CN113004127A - Vitinomod impurity compound and preparation method, detection method and application thereof - Google Patents

Vitinomod impurity compound and preparation method, detection method and application thereof Download PDF

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CN113004127A
CN113004127A CN202110180535.1A CN202110180535A CN113004127A CN 113004127 A CN113004127 A CN 113004127A CN 202110180535 A CN202110180535 A CN 202110180535A CN 113004127 A CN113004127 A CN 113004127A
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impurity
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胡四进
蒋荣林
温雄学
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Guangdong Zhong Hao Pharmaceutical Co ltd
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    • 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 discloses a yivinmod impurity compound, and a preparation method, a detection method and application thereof. The impurity compound of the present invention has high yield and high purity, and may be used as the impurity reference substance in the detection of the raw material medicine or preparation of the present invention to raise the accurate positioning of the impurity E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -phenyl dimer in the quality control of the present invention, to strengthen the control of the impurity and raise the quality of the present invention preparation, so as to ensure the safety and effectiveness of the present invention in clinical use.

Description

Vitinomod impurity compound and preparation method, detection method and application thereof
Technical Field
The invention relates to the field of drug synthesis, in particular to a yivinmod impurity compound, and a preparation method, a detection method and application thereof.
Background
The vitamin mode is a novel broad-spectrum bactericide and bioactive substances discovered from symbiotic microorganism nematode and bacterial metabolites, is a new generation of anti-inflammatory drugs, and can be used for treating various major autoimmune diseases, such as psoriasis, eczema, colitis ulcerosa and various allergic diseases. The chemical name of the yivitimod is 5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, and the structure is as follows:
Figure BDA0002942090900000011
one of the main factors influencing the quality of the medicine is medicine impurities, the research on the impurities is used as an important component of medicine research, whether the impurities can be reasonably and effectively controlled is directly related to the quality controllability and the safety of the medicine. Therefore, the control of the impurities in the vismod plays a key role in ensuring the efficacy of the vismod medicament and reducing the adverse reaction of the medicament. The primary condition for research on pharmaceutical impurities is to obtain an impurity control sample, however, reports on the impurities and preparation processes of the present vismod are lacking at present, so development of the impurities related to the present vismod and preparation methods thereof is needed for improving quality control of raw materials and preparations of the present vismod.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a danimod impurity compound, a preparation method, a detection method and application thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the chemical name of the impurity compound of the limod is E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, and the structure of the impurity compound is shown as the formula (I):
Figure BDA0002942090900000021
in the production and research process of the present invention, the inventor finds and separates to obtain an impurity compound, E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, which is a new present invention vitamin mode impurity, and the impurity compound is not reported in documents at present. Carrying out structural characterization on the impurity compound through data such as high-resolution mass spectrum, nuclear magnetic resonance spectrum and the like, confirming that the structure of the impurity compound is shown as a formula (I), wherein the parameter description is as follows:
HRMS(ESI)：m/z 531.25[M+Na]+；
1H-NMR(600MHz，DMSO-d6)δ：1.27(d，6H)，3.44(m，1H)，3.38(t，2H)，6.21(s，2H)，7.17(t，1H)，7.29(t，2H),7.33(d，2H)；
13C-NMR(150MHz，CD3OD)δ：21.12，23.95，51.70，105.84，118.52，126.90，127.72，128.92，140.56，142.94，156.62。
the invention also provides a preparation method of the above-mentioned yimod impurity compound, which takes a compound of formula (II), namely 5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, as a raw material to perform cycloaddition reaction under the condition of illumination, so as to prepare the compound of formula (I), wherein the specific route is as follows:
Figure BDA0002942090900000022
preferably, the preparation method of the impurity compound of the present vismod comprises the following steps:
(1) taking a compound of a formula (II) as a raw material, and carrying out cycloaddition reaction under the condition of ultraviolet irradiation to prepare a crude product containing the compound of the formula (I);
(2) recrystallizing said crude product to obtain a solid comprising the compound of formula (I);
(3) and purifying and separating the solid containing the compound shown in the formula I by column chromatography to obtain the compound shown in the formula (I).
