Preparation method of medicinal bifonazole

Abstract

The invention belongs to the technical field of medicine refining and purification, and relates to a preparation method of medicinal bifonazole. The process comprises the following steps: reacting 4-phenyl benzhydrol with thionyl chloride and imidazole in a solvent toluene, adding water into the reaction liquid at high temperature, heating an organic phase, slowly adding acyl chloride, heating, stirring, cooling and crystallizing to obtain the bifonazole. The post-treatment process is simple, in the obtained product, the content of imidazole and isomer impurities and dimer impurities generated by reaction is 0.1% or below, the content of other single impurities is smaller than 0.1%, and the purity of the product is higher than 99%. The method has the advantages of low equipment requirement, low energy consumption and low production cost, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a medicinal bifonazole. BACKGROUND

[0002] Bifonazole is a new imidazole local antifungal drug, which has a broad-spectrum antifungal effect on various dermatophytes (such as Trichophyton rubrum, Trichophyton tonsurans, etc.), Candida albicans, dimorphic fungi, filamentous fungi and yeasts, etc.

[0003] At present, the preparation method of bifonazole mainly reported by the original research German Bayer Company (US118487) is as follows: bifonazole is prepared from biphenyl and benzoyl chloride to prepare 4-phenyl benzophenone, 4-phenyl benzophenone is reduced to 4-phenyl benzhydrol, and then reacted with imidazole to prepare bifonazole. Acetonitrile or acetone is used for post-treatment to obtain bifonazole product by recrystallization purification. In this post-treatment purification process, the removal rate of the reaction material imidazole and the isomer impurities and dimer impurities generated in the reaction is low, and multiple purifications are required to control the impurities within the limit, resulting in low product yield and more process, thereby increasing the production cost.

[0004] The purification method is improved in patent CN11674429, the crude bifonazole is once purified by using alcohol-water-acid mixed solvent, and then twice purified by using acetone-water mixed solvent, so as to improve the purity of bifonazole. This method has a complex purification process, increases the production cost, and has a large content of some impurities.

[0005] In patent CN118852020, the purification method is adjusted. In the purification process, an acid anhydride is added, and after reaction, concentration, water washing and concentration, the concentrate is recrystallized in acetonitrile solvent again. This purification method is complex, and the product is obtained by multiple concentration and multiple recrystallization purification, thereby increasing the production cost.

[0006] In patent CN120097918, the purification solvent is adjusted. The crude bifonazole is purified by using a mixed solvent of solvent A and solvent B. Solvent A includes one of ethanol, methanol, isopropyl alcohol, acetone and ethyl acetate, and solvent B includes one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran. It is found by experiment that the removal rate of some impurities is low, and it is difficult to control the residual solvent in the product. SUMMARY

[0007] Based on the existing preparation process of bifonazole, there are problems such as complex preparation process, high impurity content and increased production cost, and the present application provides a bifonazole preparation method with simple process and high impurity removal efficiency.

[0008] The technical scheme of the present application is as follows:

[0009] 4-Phenylenol was obtained by Friedel-Crafts acylation and reduction of biphenyl and benzoyl chloride. 4-Phenylenol was then reacted with thionyl chloride and imidazole in toluene at 80–100 °C. Water was added, and the mixture was stirred and separated. The organic phase of toluene was heated, and acyl chloride was slowly added. The mixture was heated and stirred for 1 hour. After cooling and crystallization, the crystals were filtered and dried to obtain bifonazole.

[0010] 1. Wherein, the acyl chloride is formyl chloride, acetyl chloride, propionyl chloride, benzoyl chloride, or chloroacetyl chloride, with acetyl chloride being preferred.

[0011] 2. Wherein, the ratio of the acyl chloride to 4-phenyldiphenylmethanol is 0.05 to 0.55 g / g, preferably 0.20 to 0.35 g / g.

[0012] 3. Wherein, the temperature of the high-temperature water added after the reaction is 40-100℃, preferably 60-80℃.

[0013] 4. Wherein, the volume ratio of the amount of water added at high temperature after the reaction to 4-phenyldiphenylmethanol is 5:1 to 15:1, preferably 5:1 to 10:1.

[0014] 5. Wherein, the temperature at which the organic phase after separation is added with acyl chloride is 30–100°C, preferably 60–80°C.

[0015] 6. Wherein, the temperature of the stirring and heat preservation after adding acyl chloride is 30-100℃, preferably 60-80℃.

[0016] 7. The stirring and heat preservation time after adding acyl chloride is 1 to 3 hours, preferably 1 hour.

[0017] 8. Wherein, after adding acyl chloride, the cooling and crystallization temperature is 0-40℃, preferably 20-30℃.

