Preparation method of bromophenolic acid impurity
The preparation of bromophenolate impurities through a series of steps has solved the problem of lack of synthetic methods in the prior art, achieved the preparation of high-purity impurities, and provided high-quality standard products for drug quality control and API sodium bromophenolate analysis and detection.
Patent Information
- Application Number
- CN202510090973.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-21
- Publication Date
- 2025-04-29
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The lack of synthesis methods of bromophenolic acid impurities in the prior art makes it difficult to provide high-quality impurity standards for drug quality control and analysis and detection of API sodium bromophenolate.
The bromophenol acid impurity compound VII is finally obtained by a series of steps, including the dissolution of Compound I and Compound II, the reaction of adding a catalyst and a base, the dehydrogenation reaction, the reaction of adding Lewis acid and bromination reagent.
The preparation of high-purity bromophenolate impurities is achieved, with a purity of up to 97%, and high-quality impurity standards are provided for drug quality control and analysis and detection of API sodium bromophenolate.
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Figure CN119899145A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of compound synthesis, and in particular to a method for preparing bromophenolic acid impurities. Background Art
[0002] With the progress of the times and the improvement of science and technology, people have a more comprehensive understanding of the importance of scientific evaluation of the quality, safety and efficacy of drugs before they are put on the market. Among them, the control of impurities contained in drugs is closely related to the quality of drugs. Impurities are often directly related to the safety of drugs. Pharmacopoeias of various countries have made strict regulations on the content and types of drug impurities. According to the requirements of the International Conference on Harmonization of Technical Specifications for Registration of Pharmaceuticals for Human Use (ICH) guidelines, the limit of impurities in drugs is only 0.10% (the limit for toxic drugs is lower), and all unknown impurities above this level should be identified and quantified. In addition, toxicity studies should be conducted on these impurities. Therefore, the determination of related substances is very necessary to ensure the quality of drugs and the safety and effectiveness of medication. High-quality reference substances or standard substances for impurities related to raw materials are important substances in the implementation of this monitoring work.
[0003] Bromfenac, chemically known as 2-amino-3-(4-bromobenzoyl)phenylacetic acid, is a nonsteroidal anti-inflammatory drug developed by Japan's Senju Pharmaceutical Co., Ltd. and approved for marketing by Japan's PMDA in March 2000. It is used for symptomatic treatment of inflammatory diseases of the external eye and anterior eye.
[0004] Journal of Chromatographic Science (2016), 54(9), 1514-1521. The literature points out that compound VII is an impurity of bromophenolic acid, with the following structural formula and chemical name: (3,3'-dibromo-1H,1'H-[5,5'-biindole]-7,7'-diyl)bis((4-bromophenyl)methanone), molecular weight of 756.09, molecular formula of C30H16Br4N2O2, and can provide assistance for the development of analytical detection methods for API sodium bromophenolate:
[0005]
[0006] According to the survey, there is no literature reporting its synthesis method. As a relatively important impurity of bromophenolic acid, it should be given high attention in quality research and formulation research. Therefore, it is necessary to design a synthesis method for this compound to provide high-quality impurity standards for subsequent research. Summary of the invention
[0007] Purpose of the invention: In view of the shortcomings and defects of the prior art, the present invention provides a method for preparing bromophenolic acid impurities. The synthesis process is reasonably designed and has strong operability. The reagents used in the preparation method are simple and easy to obtain. Bromophenolic acid impurities with higher purity can be obtained, and high-quality impurity standards can be provided for subsequent research.
[0008] Technical solution: A method for preparing bromophenolic acid impurities of the present invention is characterized by comprising the following steps:
[0009] 1) Dissolve compound I in an organic solvent:
[0010]
[0011] 2) Dissolve compound II in the organic solvent of step 1):
[0012]
[0013] 3) Adding a catalyst and a base to the mixed solution obtained in step 2) to react to obtain compound III:
[0014]
[0015] 4) Compound III is dissolved in an organic solvent and subjected to a dehydrogenation reaction to obtain compound IV:
[0016]
[0017] 5) Dissolve compound V in an organic solvent:
[0018]
[0019] 6) Compound IV is dissolved in the organic solvent of step 5), and Lewis acid is added to react to obtain compound VI:
[0020]
[0021] 7) Compound VI is dissolved in a solvent, and a bromination reagent is added to react to obtain compound VII, i.e., bromophenolic acid impurity:
[0022]
[0023] Wherein, the organic solvent in steps 1) and 2) is toluene, DMF, dioxane or ethanol.
