Refining method and preparation method of bifonazole

Abstract

The invention discloses a refining method and a preparation method of bifonazole, which comprises the following steps: taking biphenyl and benzoyl chloride as initial raw materials to generate an intermediate 1; carrying out sodium borohydride reduction reaction on the intermediate 1 to obtain an intermediate 2, carrying out thionyl chloride chlorination on the intermediate 2 to obtain an intermediate 3, and substituting the intermediate 3 with imidazole to obtain a bifonazole crude product; the bifonazole crude product passes through a combined solvent and is subjected to multiple times of cooling refining to obtain bifonazole; the combined solvent comprises a solvent A and a solvent B, the solvent A is one of ethanol, methanol, isopropanol, acetone and ethyl acetate, and the solvent B is one of acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran. The dosage ratio of the volume ml of the solvent A to the volume ml of the solvent B in the combined solvent is (4.5-5.5): 1, ml: ml. According to the refining process of the bifonazole crude product, the purity of the bifonazole finished product is improved, the maximum single impurity is reduced, the yield of the bifonazole is improved, the solvent residue is relatively low, and an unexpected effect is achieved.

Description

Technical Field

[0001] The present application belongs to the technical field of raw material drug purification and relates to a method for preparing medicinal bifonazole. Background Art

[0002] Bifonazole is a broad-spectrum antifungal drug belonging to the imidazole class of compounds. It is mainly used to treat skin diseases caused by fungal infections, such as tinea, candidiasis, tinea cruris, tinea pedis (athlete's foot), tinea corporis, and tinea versicolor. Bifonazole inhibits the synthesis of ergosterol in the fungal cell membrane and changes the permeability of the fungal cell membrane, thereby causing the loss of important substances in the fungal cell and ultimately causing the death of the fungus. It has strong antibacterial activity against a variety of dermatophytes, yeasts, and other fungi.

[0003] The preparation method of bifonazole reported by Bayer, Germany (US4118487) is adopted. Biphenyl and benzoyl chloride are catalyzed by anhydrous aluminum chloride to generate raw material 1 (4-phenylbenzophenone), which is recorded as intermediate 1 here. Intermediate 1 is reduced by sodium borohydride to obtain intermediate 2, intermediate 2 is chlorinated by dithionyl chloride to obtain intermediate 3, and intermediate 3 is replaced by imidazole to obtain crude bifonazole. In the prior art, recrystallization is often used to refine crude bifonazole, that is, crude bifonazole is dissolved in a suitable solvent (such as ethanol, methanol, acetonitrile, etc.), heated to dissolve and then cooled, crystals are precipitated, filtered and dried. Since imidazole is excessive and imidazole 4 carbon can participate in the reaction, imidazole and C-4 isomer impurities in bifonazole are easily residual. However, the above-mentioned recrystallization solvent has a poor effect on impurity removal. CN116874429A improves the recrystallization solvent, that is, alcohol-water-acid is selected to form a combined solvent in a certain ratio, and after heating and dissolving, cooling and crystallizing, an acetone-water mixed solvent is added, and heating and dissolving, cooling and crystallizing are performed again. The purity of bifonazole is improved by adding different recrystallization solvents multiple times. This method is complicated to operate, and the content of individual impurities is relatively large, and there is still room for improvement in yield and residual solubility. It is still challenging to simply obtain high-purity medicinal bifonazole. Summary of the invention

[0004] The present application provides a method for refining bifonazole and a method for preparing the same, in order to solve the problems of low purity, large maximum single impurity, low yield and high residual solvent in the refining process of crude bifonazole. The present application provides a method for refining crude bifonazole, wherein the crude bifonazole is subjected to combined solvents and multiple cooling and refining to obtain a finished bifonazole product.

[0005] The combined solvent includes solvent A and solvent B, wherein solvent A is one of ethanol, methanol, isopropanol, acetone, and ethyl acetate, and solvent B is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0006] Preferably, the combined solvent is one of ethanol and acetonitrile, ethanol and N,N-dimethylformamide, ethanol and dimethyl sulfoxide, ethanol and tetrahydrofuran, methanol and acetonitrile, isopropanol and acetonitrile, acetone and acetonitrile, and ethyl acetate and acetonitrile.

[0007] Preferably, the volume ml usage ratio of solvent A to solvent B in the combined solvent is 4.5-5.5:1, ml:ml.