[0018] 9. The cooling and crystallization time is 0.5 to 2 hours, preferably 0.5 to 1 hour.

[0019] Compared with the prior art, the present invention has the following obvious advantages:

[0020] The post-processing is simple. After the reaction, water is added to the liquid phase, then acyl chloride is added to the organic phase. After stirring, cooling, and crystallization, the product is filtered and dried to obtain bifonazole. The obtained product contains less than 0.1% of imidazole, isomers, and dimer impurities generated during the reaction, and other single impurities are all less than 0.1%, with a product purity exceeding 99%. The production requires minimal equipment, consumes little energy, has low production costs, and is easy to promote and implement. Attached Figure Description

[0021] Figure 1This is the related substances liquid phase (HPLC) spectrum of the bifonazole reaction solution.

[0022] Figure 2 This is the liquid chromatography (HPLC) spectrum of bifonazole-related substances prepared in Example 1. Detailed Implementation

[0023] The present invention can be better understood from the following embodiments. At the same time, those skilled in the art should understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as described in detail in the claims.

[0024] Example 1

[0025] Add 5L of toluene to a 20L reaction flask, start stirring, and then add 0.73kg of imidazole, 0.32kg of thionyl chloride, and 0.50kg of 4-phenyldiphenylmethanol sequentially. Heat to 80℃ and react for 15 hours, monitoring for completion. Cool the reaction solution to 60℃, add 5.00kg of water, stir, separate the liquids, collect the organic phase, maintain the temperature at 60℃, add 0.20kg of acetyl chloride, stir for 1 hour, cool to 20℃, stir for 1 hour, filter, and dry the filter cake to obtain 0.46kg of bifonazole, yield 77.3%.

[0026] Example 2

[0027] Add 5L of toluene to a 20L reaction flask, start stirring, and then add 0.73kg of imidazole, 0.32kg of thionyl chloride, and...

[0028] 0.50 kg of 4-phenyldiphenylmethanol was added and heated to 90 °C for 15 h, with the reaction monitored until completion. The reaction solution was cooled to 70 °C, and 5.00 kg of water was added. The mixture was stirred, separated, and the organic phase was collected. The temperature was maintained at 70 °C, and 0.30 kg of acetyl chloride was added. The mixture was stirred for 1 h, cooled to 25 °C, stirred for 1 h, filtered, and the filter cake was dried to obtain 0.486 kg of bifonazole, with a yield of 81.6%.

[0029] Example 3

[0030] Add 5L of toluene to a 20L reaction flask, start stirring, and then add 0.73kg of imidazole, 0.32kg of thionyl chloride, and 0.50kg of 4-phenyldiphenylmethanol sequentially. Heat to 100℃ and react for 15 hours, monitoring for completion. Cool the reaction solution to 80℃, add 5.00kg of water, stir, separate the liquids, collect the organic phase, maintain the temperature at 80℃, add 0.35kg of acetyl chloride, stir for 1 hour, cool to 30℃, stir for 1 hour, filter, and dry the filter cake to obtain 0.471kg of bifonazole, yield 79.1%.

[0031] Comparative Example 1

[0032] 1 L of toluene was added to a 3 L reaction flask, and stirring was started. 0.15 kg of imidazole, 0.06 kg of thionyl chloride, and 0.10 kg of 4-phenyldibenzyl alcohol were added sequentially. The mixture was heated to 80–100 °C and reacted for 15 h, monitoring for completion. The reaction solution was cooled to 60–80 °C, and 1.00 kg of water was added. The mixture was stirred, separated, and the organic phase was collected. The temperature was maintained at 60–80 °C, and 0.05 kg of formyl chloride was added. The mixture was stirred for 1 h, cooled to 20–30 °C, stirred for 1 h, filtered, and the filter cake was dried to obtain 86.5 g of bifonazole, with a yield of 72.7%.

[0033] Comparative Example 2

[0034] 1L of toluene was added to a 3L reaction flask, and stirring was started. 0.15kg of imidazole, 0.06kg of thionyl chloride, and 0.10kg of 4-phenyldibenzyl alcohol were added sequentially. The mixture was heated to 80-100℃ and reacted for 15 hours. After monitoring the reaction to complete, the reaction solution was cooled to 60-80℃, and 1.00kg of water was added. The mixture was stirred, separated, and the organic phase was collected. The temperature was controlled at 60-80℃, and 0.05kg of propionyl chloride was added. The mixture was stirred for 1 hour, cooled to 20-30℃, and stirred for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 83.5g of bifonazole, with a yield of 70.2%.

