CN113024357A - Bendanimod impurity, preparation method and application thereof - Google Patents
Bendanimod impurity, preparation method and application thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title abstract description 31
- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 claims abstract description 61
- 238000001514 detection method Methods 0.000 claims abstract description 10
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- 238000000034 method Methods 0.000 claims description 22
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/72—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by liquid-liquid treatment
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/82—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by solid-liquid treatment; by chemisorption
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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
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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- 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 discloses a benvitimod impurity and a preparation method and application thereof. The impurity of the benvitimod prepared by the invention has high purity, can be used as an impurity reference substance in the detection of the raw material medicine or the preparation of the benvitimod, improves the accurate positioning of the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the production quality control of the benvitimod, is beneficial to strengthening the control of the impurity and improving the quality of the benvitimod preparation, thereby ensuring the safety and the effectiveness of the clinical use of the benvitimod preparation.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a benvitimod impurity, a preparation method and application thereof.
Background
The benvitimod is a non-hormone low-toxicity small molecular compound (mw ═ 254) discovered and separated from metabolites of soil nematode symbiotic bacteria, has unique biological activity of inhibiting lymphozyme, 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 benvitimod is 5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, and the structure of the benvitimod is shown as the formula I:
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 impurity of the benvitimod plays a key role in ensuring the efficacy of the benvitimod 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 impurity of the benvitimod and the preparation process thereof are few at present, so that the impurity related to the benvitimod and the preparation method thereof need to be developed for quality control of the raw material and preparation of the benvitimod.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a benvitimod impurity, a preparation method and application thereof, so that the impurity is applied to detecting the quality of a benvitimod bulk drug or a preparation sample thereof, analyzing the impurity in the benvitimod, and improving the quality standard of the benvitimod bulk drug or the preparation thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
an impurity of benvitimod, which has a structure shown in formula II:
in the process of preparing the benvitimod (5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol), the inventor discovers an impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol (hereinafter referred to as BZ07 impurity), and the impurity is not reported in documents and is a new impurity of the benvitimod.
The inventor carries out structural characterization on the impurity through data such as high-resolution mass spectrum, nuclear magnetic resonance spectrum and the like, confirms that the BZ07 impurity has a structure shown in a formula II, and parameters are described as follows:
HRMS(ESI)：m/z 269.15[M+H]+、310.18[M+Na+H2O+H]+。1H-NMR(600MHz，MeOD)δ：1.35(d，6H)，2.22(s，3H)，3.54(m，1H)，6.66(s，1H)，6.87(d，1H)，7.23(t，1H)，7.34(m，3H)，7.50(d，2H)。13C-NMR(150MHz，MeOD)δ10.54，19.76，24.90，47.62，104.89，114.87，122.13，125.75，126.61，128.27，134.34，137.94，153.15，153.75。
the invention also provides a preparation method of the benvitimod impurity shown as the formula II, which comprises the following steps: the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and a demethylating reagent are subjected to demethylation reaction to obtain the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, and the specific route is as follows:
the preferable embodiment of the preparation method of the impurity in the benvitimod provided by the invention comprises the following steps:
(1) taking E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and a demethylating reagent to perform demethylating reaction at the temperature of 140-220 ℃ for 2-20 h;
(2) extracting the reaction product obtained in the step (1) by using an organic solvent, washing by using acid water and crystallizing, and collecting filtrate containing a target product;
(3) and (3) concentrating, enriching and purifying the filtrate obtained in the step (2) to obtain the impurities.
As a preferred embodiment of the method for preparing the benvitimod impurity, the demethylating agent is aluminum trichloride, boron tribromide or pyridine hydrochloride.
As a preferred embodiment of the method for preparing the impurity in the benvitimod according to the present invention, in the step (2), the organic solvent is tetrahydrofuran, methyl tert-butyl ether or ethyl acetate.
As a preferred embodiment of the method for preparing the impurity in the present invention, in the step (2), the acid is hydrochloric acid, sulfuric acid or acetic acid.
As a preferred embodiment of the method for preparing the impurity in the benvitimod according to the present invention, in the step (2), methanol, n-hexane, toluene or dichloromethane is used as a crystallization solvent.
As a preferred embodiment of the preparation method of the benvitimod impurity, in the step (3), after concentrating the filtrate, performing column chromatography separation to obtain a target product, wherein the specification of column chromatography silica gel is 200-400 meshes, and an elution solvent is a mixture of n-hexane and ethyl acetate.
As a preferred embodiment of the method for preparing the phenyllimod impurity, in the step (3), the purified phenyllimod impurity is obtained by further performing preparative liquid phase separation treatment on the target product obtained by the column chromatography separation, and acetonitrile and water are used as a mobile phase for preparing the mobile phase of the liquid phase.
