A method for preparing high-purity medicinal bifonazole

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, discloses a method for preparing a high-purity medicinal bifonazole, comprising the following steps: imidazole and a first solvent are stirred to obtain a mixed solution, thionyl chloride and 4-phenylbenzhydrol are added to the mixed solution, and after heating reaction, a crude bifonazole product is obtained by concentrating, washing, refining crystallization of concentrate, and drying; the crude bifonazole product is added to a second solvent, anhydride is added, and room temperature reaction is performed, and a medicinal bifonazole product is obtained by concentrating, washing, refining crystallization of concentrate, and drying. The present invention improves the removal efficiency of impurities by preparing the crude bifonazole product and refining the crude bifonazole product in two stages, and isomer impurity B and dimer impurity D can be reduced to less than 0.3%, which is much lower than the limit of 0.50% reported in the pharmacopoeia, and the unknown single impurity is less than 0.10%, meeting the production demand of pharmaceutical preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing high-purity medicinal bifonazole. Background Art

[0002] Bifonazole is a new type of imidazole topical antifungal drug. The currently known preparation methods of bifonazole are mostly the original methods reported by Bayer, Germany (US4118487), which use 4-phenylbenzophenone as the starting material, and prepare 4-phenylbenzhydrol by reduction. 4-phenylbenzhydrol is directly obtained by reacting with thionyl chloride and imidazole to obtain the crude bifonazole. The refining method of the crude bifonazole also uses acetonitrile or acetone for multiple recrystallization to obtain the finished bifonazole. Isomer impurities (EP impurity B) and dimer impurities (EP impurity D) are generated in the reaction, and the acetonitrile refining has a low efficiency in removing these two impurities. It needs to be repeated many times to reduce the impurities below the limit, which greatly reduces the production efficiency and product yield.

[0003] ;

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[0005] . Summary of the invention

[0006] In view of the above problems existing in the prior art, the present application provides a method for preparing high-purity medicinal bifonazole to improve the efficiency of removing impurities.

[0007] To solve the above problems, the present invention provides the following technical solutions:

[0008] The present application provides a method for preparing high-purity medicinal bifonazole, comprising the following steps:

[0009] S1, stirring imidazole and the first solvent to obtain a mixed solution, adding thionyl chloride and 4-phenylbenzhydrol to the mixed solution, heating the mixture for reaction, concentrating, washing, refining and crystallizing the concentrate, and drying to obtain a crude bifonazole product;

[0010] S2, adding the crude bifonazole to the second solvent, adding anhydride, reacting at room temperature, concentrating, washing, refining and crystallizing the concentrate, and drying to obtain medicinal bifonazole.

[0011] In one embodiment of the present application, in step S1, the first solvent is selected from one of acetonitrile, toluene, and 1,4-dioxane.

[0012] In one embodiment of the present application, in step S1, the first solvent is selected from toluene.

[0013] In one embodiment of the present application, in step S1, the molar ratio of imidazole, thionyl chloride and 4-phenylbenzhydrol is 1.1-1.5:4.4-6.0:1.

[0014] In one embodiment of the present application, in step S1, the molar ratio of imidazole, thionyl chloride and 4-phenylbenzhydrol is 1.3:5.2:1.

[0015] In one embodiment of the present application, in step S1, the usage ratio of imidazole to the first solvent is 1 g:5-15 mL.

[0016] In one embodiment of the present application, in step S1, the usage ratio of imidazole to the first solvent is 1 g:10 mL.

[0017] In one embodiment of the present application, in step S1, the temperature of the heating reaction is 80-100°C.

[0018] In one embodiment of the present application, in step S1, the temperature of the heating reaction is 80-90°C.

[0019] In one embodiment of the present application, in step S1, the heating reaction time is 14-16 hours.

[0020] In one embodiment of the present application, in step S1, the refining solvent used in the concentrate refining process is selected from one of acetone, ethyl acetate and acetonitrile.

[0021] In one embodiment of the present application, in step S1, the refining solvent used in the concentrate refining process is selected from acetonitrile.

[0022] In one embodiment of the present application, in step S1, the usage ratio of the concentrate to the refined solvent is 1 g-5-15 mL.

[0023] In one embodiment of the present application, in step S1, the usage ratio of the concentrate to the refined solvent is 1 g-5 mL.

[0024] In one embodiment of the present application, in step S1, the crystallization temperature is 0-40°C, and the crystallization time is 1-3h.