[0035] Comparative Example 3

[0036] 0.2 L of toluene was added to a 1 L reaction flask, and stirring was started. 30.1 g of imidazole, 12.8 g of thionyl chloride, and 20 g of 4-phenyldibenzyl alcohol were added sequentially. The mixture was heated to 80–100 °C and reacted for 15 h. After monitoring the reaction to complete, the reaction solution was cooled to 60–80 °C, and 200 g of water was added. The mixture was stirred, separated, and the organic phase was collected. The temperature was controlled at 60–80 °C, and 6 g of benzoyl chloride was added. The mixture was stirred for 1 h, cooled to 20–30 °C, and stirred for 1 h. The mixture was filtered, and the filter cake was dried to obtain 14.9 kg of bifonazole, with a yield of 62.8%.

[0037] The product quality and yield statistics for all embodiments and comparative examples are shown in Table 1:

[0038] Serial number Bifonazol Imidazole Isomer impurities Dimer impurities Yield Example 1 99.53％ Not detected 0.02％ 0.04％ 77.3％ Example 2 99.62％ Not detected 0.03％ 0.02％ 81.6％ Example 3 99.58％ Not detected 0.04％ 0.05％ 79.1％ Comparative example 1 99.45％ Not detected 0.06％ 0.05％ 72.7％ Comparative example 2 99.32％ Not detected 0.05％ 0.07％ 70.2％ Comparative example 3 99.40％ Not detected 0.07％ 0.03％ 62.8％

[0039] The above embodiments and exemplary examples are merely detailed descriptions of this application and should not be construed as limiting the application. Those skilled in the art can make various equivalent substitutions, modifications, or improvements to the technical solutions and implementation methods of this application without departing from the spirit and scope of this application, and all such modifications and improvements fall within the protection scope of this application.

Claims

1. A method for preparing a pharmaceutical biphenyl benzazole, comprising the following steps: 1) preparing 2-phenyl benzophenone by subjecting biphenyl to Friedel-Crafts acylation with benzoyl chloride; 2) preparing 4-phenyl benzhydrol by reducing the 2-phenyl benzophenone; 3) preparing the biphenyl benzazole by subjecting the 4-phenyl benzhydrol to reaction with thionyl chloride and imidazole in a solvent of toluene.

4. The method according to claim 1, wherein the biphenyl benzazole is prepared by the following steps: 1) preparing 2-phenyl benzophenone by subjecting biphenyl to Friedel-Crafts acylation with benzoyl chloride; 2) preparing 4-phenyl benzhydrol by reducing the 2-phenyl benzophenone; 3) preparing the biphenyl benzazole by subjecting the 4-phenyl benzhydrol to reaction with thionyl chloride and imidazole in a solvent of toluene; 4) adding acyl chloride to the reaction solution after the reaction of the 4-phenyl benzhydrol with thionyl chloride and imidazole in the solvent of toluene, and then heating, stirring, cooling and crystallizing to obtain the biphenyl benzazole. characterized in that 5. The method according to claim 4, wherein the acyl chloride is one or more of formyl chloride, acetyl chloride, propionyl chloride, benzoyl chloride and chloroacetyl chloride.

2. The process for preparing bipenazole as claimed in claim 1, wherein, 6. The method according to claim 4, wherein the ratio of the acyl chloride to the 4-phenyl benzhydrol is 0.05-0.55 g / g.

3. The method for preparing bifonazole as described in claim 1, characterized in that, 7. The method according to claim 4, wherein the temperature of the high-temperature water addition is 40-100℃.

4. The method for preparing bifonazole as described in claim 1, characterized in that, 8. The method according to claim 4, wherein the ratio of the water amount to the volume of the 4-phenyl benzhydrol is 5:1-15:

1.

5. The process for preparing bipenazole as claimed in claim 1, wherein, ###00002### bipenazole.

9. The method according to claim 4, wherein the temperature of the acyl chloride addition is 30-100℃.

6. The process according to claim 1, wherein the biphenylbenzazole is prepared by the reaction of biphenyl-4,4'-dicarboxylic acid with 2-aminobenzimidazole in the presence of a base.

10. The method according to claim 4, wherein the temperature of the post-acyl chloride addition heating and stirring is 30-100℃.

7. The process according to claim 1, wherein the biphenylbenzazole is prepared by the reaction of biphenyl-4,4'-dicarboxylic acid with 2-aminobenzimidazole in the presence of a base.

11. The method according to claim 4, wherein the temperature of the cooling and crystallization is 0-30℃.

8. The process according to claim 1, wherein the biphenylbenzazole is prepared by the reaction of biphenyl-4,4'-dicarboxylic acid with 2-aminobenzimidazole in the presence of a base.

12. The method according to claim 4, wherein the time of the cooling and crystallization is 0.5-2 h.

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