According to the technical scheme, the purity of the BZ07 impurity is further improved through column chromatography and liquid phase separation treatment.
The invention also provides application of the above-mentioned impurity in quality control of the raw material drug or preparation of the benvitimod as a reference substance for impurity detection.
The inventor finds that BZ07 impurities exist in a final product of the benvitimod, and therefore, in the process of preparing the benvitimod, if the generation of the BZ07 impurities is not controlled, the content of the BZ 3578 impurities is not controlled, the quality of the final product is unqualified, and the quality of the final product is affected on human health, so that the quality control of the benvitimod BZ07 impurities is carried out. For quality control of the benvitimod raw material and the preparation, impurities with qualified quality are required to be used as reference substances. The new impurity of the benvitimod provided by the invention can be used as an impurity reference substance to carry out quality control on the benvitimod bulk drug or the preparation.
Compared with the prior art, the invention has the beneficial effects that:
the invention prepares high-purity benvitimod impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, can be used as a reference substance of impurities in the detection of a benvitimod raw material or a preparation, improves the accurate positioning and the qualitative performance of the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the production quality control of the benvitimod, is favorable for enhancing the control of the impurities, and improves the quality of the benvitimod preparation, thereby ensuring the safety and the effectiveness of the clinical use of the benvitimod preparation.
Drawings
Figure 1 is a chromatogram of the BZ07 impurity prepared in example 1.
FIG. 2 shows the LC-MS spectrum of BZ07 impurity (A is TIC diagram; B is UV diagram).
FIG. 3 is a high resolution mass spectrum of BZ07 impurity.
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of BZ07 impurity.
FIG. 5 is the NMR carbon spectrum of BZ07 impurity.
FIG. 6 is a chromatogram of a BZ07 control.
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
As an embodiment of the method for preparing the impurity in the present invention, the method for preparing the impurity in the present embodiment includes the following steps:
(1) taking 1kg of E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and 2.0kg of pyridine hydrochloride, putting the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and the pyridine hydrochloride into a reaction container, heating, keeping the temperature at 200 ℃, stirring for reaction, monitoring by HPLC (high performance liquid chromatography), and stopping the reaction until the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene is completely reacted;
(2) taking 13.0L of ethyl acetate, 9.0L of drinking water and 0.28L of hydrochloric acid, placing the mixture in an extraction container, stirring, transferring the reaction solution in the step (2) to the extraction container while the reaction solution is hot, stirring, standing, and removing a lower-layer water phase; adding 8.5L of drinking water and 0.14L of hydrochloric acid, stirring, standing, and removing the lower water phase; adding 4.0L of drinking water, stirring, standing, removing lower water phase, and concentrating under reduced pressure to remove ethyl acetate to obtain crude BZ07 containing compound of formula II;
(3) adding toluene into a BZ07 crude product, heating to 70 ℃ to completely dissolve the BZ07 crude product and the toluene at a mixing ratio of 1kg to 5.0L, cooling, separating out crystals, filtering, collecting filtrate to obtain a BZ07 crude product mother liquor containing the formula II, and concentrating under reduced pressure;
(4) taking 11.2g of the concentrated crude BZ07 mother liquor, taking a normal hexane-ethyl acetate (5:1) solution as an eluent and 300-mesh 400-mesh column chromatography silica gel as a filling agent, carrying out column chromatography purification, collecting the eluent with higher concentration of BZ07, and carrying out reduced pressure concentration to obtain a crude BZ 07;
(5) preparation and liquid phase separation: and (2) using octadecylsilane chemically bonded silica as a filler, using water and methanol as mobile phases, taking the crude BZ07 obtained in the step (4), preparing a liquid phase, performing gradient elution separation, collecting a BZ07 separation solution, concentrating and drying under reduced pressure to obtain 363mg of the benvitimod impurity BZ07 (formula II), wherein the purity is 98.84% and the yield is 3.2% as shown in a chromatogram map 1.
The purity detection method of BZ07 in the invention is 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 the detection wavelength of 220nm, the flow rate of 1.0mL/min and the column temperature of 25 ℃;
gradient elution ratios are shown, for example, in table 1:
TABLE 1
| Time (minutes) | Water (W) | |
| 0 | 60 | 40 |
| 20 | 10 | 90 |
| 30 | 10 | 90 |
| 32 | 60 | 40 |
| 40 | 60 | 40 |
(2) Preparing a sample solution: taking a proper amount of BZ07, and taking water-acetonitrile (50:50) as a diluent to prepare a solution with the concentration of about 0.1 mg/mL;
(3) and (3) detection: precisely sucking 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 BZ 07.