[0008] Preferably, the volume ml usage ratio of solvent A to solvent B in the combined solvent is 4.8-5:1, ml:ml.

[0009] Preferably, the combined solvent is one of methanol and N,N-dimethylformamide, ethanol and dimethyl sulfoxide, ethanol and tetrahydrofuran, isopropanol and N,N-dimethylformamide, isopropanol and dimethyl sulfoxide, isopropanol and tetrahydrofuran, acetone and N,N-dimethylformamide, acetone and dimethyl sulfoxide, acetone and tetrahydrofuran, ethyl acetate and N,N-dimethylformamide, ethyl acetate and dimethyl sulfoxide, ethyl acetate and tetrahydrofuran.

[0010] Preferably, the multiple coolings are two coolings.

[0011] Preferably, in the two cooling steps, the first cooling temperature is controlled at 40-50°C.

[0012] Preferably, in the two cooling steps, the second cooling temperature is controlled at 0-10°C.

[0013] Preferably, in the two cooling steps, the second cooling temperature is controlled at 2-10°C.

[0014] Preferably, in the two cooling steps, the second cooling temperature is controlled at 5-10°C.

[0015] On the other hand, the present invention provides a method for preparing bifonazole, comprising: 1) preparing a crude bifonazole product:

[0016] Using biphenyl and benzoyl chloride as starting materials, intermediate 1 is generated; intermediate 1 is reduced with sodium borohydride to obtain intermediate 2, intermediate 2 is chlorinated with thionyl chloride to obtain intermediate 3, and intermediate 3 is substituted with imidazole to obtain crude bifonazole;

[0017] 2) Purifying the crude bifonazole according to the above purification method to obtain the bifonazole, the preparation route is as follows:

[0018]

[0019] Beneficial effects:

[0020] The inventor has found through a large number of experiments that in the process of refining bifonazole, the type and amount of the recrystallization solvent and the temperature of the recrystallization cooling crystallization are particularly important for the purity, yield and residual solvent of the target product bifonazole. The inventor has selected a recrystallization combination solvent, adjusted the type and amount of the combination solvent in the recrystallization solvent, and after multiple cooling crystallizations, controlled the temperature of each cooling in a specific range, greatly reduced the residual impurities such as imidazole and C-4 isomers, improved the purity of the finished product of bifonazole, reduced the maximum single impurity, and improved the yield of bifonazole, and the residual solvent is low, achieving an unexpected effect. At the same time, the refining and preparation method of bifonazole of the present invention is simple to operate and easy to promote on a large scale in industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the HPLC spectrum of related substances in the crude product of bifonazole.

[0022] Figure 2 This is the HPLC spectrum of related substances in bifonazole prepared in Example 1. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0024] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0025] The present application is not limited to the above-mentioned specific implementation modes, which are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

[0026] The present application provides a method for refining bifonazole and a method for preparing the same, including the preparation of a crude bifonazole product and a refining process of the crude bifonazole product.

[0027] Specifically, biphenyl and benzoyl chloride are used as starting materials, and Friedel-Crafts acylation is carried out by catalysis of anhydrous aluminum chloride, followed by extraction and separation, and purification by ethanol to obtain intermediate 1; intermediate 1 is subjected to sodium borohydride reduction reaction to obtain intermediate 2, intermediate 2 is chlorinated by dichlorothionyl to obtain intermediate 3, and intermediate 3 is substituted with imidazole to obtain crude bifonazole; the crude bifonazole is dissolved by combining solvents and heating, and then cooled and crystallized multiple times to obtain high-purity pharmaceutical-grade bifonazole. The combined solvent includes solvent A and solvent B, wherein solvent A is one of ethanol, methanol, isopropanol, acetone, and ethyl acetate, and solvent B is one of acetonitrile, N,N-dimethylformamide (hereinafter referred to as DMF), dimethyl sulfoxide (hereinafter referred to as DMSO), and tetrahydrofuran (hereinafter referred to as THF).

[0028] As a specific embodiment of the present invention, the combined solvent is one of ethanol and acetonitrile, ethanol and DMF, ethanol and DMSO, ethanol and THF, methanol and acetonitrile, isopropanol and acetonitrile, acetone and acetonitrile, ethyl acetate and acetonitrile, methanol and DMF, ethanol and DMSO, ethanol and THF, isopropanol and DMF, isopropanol and DMSO, isopropanol and THF, acetone and DMF, acetone and DMSO, acetone and THF, ethyl acetate and DMF, ethyl acetate and DMSO, ethyl acetate and THF.

