A method for synthesizing biphenyl benzazole

Abstract

This invention discloses a method for synthesizing bifonazole, belonging to the field of pharmaceutical synthesis technology. The method uses 4-phenyldibenzyl alcohol and imidazole as raw materials, and phosphorus tribromide, phosphorus trichloride, or phosphorus oxychloride as condensing agents, to directly condense bifonazole in a solvent. The reaction conditions are mild, can be carried out at room temperature, the reaction is complete with few impurities, and the yield is high; it has low equipment requirements and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and more specifically, to a method for synthesizing bifonazole. Background Technology

[0002] Bifonazole (trade name Canespor), also known as Bifonazole, is an imidazole antifungal drug that specifically inhibits the synthesis of ergosterol by fungi, disrupts the cell wall structure of fungi, and suppresses fungal growth. It can be used to treat skin lesions caused by fungal infections, including tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor, and tinea scrotum.

[0003] Currently, the main method for synthesizing bifonazole is to reduce 4-phenylbenzophenone to 4-phenylbenzyl alcohol, then use thionyl chloride to chlorinate the alcohol, and finally replace it with imidazole to obtain bifonazole. This method was first proposed by Bayer (DE 2643563). In addition, there are other reported methods for synthesizing bifonazole.

[0004] Patent IT8522818A0 proposes a one-step reaction of 4-phenylbenzophenone with imidazole and formic acid to obtain bifonazole. The drawback is the high reaction temperature.

[0005] Chinese patent CN 107459486A proposes a method to synthesize bifonazole directly from 4-phenylbenzophenone using a one-pot reaction with imidazole without further treatment after reduction with potassium borohydride. However, using imidazole, which is solid at room temperature, as a solvent requires high-temperature dissolution (195°C), and in industrial production, the reaction is highly susceptible to sequestration after cooling. Furthermore, the reduction with potassium borohydride generates a large amount of hydrogen gas, posing a significant safety hazard under high-temperature reaction conditions.

[0006] Chinese patent CN 1429214A proposes to use a microwave reactor to realize the direct reaction of 4-phenyldibenzyl alcohol and imidazole to obtain bifonazole. However, using this reaction device requires a small batch feed, and the equipment is special, with strict requirements for the plant and process, making it difficult to produce on a large scale.

[0007] Chinese patent CN 104788439A proposes a direct synthesis of bifonazole from 4-phenyldiphenylmethanol and readily available diimidazolium sulfoxide. However, the purification of the crude bifonazole is extremely difficult: recrystallization with single solvents such as acetonitrile, acetone, ethyl acetate, isopropanol, and toluene yields low yields and has very poor impurity removal; recrystallization with dual solvents such as methanol / water, ethanol / water, and acetone / water only yields a viscous semi-solid. This route makes it difficult to obtain pure bifonazole using slurrying or recrystallization methods. Currently, the best purification method is column chromatography, but industrial production costs are relatively high.

[0008] US Patent 4118487 reports the reduction of 4-phenylbenzophenone to obtain 4-phenylbenzyl alcohol, followed by a substitution reaction with thionyl chloride to obtain 4-(biphenyl)chlorophenylmethane, and then a substitution reaction with imidazole to obtain crude bifonazole, with a maximum yield of 56%. Chinese Patent CN 116874429A further refines this process through secondary dissolution and crystallization to improve purity. However, it still suffers from low yield, complex refining process, and high equipment requirements, making it unsuitable for large-scale production.

[0009] The literature Chem. 2019, 5, 2718–2730 mentions that after 4-phenyldiphenylmethanol reacts with methanesulfonyl chloride (MsCl), it is then replaced with imidazole. However, 4-phenyldiphenylmethanol and MsCl cannot react completely, with about half of the raw material remaining, resulting in a low overall yield. Summary of the Invention

[0010] Addressing the technical challenges of existing bifonazole processes, such as high impurity content, low yield, difficult purification, and high process risk, this invention aims to provide a method for synthesizing bifonazole. This method utilizes phosphorus tribromide, phosphorus trichloride, or phosphorus oxychloride as catalysts to directly condense 4-phenyldibenzyl alcohol with imidazole to obtain bifonazole. This route offers mild reaction conditions, low equipment requirements, complete reaction, low impurity content, and high yield. Pure bifonazole can be obtained through simple two-solvent recrystallization.

[0011] To achieve the above objectives, the technical solution of the present invention is as follows:

[0012] A method for synthesizing bifonazole involves using 4-phenyldibenzyl alcohol and imidazole as raw materials, and phosphorus tribromide, phosphorus trichloride, or phosphorus oxychloride as condensing agents, to directly condense bifonazole in a solvent.

