A method for preparing a pharmaceutical biphenyl benzazole

Abstract

The application belongs to the technical field of medicine purification, and relates to a preparation method of medicinal bifonazole. The preparation method comprises a preparation process of crude bifonazole and a refining process of bifonazole. The refining process of bifonazole is as follows: the obtained crude bifonazole is added into an alcohol-water-acid mixed solvent system for one-time heating dissolution, heat filtration is carried out, and one-time cooling crystallization is carried out; the solid after one-time cooling crystallization is added into an acetone-water mixed solvent system for two-time heating dissolution, and two-time cooling crystallization is carried out; and the solid after two-time cooling crystallization is dried, so that medicinal bifonazole is obtained. According to the preparation method, the maximum single impurity of the prepared bifonazole is not more than 0.1%, the total impurity is not more than 0.5%, and the purity is greater than 99.5%, so that the demand of medicinal preparation production is met. Meanwhile, the preparation method has the advantages of simple operation, high purity of refined products and high yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical purification technology and relates to a method for preparing pharmaceutical-grade bifonazole. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Bifonazole is a novel imidazole-based topical antifungal drug. According to the inventors' research, the current preparation of bifonazole mostly follows the method reported by Bayer (US4118487), where 4-phenylbenzophenone is reduced to 4-phenylbenzyl alcohol, which then reacts with thionyl chloride and imidazole to obtain crude bifonazole. The crude bifonazole is usually recrystallized from acetonitrile or acetone to obtain the final product. Due to the excess imidazole and the ability of the 4-carbon of imidazole to participate in the reaction, imidazole and C-4 isomer impurities are easily retained in bifonazole. Acetonitrile or acetone, the recrystallization solvents, are ineffective at removing these impurities. The inventors' research found that when using a detection method with a wavelength of 254 nm, it is difficult to detect these impurities in bifonazole prepared by recrystallization from acetonitrile or acetone. However, when using a detection method with a wavelength of 210 nm, all of these impurities exceed the standard requirements. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing pharmaceutical-grade bifonazole. The method of the present invention yields bifonazole with a maximum single impurity content of no more than 0.1%, a total impurity content of no more than 0.5%, and a purity greater than 99.5%, meeting the requirements for pharmaceutical formulation production. Furthermore, the preparation method of the present invention also has advantages such as simplicity, ease of operation, and high purity and yield of the purified product.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows:

[0006] On the one hand, a method for preparing pharmaceutical bifonazole includes a process for preparing crude bifonazole and a process for purifying bifonazole;

[0007] The preparation process of crude bifonazole is as follows: 4-phenylbenzophenone is reduced to obtain 4-phenylbenzyl alcohol, which is then subjected to a substitution reaction with thionyl chloride to obtain 4-(biphenyl)chlorophenylmethane, which is then subjected to a substitution reaction with imidazole to obtain crude bifonazole.

[0008] The purification process of bifonazole is as follows: The crude bifonazole is added to an alcohol-water-acid mixed solvent system for a first heating to dissolve, followed by hot filtration and then a first cooling to crystallize. The solid after the first cooling and crystallization is added to an acetone-water mixed solvent system for a second heating to dissolve, followed by a second cooling to crystallize. The solid after the second cooling and crystallization is dried to obtain pharmaceutical-grade bifonazole. In the alcohol-water-acid mixed solvent system, the alcohol is methanol, ethanol, isopropanol, or n-butanol, and the acid is formic acid, glacial acetic acid, or oxalic acid. The ratio of alcohol, water, and acid is 1:0.3–0.7:1.2–2.0 (ml:ml:mg). In the acetone-water mixed solvent system, the volume ratio of acetone to water is 1–10:1.

[0009] This invention addresses the problem that existing bifonazole preparation methods, which only use acetonitrile or acetone for purification, produce products with excessive impurities that do not meet standard requirements at a detection wavelength of 210 nm. Further research into the purification process revealed that by first using an alcohol-water-acid mixed solvent for hot filtration followed by recrystallization, and then using an acetone-water mixed solvent for recrystallization, bifonazole with a purity exceeding 99.5% can be obtained, with a maximum single impurity not exceeding 0.1% and total impurities not exceeding 0.5%, thus meeting the production requirements for pharmaceutical preparations.