Preferably, in the step (1), the compound of formula (II) is exposed to UV light with a wavelength of 254-365nm for 1-10 days, preferably 2-10 days, more preferably 5-10 days, to obtain a crude product containing the compound of formula (I). The influence of the wavelength of ultraviolet light and the irradiation time on the yield of the compound shown in the formula (I) is large, the yield of the compound shown in the formula (I) is low due to the excessively short irradiation time, the yield of the compound shown in the formula (I) is improved by the aid of the irradiation time of 2-10 days, particularly, the yield is higher than 10% when the irradiation time is 5-10 days, and the yield is not changed greatly after the irradiation time is higher than 10 days.
Preferably, in the step (2), the recrystallization solvent may be methanol, ethanol or toluene.
Preferably, in the step (3), the specification of the column chromatography silica gel is 100-400 mesh, and the elution solvent is a mixture of n-hexane and ethyl acetate, so as to improve the purity of the compound of the formula (I).
The preparation method of the invention has the advantages of simple process, high yield and high purity of the impurity compound E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer.
The invention provides a detection method of the above-mentioned impurity compound in the present invention, and the detection method adopts high performance liquid chromatography for determination. Preferably, the filler is octyl silane bonded silica gel or octadecyl silane bonded silica gel, the mobile phase is water and acetonitrile, the flow rate of the mobile phase is 0.5-1.5mL/min, the detection wavelength is 200nm-250nm, and the column temperature is 25-40 ℃.
The invention also provides application of the above impurity compound or the impurity compound prepared by the method as an impurity reference substance in quality control of the bulk drug or preparation of the above. Research finds that the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer exists in the bulk drug or preparation product of the vismod, and if the generation of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer is not controlled during the preparation of the vismod, the lack of control on the content of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer can cause unqualified final product quality, thereby affecting the safety and effectiveness of clinical use of the vismod preparation, and therefore, the quality of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer should be controlled. And the quality control of the raw materials and the preparation of the vismod needs to have qualified impurity reference substances. The E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer prepared by the invention has high purity, can be used as an impurity reference substance in the detection of the raw material medicine or preparation of the vismod, and can improve the accurate positioning of the impurity E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer in the production quality control of the vismod.
The invention also provides a method for detecting impurities in the raw material medicine or preparation of the danimod, wherein the detection method adopts high performance liquid chromatography for determination, and specifically comprises the following steps:
s1, taking the vismoded raw material medicine or preparation, dissolving the raw material medicine or preparation by adopting a mixed solvent of water and acetonitrile, diluting and fixing the volume to obtain a test solution;
s2, taking the impurity compound or the impurity compound prepared by the method as an impurity reference substance, dissolving the impurity compound or the impurity compound prepared by the method by adopting a mixed solvent of water and acetonitrile, diluting and fixing the volume to obtain a reference substance solution;
s3, injecting the test solution prepared in the step S1 and the reference solution prepared in the step S2 into a high performance liquid chromatograph, recording a chromatogram, and calculating the content of the impurity compound by the peak area if the impurity compound peak exists in the chromatogram of the test solution;
compared with the prior art, the invention has the beneficial effects that:
the high-purity E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer prepared by the invention can be used as an impurity reference substance in the detection of the raw material or preparation of the vismod, so that the accurate positioning and qualitative determination of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer in the production quality control of the vismod are improved, the control of the impurity is strengthened, and the quality of the preparation of the vismod is improved, thereby ensuring the safety and effectiveness of the clinical use of the preparation of the vismod.
Drawings
FIG. 1 is a high performance liquid chromatogram of an impurity compound of the present invention.