[0024] Wherein, the catalyst in step 3) is palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium or palladium carbon; the base is Cs 2 CO 3 , K 2 CO 3、Na 2 CO 3 Or Li 2 CO 3 .
[0025] Wherein, in the step 3), the compound I is 1 equivalent, the compound II is 0.8-3 equivalents, and the base is 1-5 equivalents; the reaction temperature is 0-150° C., and the reaction time is 3h-24h.
[0026] Preferably, the base is Cs 2 CO 3 The reaction solvent is toluene, the compound I is 1 equivalent, the compound II is 1.1 equivalents, the base is 2 equivalents, the palladium catalyst is tetrakis(triphenylphosphine)palladium, the reaction temperature is 100°C, and the reaction time is 12h.
[0027] Wherein, the organic solvent in step 4) is dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene, toluene, xylene or dioxane; the dehydrogenation reagent used in the dehydrogenation reaction is manganese dioxide, oxygen, palladium carbon, tetrachlorobenzoquinone or 2,2,6,6-tetramethylpiperidinoxide.
[0028] Wherein, in the step 4), the dehydrogenation reagent is 1-20 equivalents; the reaction temperature is 0-120° C., and the reaction time is 0.5h-24h.
[0029] Preferably, the dehydrogenation reagent is 15 equivalents; the reaction temperature is 50° C.; the reaction time is 20 h; the reaction solvent is chloroform; and the dehydrogenation reagent is manganese dioxide.
[0030] Wherein, the organic solvent in steps 5) and 6) is dichloromethane, tetrahydrofuran, chloroform or toluene; and the Lewis acid is aluminum trichloride, boron trichloride, zinc chloride, titanium tetrachloride or tin tetrachloride.
[0031] Wherein, in the step 6), the compound V is 1-5 equivalents, the Lewis acid is 1-10 equivalents; the reaction temperature is 0-120°C, and the reaction time is 4h-120h.
[0032] Preferably, the Lewis acid is aluminum chloride, the organic solvent is toluene, the compound V is 1.5 equivalents, the Lewis acid is 3 equivalents; the reaction temperature is 80° C.; and the reaction time is 48 h.
[0033] Wherein, the solvent in step 7) is DMSO, acetonitrile, tetrahydrofuran, dichloromethane or acetic acid; and the bromination reagent is N-bromosuccinimide, liquid bromine or pyridinium tribromide.
[0034] Wherein, in the step 7), the compound VI is 1 equivalent, the amount of solvent is 5-30 times the volume, and the bromination reagent is 1-10 equivalents; the reaction temperature is 0-120° C., and the reaction time is 2h-24h.
[0035] Preferably, the compound VI is 1 equivalent, the amount of solvent is 20 times the volume, the bromination reagent is 3 equivalents; the reaction time is 12 hours; the reaction temperature is 25° C.; the solvent is acetic acid; and the bromination reagent is liquid bromine.
[0036] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the present invention provides a method for synthesizing bromophenic acid impurities, the synthetic process design is reasonable, the operability is strong, and the reagents used in the preparation method are simple and easy to obtain; bromophenic acid impurities with high purity can be obtained, and the correct structure is verified by HNMR and MS characterization, and the purity can reach more than 97%, which provides a control sample for the quality control of the raw material bromophenic acid, and provides assistance for the development of analytical detection methods for API sodium bromophenate, and has important application value in drug declaration. BRIEF DESCRIPTION OF THE DRAWINGS
[0037] Figure 1 The synthetic route of the bromophenolic acid impurity (Compound VII) of the present invention;
[0038] Figure 2 This is the mass spectrum of the bromophenolic acid impurity (Compound VII) prepared in Example 1;
[0039] Figure 3 This is the NMR spectrum of the bromophenolic acid impurity (Compound VII) prepared in Example 1;
[0040] Figure 4 This is the liquid phase spectrum of the bromophenolic acid impurity (Compound VII) prepared in Example 1. DETAILED DESCRIPTION
[0041] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and specific implementation methods.