[0025] In one embodiment of the present application, in step S1, the crystallization temperature is 20-30°C, and the crystallization time is 1 hour.

[0026] In one embodiment of the present application, in step S2, the acid anhydride is selected from one of di-tert-butyl dicarbonate, acetic anhydride, propionic anhydride, and butyric anhydride.

[0027] In one embodiment of the present application, in step S2, the acid anhydride is selected from acetic anhydride.

[0028] In one embodiment of the present application, in step S2, the second solvent is selected from one of tetrahydrofuran, dichloromethane, methanol, toluene, and 1,4-dioxane.

[0029] In one embodiment of the present application, in step S2, the second solvent is selected from tetrahydrofuran.

[0030] In one embodiment of the present application, in step S2, the molar ratio of the crude bifonazole to the acid anhydride is 1:0.5-2.0.

[0031] In one embodiment of the present application, in step S2, the molar ratio of the crude bifonazole to the acid anhydride is 1:1.5.

[0032] In one embodiment of the present application, in step S2, the usage ratio of the crude bifonazole to the second solvent is 1 g: 5-15 mL.

[0033] In one embodiment of the present application, in step S2, the usage ratio of the crude bifonazole to the second solvent is 1 g:10 mL.

[0034] In one embodiment of the present application, in step S2, the temperature of the room temperature reaction is 20-30°C, and the time of the room temperature reaction is 2-3h.

[0035] In one embodiment of the present application, in step S2, the refining solvent used in the concentrate refining process is selected from one of acetone, ethyl acetate and acetonitrile.

[0036] In one embodiment of the present application, in step S2, the refining solvent used in the concentrate refining process is selected from acetonitrile.

[0037] In one embodiment of the present application, in step S2, the usage ratio of the crude bifonazole to the refined solvent is 1 g-5-15 mL.

[0038] In one embodiment of the present application, in step S2, the usage ratio of the crude bifonazole to the refining solvent is 1 g-5 mL.

[0039] In one embodiment of the present application, in step S2, the crystallization temperature is 0-40°C, and the crystallization time is 1-3h.

[0040] In one embodiment of the present application, in step S2, the crystallization temperature is 20-30°C, and the crystallization time is 1 hour.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] (1) The method for preparing high-purity medicinal bifonazole provided by the present invention improves the impurity removal efficiency through two stages: preparation of crude bifonazole and refining of crude bifonazole. The isomer impurity B and dimer impurity D can be reduced to below 0.3%, which is far lower than the limit of 0.50% reported in the pharmacopoeia. The unknown single impurities are all less than 0.10%, meeting the production requirements of pharmaceutical preparations.

[0043] (2) Compared with the original patented method, the method for preparing high-purity medicinal bifonazole provided by the present invention has a higher reaction liquid conversion rate, a lower impurity content, and greatly improved refining efficiency, is easy to operate, and has low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The HPLC spectrum of the crude bifonazole obtained in Comparative Example 1;

[0045] Figure 2 The HPLC spectrum of the high-purity crude bifonazole obtained in Example 1;

[0046] Figure 3 The HPLC spectrum of the high-purity crude bifonazole obtained in Example 2;

[0047] Figure 4 The HPLC spectrum of bifonazole prepared in Comparative Example 1;

[0048] Figure 5 The HPLC spectrum of high-purity bifonazole prepared in Example 1;

[0049] Figure 6 The HPLC spectrum of high-purity bifonazole prepared in Example 2;

[0050] Figure 7 The HPLC spectrum of high-purity bifonazole prepared in Example 3 is shown. DETAILED DESCRIPTION

[0051] The following will provide a clear and complete description of the technical solutions in the embodiments of the present application in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments.

[0052] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.

[0053] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages. Example 1

[0054] 1. Preparation of high-purity crude bifonazole for medicinal use

[0055] In the reaction bottle, add 43.90g imidazole and 300mL 1,4-dioxane, stir evenly and then cool to 0-10℃, control the temperature at 0-10℃, add 19.20g thionyl chloride and 30g 4-phenylbenzhydrol in turn, stir at 80-90℃ for 15h, concentrate the reaction solution at 50℃ in vacuum, add 300mL DCM and 300mL water to the concentrate, stir for 0.5h, separate the organic phase, concentrate at 45℃ under reduced pressure until no droplets flow out, add 150mL acetonitrile to the concentrate, heat to 75-85℃ to dissolve, slowly cool to 20-30℃ to crystallize for 1h, filter, and dry at 45℃ in vacuum for 18h to obtain 30.00g crude bifonazole.