[0010] On the other hand, the application of a pharmaceutically grade bifonazole obtained by the above preparation method in the preparation of bifonazole drugs.

[0011] The beneficial effects of this invention are as follows:

[0012] 1. The preparation method of pharmaceutical bifonazole provided by the present invention produces pharmaceutical bifonazole with a purity greater than 99.5%, a maximum single impurity of no more than 0.1% and a total impurity of no more than 0.5%, which simultaneously meets the standards of the Chinese Pharmacopoeia and the European Pharmacopoeia, thereby meeting the needs of pharmaceutical preparation production.

[0013] 2. The preparation method of pharmaceutical bifonazole provided by the present invention is simple and easy to operate, which can not only improve the purity of bifonazole, but also achieve a high yield in the purification process. Attached Figure Description

[0014] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0015] Figure 1 The liquid phase spectrum of bifonazole prepared in Example 1 of this invention;

[0016] Figure 2 for Figure 1 A magnified view of a portion of the image;

[0017] Figure 3 The liquid phase spectrum of bifonazole prepared in Example 2 of this invention;

[0018] Figure 4 for Figure 1 A magnified view of a portion of the image;

[0019] Figure 5 The liquid phase spectrum of bifonazole prepared in Example 3 of this invention;

[0020] Figure 6 for Figure 1 A magnified view of a portion of the image;

[0021] Figure 7 The liquid phase spectrum of bifonazole prepared in Example 4 of this invention;

[0022] Figure 8 for Figure 1 A magnified view of a portion of the image. Detailed Implementation

[0023] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, 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.

[0024] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0025] Given that the existing bifonazole preparation process using acetonitrile or acetone produces bifonazole with low purity, only meeting the standard requirements of detection methods with a detection wavelength of 254 nm, but not the standard requirements of detection methods with a detection wavelength of 210 nm, thus failing to meet the needs of pharmaceutical preparation production, this invention proposes a method for preparing pharmaceutical-grade bifonazole.

[0026] A typical embodiment of the present invention provides a method for preparing pharmaceutical-grade bifonazole, including a preparation process of crude bifonazole and a purification process of bifonazole;

[0027] The preparation process of crude bifonazole is as follows: 4-phenylbenzophenone is reduced to obtain 4-phenylbenzyl alcohol, which is then subjected to a substitution reaction with thionyl chloride to obtain 4-(biphenyl)chlorophenylmethane, which is then subjected to a substitution reaction with imidazole to obtain crude bifonazole.

[0028] The purification process of bifonazole is as follows: The crude bifonazole is added to an alcohol-water-acid mixed solvent system for a first heating to dissolve, followed by hot filtration and then a first cooling to crystallize. The solid after the first cooling and crystallization is added to an acetone-water mixed solvent system for a second heating to dissolve, followed by a second cooling to crystallize. The solid after the second cooling and crystallization is dried to obtain pharmaceutical-grade bifonazole. In the alcohol-water-acid mixed solvent system, the alcohol is methanol, ethanol, isopropanol, or n-butanol, and the acid is formic acid, glacial acetic acid, or oxalic acid. The ratio of alcohol, water, and acid is 1:0.3–0.7:1.2–2.0 (ml:ml:mg). In the acetone-water mixed solvent system, the volume ratio of acetone to water is 1–10:1.

[0029] The preparation process of crude bifonazole is based on US4118487, and its reaction route is as follows:

[0030]

[0031] In some embodiments, the ratio of crude bifonazole to an alcohol-water-acid mixed solvent is 1:8 to 20, g:ml, preferably 1:10 to 15, g:ml.

[0032] In some embodiments, in the alcohol-water-acid mixed solvent system, the amount of acid used is 0.5% to 2% of the crude bifonazole mass, preferably 0.8% to 1.2%.