FIG. 2 is a high resolution mass spectrum of an impurity compound of the present invention.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of an impurity compound of the present invention.
FIG. 4 is a nuclear magnetic resonance carbon spectrum of an impurity compound of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. It will be understood by those skilled in the art that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the examples, the experimental methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available without otherwise specified.
Example 1
A preparation method of the impurity compound of the guidotimod comprises the following steps:
(1) irradiating E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene A g under 254nm ultraviolet light for 1 day to obtain crude product containing compound of formula (I);
(2) taking a crude product containing the compound shown in the formula (I), adding 2.5A mL of toluene, heating to 60 ℃ to completely dissolve the crude product, cooling, separating out crystals, filtering, collecting filtrate, and concentrating to obtain a solid containing the compound shown in the formula (I);
(3) taking a solid containing the compound shown in the formula (I), taking a mixture of normal hexane and ethyl acetate as an eluent, purifying by column chromatography, collecting eluent containing high-purity impurities, and concentrating under reduced pressure to obtain 0.6g of the high-purity compound shown in the formula (I), wherein the yield is 6%, and the purity is 99.4%.
The purity of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer in this example was determined as follows:
1) using octyl silane bonded silica gel as a filling agent, acetonitrile and water as mobile phases, and carrying out gradient elution detection by using an ultraviolet detector at a detection wavelength of 240nm, a flow rate of 1.0mL/min and a column temperature of 30 ℃;
gradient elution ratios are shown, for example, in table 1:
TABLE 1
Time (minutes) Water (W) Acetonitrile
0 55 45
20 15 85
40 15 85
2) Preparing a sample solution: taking a proper amount of E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, and taking water-acetonitrile (50:50) as a diluent to prepare a solution with the concentration of about 0.4 mg/mL;
3) and (3) detection: precisely sucking 10 mu L of sample solution, injecting into a high performance liquid chromatograph, obtaining the content of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer by calculating according to an area normalization method, wherein a chromatogram is shown in figure 1.
In the step (2), the recrystallization solvent can also be methanol or ethanol; in the step (3), the specification of the adopted column chromatography silica gel is 100-400 meshes.
In the invention, the gradient elution condition can be properly adjusted, the filling agent is octadecylsilane chemically bonded silica, the mobile phase is water and acetonitrile, the flow rate of the mobile phase is 0.5-1.5mL/min, the detection wavelength is 200-250nm, and the column temperature is 25-40 ℃.
Example 2
A preparation method of the impurity compound of the guidotimod comprises the following steps:
(1) irradiating E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -Ag benzene under 365nm ultraviolet light for 10 days to obtain a crude product containing the compound shown in the formula (I);
(2) taking a crude product containing the compound shown in the formula (I), adding 2.5A mL of toluene, heating to 60 ℃ to completely dissolve the crude product, cooling, separating out crystals, filtering, collecting filtrate, and concentrating to obtain a solid containing the compound shown in the formula (I);
(3) taking a solid containing the compound shown in the formula (I), taking a mixture of normal hexane and ethyl acetate as an eluent, purifying by column chromatography, collecting eluent containing high-purity impurities, and concentrating under reduced pressure to obtain 2g of the compound shown in the formula (I) with high purity, wherein the yield is 20%, and the purity is 99.6%.
The purity of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer in this example was determined as follows:
1) using octyl silane bonded silica gel as a filling agent, acetonitrile and water as mobile phases, and carrying out gradient elution detection by using an ultraviolet detector at a detection wavelength of 240nm, a flow rate of 1.0mL/min and a column temperature of 30 ℃;
gradient elution ratios are shown, for example, in table 2:
TABLE 2
Time (minutes) Water (W) Acetonitrile
0 55 45
20 15 85
40 15 85
2) Preparing a sample solution: taking a proper amount of E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, and taking water-acetonitrile (50:50) as a diluent to prepare a solution with the concentration of about 0.4 mg/mL;
3) and (3) detection: precisely absorbing 10 mu L of sample solution, injecting into a high performance liquid chromatograph, and calculating according to an area normalization method to obtain the content of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer.