[0013] The reaction process is as follows:

[0014]

[0015] Furthermore, the molar ratio of the 4-phenylbenzyl alcohol to the condensing agent is 1:0.3 to 2. Too much or too little condensing agent will reduce the final yield; a molar ratio of 1:1 is preferred.

[0016] Furthermore, the condensing agent is phosphorus tribromide, phosphorus trichloride, or phosphorus oxychloride. Phosphorus tribromide is preferred.

[0017] Further, the molar ratio of 4-phenyldiphenylethanol to imidazole is 1:2 to 8. Preferably, the molar ratio is 1:3.8.

[0018] Further, the solvent includes any one of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, and acetone. Dichloromethane is preferred.

[0019] Furthermore, the mass ratio of 4-phenyldiphenylethanol to solvent is preferably 1:15.

[0020] Furthermore, the condensation reaction is carried out at a temperature of 10°C to 100°C for a time of 1 hour to 17 hours.

[0021] Furthermore, the condensation reaction is preferably carried out at room temperature for 12 hours.

[0022] Furthermore, the process includes adding water and solvent after the condensation reaction is complete, adjusting the pH, allowing the mixture to stand and separate, extracting the aqueous phase with the solvent, combining the organic phases, and concentrating to obtain the crude product. The preferred pH range is 7–8.

[0023] Furthermore, the method also includes recrystallizing the crude product, wherein the solvent for recrystallization is any one of methanol / water, acetonitrile / water, or ethanol / water. Preferably, the solvent for recrystallization is methanol / water or ethanol / water.

[0024] It should be noted that the 4-phenyldiphenylethanol in this application can be synthesized according to patent DE 2643563, or a commercially available product can be purchased directly. Outside the preferred parameter range, the yield and purity of the reaction will decrease.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] The synthesis method provided by this invention only requires a common enamel kettle, with simple equipment and low requirements; the reaction process can be carried out at room temperature, or only requires simple water bath or steam bath heating, without involving high temperature, and the reaction risk is low; the reaction is complete with few impurities and high yield, and pure bifonazole can be obtained by simple dual solvent recrystallization, which is suitable for large-scale production. Detailed Implementation

[0027] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways than those described herein, and similar modifications can be made by those skilled in the art without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. It should be noted that the reagents and other materials used in these embodiments are all commercially available products.

[0029] Example 1

[0030] 20.01 g of 4-phenylbenzophenone was added to 100.0 mL of ethanol, followed by the slow addition of 2.61 g of sodium borohydride. The mixture was then slowly heated to 78 °C. After the reaction was complete, an aqueous solution of sodium hydroxide was added, followed by 200.0 mL of water. The mixture was cooled to room temperature, filtered, and the solution was slurried with 200.0 mL of water. After filtration and drying, 19.84 g of a white solid, 4-phenylbenzoethanol, was obtained in 99% yield.

[0031] 1.00 g of 4-phenyldiphenylmethanol (M = 260.33000 g / mol, 0.0038 mol) was added to 5.00 g of dichloromethane, followed by dropwise addition of 1.00 g of phosphorus tribromide (M = 270.686 g / mol, 0.0036 mol), and then 1.00 g of imidazole (M = 68.077 g / mol, 0.015 mol). The reaction was allowed to proceed overnight. After the reaction was completed, 10.0 mL of water and 20.0 mL of dichloromethane were added, followed by 11.18 g of potassium hydroxide aqueous solution. The mixture was stirred until both phases were clear, allowed to stand, and separated. The aqueous phase was extracted with 10.0 mL of dichloromethane, and the organic phases were combined and washed twice with 20.0 mL of water. The organic phase was concentrated to a solid and recrystallized from it using methanol / water at a ratio of 2:1 to give 0.83 g of a white solid, 70% yield, with a purity of 99% according to pharmacopoeia methods.

[0032] Example 2

[0033] 40.00 g of 4-phenylbenzophenone was added to 200.0 mL of ethanol, followed by the slow addition of 5.20 g of sodium borohydride. The mixture was then slowly heated to 78 °C. After the reaction was complete, an aqueous sodium hydroxide solution was added, followed by 37.83 mL of water. The mixture was cooled to room temperature, and then 362.17 mL of water was added. The mixture was filtered, slurried with 400.0 mL of water, filtered, and dried to obtain 40.01 g of a white solid, 4-phenylbenzoethanol, in 99% yield.