[0033] In some embodiments, in the alcohol-water-acid mixed solvent system, the volume ratio of alcohol to water is 1:0.3 to 0.5.

[0034] In some embodiments, the temperature for melting by heating is 40–80°C, preferably 60–70°C.

[0035] In some embodiments, the temperature for the first cooling crystallization is 0–30°C, preferably 10–30°C.

[0036] In some embodiments, the time for one cooling crystallization is 0.5 to 10 hours, preferably 3 to 5 hours.

[0037] In some embodiments, the ratio of crude bifonazole to acetone-water mixed solvent is 1:10-20, g:ml, preferably 1:13-17, g:ml.

[0038] In some embodiments, in the acetone-water mixed solvent system, the volume ratio of acetone to water is 2 to 5:1.

[0039] In some embodiments, the temperature for secondary heating and melting is 40–60°C, preferably 45–55°C.

[0040] In some embodiments, the temperature for secondary cooling crystallization is 0–20°C, preferably 10–20°C.

[0041] In some embodiments, the solid after secondary cooling and crystallization is dried by vacuum drying. The drying temperature is 40–50°C. The drying time is 6–10 hours.

[0042] Another embodiment of the present invention provides the application of pharmaceutical bifonazole obtained by the above preparation method in the preparation of bifonazole drugs.

[0043] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0044] Example 1: Purification of bifonazole using conventional methods (acetonitrile purification, Comparative Example 1)

[0045] In a 500 ml four-necked reaction flask, 20 g of crude bifonazole (prepared using method US4118487) and 200 ml of acetonitrile were added. The mixture was heated to reflux to dissolve, hot-filtered, and the filtrate was slowly cooled to 15 °C with stirring to induce crystallization for 3 h. After filtration, the filter cake was dried under vacuum at 45 °C for 6 h to obtain 14.7 g of bifonazole. Yield: 73.5%, Purity: 96.488%. The liquid chromatography spectrum is shown below. Figures 1-2 .

[0046] Example 2: Purification of bifonazole using conventional methods (acetone purification, Comparative Example 2)

[0047] In a 500ml four-necked reaction flask, 15g of crude bifonazole (from the same batch as the crude bifonazole in Example 1) and 150ml of acetone were added. The mixture was heated to reflux to dissolve, hot-filtered, and the filtrate was slowly cooled to 15°C with stirring to induce crystallization for 3 hours. After filtration, the filter cake was dried under vacuum at 45°C for 6 hours to obtain 10.7g of bifonazole. Yield: 71.3%, purity: 97.126%. The liquid chromatography spectrum is shown below. Figures 3-4 .

[0048] Example 3: Purification of bifonazole by the method of the present invention

[0049] In a 500ml four-necked reaction flask, add 20g of crude bifonazole (from the same batch as the crude bifonazole in Example 1), 140ml of methanol, 70ml of water, and 0.2g of glacial acetic acid. Dissolve by heating to 55°C, hot filter, and slowly cool the filtrate to 25°C while stirring to crystallize for 5 hours. Filter again, and add the filter cake to a mixed solvent of 250ml acetone and 50ml water. Heat to 50°C and stir for 1 hour, then slowly cool to 15°C and stir to crystallize for 3 hours. Filter again, and vacuum dry the filter cake at 45°C for 8 hours to obtain 17.1g of bifonazole. Yield: 85.5%, Purity: 99.725%. See the liquid chromatography chromatogram below. Figures 5-6 .

[0050] Example 4: Purification of bifonazole by the method of the present invention

[0051] In a 500ml four-necked reaction flask, 15g of crude bifonazole (from the same batch as the crude bifonazole in Example 1), 170ml of ethanol, 55ml of water, and 0.3g of formic acid were added. The mixture was heated to 65°C to dissolve, hot-filtered, and the filtrate was slowly cooled to 15°C and stirred to crystallize for 4 hours. After filtration, the filter cake was added to a mixed solvent of 130ml acetone and 65ml water, heated to 50°C and stirred for 1 hour, slowly cooled to 15°C, and stirred to crystallize for 3 hours. After filtration, the mixture was vacuum dried at 45°C for 8 hours to obtain 13.3g of bifonazole. Yield: 88.7%, Purity: 99.796%. The liquid chromatography spectrum is shown below. Figures 7-8 .