[0042] Embodiment 1:
[0043] Preparation of compound III: Compound I (5.60 g) was dissolved in 112.0 mL toluene, and 7.48 g of compound II, 22.39 g of cesium carbonate, and 0.56 g of tetrakis(triphenylphosphine)palladium were added. The mixture was stirred at 100 degrees for 12 hours. The reaction was completed on a plate. After purification, 7.61 g of compound III was obtained with a yield of 93.72%.
[0044] Preparation of compound IV: Compound III (8.10 g) was dissolved in 162.0 mL of chloroform, and 44.70 g of manganese dioxide was added. The mixture was stirred at 50 degrees for 20 hours. The reaction was completed on a plate. After treatment and purification, 7.01 g of compound IV was obtained with a yield of 87.84%.
[0045] Preparation of compound VI: Compound IV (6.90 g) was dissolved in 138.0 mL toluene, and 8.11 g of compound V and 13.49 g of aluminum chloride were added. The mixture was stirred at 80 degrees for 48 hours. The reaction was completed on a plate. After treatment and purification, 12.45 g of compound VI was obtained with a yield of 70.06%.
[0046] Preparation of compound VII: Compound VI (12.30 g) was dissolved in 246.0 mL of acetic acid, and 9.86 g of liquid bromine was added. The mixture was stirred at 25 degrees for 12 hours. The reaction was completed by spotting. After treatment and purification, 12.18 g of compound VII was obtained, with a yield of 78.38%. MS: 754.8 [MH] - ; HNMR (DMSO-d6): δ11.87 (s, 2H), 8.10 (s, 2H), 7.78-7.71 (m, 10H), 7.66 (s, 2H); Liquid phase 97.1697%.
[0047] Embodiment 2:
[0048] Preparation of compound III: Compound I (4.00 g) was dissolved in 80.0 mL DMF, and 5.35 g of compound II, 6.78 g of potassium carbonate, and 0.40 g of tetrakis(triphenylphosphine)palladium were added. The mixture was stirred at 100 degrees for 12 hours. The reaction was completed on a plate. After purification, 4.52 g of compound III was obtained with a yield of 77.93%.
[0049] Preparation of compound IV: Compound III (4.40 g) was dissolved in 88.0 mL toluene, 68.67 g chlorobenzoquinone was added, and the mixture was stirred at 110 degrees for 20 hours. The reaction was completed on a plate, and 2.95 g of compound IV was obtained after purification with a yield of 68.29%.
[0050] Preparation of compound VI: Compound IV (2.90 g) was dissolved in 58.0 mL toluene, and 3.41 g of compound V and 5.10 g of zinc chloride were added. The mixture was stirred at 80 degrees for 48 hours. The reaction was completed on a plate. After treatment and purification, 3.88 g of compound VI was obtained with a yield of 51.94%.
[0051] Preparation of compound VII: Compound VI (3.80 g) was dissolved in 76.0 mL of acetic acid, and 3.39 g of N-bromosuccinimide was added. The mixture was stirred at 25 degrees for 12 hours. The reaction was completed on a plate. After treatment and purification, 3.21 g of compound VII was obtained with a yield of 66.87%.
[0052] Embodiment 3:
[0053] Preparation of compound III: Compound I (20.00 g) was dissolved in 400.0 mL toluene, and 26.73 g of compound II, 380.61 g of sodium carbonate, and 2.00 g of tetrakis(triphenylphosphine)palladium were added. The mixture was stirred at 100 degrees for 12 hours. The reaction was completed on a plate. After purification, 16.79 g of compound III was obtained with a yield of 57.89%.
[0054] Preparation of compound IV: Compound III (16.50 g) was dissolved in 330.0 mL toluene, and 91.05 g of manganese dioxide was added. The mixture was stirred at 50 degrees for 20 hours. The reaction was completed on a plate. After treatment and purification, 8.89 g of compound IV was obtained with a yield of 54.81%.