[0034] 10.00 g of 4-phenylbenzyl alcohol was added to 100.00 g of dichloromethane, and 10.00 g of phosphorus tribromide was added dropwise. The mixture was stirred at room temperature for 2 hours, and then a dichloromethane solution of imidazole (10.00 g imidazole, 50.00 g dichloromethane) was added. The mixture was stirred overnight at room temperature. After the reaction was completed, 40.0 mL of water was added, followed by an aqueous solution of potassium hydroxide (5.36 g potassium hydroxide, 53.64 g water). The pH was adjusted to 7-8, and the mixture was filtered. The filtrate was allowed to stand and separated. The aqueous phase was extracted with 10.0 g of dichloromethane, and the organic phases were combined and washed with 20.0 mL of water twice. After the organic phase was concentrated, it was recrystallized from methanol / water at a ratio of 2:1 to give 9.88 g of white solid, with a yield of 83% and a purity of 98% according to pharmacopoeia methods.

[0035] Example 3

[0036] 5.01 g of 4-phenylbenzyl alcohol (M = 260.33000 g / mol, 0.019 mol) was added to 75.31 g of dichloromethane, followed by dropwise addition of 5.12 g of phosphorus tribromide (M = 270.686 g / mol, 0.019 mol), and then 5.01 g of imidazole (M = 68.077 g / mol, 0.073 mol). The reaction was allowed to proceed overnight. After the reaction was completed, an aqueous solution of potassium hydroxide (6.01 g potassium hydroxide, 50.0 g / mol) was added. The aqueous phase was stirred with 10.0 mL of dichloromethane until both phases were clear, pH 10–11. The mixture was allowed to stand and separated. The aqueous phase was extracted with 10.0 mL of dichloromethane, and the organic phases were combined and washed twice with 20.0 mL of water. The organic phase was concentrated to a solid to give 5.49 g of crude product, a light brown solid, with a yield of 92% and a purity of 95% according to pharmacopoeia methods. 2.00 g of the crude product was recrystallized from methanol / water at a ratio of 4:1 to give 1.54 g of white solid, with a yield of 77% and a purity of 99% according to pharmacopoeia methods.

[0037] Example 4

[0038] 2.02 g of 4-phenylbenzyl alcohol was added to 20.13 g of dichloromethane, and 2.01 g of phosphorus tribromide was added dropwise. The mixture was heated to 40 °C and reacted for 1 h. A dichloromethane solution of imidazole (2.01 g imidazole, 20.14 g dichloromethane) was added, and the mixture was reacted overnight at 40 °C. After the reaction was completed, 8.15 mL of water and 20.45 g of dichloromethane were added, followed by an aqueous solution of potassium hydroxide (1.07 g potassium hydroxide, 10.73 g water). The pH was adjusted to 7–8, and the mixture was filtered. The filtrate was allowed to stand and separated. The aqueous phase was extracted with 5.00 g of dichloromethane. The organic phases were combined and washed with 10.0 mL × 2 water. The organic phase was concentrated to obtain a crude product, 2.25 g, white solid, 94% yield, with a purity of 96% according to pharmacopoeia methods. The crude product was recrystallized from an acetonitrile / water system to give 1.36 g of a white solid, 60% yield, with a purity of 99% as determined by pharmacopoeia methods.

[0039] Example 5

[0040] 10.00 g of 4-phenylbenzyl alcohol was added to 100.00 g of dichloromethane, and 10.00 g of phosphorus tribromide was added dropwise. The reaction was carried out at room temperature for 2 h. A dichloromethane solution of imidazole (10.00 g imidazole, 50.00 g dichloromethane) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, potassium hydroxide aqueous solution was added to adjust the pH to 7-8. The mixture was filtered, and the filtrate was allowed to stand and separated. The aqueous phase was extracted with 10.00 g of dichloromethane, and the organic phases were combined and washed with 20.0 mL × 2 water. The organic phase was concentrated to a solid and dried with methanol entrainment. Recrystallization was then performed using methanol / water at a 1:1 ratio to give 11.51 g of a white solid (96% yield, 97% purity according to pharmacopoeia methods). Recrystallization was performed again using methanol / water at a 4:3 ratio to give 10.59 g of a white solid (92% yield, 99% purity according to pharmacopoeia methods).