Example 2
As an embodiment of the method for preparing the impurity in the present invention, the method for preparing the impurity in the present embodiment includes the following steps:
(1) placing E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene Akg and pyridine hydrochloride 2.0Akg in a reaction vessel, heating, keeping the temperature at 140 ℃, stirring for reaction, and stopping the reaction by HPLC (high performance liquid chromatography) until the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene is completely reacted for 20 h;
(2) taking 13.0AL tetrahydrofuran, 9.0AL drinking water and 0.28L sulfuric acid, placing in an extraction container, stirring, transferring the reaction solution in the step (2) to the extraction container while the reaction solution is hot, stirring, standing, and removing the lower-layer water phase; adding 8.5A L drinking water and 0.14A L sulfuric acid, stirring, standing, and removing lower water phase; adding 4.0A L drinking water, stirring, standing, discarding the lower water phase, and concentrating under reduced pressure to remove ethyl acetate to obtain crude product B containing BZ07 of formula II;
(3) adding 6.0B L n-hexane into the BZ07 crude product, heating to 70 ℃ to completely dissolve the BZ07 crude product, cooling, separating out crystals, filtering, collecting filtrate to obtain a mother solution containing the BZ07 crude product of the formula II, and concentrating under reduced pressure;
(4) taking 11.2g of the concentrated crude BZ07 mother liquor, taking a normal hexane-ethyl acetate (5:1) solution as an eluent and 300-mesh 400-mesh column chromatography silica gel as a filling agent, carrying out column chromatography purification, collecting the eluent with higher concentration of BZ07, and carrying out reduced pressure concentration to obtain a crude BZ 07;
(5) preparation and liquid phase separation: and (3) using octadecylsilane chemically bonded silica as a filler, using water and methanol as mobile phases, taking the crude BZ07 obtained in the step (4), performing gradient elution separation on a prepared liquid phase, collecting a separated solution of BZ07, concentrating and drying under reduced pressure to obtain 363mg of the benvitimod impurity BZ07 (formula II), wherein the yield is 3.2%.
Example 3
As an embodiment of the method for preparing the impurity in the present invention, the method for preparing the impurity in the present embodiment includes the following steps:
(1) taking kg of E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene A and 2.0Akg pyridine hydrochloride, placing the mixture in a reaction container, heating, keeping the temperature at 220 ℃, stirring for reaction, monitoring by HPLC (high performance liquid chromatography) until the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene completely reacts for 2 hours, and stopping the reaction;
(2) taking 13.0A L methyl tert-butyl ether, 9.0A L drinking water and 0.28L acetic acid, placing in an extraction container, stirring, transferring the reaction solution in the step (2) to the extraction container while the reaction solution is hot, stirring, standing, and removing the lower-layer water phase; adding 8.5AL drinking water and 0.14A L acetic acid, stirring, standing, and removing lower water phase; adding 4.0A L drinking water, stirring, standing, discarding the lower water phase, and concentrating under reduced pressure to remove ethyl acetate to obtain crude product B containing BZ07 of formula II;
(3) adding 6.0B L methanol into a BZ07 crude product, heating to 70 ℃ to completely dissolve the BZ07 crude product, cooling, separating out crystals, filtering, collecting filtrate to obtain a mother solution containing the BZ07 crude product of the formula II, and concentrating under reduced pressure;
(4) taking 11.2g of the concentrated crude BZ07 mother liquor, taking a normal hexane-ethyl acetate (5:1) solution as an eluent and 200-mesh 300-mesh column chromatography silica gel as a filling agent, carrying out column chromatography purification, collecting the eluent with higher concentration of BZ07, and carrying out reduced pressure concentration to obtain a crude BZ 07;
(5) preparation and liquid phase separation: and (3) using octadecylsilane chemically bonded silica as a filler, using water and methanol as mobile phases, taking the crude BZ07 obtained in the step (4), performing gradient elution separation on a prepared liquid phase, collecting a separated solution of BZ07, concentrating and drying under reduced pressure to obtain 363mg of the benvitimod impurity BZ07 (formula II), wherein the yield is 3.2%.
The preparation method of the invention can also select other demethylating reagents to replace pyridine hydrochloride, such as aluminum trichloride and boron tribromide.
The preparation method of the invention can also select other crystallization reagents instead of methanol, such as dichloromethane.
