A method for preparing biphenylbenzazole EP impurity B

Abstract

The application discloses a preparation method of biphenyl benzazole EP impurity B, and steps include: (1) taking a compound shown in formula II and a compound shown in formula III as starting materials to obtain an intermediate compound shown in formula IV through nucleophilic addition, (2) synthesizing a compound shown in formula I through reduction hydrogenation of the compound shown in formula IV to obtain the biphenyl benzazole EP impurity B. Advantages include: the starting materials are cheap and easy to obtain, reaction steps are less, preparation period is short, total yield of the route is high, by-products are less, the route is environment-friendly and no pollutants are generated; the prepared impurity has high purity and fully meets quality requirements of impurity reference substances.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for preparing bifonazole EP impurity B. Background Technology

[0002] Bifonazole EP impurity B, chemically named 4-([1,1'-biphenyl]-4-yl(phenyl)methyl)-1H-imidazole, CAS number 91679-37-7, is one of the key impurities of bifonazole that are explicitly required to be strictly monitored in the European Pharmacopoeia (EP). Its structure is as follows:

[0003] .

[0004] The accuracy of the structure confirmation of this impurity and the stability of the batch supply of standard products directly determine the quality control level of bifonazole raw materials and preparations, and are one of the core quality control indicators to ensure the safety and efficacy of drugs.

[0005] As an unavoidable byproduct in the synthesis of bifonazole, the standard of bifonazole EP impurity B has irreplaceable application value: it is not only an important reference for optimizing the bifonazole production process and controlling the amount of impurity generated, but also a core supporting substance for carrying out drug degradation research (assessing changes in impurities during storage and use) and completing drug registration regulatory applications (meeting the technical requirements of regulatory agencies for impurity control).

[0006] Among the existing industrial synthesis routes, the classic process disclosed by Bayer AG (patent number: US4118487) is one of the mainstream schemes. Its synthesis route is as follows: starting with 4-phenylbenzophenone as the starting material, the key intermediate 4-(chloro(phenyl)methyl)-1,1'-biphenyl is obtained through reduction and chlorination reactions; finally, the intermediate undergoes a substitution reaction with imidazole to obtain crude bifonazole. The C-4 position of the imidazole molecule can participate in the reaction, thereby generating the isomer of bifonazole, namely bifonazole EP impurity B.

[0007] To obtain bifonazole EP impurity B using this method, thionyl chloride ( ) is required. High-risk chlorination reagents such as diimidazole are used, and the yield is low, unstable (less than 10%), and is accompanied by the formation of polychlorinated byproducts (such as diimidazole derivatives), making them unsuitable for the precise preparation of standards. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing bifonazole EP impurity B, so as to solve the problems of unstable yield, low efficiency and environmental unfriendliness of existing production technologies.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A method for preparing bifonazole EP impurity B includes the following steps: (1) using the compound with the structure shown in Formula II and the compound with the structure shown in Formula III as starting materials, the intermediate product compound with the structure shown in Formula IV is obtained by nucleophilic addition; (2) the compound with the structure shown in Formula IV is synthesized by reducing hydrogenation to form the compound with the structure shown in Formula I, thereby obtaining bifonazole EP impurity B.

[0011] The compound with the structure shown in Formula I is named 4-([1,1'-biphenyl]-4-yl(phenyl)methyl)-1H-imidazol; the compound with the structure shown in Formula II is named 4-phenylbenzophenone; the compound with the structure shown in Formula III is named 1-triphenylmethyl-4-iodoimidazole; and the compound with the structure shown in Formula IV is named [1,1'-biphenyl]-4-yl(phenyl)(1-trimethylphenyl-1H-imidazol-4-yl)methanol.

[0012] .

[0013] Further, the process of step (1) includes: dissolving the compound with the structure shown in Formula III in a first solvent, clarifying it, adding Grignard reagent dropwise at low temperature, stirring after the addition is complete, dissolving the compound with the structure shown in Formula II in a second solvent, adding it dropwise to the system containing the compound with the structure shown in Formula III, reacting at room temperature to obtain the compound with the structure shown in Formula IV.

[0014] Furthermore, the amount of the compound with the structure shown in Formula III used is 1.0 to 3.0 equivalents of the molar amount of the compound with the structure shown in Formula II.

[0015] Furthermore, the compound with the structure shown in Formula III dissolves in the first solvent at a concentration of 0.2 to 1.0 mol / L.

[0016] Furthermore, the compound with the structure shown in Formula II dissolves in the second solvent at a concentration of 0.4 to 2.0 mol / L.