[0029] As a specific embodiment of the present invention, in the bifonazole crude product refining process, the volume ml usage ratio of solvent A and solvent B in the combined solvent is 4.5-5.5:1, ml:ml. The volume ml usage ratio of solvent A and solvent B in the combined solvent can be 4.5:1, ml:ml, 4.8:1, ml:ml, 5.0:1, ml:ml, 5.2:1, ml:ml, 5.5:1, ml:ml, preferably 4.8-5.0:1, ml:ml, can be 4.8:1, ml:ml, 4.9:1, ml:ml, 5.0:1, ml:ml, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0030] As a specific embodiment of the present invention, in the bifonazole crude product refining process, the multiple coolings may be two or more times, preferably two times.

[0031] As a specific embodiment of the present invention, in the bifonazole crude product refining process, the two coolings, the first cooling temperature is controlled at 40-50°C, which can be 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, preferably 45-50°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0032] As a specific embodiment of the present invention, in the bifonazole crude product refining process, the two coolings, the second cooling temperature is controlled at 0-10°C, which can be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, preferably 2-10°C, more preferably 5-10°C, but not limited to the listed values, other values ​​not listed within the numerical range are also applicable.

[0033] The inventors optimized the recrystallization solvent combination, adjusted the type and amount of the solvent combination in the recrystallization solvent, and performed multiple cooling and crystallization. The temperature of each cooling was controlled within a specific range, thereby significantly reducing the residual impurities such as imidazole and C-4 isomers, improving the purity of the bifonazole product, reducing the maximum single impurity, and increasing the yield of bifonazole. The residual solvent was also low, achieving an unexpected effect.

[0034] The following is further described with reference to specific embodiments and comparative examples.

[0035] The present invention does not limit the preparation method / conditions of the crude bifonazole. The crude bifonazole can be prepared by the method of US4118487. The reaction scheme is as follows:

[0036]

[0037] Preparation of Intermediate 1:

[0038] Add 47.6g of anhydrous aluminum trichloride to a 500ml three-necked flask, add 195.0g of dichloromethane and stir; add 45.6g of benzoyl chloride, and control the temperature not higher than 30℃. After the addition, control the temperature not higher than 8℃, add 1,1'-biphenyl / dichloromethane (50g / 130g) solution dropwise, and heat to 25℃ for 4h after the addition. TLC shows that the raw material has reacted completely. Stop the reaction. Control the temperature not higher than 25℃, and slowly add the reaction solution to 250ml of 5% hydrochloric acid solution at 8℃. After the addition, stir for 10min, stand still, and separate the liquids. Collect the organic phase and wash it once with 125ml of purified water. The organic phase is concentrated to dryness to obtain a light yellow solid, add 350ml of anhydrous ethanol, heat and reflux until it is clear, keep warm for 1h, slowly cool to 25℃, cool to 5℃ with ice water, and keep warm and stir for 2h. The solid was filtered and dried at 40°C to obtain 67.4 g of an off-white solid.

[0039] Preparation of Intermediate 2

[0040] Add 250 ml of anhydrous ethanol and 50.0 g of intermediate 1 to a three-necked flask. Add 7 ml of 40% sodium hydroxide aqueous solution, slowly add 7.3 g of sodium borohydride under stirring, keep warm at 30°C for 4 h, after TLC confirms that the reaction is complete, add concentrated hydrochloric acid dropwise to adjust the pH to 5-6, add 250 ml of purified water to precipitate a large amount of solid, keep warm at 25°C and stir for 2 h, filter, and air dry at 50°C to obtain 47.1 g of off-white solid.

[0041] Preparation of Intermediate 3

[0042] Add 100 ml of dichloromethane to a 250 ml three-necked flask, add 40.0 g of intermediate 2, and stir to dissolve the system. After the system is dissolved, add 21.0 g of thionyl chloride dropwise, and after the addition is complete, heat to reflux, keep the temperature under reflux for 2 hours, monitor the reaction to be complete by HPLC, cool to room temperature, add 50 ml of purified water dropwise to quench the reaction, stir, stand, separate, collect the dichloromethane phase, add 50 ml of water to wash once, and concentrate under reduced pressure at 50°C to obtain 42.2 g of a light yellow foamy solid.

