude bicalutamide impurity was recrystallized from ethyl acetate and n-heptane (volume ratio 1: 3) to yield 4.61g of white powder.
Example 5
The embodiment provides a method for detecting a bicalutamide impurity compound in bicalutamide, which comprises the following steps:
instruments and reagents: a high performance liquid chromatograph; a bicalutamide raw material drug sample and a bicalutamide reference substance (the purity is 99.9 percent); water is ultrapure water, and other reagents are pure chromatogram; the concentration of the test solution is 1mg/mL, and the concentration of the reference solution is 1 mug/mL; the preparation method of the test solution comprises the following steps: taking a proper amount of carrotene raw material medicine samples, precisely weighing, adding acetonitrile-water (v/v ═ 1: 1) for dissolving, and quantitatively diluting to prepare a solution containing about 1mg of carrotene raw material medicine per 1ml, wherein the solution is used as a sample solution; the preparation method of the reference substance solution comprises the following steps: taking a proper amount of bicalutamide reference substance, precisely weighing, dissolving with acetonitrile-water (v/v ═ 1: 1), and quantitatively diluting to obtain a solution containing about 1 μ g of bicalutamide per 1ml, wherein the solution is used as a reference substance solution;
chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler (C18, 4.0 × 100mm, 3 μm or equivalent efficiency); the mobile phase A is a trifluoroacetic acid aqueous solution with the volume fraction of 0.01%, the mobile phase B is a trifluoroacetic acid acetonitrile solution with the volume fraction of 0.01%, gradient elution (0min, 67% A, 16.5min, 67% A, 26.5min, 40% A, 32.5min, 5% A, 32.6min, 67% A, 35min, 67% A), the flow rate is 1.0mL/min, the column temperature is 30 ℃, the detection wavelength is 254nm, and the sample injection is 10 muL; the diluent is water and acetonitrile in a volume ratio of 1: 1;
the specific test method comprises the following steps: precisely measuring 10 μ L of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram with 254nm as detection wavelength; if an impurity peak exists in the chromatogram of the test solution, calculating the peak area of bicalutamide in the reference solution according to an external standard method;
and calculating the content of impurities in the sample according to an external standard method calculation formula: the calculation formula is as follows:
wherein, impurity J: the content of the bicalutamide impurity compound J in the test solution;
Cto pair: control concentration (mg/ml);
Csample (A): the concentration of the test sample (mg/ml);
Ato pair: major peak area of bicalutamide control solution;
Aimpurity J: peak area of impurity J in the test solution;
the content of the reference substance is 99.9%.
Example 6
This example provides calculation of correction factors for bicalutamide impurity compounds, including specifically the following:
(1) solution preparation
Blank solvent: acetonitrile and water at a volume ratio of 50: 50
Linear stock solution (100. mu.g/mL): respectively taking 10mg of a bicalutamide reference substance and a bicalutamide impurity compound reference substance, precisely weighing, placing in a 100mL measuring flask, adding a proper amount of solvent, performing ultrasonic dissolution, placing to room temperature, diluting to a scale with the solvent, and shaking up.
200% impurity limit concentration linear solution: precisely measuring 5mL of linear stock solution, placing the linear stock solution into a 100mL measuring flask, diluting the linear stock solution to a scale with a solvent, and shaking up.
100% impurity limit concentration linear solution: precisely measuring 5mL of linear solution with 200% impurity limit concentration, placing the linear solution into a 10mL measuring flask, diluting the linear solution to a scale mark with a solvent, and shaking up.
80% impurity limit concentration linear solution: precisely measuring 4mL of linear solution with 200% impurity limit concentration, placing the linear solution into a 10mL measuring flask, diluting the linear solution to a scale mark with a solvent, and shaking up.
40% impurity limit concentration linear solution: precisely measuring 2mL of linear solution with 200% impurity limit concentration, placing the linear solution into a 10mL measuring flask, diluting the linear solution to a scale mark with a solvent, and shaking up.
Quantitative limiting solution: S/N is more than or equal to 10.
(2) Testing
And (3) testing conditions are as follows: precisely measuring 10 mu L of linear solution with each concentration, respectively injecting into a liquid chromatograph, taking 254nm as detection wavelength, and recording chromatogram; chromatographic conditions reference example 5;
the test results are shown in tables 1-2;
TABLE 1 Linear test results (254nm) for bicalutamide impurity compounds
TABLE 2 Linear test results (254nm) for bicalutamide
From the above results, a correction factor, which is the slope of the main component/the slope of the impurity, was calculated, and the results are shown in table 3:
TABLE 3 correction factor calculation results
| Name (R) | Correction factor |
| Bicalutamide impurity compound | 0.71 |
| Bicalutamide | / |
Experimental example 1
Structural characterization of bicalutamide impurity compound
The structure of the bicalutamide impurity compound prepared in example 1 was confirmed by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry using example 1 as an example.
Mass spectrometryAnd (3) characterization results: FIG. 1 shows the mass spectrum of a bicalutamide impurity compound, wherein MS (LC-MS) ═ 447 (M-H)-) And is consistent with the theoretical value.
And (3) nuclear magnetic resonance hydrogen spectrum characterization results: fig. 2 is a nuclear magnetic resonance hydrogen spectrum of a bicalutamide impurity compound, and the specific data are as follows:
1HNMR(400MHZ，DMSO-d6)
δ：10.001(s，1H)，8.169-8.172(d，1H)，7.840-7.971(m，3H)，7.471-7.492(d，2H)，7.373-7.417(m，2H)，6.247(s，1H)，3.676-3.941(d，2H)，1.400(s，3H)。
ultraviolet absorption spectrum: FIG. 3 is a UV absorption spectrum of a bicalutamide impurity compound, from which it can be seen that the maximum absorption wavelength of the bicalutamide impurity compound is 254.0 nm; therefore, the impurity compound of bicalutamide can be effectively detected under the wavelength of 250-260 nm.
