Preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl

Abstract

The present invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of biphenyl benzazole intermediate 4-(α-chlorobenzyl) biphenyl. 4-Phenyldiphenylmethanol is added to N,N-dimethylformamide, and thionyl chloride is added dropwise. After the addition is complete, the mixture is heated to room temperature to 80 °C for reaction. After the reaction is complete, water is added to the reaction material, and the temperature is lowered for crystallization. It is filtered, washed with water, and dried to obtain the product. The preparation method provided by the present invention is simple in operation, low in energy consumption, high in yield, good in purity, and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of biphenyl benzazole intermediate 4-(α-chlorobenzyl) biphenyl. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] 4-(α-Chlorobenzyl) biphenyl is an important pharmaceutical intermediate in the process of preparing biphenyl benzazole raw drug, and its chemical structural formula is:

[0004]

[0005] According to the research and understanding of the inventor, the current preparation method of 4-(α-chlorobenzyl) biphenyl is: using 4-phenyldiphenylmethanol and thionyl chloride as raw materials, and heating to reflux in benzene. However, through further research, it is found that this method is difficult to carry out through conventional operations, the yield cannot reach the expected value, and the purity is relatively low. In addition, benzene is a class I solvent, which is difficult to remove in the later stage, and caking occurs during the post-treatment crystallization, making the operation difficult and not conducive to large-scale production. Summary of the Invention

[0006] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a preparation method of biphenyl benzazole intermediate 4-(α-chlorobenzyl) biphenyl. The preparation method provided by the present invention is simple in operation, low in energy consumption, high in yield, good in purity, and suitable for large-scale industrial production.

[0007] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0008] A preparation method of biphenyl benzazole intermediate 4-(α-chlorobenzyl) biphenyl, adding 4-phenyldiphenylmethanol to N,N-dimethylformamide, dropping thionyl chloride, heating to room temperature to 80 °C for reaction after dropping, adding water to the reaction material after the reaction, cooling and crystallizing, filtering, washing with water, and drying to obtain the product.

[0009] According to the present invention, the main reason why conventional operation is difficult to carry out using 4-phenylbenzhydrol and thionyl chloride as raw materials and heating reflux in benzene is that in the reaction system, the requirements for raw materials, solvents and reaction conditions are extremely high, there are many impurities in commercially available 4-phenylbenzhydrol, thionyl chloride and benzene, which cannot meet the reaction requirements, and the temperature of the reaction temperature is difficult to accurately control by conventional reactors, which all lead to the problem that the reaction system is difficult to realize the preparation of 4-(α-chlorobenzyl) biphenyl by conventional operation. And the unconventional operations such as further purification of raw materials and solvents and accurate temperature control affect its application in industrialization.

[0010] In order to avoid the problems existing in the reaction system and the problem that benzene is not conducive to production scale-up when used as a solvent, the present invention uses other similar solvents such as toluene to replace benzene for the reaction. It is found through experiments that when toluene is used as a solvent, 4-(α-chlorobenzyl)biphenyl can be prepared by conventional operations, but the yield is only about 65% and the purity is only about 98.3. When toluene is replaced by other solvents such as dichloromethane, the yield is also less than 70% and the purity does not reach 99%.

[0011] The present invention unexpectedly found in experiments that when N,N-dimethylformamide is selected as the solvent, conventional operation is adopted, and the yield of 4-(α-chlorobenzyl)biphenyl prepared by the method is significantly improved, and can reach 80.0-90.0%. At the same time, since N,N-dimethylformamide is miscible with water, when water is added to the reacted material, 4-(α-chlorobenzyl)biphenyl can be crystallized, and the precipitate after crystallization is collected, and the purity thereof can reach above 99.2, and even up to 99.85%.

[0012] Mechanism studies have shown that the reaction process of alcohol and thionyl chloride first forms chlorosulfite, then breaks the CO bond, releases sulfur dioxide to generate chlorinated hydrocarbons. The decomposition mode of chlorosulfite is related to the polarity of the solvent, and also determines the change of the carbon atom configuration of the alcohol in the chlorination reaction. When thionyl chloride and N,N-dimethylformamide are used together in the present invention, the actual form of the chlorinating agent is:

[0013]

[0014] Because it has the advantages of high activity, rapid reaction, good selectivity and the ability to effectively bind HCl generated in the reaction, it can better react 4-phenylbenzhydrol with chlorine to generate 4-(α-chlorobenzyl)biphenyl.

[0015] Generally, the dosage ratio of 4-phenyldiphenylmethanol to N,N-dimethylformamide is 2:5 to 15 (g:mL). Research shows that the addition amount of N,N-dimethylformamide has an impact on the yield of 4-phenyldiphenylmethanol. When the dosage ratio of 4-phenyldiphenylmethanol to N,N-dimethylformamide is 2:5 to 10, the yield of 4-phenyldiphenylmethanol is higher, reaching 85 to 90%.

[0016] The beneficial effects of the present invention are as follows:

[0017] 1. The preparation method of the present invention is simple to operate and does not require distillation.