Example 3
A preparation method of the impurity compound of the guidotimod comprises the following steps:
(1) irradiating E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -Ag benzene under 254nm ultraviolet light for 5 days to obtain crude product containing compound of formula (I);
(2) taking a crude product containing the compound shown in the formula (I), adding 2.5A mL of methanol, heating to 60 ℃ to completely dissolve the crude product, cooling, separating out crystals, filtering, collecting filtrate, and concentrating to obtain a solid containing the compound shown in the formula (I);
(3) taking a solid containing the compound shown in the formula (I), taking a mixture of normal hexane and ethyl acetate as an eluent, purifying by column chromatography, collecting eluent containing high-purity impurities, and concentrating under reduced pressure to obtain 1.1g of the high-purity compound shown in the formula (I), wherein the yield is 11%, and the purity is 98.9%.
The purity of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer in this example was determined as follows:
1) using octyl silane bonded silica gel as a filling agent, acetonitrile and water as mobile phases, and carrying out gradient elution detection by using an ultraviolet detector at a detection wavelength of 240nm, a flow rate of 1.0mL/min and a column temperature of 30 ℃;
gradient elution ratios are shown, for example, in table 3:
TABLE 3
Time (minutes) Water (W) Acetonitrile
0 55 45
20 15 85
40 15 85
2) Preparing a sample solution: taking a proper amount of E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, and taking water-acetonitrile (50:50) as a diluent to prepare a solution with the concentration of about 0.4 mg/mL;
3) and (3) detection: precisely absorbing 10 mu L of sample solution, injecting into a high performance liquid chromatograph, and calculating according to an area normalization method to obtain the content of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer.
The structure of the impurity compound is characterized by high-resolution mass spectrum, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum analysis methods, and the structure of the impurity compound is confirmed to be shown as the formula (I). The high-resolution mass spectrum of the impurity compound is shown in fig. 2, and HRMS (ESI): m/z 531.25[ M + Na ]]+. Of the impurity compound1The H-NMR spectrum is shown in FIG. 3, (600MHz, DMSO-d6) delta: 1.27(d, 6H), 3.44(m, 1H), 3.38(t, 2H), 6.21(s, 2H)7.17(t, 1H), 7.29(t, 2H),7.33(d, 2H). The impurity is completely removed13The C-NMR spectrum is shown in FIG. 4, (150MHz, CD)3OD)δ：21.12，23.95，51.70，105.84，118.52，126.90，127.72，128.92，140.56，142.94，156.62。
Example 4
The method for analyzing and detecting the raw material or preparation of the limod by taking the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer prepared by the invention as an impurity reference substance comprises the following steps:
the method comprises the steps of taking the raw material or preparation of the limod and the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer, precisely weighing, dissolving by using a water-acetonitrile (50:50) solution, and diluting to prepare a test solution and a reference solution with the concentration of 0.4 mg/mL. Using octyl silane bonded silica gel as a filling agent; water and acetonitrile are used as mobile phases; gradient elution is carried out according to the table 4, the detection wavelength is 240nm, the flow rate is 1.0mL per minute, the column temperature is 30 ℃, a chromatogram of the sample solution has an E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer peak, and the content of the E-1, 3-dihydroxy-2-isopropyl-5- (2-styryl) -benzene dimer is calculated according to an external standard method.
TABLE 4
Figure BDA0002942090900000071
Figure BDA0002942090900000081
In the method for analyzing and detecting the raw material or preparation of the iguratimod by using the impurity reference substance, the filler can also be octadecylsilane chemically bonded silica, the mobile phase is water and acetonitrile, the flow rate of the mobile phase is 0.5-1.5mL/min, the detection wavelength is 200-250nm, and the column temperature is 25-40 ℃.