Purity testing of bicalutamide impurity compounds
Taking example 1 as an example, the purity is detected by HPLC, and FIG. 4 is a high performance liquid chromatography purity chart of the bicalutamide impurity compound, the purity is 99.35%.
Wherein, the purity test method comprises the following steps: the detection wavelength is 254nm, and other detection conditions refer to a bicalutamide related substance detection method provided by United states pharmacopoeia (40 edition).
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The bicalutamide impurity compound is characterized in that the structural formula is shown as the formula (I):
2. a process for preparing a bicalutamide impurity compound as claimed in claim 1, comprising:
under the action of alkali, bicalutamide and an oxidant are mixed and reacted.
3. The process for the preparation of a bicalutamide impurity compound according to claim 2, wherein said base is selected from the group consisting of inorganic bases;
preferably, the inorganic base comprises at least one of potassium carbonate, sodium bicarbonate, potassium bicarbonate and potassium phosphate;
preferably, the molar ratio of the inorganic base to the bicalutamide is 1: 1 to 10.
4. The method for preparing the bicalutamide impurity compound according to claim 2, wherein the system of said mixed reaction further comprises an organic solvent;
preferably, the organic solvent comprises an aprotic organic solvent;
more preferably, the aprotic organic solvent is selected from at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and acetone;
preferably, the ratio of the bicalutamide to the organic solvent is 1 g/1-30 mL.
5. The method of any one of claims 2-4, wherein the oxidizing agent is selected from at least one of hydrogen peroxide and sodium hypochlorite;
preferably, the molar ratio of the oxidant to the bicalutamide is 1: 1 to 50;
more preferably, the molar ratio of the oxidant to the bicalutamide is 1: 2-20.
6. The preparation method of the bicalutamide impurity compound according to claim 5, wherein the reaction temperature of the mixing reaction is 20-40 ℃;
preferably, the reaction time of the mixing reaction is 1-8 h.
7. The method of preparing a bicalutamide impurity compound according to claim 2, further comprising a post-treatment step, said post-treatment step comprising: stirring and crystallizing in a water system, and separating to obtain a coarse product of the bicalutamide impurity compound;
preferably, the stirring crystallization in the water system comprises: adding water into the system after the mixed reaction, stirring and crystallizing, or adding the system after the mixed reaction into water, stirring and crystallizing;
more preferably, the adding amount of the water is 2-60 times of the mass of the bicalutamide;
more optionally, the stirring time is 1-3 h.
8. The method of preparing a bicalutamide impurity compound of claim 7, wherein the crude bicalutamide impurity compound is recrystallized;
preferably, the solvent used for recrystallization comprises ethyl acetate and n-heptane;
more preferably, the volume ratio of the ethyl acetate to the n-heptane is 1: 3 to 10.
9. The method of detecting a bicalutamide impurity compound as claimed in claim 1, comprising the steps of:
detecting the test solution on a high performance liquid chromatograph, wherein the detection wavelength is 250-260 nm;
preferably, the detection wavelength is 252-256 nm;
more preferably, the detection wavelength is 254 nm;
preferably, after the test solution and the bicalutamide reference solution with the same volume are respectively detected on a high performance liquid chromatograph, calculating the bicalutamide impurity compound in the test solution by adopting an external standard method; the calculation formula of the external standard method is as follows:
wherein, impurity J: the content of the bicalutamide impurity compound in the test solution is unit percent;
Cto pair: control concentration in mg/ml;
Csample (A): the concentration of the test sample is unit mg/ml;
Ato pair: major peak area of bicalutamide control solution;
AimpuritiesJ: peak area of impurity J in the test solution;
preferably, the conditions for performing detection on the high performance liquid chromatograph further include: the mobile phase A was 0.01% trifluoroacetic acid in water and the mobile phase B was 0.01% trifluoroacetic acid in acetonitrile, and gradient elution was performed.
10. Use of the bicalutamide impurity compound of claim 1 as a standard or control in the quality control of bicalutamide and/or its formulations.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351762A (en) * | 2011-07-21 | 2012-02-15 | 宁波人健药业集团有限公司 | Method for preparing bicalutamide from N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfenyl)-2-hydroxy-2-methyl-propanamide |
| CN104897818A (en) * | 2015-06-19 | 2015-09-09 | 重庆医药高等专科学校 | UPLC (ultra-high performance liquid chromatography) method for simultaneously determining six related substances in bicalutamide |
| CN107949559A (en) * | 2015-08-27 | 2018-04-20 | 辉瑞公司 | Bicyclic condensed heteroaryl or aryl compound as IRAK4 conditioning agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351762A (en) * | 2011-07-21 | 2012-02-15 | 宁波人健药业集团有限公司 | Method for preparing bicalutamide from N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfenyl)-2-hydroxy-2-methyl-propanamide |
| CN104897818A (en) * | 2015-06-19 | 2015-09-09 | 重庆医药高等专科学校 | UPLC (ultra-high performance liquid chromatography) method for simultaneously determining six related substances in bicalutamide |
| CN107949559A (en) * | 2015-08-27 | 2018-04-20 | 辉瑞公司 | Bicyclic condensed heteroaryl or aryl compound as IRAK4 conditioning agents |
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