[0018] 2. The process conditions of the preparation method of the present invention are easy to achieve. To ensure the safety of experimental personnel, thionyl chloride is added dropwise at room temperature; HPLC detection shows that when the reaction is carried out at room temperature for 3 hours, 0.5% of 4-phenyldiphenylmethanol remains, and when the reaction is carried out at 55 to 65 °C for 2 hours, 4-phenyldiphenylmethanol is not detected.

[0019] 3. The reaction time of the preparation method of the present invention is short. The reaction process is monitored by HPLC. When the reaction time is extended, there is no increasing trend of other impurities.

[0020] 4. The post-treatment of the preparation method of the present invention is to add water to cool down to 20 to 30 °C for crystallization, filtration. The operation is simple and does not require a large amount of water washing. The obtained product has a purity ≥ 99% and a high yield.

[0021] In summary, the process of the present invention is simple and convenient, with few operation steps, high controllability, good purity and content of the prepared 4-(α-chlorobenzyl)biphenyl, and high yield, having good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The attached drawings in the specification that form a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation to the present invention.

[0023] Figure 1 It is the high performance liquid chromatography diagram of 4-(α-chlorobenzyl)biphenyl prepared in Example 1 of the present invention;

[0024] Figure 2 It is the high performance liquid chromatography diagram of 4-(α-chlorobenzyl)biphenyl prepared in Example 2 of the present invention;

[0025] Figure 3 It is the high performance liquid chromatography diagram of 4-(α-chlorobenzyl)biphenyl prepared in Example 3 of the present invention;

[0026] Figure 4 It is the high performance liquid chromatography diagram of 4-(α-chlorobenzyl)biphenyl prepared in Example 4 of the present invention;

[0027] Figure 5 The HPLC chromatogram of 4-(α-chlorobenzyl)biphenyl prepared in Example 5 of the present invention. Detailed implementation manners

[0028] It should be noted that the following detailed descriptions are all exemplary and are intended to provide further explanations of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0029] The raw materials used in the present invention are all commercially available without further description and are directly used without purification.

[0030] It should be noted that the terms used herein are only for describing specific implementation manners and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular forms are also intended to include the plural forms. In addition, 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.

[0031] In order to solve the problems existing in the existing methods for preparing 4-(α-chlorobenzyl)biphenyl, such as strict requirements, low yield, and low purity, the present invention proposes a method for preparing 4-(α-chlorobenzyl)biphenyl, an intermediate of bifonazole.

[0032] In a typical embodiment of the present invention, a method for preparing 4-(α-chlorobenzyl)biphenyl, an intermediate of bifonazole, is provided. 4-Phenyldiphenylmethanol is added to N,N-dimethylformamide, and thionyl chloride is added dropwise. After the addition is complete, the mixture is heated to room temperature to 80 °C for reaction. After the reaction is complete, water is added to the reaction material, and the temperature is lowered for crystallization. Then, filtration, washing with water, and drying are carried out to obtain the product.

[0033] The room temperature mentioned in the present invention refers to the temperature of the indoor environment, generally 15 to 30 °C.

[0034] The feeding ratio of 4-phenyldiphenylmethanol to N,N-dimethylformamide is 2:5 to 15, g:mL. In some embodiments, the feeding ratio of 4-phenyldiphenylmethanol to N,N-dimethylformamide is 2:5 to 10, g:mL. The yield is higher under this condition. When the amount of N,N-dimethylformamide is further reduced (such as 2:5 to 7, g:mL; 2:5 to 6.5, g:mL; 2:5 to 6, g:mL; 2:5 to 5.5, g:mL, etc.), not only can the yield be further improved, but also the reaction rate can be accelerated, and the reaction can be completed within 30 minutes.

[0035] In some embodiments, the molar ratio of 4-phenyldiphenylmethanol to thionyl chloride is 1:1.0 to 2.0, preferably 1:1.2 to 1.7.

[0036] In some embodiments, after the dropping is completed, the temperature for the heating reaction is 40 to 80 °C, preferably 55 to 65 °C.

[0037] In some embodiments, after the dropping is completed, the time for the heating reaction is 0.5 to 8 h; preferably 0.5 to 5 h.

[0038] In some embodiments, during the process of adding water to the reaction material after the reaction is completed, the addition amount of water is 5 to 15 times that of 4-phenyldiphenylmethanol, preferably 6 to 10 times.

[0039] In some embodiments, the way of adding water to the reaction material after the reaction is completed is by dropping.

[0040] In order to avoid the influence of impurities in water on the purity, in some embodiments, purified water is added to the reaction material after the reaction is completed.

[0041] In some embodiments, crystallization occurs after cooling to 20 to 30 °C.

[0042] In some embodiments, the time for crystallization by cooling is 1 to 3 h.

[0043] In some embodiments, the drying temperature is 40 to 60 °C.