[0052] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing pharmaceutical-grade bifonazole, comprising a process for preparing crude bifonazole and a process for purifying bifonazole; The preparation process of crude bifonazole is as follows: 4-phenylbenzophenone is reduced to obtain 4-phenylbenzyl alcohol, which is then subjected to a substitution reaction with thionyl chloride to obtain 4-(biphenyl)chlorophenylmethane, which is then subjected to a substitution reaction with imidazole to obtain crude bifonazole. The purification process of bifonazole is as follows: the obtained crude bifonazole is added to an alcohol-water-acid mixed solvent system for a first heating to dissolve, followed by hot filtration, and then a first cooling to crystallize; the solid after the first cooling to crystallize is added to an acetone-water mixed solvent system for a second heating to dissolve, followed by a second cooling to crystallize, and the solid after the second cooling to crystallize is dried to obtain pharmaceutical-grade bifonazole; in the alcohol-water-acid mixed solvent system, the alcohol is methanol, ethanol, isopropanol or n-butanol, and the acid is formic acid, glacial acetic acid or oxalic acid, and the addition ratio of alcohol, water and acid is 1:0.3~0.7:1.2~2.0, ml: ml: mg; in the acetone-water mixed solvent system, the volume ratio of acetone to water is 1~10:1; The ratio of crude bifonazole to a mixed alcohol-water-acid solvent is 1:8~20, g: ml.

2. The method for preparing pharmaceutical-grade bifonazole as described in claim 1, characterized in that, The ratio of crude bifonazole to a mixed alcohol-water-acid solvent is 1:10~15, g: ml.

3. The method for preparing pharmaceutical-grade bifonazole as described in claim 1, characterized in that, In the alcohol-water-acid mixed solvent system, the amount of acid used is 0.5% to 2% of the crude bifonazole mass.

4. The method for preparing pharmaceutical-grade bifonazole as described in claim 3, characterized in that, In the alcohol-water-acid mixed solvent system, the amount of acid used is 0.8~1.2% of the crude bifonazole mass.

5. The method for preparing pharmaceutical-grade bifonazole as described in claim 1, characterized in that, In the alcohol-water-acid mixed solvent system, the volume ratio of alcohol to water is 1:0.3~0.

5.

6. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The temperature for melting by heating is 40~80℃.

7. The method for preparing pharmaceutical-grade bifonazole as described in claim 6, characterized in that, The temperature for melting during a single heating process is 60~70℃.

8. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The temperature range for crystallization during the first cooling process is 0~30℃.

9. The method for preparing pharmaceutical-grade bifonazole as described in claim 8, characterized in that, The temperature for crystallization during the first cooling process is 10~30℃.

10. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The time required for one cooling crystallization is 0.5~10 hours.

11. The method for preparing pharmaceutical-grade bifonazole according to claim 10, characterized in that, The time required for one cooling crystallization is 3-5 hours.

12. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The ratio of crude bifonazole to acetone-water mixed solvent is 1:10~20, g: ml.

13. The method for preparing pharmaceutical-grade bifonazole according to claim 12, characterized in that, The ratio of crude bifonazole to acetone-water mixed solvent is 1:13~17, g: ml.

14. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, In the acetone-water mixed solvent system, the volume ratio of acetone to water is 2~5:

1.

15. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The temperature for secondary heating and melting is 40~60℃.

16. The method for preparing pharmaceutical-grade bifonazole according to claim 14, characterized in that, The temperature for secondary heating and melting is 45~55℃.

17. The method for preparing pharmaceutical-grade bifonazole according to claim 1, characterized in that, The temperature for secondary cooling and crystallization is 0~20℃.

18. The method for preparing pharmaceutical-grade bifonazole as described in claim 17, characterized in that, The temperature for secondary cooling and crystallization is 10~20℃.

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