[0056] 2. Preparation of high-purity medicinal bifonazole

[0057] In a reaction bottle, 30 g of the crude bifonazole obtained in Example 2 and 300 mL of tetrahydrofuran were added, and after stirring evenly, 22.93 g of butyric anhydride was added thereto. After stirring at 20-30 ° C for 2-3 h, the mixture was concentrated under reduced pressure at 45 ° C until no liquid flowed out. 300 mL of DCM and 300 mL of water were added to the obtained concentrate. After stirring for 0.5 h, the organic phase was separated and concentrated under reduced pressure at 45 ° C until no liquid flowed out. 150 mL of acetonitrile was added to the obtained concentrate, heated to 75-85 ° C to dissolve, and then slowly cooled to 20-30 ° C for crystallization for 1 h, filtered, and vacuum dried at 45 ° C for 18 h to obtain 17.63 g of bifonazole. Example 2

[0058] 1. Preparation of high-purity crude bifonazole for medicinal use

[0059] In the reaction bottle, add 439.0g imidazole and 3000mL toluene, stir evenly and cool to 0-10℃, add 192.0g thionyl chloride and 300.0g 4-phenylbenzhydrol in sequence at 0-10℃, stir at 80-90℃ for 15h, add 3000mL DCM and 3000mL water to the concentrate, stir for 0.5h, separate the organic phase, concentrate at 45℃ under reduced pressure until no droplets flow out, add 1500mL acetonitrile to the concentrate, heat to 75-85℃ to dissolve, slowly cool to 20-30℃ for crystallization for 1h, filter, and vacuum dry at 45℃ for 18h to obtain 320.00g crude bifonazole.

[0060] 2. Preparation of high-purity medicinal bifonazole

[0061] In a reaction flask, 30 g of the crude bifonazole obtained in Example 2 and 300 mL of tetrahydrofuran were added, and after stirring evenly, 14.80 g of acetic anhydride was added thereto. After stirring at 20-30 ° C for 2-3 h, the mixture was concentrated under reduced pressure at 45 ° C until no liquid flowed out. 300 mL of DCM and 300 mL of water were added to the obtained concentrate. After stirring for 0.5 h, the organic phase was separated and concentrated under reduced pressure at 45 ° C until no liquid flowed out. 150 mL of acetonitrile was added to the obtained concentrate, heated to 75-85 ° C to dissolve, and then slowly cooled to 20-30 ° C for crystallization for 1 h, filtered, and vacuum dried at 45 ° C for 18 h to obtain 19.70 g of bifonazole. Example 3

[0062] 1. Preparation of high-purity crude bifonazole for medicinal use

[0063] In the reaction bottle, add 439.0g imidazole and 3000mL toluene, stir evenly and cool to 0-10℃, add 192.0g thionyl chloride and 300.0g 4-phenylbenzhydrol in sequence at 0-10℃, stir at 80-90℃ for 15h, add 3000mL DCM and 3000mL water to the concentrate, stir for 0.5h, separate the organic phase, concentrate at 45℃ under reduced pressure until no droplets flow out, add 1500mL acetonitrile to the concentrate, heat to 75-85℃ to dissolve, slowly cool to 20-30℃ for crystallization for 1h, filter, and vacuum dry at 45℃ for 18h to obtain 320.00g crude bifonazole.

[0064] 2. Preparation of high-purity medicinal bifonazole

[0065] In a reaction flask, 30 g of the crude bifonazole obtained in Example 2 and 300 mL of tetrahydrofuran were added, and after stirring evenly, 18.87 g of propionic anhydride was added thereto. After stirring at 20-30 ° C for 2-3 h, the mixture was concentrated under reduced pressure at 45 ° C until no liquid flowed out. 300 mL of DCM and 300 mL of water were added to the obtained concentrate. After stirring for 0.5 h, the organic phase was separated and concentrated under reduced pressure at 45 ° C until no liquid flowed out. 150 mL of acetonitrile was added to the obtained concentrate, and after heating to 75-85 ° C to dissolve, the mixture was slowly cooled to 20-30 ° C for crystallization for 1 h, filtered, and dried under vacuum at 45 ° C for 18 h to obtain 18.76 g of bifonazole.