In summary, the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the vismod prepared by the invention has high yield and high purity, and can be used as a reference substance of impurities in the raw material or preparation detection of the vismod, so that the accurate positioning and characterization of the 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the production quality control of the vismod are improved, the impurity hidden danger in the vismod is eliminated, and the quality of the vismod is further improved.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

1. The structure of the impurity compound of the invention is shown as the formula (I):
Figure FDA0002942090890000011
2. the method for preparing the impurity compound of iguratimod according to claim 1, wherein the compound of formula (II) is used as a raw material, and cycloaddition reaction is performed under light condition to obtain the compound of formula (I), wherein the specific route is as follows:
Figure FDA0002942090890000012
3. the method for preparing the impurity compound in the iguratimod according to claim 2, which comprises the following steps:
(1) taking a compound of a formula (II) as a raw material, and carrying out cycloaddition reaction under the condition of ultraviolet irradiation to prepare a crude product containing the compound of the formula (I);
(2) recrystallizing said crude product to obtain a solid comprising the compound of formula (I);
(3) and purifying and separating the solid containing the compound shown in the formula I by column chromatography to obtain the compound shown in the formula (I).
4. The method for preparing the impurity compound in the above-mentioned claim 3, wherein in the step (1), the compound of formula (II) is irradiated under the UV light with wavelength of 254-365nm for 1-10 days, preferably 2-10 days, to obtain the crude product containing the compound of formula (I).
5. The method for preparing the impurity compound in the iguratimod according to claim 3, wherein the recrystallization solvent used in step (2) is methanol, ethanol or toluene.
6. The method for preparing the impurity compound in the above claim 3, wherein in the step (3), the column chromatography silica gel specification adopted is 100-400 mesh, and the elution solvent is a mixture of n-hexane and ethyl acetate.
7. The method for detecting an impurity compound in the iguratimod according to claim 1, wherein the detection method is performed by high performance liquid chromatography.
8. The method for detecting the impurity compound in the iguratimod according to claim 7, wherein the detecting conditions are as follows: the filler is octyl silane bonded silica gel or octadecyl silane bonded silica gel, the mobile phase is water and acetonitrile, the flow rate of the mobile phase is 0.5-1.5mL/min, the detection wavelength is 200-250nm, and the column temperature is 25-40 ℃.
9. Use of the impurity compound in iguratimod according to claim 1 or the impurity compound in iguratimod prepared by the method according to any one of claims 2 to 6 as an impurity control in quality control of an iguratimod drug substance or formulation.
10. The method for detecting impurities in the danimod bulk drug or the preparation is characterized in that the detection method adopts high performance liquid chromatography for determination, and specifically comprises the following steps:
s1, taking the vismoded raw material medicine or preparation, dissolving the raw material medicine or preparation by adopting a mixed solvent of water and acetonitrile, diluting and fixing the volume to obtain a test solution;
s2, taking the impurity compound in claim 1 or the impurity compound prepared by the method according to any one of claims 2 to 6 as an impurity reference substance, dissolving the impurity compound by using a mixed solvent of water and acetonitrile, diluting the impurity compound to a constant volume to obtain a reference substance solution;
s3, injecting the test solution prepared in the step S1 and the reference solution prepared in the step S2 into a high performance liquid chromatograph respectively, recording a chromatogram, and calculating the content of the impurity compound by using a peak area if the impurity compound peak exists in the chromatogram of the test solution;
wherein the filler is octane silane bonded silica gel or octadecylsilane chemically bonded silica, the mobile phase is water and acetonitrile, the flow rate of the mobile phase is 0.5-1.5mL/min, the detection wavelength is 200-250nm, and the column temperature is 25-40 ℃.
CN202110180535.1A 2021-02-08 2021-02-08 Vitinomod impurity compound and preparation method, detection method and application thereof Pending CN113004127A (en)

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Application publication date: 20210622