[0041] Example 6

[0042] 2.00 g of 4-phenylbenzyl alcohol was added to 20.00 g of dichloromethane, and 0.60 g of phosphorus tribromide was added dropwise. The reaction was carried out at room temperature for 2 h. A dichloromethane solution of imidazole (2.00 g imidazole, 10.00 g dichloromethane) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, potassium hydroxide aqueous solution was added to adjust the pH to 7–8. The mixture was filtered, and the filtrate was allowed to stand and separated. The aqueous phase was extracted with 5.00 g of dichloromethane. The organic phases were combined and washed with 10.0 mL × 2 water. The organic phase was concentrated to a solid and recrystallized from it using methanol / water at a ratio of 2:1 to give 1.34 g of an off-white solid, 56% yield, with a purity of 95% according to pharmacopoeia methods.

[0043] Example 7

[0044] 2.00 g of 4-phenylbenzyl alcohol was added to 20.00 g of dichloromethane, and 4.00 g of phosphorus tribromide was added dropwise. The reaction was carried out at room temperature for 2 h. A dichloromethane solution of imidazole (3.00 g imidazole, 10.00 g dichloromethane) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, potassium hydroxide aqueous solution was added to adjust the pH to 7–8. The mixture was filtered, and the filtrate was allowed to stand and separated. The aqueous phase was extracted with 5.00 g of dichloromethane, and the organic phases were combined and washed with 10.0 mL × 2 water. The organic phase was concentrated to a solid and recrystallized from it using methanol / water at a ratio of 2:1 to give 1.99 g of an off-white solid, with a yield of 83% and a purity of 93% according to pharmacopoeia methods.

[0045] Example 8

[0046] 2.00 g of 4-phenyldiphenylmethanol was added to 10.00 g of DMF, followed by dropwise addition of 2.00 g of phosphorus tribromide. The reaction was carried out at 100°C for 1 h. Then, 2.00 g of imidazole was added, and the reaction was carried out at 100°C for 2 h. After the reaction was completed, the mixture was cooled, water was added, and the mixture was filtered. The filter cake was washed with water. 1.61 g of an off-white solid was obtained, with a yield of 68% and a purity of 91% as determined by pharmacopoeia methods.

[0047] Example 9

[0048] 2.00 g of 4-phenylbenzyl alcohol was added to 20.00 g of dichloromethane, and 2.00 g of phosphorus trichloride was added dropwise. The reaction was carried out at room temperature for 2 h. A dichloromethane solution of imidazole (3.00 g imidazole, 10.00 g dichloromethane) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, potassium hydroxide aqueous solution was added to adjust the pH to 7–8. The mixture was filtered, and the filtrate was allowed to stand and separated. The aqueous phase was extracted with 5.00 g of dichloromethane. The organic phases were combined and washed with 10.0 mL × 2 water. The organic phase was concentrated to a solid and recrystallized from it using methanol / water at a ratio of 4:1 to give 1.45 g of an off-white solid, with a yield of 61% and a purity of 92% according to pharmacopoeia methods.

[0049] Example 10

[0050] 2.00 g of 4-phenylbenzyl alcohol was added to 20.00 g of dichloromethane, and 2.00 g of phosphorus oxychloride was added dropwise. The reaction was carried out at room temperature for 2 h. A dichloromethane solution of imidazole (3.00 g imidazole, 10.00 g dichloromethane) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, potassium hydroxide aqueous solution was added to adjust the pH to 7–8. The mixture was filtered, and the filtrate was allowed to stand and separated. The aqueous phase was extracted with 5.00 g of dichloromethane. The organic phases were combined and washed with 10.0 mL × 2 water. The organic phase was concentrated to a solid and recrystallized from it using methanol / water at a ratio of 4:1 to give 1.52 g of an off-white solid, with a yield of 64% and a purity of 91% according to pharmacopoeia methods.

[0051] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing bifonazole, characterized in that, Bifonazole was obtained by direct condensation in a solvent using 4-phenyldiphenylmethanol and imidazole as raw materials and phosphorus tribromide as the condensing agent; the molar ratio of 4-phenyldiphenylmethanol to the condensing agent was 1:0.3~2; the condensation reaction was carried out at room temperature; after the condensation reaction was completed, water and solvent were added, the pH was adjusted to 7~8, the mixture was allowed to stand and separated, the aqueous phase was extracted with solvent, the organic phases were combined and concentrated to obtain a crude product; the crude product was recrystallized, and the solvent for recrystallization was any one of methanol / water or ethanol / water.

2. The method for synthesizing bifonazole according to claim 1, characterized in that, The molar ratio of 4-phenyldiphenylethanol to imidazole is 1:2 to 8.

3. The method for synthesizing bifonazole according to claim 1, characterized in that, The solvent includes any one of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, and acetone.

4. The method for synthesizing bifonazole according to claim 1, characterized in that, The condensation reaction takes 1 to 17 hours.

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