[0043] Preparation of crude bifonazole:

[0044] Add 200 ml of acetonitrile to a three-necked flask, then add 40.0 g of intermediate 3 and 48.9 g of imidazole in sequence. Raise the temperature to reflux and keep the reaction for 4 hours. Monitor by TLC until the reaction is complete, stop the reaction, cool to 5°C and keep the crystallization for 3 hours, filter, and dry at 40°C to obtain 40.2 g of a light yellow solid.

[0045] Refining process of crude bifonazole: (Use high performance liquid chromatography to determine the purity and impurity content of bifonazole)

[0046] Example 1

[0047] Preparation of Bifonazole:

[0048] Add 200 ml of ethanol, 40 ml of acetonitrile, and 40.2 g of crude bifonazole to a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C, stir for 3 h, and dry to obtain 37.9 g of off-white solid with a yield of 94.28%. The liquid chromatogram is shown in Figure 2 , purity of bifonazole: 99.97%, maximum single impurity: 0.03%.

[0049] Example 2

[0050] Preparation of Bifonazole:

[0051] Add 200 ml of ethanol, 40 ml of DMSO and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.2 g of off-white solid, with a yield of 90.05%, bifonazole purity: 99.88%, and maximum single impurity: 0.06%.

[0052] Example 3

[0053] Preparation of Bifonazole:

[0054] Add 200 ml of ethanol, 40 ml of THF, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.2 g of off-white solid, with a yield of 90.05%, bifonazole purity: 99.92%, and maximum single impurity: 0.07%.

[0055] Example 4

[0056] Preparation of Bifonazole:

[0057] Add 200 ml of ethanol, 40 ml of DMF, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.6 g of off-white solid, with a yield of 91.04%, bifonazole purity: 99.87%, and maximum single impurity: 0.08%.

[0058] Example 5

[0059] Preparation of Bifonazole:

[0060] Add 200 ml of methanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 37.0 g of off-white solid, with a yield of 92.04%, bifonazole purity: 99.92%, and maximum single impurity: 0.04%.

[0061] Example 6

[0062] Preparation of Bifonazole:

[0063] Add 200 ml of isopropanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.8 g of off-white solid, the yield is 91.54%, the purity of bifonazole is 99.86%, and the maximum single impurity is 0.06%.

[0064] Example 7

[0065] Preparation of Bifonazole:

[0066] Add 200 ml of acetone, 40 ml of acetonitrile, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.7 g of off-white solid, with a yield of 91.29%, purity of bifonazole: 99.80%, and maximum single impurity: 0.08%.

[0067] Example 8

[0068] Preparation of Bifonazole:

[0069] Add 200 ml of ethyl acetate and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.3 g of off-white solid, the yield is 90.29%, the purity of bifonazole is 99.95%, and the maximum single impurity is 0.05%.

[0070] Example 9

[0071] Preparation of Bifonazole:

[0072] Add 180 ml of ethanol, 40 ml of acetonitrile, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C, stir for 3 h, and dry to obtain 35.9 g of off-white solid. The yield is 89.30%, the purity of bifonazole is 99.89%, and the maximum single impurity is 0.04%.

[0073] Example 10

[0074] Preparation of Bifonazole:

[0075] Add 220 ml of ethanol, 40 ml of acetonitrile and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 35.1 g of off-white solid, with a yield of 87.31%, purity of bifonazole: 99.92%, and maximum single impurity: 0.04%.

[0076] Embodiment 11

[0077] Preparation of Bifonazole:

[0078] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 40 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 34.7 g of off-white solid, with a yield of 86.32%, bifonazole purity: 99.87%, and maximum single impurity: 0.07%.

[0079] Example 12

[0080] Preparation of Bifonazole:

[0081] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 50 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 33.9 g of off-white solid, with a yield of 84.33%, purity of bifonazole: 99.82%, and maximum single impurity: 0.09%.

[0082] Embodiment 13

[0083] Preparation of Bifonazole:

[0084] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 0 ° C and stir for 3 h, dry to obtain 36.0 g of off-white solid, with a yield of 89.55%, bifonazole purity: 99.90%, and maximum single impurity: 0.07%.