[0017] Furthermore, the Grignard reagent is any one of ethyl magnesium bromide, methyl magnesium bromide, or ethyl magnesium chloride, and its amount used is 1.5 to 5.0 equivalents of the molar amount of the compound with the structure shown in Formula II.

[0018] Furthermore, in step (1), the temperature range for adding Grignard reagent is -5 to 10°C, and the reaction time is 0.5 to 2 hours; the reaction temperature range after mixing all raw materials is 25 to 35°C, and the reaction time is 2 to 20 hours.

[0019] Further, the process of step (2) includes: adding the compound with the structure shown in Formula IV to a third solvent, dissolving and clarifying it, adding an acid and a reducing agent, and heating to react.

[0020] Furthermore, the compound with the structure shown in Formula IV is added to the third solvent at a concentration of 0.2 to 1.0 mol / L.

[0021] Further, in step (2), the acid is any one of trifluoroacetic acid, aluminum chloride, or boron trifluoride ether, and the amount used is 5 to 20 equivalents of the molar amount of the compound with the structure shown in Formula IV;

[0022] The reducing agent is any one of triethoxysilane, triethylsilane, and trimethylsilane, and its amount used is 5 to 20 equivalents of the molar amount of the compound with the structure shown in Formula IV;

[0023] The reaction temperature range after adding all materials is 50~75℃, and the reaction time is 1~20 hours.

[0024] The advantages of this invention are as follows: In view of the shortcomings of existing synthesis and preparation techniques for bifonazole EP impurity B, this invention provides a novel synthetic route: using 4-phenylbenzophenone as a raw material, bifonazole EP impurity B can be obtained through a two-step reaction of nucleophilic addition and reductive hydrogenation.

[0025] The raw materials are inexpensive and readily available, the reaction steps are few and the preparation cycle is short, the overall yield is high, and there are few byproducts, making it environmentally friendly and generating no pollutants. The obtained impurities have high purity, fully meeting the quality requirements of impurity reference standards. This method not only provides a new route for the efficient preparation of bifonazole EP impurity B, but also has significant implications for the quality research of bifonazole EP impurity B. Attached Figure Description

[0026] The accompanying drawings, which are included to provide a further understanding of the invention and form part of this application, do not constitute an undue limitation of the invention. In the drawings:

[0027] Figure 1 This is the synthetic route diagram for impurity B of bifonazole EP;

[0028] Figure 2 The image shows the one-dimensional hydrogen NMR spectrum of the compound with the structure shown in Formula IV.

[0029] Figure 3 The mass spectrum of the compound with the structure shown in Formula IV is shown.

[0030] Figure 4 The image shows the one-dimensional hydrogen NMR spectrum of the compound with the structure shown in Formula I.

[0031] Figure 5 The mass spectrum of the compound with the structure shown in Formula I is shown.

[0032] Figure 6 The image shows the high-performance liquid chromatography (HPLC) spectrum of the compound with the structure shown in Formula I. Detailed Implementation

[0033] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

[0034] Example 1

[0035] The specific process for synthesizing the compound shown in Formula IV, based on a molar amount of 1.50 eq for the compound with the structure shown in Formula III, is as follows:

[0036] Take a dry reaction vessel and dissolve the compound with the structure shown in Formula III (6.54 g, 15.00 mmol, 1.50 eq) in dry tetrahydrofuran (30.00 mL), C=0.50 M. After clarification, add 1.00 M tetrahydrofuran solution of ethyl magnesium chloride (20.00 mL, 20.00 mmol, 2.00 eq) dropwise at 0 °C. After the addition is complete, keep warm and stir for 1 hour.

[0037] Dissolve 2.58 g (10.00 mmol, 1.00 eq) of the compound with the structure shown in Formula II in 10.00 mL of dichloromethane (C = 1.00 M). Add this freshly prepared solution dropwise to the system containing the compound with the structure shown in Formula III and react at room temperature for 12 h. After the reaction is complete as monitored by TLC, add 50 mL of saturated ammonium chloride to terminate the reaction.

[0038] Add 100.00 mL of water, allow to stand and separate into layers, collect the organic phase, and extract the aqueous phase with dichloromethane. Combine the organic phases and extract with saturated sodium chloride (SCI). The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain an orange viscous substance. The orange viscous substance was recrystallized from petroleum ether and dichloromethane to give the compound shown in Formula IV, 5.11 g of white solid, yield 90%.