The structure of the BZ07 impurity is characterized by high-resolution mass spectrometry, nuclear magnetic resonance hydrogen spectroscopy and nuclear magnetic resonance carbon spectroscopy. FIG. 2 shows the LC-MS spectrum of BZ07 impurity (A is TIC diagram; B is UV diagram). The high-resolution mass spectrum of BZ07 impurity is shown in FIG. 3, and HRMS (ESI): m/z 269.15[ M + H ]]+、310.18[M+Na+H2O+H]+. Of BZ07 impurity1The H-NMR spectrum is shown in FIG. 4, (600MHz, MeOD) Δ: 1.35(d, 6H), 2.22(s, 3H)3.54(m, 1H), 6.66(s, 1H), 6.87(d, 1H), 7.23(t, 1H), 7.34(m, 3H), 7.50(d, 2H). Of BZ07 impurity13The C-NMR spectrum is shown in FIG. 5, (150MHz, MeOD) delta 10.54, 19.76, 24.90, 47.62, 104.89, 114.87, 122.13, 125.75, 126.61, 128.27, 134.34, 137.94, 153.15, 153.75.
Example 4
The method for analyzing and detecting the p-styrenimod raw material or preparation by taking BZ07 prepared by the invention as an impurity reference substance comprises the following steps:
taking the impurities of the benvitimod and the BZ07, precisely weighing, dissolving by using a water-acetonitrile (50:50) solution, and diluting to prepare a proper test solution and a proper reference solution. Using octyl silane bonded silica gel as a filling agent; taking water as a mobile phase A and acetonitrile as a mobile phase B; gradient elution was performed as in Table 2, with a detection wavelength of 220nm, a flow rate of 1.0mL per minute, and a column temperature of 25 ℃. If the chromatogram of the test solution has a BZ07 impurity peak, the content of BZ07 is calculated according to an external standard method. The chromatogram of the BZ07 control is shown in FIG. 6.
TABLE 2
In conclusion, the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the benvitimod prepared by the invention has high purity, can be used as a reference substance of impurities in the benvitimod raw material or preparation detection, improves the accurate positioning and qualitative performance of the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol in the production quality control of the benvitimod, is favorable for enhancing the control of the impurities, and improves the quality of the benvitimod preparation, thereby ensuring the safety and effectiveness of the clinical use of the benvitimod preparation.
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. An impurity in benvitimod, which has the following structure:
2. the method for preparing the impurity benvitimod according to claim 1, which is characterized by comprising the following steps: the E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and a demethylating reagent are subjected to demethylation reaction to obtain the impurity 6-methyl-5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, and the specific route is as follows:
3. the method for preparing the impurity benvitimod according to claim 2, which is characterized by comprising the following steps:
(1) taking E-1, 3-dimethoxy-2-isopropyl-5- (2-styryl) -benzene and a demethylating reagent to perform demethylating reaction at the temperature of 140-220 ℃ for 2-20 h;
(2) extracting the reaction product obtained in the step (1) by using an organic solvent, washing by using acid water and crystallizing, and collecting filtrate containing a target product;
(3) and (3) concentrating, enriching and purifying the filtrate obtained in the step (2) to obtain the impurities.
4. The method for preparing the impurity benvitimod according to claim 2 or 3, wherein the demethylating agent is aluminum trichloride, boron tribromide or pyridine hydrochloride.
5. The method for preparing the impurity benvitimod according to claim 3, wherein in the step (2), the organic solvent is tetrahydrofuran, methyl tert-butyl ether or ethyl acetate.
6. The method for preparing the impurity benvitimod according to claim 3, wherein in the step (2), the acid is hydrochloric acid, sulfuric acid or acetic acid.
7. The method for preparing the impurity benvitimod according to claim 3, wherein in the step (2), methanol, n-hexane, toluene or dichloromethane are used as crystallization solvents.
8. The method for preparing the benvitimod impurity according to claim 3, wherein in the step (3), the filtrate is concentrated and then subjected to column chromatography separation to obtain a target product, the specification of column chromatography silica gel is 200-400 meshes, and an elution solvent is a mixture of n-hexane and ethyl acetate.
9. The method for preparing the benvitimod impurity according to claim 8, wherein in the step (3), the purified benvitimod impurity is obtained by further performing preparative liquid phase separation treatment on the target product obtained by the column chromatography separation, and acetonitrile and water are used as a mobile phase for preparing the liquid phase.
10. Use of the impurity in benvitimod according to claim 1 as a reference for impurity detection in quality control of a benvitimod drug substance or formulation.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116003226A (en) * | 2022-12-28 | 2023-04-25 | 山东创新药物研发有限公司 | Synthesis method of present-vitamin mod impurity |
| WO2024061187A1 (en) * | 2022-09-22 | 2024-03-28 | 上海泽德曼医药科技有限公司 | Stilbene derivatives as well as preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024061187A1 (en) * | 2022-09-22 | 2024-03-28 | 上海泽德曼医药科技有限公司 | Stilbene derivatives as well as preparation method therefor and use thereof |
| CN116003226A (en) * | 2022-12-28 | 2023-04-25 | 山东创新药物研发有限公司 | Synthesis method of present-vitamin mod impurity |
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