[0085] Embodiment 14

[0086] Preparation of Bifonazole:

[0087] Add 200 ml of ethanol, 40 ml of acetonitrile and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 10 ° C and stir for 3 h, dry to obtain 35.2 g of off-white solid, with a yield of 87.56%, purity of bifonazole: 99.94%, and maximum single impurity: 0.05%.

[0088] Comparative Example 1

[0089] Preparation of Bifonazole:

[0090] Add 200 ml of ethanol, 40 ml of isopropanol, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 34.0 g of off-white solid, with a yield of 84.58%, bifonazole purity: 99.80%, and maximum single impurity: 0.07%.

[0091] Comparative Example 2

[0092] Preparation of Bifonazole:

[0093] Add 200 ml of acetonitrile, 40 ml of DMSO and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 32.5 g of off-white solid, with a yield of 80.85%, purity of bifonazole: 99.93%, and maximum single impurity: 0.03%.

[0094] Comparative Example 3

[0095] Preparation of Bifonazole:

[0096] Add 200 ml of ethanol and 40 ml of water to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 36.0 g of off-white solid, the yield is 89.55%, the purity of bifonazole is 96.62%, and the maximum single impurity is 2.35%.

[0097] Comparative Example 4

[0098] Preparation of Bifonazole:

[0099] Add 200 ml of ethanol and 40 ml of acetic acid to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 33.38 g of off-white solid, with a yield of 83.03%, purity of bifonazole: 99.94%, and maximum single impurity: 0.04%.

[0100] Comparative Example 5

[0101] Preparation of Bifonazole:

[0102] Add 200 ml of water and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 38.8 g of off-white solid, the yield is 96.52%, the purity of bifonazole is 95.88%, and the maximum single impurity is 3.46%.

[0103] Comparative Example 6

[0104] Preparation of Bifonazole:

[0105] Add 200 ml of acetic acid, 40 ml of acetonitrile and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 28.8 g of off-white solid, the yield is 71.64%, the purity of bifonazole is 99.87%, and the maximum single impurity is 0.04%.

[0106] Comparative Example 7

[0107] Preparation of Bifonazole:

[0108] Add 200 ml of water and 40 ml of acetic acid to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 39.2 g of off-white solid, the yield is 97.51%, the purity of bifonazole is 98.68%, and the maximum single impurity is 0.54%.

[0109] Comparative Example 8

[0110] Preparation of Bifonazole:

[0111] Add 160 ml of ethanol, 40 ml of acetonitrile and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 35.8 g of off-white solid, with a yield of 89.05%, purity of bifonazole: 99.82%, and maximum single impurity: 0.11%.

[0112] Comparative Example 9

[0113] Preparation of Bifonazole:

[0114] Add 240 ml of ethanol, 40 ml of acetonitrile, and 40.2 g of crude bifonazole into a three-necked flask, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C, stir for 3 h, and dry to obtain 37.2 g of off-white solid. The yield is 92.54%, the purity of bifonazole is 99.85%, and the maximum single impurity is 0.10%.

[0115] Comparative Example 10

[0116] Preparation of Bifonazole:

[0117] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 35 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 37.7 g of off-white solid, with a yield of 93.78%, bifonazole purity: 99.88%, and maximum single impurity: 0.11%.

[0118] Comparative Example 11

[0119] Preparation of Bifonazole:

[0120] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 55 ° C, keep stirring until a large amount of solid precipitates, then cool to 5 ° C and stir for 3 h, dry to obtain 35.9 g of off-white solid, with a yield of 89.30%, bifonazole purity: 99.76%, and maximum single impurity: 0.16%.

[0121] Comparative Example 12

[0122] Preparation of Bifonazole:

[0123] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to -5 ° C and stir for 3 h, dry to obtain 38.0 g of off-white solid, the yield is 94.53%, the purity of bifonazole is 99.80%, and the maximum single impurity is 0.14%.

[0124] Comparative Example 13

[0125] Preparation of Bifonazole:

[0126] Add 200 ml of ethanol and 40 ml of acetonitrile to a three-necked flask, add 40.2 g of crude bifonazole, heat and reflux for 10 min, slowly cool to 45 ° C, keep stirring until a large amount of solid precipitates, then cool to 15 ° C and stir for 3 h, dry to obtain 37.8 g of off-white solid, the yield is 94.03%, the purity of bifonazole is 99.44%, and the maximum single impurity is 0.33%.