[0039] The proton NMR spectrum data of the compound shown in Formula IV: 1 H NMR (400 MHz, DMSO-d6) δ 7.66–7.59 (m, 2H), 7.58–7.51 (m, 2H), 7.49–7.34 (m, 16H), 7.38–7.30 (m, 1H), 7.30–7.22 (m, 2H), 7.22–7.16 (m, 1H), 7.20–7.07 (m, 6H), 6.77 (d, J=1.5 Hz, 1H), 6.17 (s, 1H), 1.24 (s, 1H), 0.90–0.80 (m, 1H).

[0040] The one-dimensional hydrogen NMR spectrum of the compound with the structure shown in Formula IV is as follows: Figure 2 As shown.

[0041] The mass spectrum of the compound with the structure shown in Formula IV is as follows: Figure 3 As shown.

[0042] The specific process for synthesizing the compound shown in Formula I, based on a molar amount of 1 eq for the compound with the structure shown in Formula IV, is as follows:

[0043] Take a dry reaction vessel, add the compound with the structure shown in Formula IV (4.83 g, 8.50 mmol, 1.00 eq) and dichloromethane (8.50 mL), C=1.00 M, dissolve and clarify, add trifluoroacetic acid (3.25 mL, 42.50 mmol, 5.00 eq) and triethylsilane (6.79 mL, 42.5 mmol, 5.00 eq), and heat to 55 °C. After reacting for 2 hours, the starting materials are completely consumed. After the reaction has returned to room temperature, adjust the pH of the reaction solution to 8-9 with 2.00 M sodium hydroxide aqueous solution, then add 500.00 mL of water and 100.00 mL of dichloromethane for extraction. Allow to stand and separate into layers, collect the organic phase, and extract the aqueous phase with dichloromethane. Combine the organic phases and extract with saturated sodium chloride (SCI). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent, yielding a light yellow oil. The light yellow oil was then purified by column chromatography using silica gel as the stationary phase and a mixed solvent of DCM:MeOH = 20:1 as the mobile phase, yielding the compound shown in Formula I, 1.58 g of white solid, with an HPLC purity of 99.72% and a yield of 60%.

[0044] The proton NMR spectrum data of the compound shown in Formula I: 1 H NMR(400 MHz, DMSO-d6) δ11.93(s,1H), 7.70–7.54(m,5H), 7.44(dd, J = 8.4, 6.9 Hz, 2H), 7.41–7.24 (m ,7H), 7.23–7.18 (m,1H), 6.67 (s, 1H), 5.44 (s, 1H).

[0045] The one-dimensional hydrogen NMR spectrum of the compound with the structure shown in Formula I is as follows: Figure 4 As shown.

[0046] The mass spectrum of the compound with the structure shown in Formula I is as follows: Figure 5 As shown.

[0047] The high-performance liquid chromatography (HPLC) spectrum of the compound with the structure shown in Formula I is as follows: Figure 6 As shown.

[0048] Example 2

[0049] The specific process for synthesizing the compound shown in Formula IV, based on a molar amount of 1.50 eq for the compound with the structure shown in Formula III, is as follows:

[0050] Take a dry reaction vessel and add the compound with the structure shown in Formula III (3.27 g, 7.50 mmol, 1.50 eq) dissolved in dry tetrahydrofuran (7.50 mL), C=1.00 M. After clarification, add 1.00 M tetrahydrofuran solution of ethyl magnesium bromide (10.00 mL, 10.00 mmol, 2.00 eq) dropwise at 0 °C. After the addition is complete, keep warm and stir for 1 hour.

[0051] Dissolve 2.58 g (5.00 mmol, 1.00 eq) of the compound with the structure shown in Formula II in 5.00 mL of dichloromethane (C = 1.00 M). Add this freshly prepared solution dropwise to the system containing the compound with the structure shown in Formula III and react at room temperature for 20 h. After the reaction is complete as monitored by TLC, add 50 mL of saturated ammonium chloride to terminate the reaction.

[0052] Add 100.00 mL of water, allow to stand and separate into layers, collect the organic phase, and extract the aqueous phase with dichloromethane. Combine the organic phases and extract with saturated sodium chloride (SCI). The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain an orange viscous substance. The orange viscous substance was recrystallized from petroleum ether and dichloromethane to give the compound with the structure shown in Formula IV, 2.27 g of white solid, yield 80%.