[0066] Comparative Example 1

[0067] 1. Preparation of crude bifonazole by original research method

[0068] In the reaction bottle, add 31.50g imidazole and 300mL acetonitrile, stir evenly and then cool to 0-10℃, control the temperature at 0-10℃, add 15.20g thionyl chloride and 30g 4-phenylbenzhydrol in turn, stir at 20-30℃ for 15h, concentrate the reaction solution at 50℃ in vacuum, add 300mL DCM and 300mL water to the concentrate, stir for 0.5h, separate the organic phase, concentrate at 45℃ under reduced pressure until no droplets flow out, add 150mL acetonitrile to the concentrate, heat to 75-85℃ to dissolve, slowly cool to 20-30℃ to crystallize for 1h, filter, and dry at 45℃ in vacuum for 18h to obtain 22.10g bifonazole.

[0069] 2. Preparation of bifonazole by original research method

[0070] In a reaction flask, add 20.00 g of the crude bifonazole obtained in Example 2 and 100 mL of acetonitrile, stir and heat to 75-85°C, stir and dissolve, slowly cool to 20-30°C, crystallize for 1 hour, and filter. This refining operation is repeated twice, and the obtained wet product is vacuum dried at 45°C for 18 hours to obtain 6.86 g of bifonazole.

[0071] The relevant substances of all comparative examples and embodiments are shown in Table 1. The impurities obtained by the conversion of EP B by anhydride derivatization are controlled below 0.10% as unknown single impurities and can be removed by acetonitrile purification. No specific single impurity control is performed here.

[0072] Table 1

[0073]

[0074] The present application is described in detail above in conjunction with specific implementation methods and exemplary embodiments, but these descriptions cannot be understood as limiting the present application. Those skilled in the art understand that, without departing from the spirit and scope of the present application, the technical solution of the present application and its implementation methods may be subjected to a variety of equivalent substitutions, modifications or improvements, all of which fall within the scope of the present application.

Claims

1. A method for preparing a medicinal bifonazole, characterized in that: The following steps are involved: S1, stirring imidazole and a first solvent to obtain a mixed solution, adding thionyl chloride and 4-phenylbenzhydrol to the mixed solution, heating the mixture for reaction, concentrating, washing, refining and crystallizing the concentrate, and drying to obtain a crude product of bifonazole; the first solvent is selected from one of acetonitrile, toluene, and 1,4-dioxane; the temperature of the heating reaction is 80-100°C; S2. Add the crude bifonazole to a second solvent, add anhydride, react at room temperature, concentrate, wash with water, purify and crystallize the concentrate, and dry to obtain medicinal bifonazole; the second solvent is selected from one of tetrahydrofuran, dichloromethane, methanol, toluene, and 1,4-dioxane; the acid anhydride is selected from one of acetic anhydride, propionic anhydride, and butyric anhydride.

2. The method for preparing the medicinal bifonazole according to claim 1, characterized in that: In step S1, the molar ratio of the imidazole, thionyl chloride and 4-phenylbenzhydrol is 1.1-1.5:4.4-6.0:1; and the amount ratio of the imidazole to the first solvent is 1 g:5-15 mL.

3. The method for preparing the medicinal bifonazole according to claim 2, characterized in that: In step S1, the molar ratio of the imidazole, thionyl chloride and 4-phenylbenzhydrol is 1.3:5.2:1; and the amount ratio of the imidazole to the first solvent is 1 g:10 mL.

4. The method for preparing the medicinal bifonazole according to claim 1, characterized in that: In step S1, the heating reaction time is 14-16 hours.

5. The method for preparing the medicinal bifonazole according to claim 1, characterized in that: In step S2, the molar ratio of the crude bifonazole to the acid anhydride is 1:0.5-2.0; the dosage ratio of the crude bifonazole to the second solvent is 1g:5-15mL; the temperature of the room temperature reaction is 20-30°C, and the time of the room temperature reaction is 2-3h.

6. The method for preparing the medicinal bifonazole according to claim 5, characterized in that: In step S2, the molar ratio of the crude bifonazole to the acid anhydride is 1:1.5; and the usage ratio of the crude bifonazole to the second solvent is 1 g:10 mL.

7. The method for preparing the medicinal bifonazole according to claim 1, characterized in that: In step S1 and step S2, the refining solvent used in the refining process of the concentrate is selected from one of acetone, ethyl acetate and acetonitrile; in step S1, the amount ratio of the concentrate to the refining solvent is 1g-5-15mL; in step S2, the amount ratio of the crude bifonazole to the refining solvent is 1g-5-15mL.

8. The method for preparing the medicinal bifonazole according to claim 1, characterized in that: In step S1 and step S2, the crystallization temperature is 0-40° C., and the crystallization time is 1-3 h.

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