[0127] Table 1 List of variable settings in Examples 1 to 14 and Comparative Examples 1 to 13

[0128]

[0129]

[0130] The residual dissolution test of bifonazole prepared in Examples 1 to 14 and Comparative Examples 1 to 13 was performed, and the test method was as follows:

[0131] A capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as the stationary liquid is used as the chromatographic column (Agilent DB-624UI capillary column); the starting temperature is 50°C, maintained for 5 minutes, and then increased to 200°C at a rate of 10°C per minute and maintained for 3 minutes; the injection port temperature is 200°C; the detector is a hydrogen flame ionization detector (FID), and the detector temperature is 280°C; the headspace bottle equilibrium temperature is 80°C, and the equilibrium time is 30 minutes.

[0132] The yield (yield = weight of bifonazole obtained after purification / weight of crude bifonazole input*100%), purity, maximum single impurity and residual solvent statistics of bifonazole obtained in Examples 1 to 14 and Comparative Examples 1 to 13 are shown in Table 2.

[0133] Table 2 Yield, purity, maximum single impurity and residual soluble statistics of bifonazole obtained in Examples 1 to 14 and Comparative Examples 1 to 13

[0134]

[0135]

[0136] Figure 1 is the related substance spectrum of the crude bifonazole used in the present invention, Figure 2 This is the related substance spectrum of bifonazole obtained in Example 1. It can be seen that the purification method in Example 1 can greatly reduce the types and contents of impurities.

[0137] Observing Table 2 specifically, we can draw the following conclusions:

[0138] 1) Observing Examples 1 to 8 and Comparative Examples 1 to 7, the difference between them is that the types of combined solvents are different.

[0139] The solvent types of Example 1 are ethanol and acetonitrile; the solvent types of Example 2 are ethanol and DMSO; the solvent types of Example 3 are ethanol and THF; the solvent types of Example 4 are ethanol and DMF, and the solvent types of Example 5 are methanol and acetonitrile; the solvent types of Example 6 are isopropanol and acetonitrile; the solvent types of Example 7 are acetone and acetonitrile; and the solvent types of Example 8 are ethyl acetate and acetonitrile. That is, in Examples 1 to 8, the two solvents are selected from solvent A and solvent B, respectively. Under the same conditions, the yield of the refined bifonazole crude product reaches 90% to 95%, the purity of the refined bifonazole reaches more than 99.80%, the maximum single impurity is less than the limit value of 0.10%, and the residual solvent of the refined bifonazole meets the requirements of the raw material for residual solvent (acetonitrile: 0.041%, ethanol: 0.5%, methanol: 0.3%, isopropanol: 0.5%, DMF: 0.088%, acetone: 0.5%, DMSO: 0.5%, acetic acid: 0.5%, ethyl acetate: 0.5%, tetrahydrofuran: 0.072%) and is far below the limit. In particular, the yield of the refined bifonazole in Example 1 reaches 94.28%, the purity of the refined bifonazole reaches 99.97%, and the residual solvent of the refined bifonazole is not detected.

[0140] The solvent types of Comparative Example 1 are all selected from solvent A, namely ethanol and isopropanol; the solvent types of Comparative Example 2 are all selected from solvent B, namely acetonitrile and DMSO; the solvent types of Comparative Example 3 are selected from solvent A and other solvents, namely ethanol and water; the solvent types of Comparative Example 4 are selected from solvent A and other solvents, namely ethanol and acetic acid; the solvent types of Comparative Example 5 are selected from other solvents and solvent B, namely water and acetonitrile; the solvent types of Comparative Example 6 are selected from other solvents and solvent B, namely acetic acid and acetonitrile; the solvent types of Comparative Example 7 are all selected from other solvents, namely water and acetic acid. That is, the two solvents in Comparative Examples 1 to 7 are respectively selected from solvent A or solvent B, or solvent A and other solvents, or other solvents and solvent B, or both are selected from other solvents; under the same conditions, the purification of crude bifonazole in Comparative Examples 1 to 7 presents different problems, Comparative Examples 1, 2, 4 and 6 have high purity, the maximum single impurity is less than 0.10%, but the yield is low, in addition, the maximum single impurity of Comparative Example 3 is as high as 2.35%, which is significantly higher than the limit value of 0.10%. Comparative Examples 5 and Comparative Examples 7 have high yields, but poor purity, and the maximum single impurity is greater than 0.10%, which does not meet the requirements of raw materials.