[0055] Preparation of compound VI: Compound IV (8.80 g) was dissolved in 176.0 mL of toluene, and 10.34 g of compound V and 21.56 g of titanium tetrachloride were added. The mixture was stirred at 80 degrees for 48 hours. The reaction was completed on a plate. After treatment and purification, 12.89 g of compound VI was obtained with a yield of 56.88%.
[0056] Preparation of compound VII: Compound VI (12.80 g) was dissolved in 256.0 mL DMSO, and 20.53 g pyridinium tribromide was added. The mixture was stirred at 25 degrees for 12 hours. The reaction was completed by spotting. After purification, 9.05 g of compound VII was obtained with a yield of 55.97%.
[0057] The invention provides a method for synthesizing a bromophenic acid impurity. The synthetic process is reasonably designed and has strong operability. Reagents used in the preparation method are simple and easily available. The bromophenic acid impurity with high purity can be obtained. The structure of the bromophenic acid impurity is verified to be correct through HNMR and MS characterization, and the purity can reach more than 97%. The method provides a control sample for the quality control of the raw material drug bromophenic acid, provides assistance for the development of an analytical detection method for API sodium bromophenate, and has important application value in drug declaration.
Claims
1. A method for preparing bromophenolic acid impurities, characterized in that: The steps include: 1) Dissolve compound I in an organic solvent: 2) Dissolve compound II in the organic solvent of step 1): 3) Adding a catalyst and a base to the mixed solution obtained in step 2) to react to obtain compound III: 4) Compound III is dissolved in an organic solvent and subjected to a dehydrogenation reaction to obtain compound IV: 5) Dissolve compound V in an organic solvent: 6) Compound IV is dissolved in the organic solvent of step 5), and Lewis acid is added to react to obtain compound VI: 7) Compound VI is dissolved in a solvent, and a bromination reagent is added to react to obtain compound VII, i.e., bromophenolic acid impurity:
2. The method for preparing bromophenolic acid impurities according to claim 1, characterized in that: The organic solvent in steps 1) and 2) is toluene, DMF, dioxane or ethanol.
3. The method for preparing bromophenolic acid impurities according to claim 2, characterized in that: The catalyst in step 3) is palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium or palladium on carbon; the base is Cs2CO3, K2CO3, Na2CO3 or Li2CO3.
4. The method for preparing bromophenolic acid impurities according to claim 3, characterized in that: In the step 3), the compound I is 1 equivalent, the compound II is 0.8-3 equivalents, and the base is 1-5 equivalents; the reaction temperature is 0-150° C., and the reaction time is 3h-24h.
5. The method for preparing bromophenolic acid impurities according to claim 1, characterized in that: The organic solvent in step 4) is dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene, toluene, xylene or dioxane; the dehydrogenation reagent used in the dehydrogenation reaction is manganese dioxide, oxygen, palladium carbon, tetrachlorobenzoquinone or 2,2,6,6-tetramethylpiperidinoxide.
6. The method for preparing bromophenolic acid impurities according to claim 5, characterized in that: In the step 4), the dehydrogenation reagent is 1-20 equivalents; the reaction temperature is 0-120° C., and the reaction time is 0.5 h-24 h.
7. The method for preparing bromophenolic acid impurities according to claim 1, characterized in that: In the steps 5) and 6), the organic solvent is dichloromethane, tetrahydrofuran, chloroform or toluene; and the Lewis acid is aluminum trichloride, boron trichloride, zinc chloride, titanium tetrachloride or tin tetrachloride.
8. The method for preparing bromophenolic acid impurities according to claim 7, characterized in that: In the step 6), the compound V is 1-5 equivalents, the Lewis acid is 1-10 equivalents; the reaction temperature is 0-120° C., and the reaction time is 4h-120h.
9. The method for preparing bromophenolic acid impurities according to claim 1, characterized in that: In the step 7), the solvent is DMSO, acetonitrile, tetrahydrofuran, dichloromethane or acetic acid; and the bromination reagent is N-bromosuccinimide, liquid bromine or pyridinium tribromide.
10. The method for preparing bromophenolic acid impurities according to claim 9, characterized in that: In the step 7), the compound VI is 1 equivalent, the solvent volume is 5-30 times the volume, and the bromination reagent is 1-10 equivalents; the reaction temperature is 0-120° C., and the reaction time is 2h-24h.