[0053] The specific process for synthesizing the compound shown in Formula I, based on a molar amount of 1 eq for the compound with the structure shown in Formula IV, is as follows:

[0054] Add the compound with the structure shown in Formula IV (2.84 g, 5.00 mmol, 1.00 eq) and dichloromethane (10.00 mL), C=0.5 M, to a dry single-necked flask. After dissolving and clarifying, add boron trifluoride diethyl ether (6.17 mL, 50.00 mmol, 10.00 eq) and triethylsilane (7.98 mL, 50.00 mmol, 10.00 eq) and heat to 70 °C. After reacting for 1 hour, the starting material is completely consumed. Once the reaction has returned to room temperature, adjust the pH of the reaction solution to 8-9 with a 2.00 M sodium hydroxide aqueous solution. Then add 500.00 mL of water and 100.00 mL of dichloromethane for extraction. Allow to stand and separate the layers. Collect the organic phase and extract the aqueous phase with dichloromethane. Combine the organic phases and extract with saturated sodium chloride (SCI). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was subjected to vacuum distillation to remove the solvent, yielding a light yellow oil. The light yellow oil was then purified by column chromatography using silica gel as the stationary phase and a mixed solvent of DCM:MeOH = 20:1 as the mobile phase, yielding the compound shown in Formula I, a white solid of 0.69 g, with a yield of 45.00%.

[0055] The technical solutions provided by the embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the embodiments of the present invention. The descriptions of the embodiments above are only for helping to understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the embodiments of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A method for preparing bifonazole EP impurity B, characterized in that the steps include... include: (1) Using the compound with the structure shown in Formula II and the compound with the structure shown in Formula III as starting materials, and any one of ethyl magnesium bromide, methyl magnesium bromide, and ethyl magnesium chloride as Grignard reagent, the intermediate compound with the structure shown in Formula IV is obtained by nucleophilic addition. (2) The compound with the structure shown in Formula IV is reduced and hydrogenated by acid and reducing agent to synthesize the compound with the structure shown in Formula I, that is, bifonazole EP impurity B is obtained. The acid is any one of trifluoroacetic acid and boron trifluoride ether, and the reducing agent is any one of triethoxysilane, triethylsilane, and trimethylsilane. .

2. The method for preparing bifonazole EP impurity B according to claim 1, characterized in that, The process of step (1) includes: dissolving the compound with the structure shown in Formula III in a first solvent, clarifying it, adding Grignard reagent dropwise at low temperature, stirring after the addition is complete, dissolving the compound with the structure shown in Formula II in a second solvent, adding it dropwise to a system containing the compound with the structure shown in Formula III, reacting at room temperature to obtain the compound with the structure shown in Formula IV, wherein the first solvent is tetrahydrofuran and the second solvent is dichloromethane.

3. The method for preparing bifonazole EP impurity B according to claim 2, characterized in that, The amount of the compound with the structure shown in Formula III is 1.0 to 3.0 equivalents of the molar amount of the compound with the structure shown in Formula II.

4. The method for preparing bifonazole EP impurity B according to claim 3, characterized in that, The compound with the structure shown in Formula III dissolves in the first solvent at a concentration of 0.2 to 1.0 mol / L.

5. The method for preparing bifonazole EP impurity B according to claim 3, characterized in that, The compound with the structure shown in Formula II dissolves in the second solvent at a concentration of 0.4 to 2.0 mol / L.

6. The method for preparing bifonazole EP impurity B according to claim 2, characterized in that, The amount of Grignard reagent used is 1.5 to 5.0 equivalents of the molar amount of the compound with the structure shown in Formula II.

7. The method for preparing bifonazole EP impurity B according to claim 2, characterized in that, In step (1), the temperature range for adding Grignard reagent is -5 to 10°C, and the reaction time is 0.5 to 2 hours; the reaction temperature range after mixing all raw materials is 25 to 35°C, and the reaction time is 2 to 20 hours.

8. The method for preparing bifonazole EP impurity B according to claim 1, characterized in that, The process of step (2) includes: adding the compound with the structure shown in Formula IV to a third solvent, dissolving and clarifying it, adding an acid and a reducing agent, and heating to react. The third solvent is dichloromethane.

9. The method for preparing bifonazole EP impurity B according to claim 8, characterized in that, The compound with the structure shown in Formula IV was added to the third solvent at a concentration of 0.2 to 1.0 mol / L.

10. The method for preparing bifonazole EP impurity B according to claim 9, characterized in that, In step (2), the amount of acid used is 5 to 20 equivalents of the molar amount of the compound with the structure shown in Formula IV; The amount of reducing agent used is 5 to 20 equivalents of the molar amount of the compound with the structure shown in Formula IV; The reaction temperature range after adding all materials is 50~75℃, and the reaction time is 1~20 hours.

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