[0141] It can be seen that, under the same other conditions, the selection of solvent type in the process of refining crude bifonazole is particularly important. When the two solvents are selected from solvent A and solvent B respectively, the yield of refined crude bifonazole can reach 90% to 95%, the purity of refined bifonazole can reach 99.80% and above, and the maximum single impurity is less than the limit value (0.10%). At the same time, the residual solvent of refined bifonazole is far lower than the limit requirement of residual solvent of raw materials.

[0142] 2) Observe Examples 1, 9 to 10 and Comparative Examples 8 to 9, the difference between them is that the volume ratio of the combined solvents is different.

[0143] The combined solvents of Examples 1, 9 to 10 are all ethanol and acetonitrile, but the volume ratios of ethanol and acetonitrile are different. In Example 1, ethanol and acetonitrile are 200 ml and 40 ml respectively; in Example 9, ethanol and acetonitrile are 180 ml and 40 ml respectively; in Example 10, ethanol and acetonitrile are 220 ml and 40 ml respectively; in Comparative Example 8, ethanol and acetonitrile are 160 ml and 40 ml respectively; in Comparative Example 9, ethanol and acetonitrile are 240 ml and 40 ml respectively; when other conditions are set the same, Examples 1. The yield of the refined crude bifonazole in Examples 1, 9-10 is 87.31%-94.28%; the purity of the refined bifonazole is above 99.8%; the residual acetonitrile of the refined bifonazole is not detected to 0.005%, and ethanol is not detected; while the yield of the refined crude bifonazole in Comparative Examples 8-9 is 89.05%-92.54%; the purity of the refined bifonazole is 99.82-99.85%; although the yield of bifonazole obtained in Examples 1, 9-10 is basically the same as that in Comparative Examples 8-9. However, the maximum single impurity in Examples 1, 9-10 meets the requirements for pharmaceutical use, while the maximum single impurity in Comparative Examples 8-9 is too large and does not meet the requirements for pharmaceutical use.

[0144] It can be seen that under the same other conditions, the volume ratio of the combined solvent in the process of refining crude bifonazole has a significant impact on the refining results. When the volume ratio of the two solvents in the combined solvent is 4.5-5.5:1, the yield of the refined crude bifonazole is high, and the purity of the refined bifonazole can reach 99.80% and above, and the maximum single impurity meets the limit requirements. In addition, the residual solubility of the refined bifonazole is also far below the limit requirements.

[0145] 3) Comparative Examples 1, 11-12 and Comparative Examples 10-11 were observed, and the only difference between them was the temperature of the first cooling control during the purification of the crude bifonazole.

[0146] In the process of refining the crude bifonazole product in Examples 1, 11-12, the temperatures of the first cooling control were 45°C, 40°C, and 50°C, respectively; in the process of refining the crude bifonazole product in Comparative Examples 10-11, the temperatures of the first cooling control were 35°C and 55°C, respectively. Under the same conditions, the yield of the refined crude bifonazole in Examples 1, 11-12 was 84.33%-94.28%; the purity of the refined bifonazole was 99.82%-99.97%, and the maximum single impurity was 0.03-0.09%; the residual solvent of the refined bifonazole was acetonitrile: not detected-0.003%, and ethanol: not detected; while the yield, purity and residual solvent of the refined crude bifonazole in Comparative Example 10 were all good, but the maximum single impurity was 0.11%, exceeding the limit value of 0.10%. The yield and purity of the refined crude bifonazole of Comparative Example 11 were both poor, and the maximum single impurity was 0.16%, exceeding the limit value of 0.10%.

[0147] It can be seen that under the same other conditions, the temperature of the first cooling control during the process of refining crude bifonazole has a significant impact on the refining results. When the temperature of the first cooling control is 40-50°C, the yield of the refined crude bifonazole can reach 84.33-94.28%, the purity of the refined bifonazole can reach 99.80% and above, and the residual content of the refined bifonazole can reach acetonitrile: not detected to 0.003%, ethanol: not detected, and the maximum single impurity: 0.03% to 0.09%, all of which meet the requirements for pharmaceutical use.

[0148] 4) Comparative Examples 1, 13-14 and Comparative Examples 12-13 were observed, and the only difference between them was the temperature of the second cooling control during the purification of the crude bifonazole.