[0044] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0045] Example 1:

[0046] In a 250 mL reaction flask, 150 mL of dichloromethane and 20.0 g of 4-phenyldiphenylmethanol were added, stirred and dissolved at room temperature, 15.2 g of thionyl chloride was added dropwise. After the dropping was completed, the mixture was stirred and refluxed for 2 h. TLC detection showed that part of the raw materials remained. It was concentrated under reduced pressure at 35 °C, stirred with petroleum ether for crystallization for 1 h, filtered, and dried at 40 °C to obtain 16.9 g of 4-(α-chlorobenzyl)biphenyl, with a yield of 69.3% and a purity of 98.924%, as Figure 1 shown.

[0047] Example 2:

[0048] In a 250 mL reaction flask, add 150 mL of N,N-dimethylformamide and 20.0 g of 4-phenyldiphenylmethanol. Stir and dissolve at room temperature, then dropwise add 15.2 g of thionyl chloride. After the addition is complete, stir and heat to 70 °C and react for 5 h. TLC detection shows that there is basically no raw material remaining. Dropwise add 200 mL of purified water and stir at 22 °C for 1 h. Filter and dry at 60 °C to obtain 17.2 g of 4-(α-chlorobenzyl)biphenyl, with a yield of 80.8% and a purity of 99.298%, as Figure 2 shown.

[0049] Example 3:

[0050] In a 250 mL reaction flask, add 100 mL of toluene and 20.0 g of 4-phenyldiphenylmethanol. Stir and dissolve at room temperature, then dropwise add 16.8 g of thionyl chloride. After the addition is complete, stir and heat to 80 °C and react for 2 h. TLC detection shows that there is some raw material remaining. Concentrate under reduced pressure at 50 °C, add petroleum ether and stir for 1 h to crystallize. Filter and dry at 40 °C to obtain 14.8 g of 4-(α-chlorobenzyl)biphenyl, with a yield of 65.5% and a purity of 98.294%, as Figure 3 shown.

[0051] Example 4:

[0052] In a 250 mL reaction flask, add 100 mL of N,N-dimethylformamide and 20.0 g of 4-phenyldiphenylmethanol. Stir and dissolve at room temperature, then dropwise add 11.9 g of thionyl chloride. After the addition is complete, stir and heat to 60 °C and react for 1 h. TLC detection shows that there is basically no raw material remaining. Dropwise add 140 mL of purified water and stir at 22 °C for 1 h. Filter and dry at 60 °C to obtain 18.6 g of 4-(α-chlorobenzyl)biphenyl, with a yield of 87.3% and a purity of 99.785%, as Figure 4 shown.

[0053] Example 5:

[0054] In a 250 mL reaction flask, add 50 mL of N,N-dimethylformamide and 20.0 g of 4-phenyldiphenylmethanol. Stir and dissolve at room temperature, then dropwise add 11.9 g of thionyl chloride. After the addition is complete, stir and heat to 25 °C and react for 0.5 h. TLC detection shows that there is basically no raw material remaining. Dropwise add 140 mL of purified water and stir at 22 °C for 1 h. Filter and dry at 60 °C to obtain 18.7 g of 4-(α-chlorobenzyl)biphenyl, with a yield of 87.8% and a purity of 99.847%, as Figure 5 shown.

[0055] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl, characterized in that, 4-phenyldiphenylmethanol is added to N,N-dimethylformamide, thionyl chloride is added dropwise, and after the addition is completed, the mixture is heated to room temperature to 80 °C for reaction. After the reaction is completed, water is added to the reaction material, the temperature is lowered for crystallization, filtration, washing with water, and drying are carried out to obtain the product; The dosage ratio of 4-phenyldiphenylmethanol to N,N-dimethylformamide is 2:5 to 10, g:mL; Crystallization is carried out by lowering the temperature to 20 to 30 °C; The molar ratio of 4-phenyldiphenylmethanol to thionyl chloride is 1:1.0 to 2.0; After the addition is completed, the temperature for the heating reaction is 40 to 80 °C; the time for the heating reaction is 0.5 to 8 h; During the process of adding water to the reaction material after the reaction is completed, the addition amount of water is 5 to 15 times that of 4-phenyldiphenylmethanol; The way of adding water to the reaction material after the reaction is completed is by dropwise addition; Purified water is added to the reaction material after the reaction is completed; The time for crystallization by lowering the temperature is 1 to 3 h.

2. The preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl as described in claim 1, characterized in that, The molar ratio of 4-phenyldiphenylmethanol to thionyl chloride is 1:1.2 to 1.

7.

3. The preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl as described in claim 1, characterized in that, After the addition is completed, the temperature for the heating reaction is 55 to 65 °C.

4. The preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl as described in claim 1, characterized in that, After the addition is completed, the time for the heating reaction is 0.5 to 5 h.

5. The preparation method of bifonazole intermediate 4-(α-chlorobenzyl) biphenyl as described in claim 1, characterized in that during the reaction after completion, during the process of adding water to the reaction material, the addition amount of water is 6 to 10 times that of 4-phenyldiphenylmethanol.

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