[0149] In the process of refining the crude bifonazole, the temperatures of the second cooling control in Examples 1, 13 and 14 were 5°C, 0°C and 10°C respectively; in Comparative Examples 12 and 13, the temperatures of the second cooling control in the process of refining the crude bifonazole were -5°C and 15°C respectively. When other conditions were set the same, the yield of the refined crude bifonazole in Examples 1, 13 and 14 was 87.56% to 94.28%; the purity of the refined bifonazole was 99.90% to 99.97%; the residual content of the refined bifonazole was acetonitrile: not detected to 0.002%, ethanol: not detected, and the maximum single impurity: 0.03 to 0.07%. The yield of the refined crude bifonazole in Comparative Examples 12-13 is 94.03%-94.53%; the purity of the refined bifonazole is 99.44%-99.80%, and the maximum single impurity is 0.14%-0.33%, which does not meet the requirements for pharmaceutical use; the residual content of the refined bifonazole is acetonitrile: 0.001%-0.003%, and ethanol: not detected.

[0150] It can be seen that under the same other conditions, the temperature of the second cooling control during the refining of crude bifonazole has a significant impact on the refining results. When the temperature of the second cooling control is 0-10°C, the yield of the refined crude bifonazole can reach 87%-95%, the purity of the refined bifonazole can reach 99.80% and above, and the residual content of the refined bifonazole can reach acetonitrile: not detected to 0.003%, ethanol: not detected, and the maximum single impurity: 0.03%-0.07%.

[0151] It is to be understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present application, but the present application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and essence of the present application, and these modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A method for refining a crude bifonazole product, characterized in that: The crude product of bifonazole is purified by combining solvents and cooling for multiple times to obtain bifonazole; The combined solvent includes solvent A and solvent B, wherein solvent A is one of ethanol, methanol, isopropanol, acetone, and ethyl acetate, and solvent B is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

2. The method for refining the crude bifonazole according to claim 1, characterized in that: The combined solvent is one of ethanol and acetonitrile, ethanol and N,N-dimethylformamide, ethanol and dimethyl sulfoxide, ethanol and tetrahydrofuran, methanol and acetonitrile, isopropanol and acetonitrile, acetone and acetonitrile, and ethyl acetate and acetonitrile.

3. The method for refining the crude bifonazole according to claim 1, characterized in that: The volume ml usage ratio of solvent A and solvent B in the combined solvent is 4.5-5.5:1, ml:ml.

4. The method for refining the crude bifonazole according to claim 3, characterized in that: The volume ratio of solvent A to solvent B in the combined solvent is 4.8-5.0:1, ml:ml.

5. The method for refining the crude bifonazole according to claim 1, characterized in that: The combined solvent is one of methanol and N,N-dimethylformamide, ethanol and dimethyl sulfoxide, ethanol and tetrahydrofuran, isopropanol and N,N-dimethylformamide, isopropanol and dimethyl sulfoxide, isopropanol and tetrahydrofuran, acetone and N,N-dimethylformamide, acetone and dimethyl sulfoxide, acetone and tetrahydrofuran, ethyl acetate and N,N-dimethylformamide, ethyl acetate and dimethyl sulfoxide, ethyl acetate and tetrahydrofuran.

6. The method for refining the crude bifonazole according to claim 4, characterized in that: In the bifonazole crude product refining process, the multiple coolings are two coolings.

7. The method for refining the crude bifonazole according to claim 6, characterized in that: In the bifonazole crude product refining process, the temperature is lowered twice, and the first cooling temperature is controlled at 40-50°C.

8. The method for refining the crude bifonazole according to claim 7, characterized in that: The temperature of the second cooling is controlled at 0-10°C.

9. The method for refining the crude bifonazole according to claim 8, characterized in that: The temperature of the second cooling is controlled at 5-10°C.

10. A method for preparing bifonazole, characterized in that: 1) Preparation of crude bifonazole: Using biphenyl and benzoyl chloride as starting materials, intermediate 1 is generated; intermediate 1 is reduced with sodium borohydride to obtain intermediate 2, intermediate 2 is chlorinated with thionyl chloride to obtain intermediate 3, and intermediate 3 is substituted with imidazole to obtain crude bifonazole; 2) Purify the crude bifonazole according to the purification method of claims 1 to 9 to obtain the bifonazole preparation route as follows:

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