A process for the preparation of clotrimazole

Abstract

This invention belongs to the field of chemical drug synthesis technology and relates to a method for preparing clotrimazole. It includes steps using (2-chlorophenyl)diphenylmethanol as a raw material according to the following reaction route; wherein R is methyl, ethyl, trifluoromethyl, phenyl, or p-methylphenyl. The preparation method provided by this invention is simple, efficient, clean, environmentally friendly, and energy-saving, and the prepared clotrimazole has high purity and excellent quality.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis technology and relates to a method for preparing clotrimazole. 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] Traditional methods for synthesizing clotrimazole all revolve around first preparing (2-chlorophenyl)diphenylchloromethane, and then condensing it with imidazole. The synthetic route is as follows:

[0004]

[0005] As can be seen from the above synthetic routes, the preparation of clotrimazole always requires the intermediate (2-chlorophenyl)diphenylchloromethane. The inventors have found the following problems in preparing this intermediate: 1. It requires the use of aluminum trichloride or thionyl chloride, which is fuming, highly irritating, environmentally unfriendly, and involves numerous side reactions; 2. (2-chlorophenyl)diphenylchloromethane has poor stability and is easily hydrolyzed to (2-chlorophenyl)diphenylmethanol. For example, patent CN107629006B uses the unstable intermediate (2-chlorophenyl)diphenylchloromethane to react with imidazole for up to 48 hours. Although the yield is high and the conditions are mild, the poor stability of (2-chlorophenyl)diphenylchloromethane makes it difficult to guarantee purity, and its market availability is poor. The resulting clotrimazole contains a high content of the degradation impurity (2-chlorophenyl)diphenylmethanol, which poses a significant challenge for subsequent impurity removal, requiring column chromatography separation, which is detrimental to industrial production. For example, patent CN111423380B uses a one-pot method to prepare clotrimazole. The process of preparing the intermediate (2-chlorophenyl)diphenylchloromethane requires high-temperature atmospheric pressure distillation first, and then vacuum distillation to obtain the toluene solution of the intermediate. The process is cumbersome and energy-intensive. The process of preparing the final clotrimazole product requires nitrogen protection, and the product is not easy to precipitate, so seed crystals need to be added, which is not conducive to the convenience of production. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing clotrimazole that is simple, efficient, clean, environmentally friendly, and energy-saving, and produces clotrimazole with high purity and excellent quality.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] A method for preparing clotrimazole includes the steps of using (2-chlorophenyl)diphenylmethanol as a raw material according to the following reaction route;

[0009]

[0010] Wherein, R is methyl, ethyl, trifluoromethyl, phenyl, or p-methylphenyl.

[0011] The raw material used in this invention, (2-chlorophenyl)diphenylmethanol, is a tertiary alcohol with three phenyl groups attached to its α-carbon, resulting in significant steric hindrance and making its reaction with hydroxyl groups more difficult. Therefore, its synthesis route for clotrimazole is more fixed. However, this invention unexpectedly discovered during research that using… (Sulfonyl chloride) reacts more readily with the hydroxyl group of (2-chlorophenyl)diphenylmethanol, and the resulting intermediate is also more readily condensed with imidazole. Therefore, this invention provides a novel synthetic route for clotrimazole.

[0012] Further research revealed that whether the intermediate after the first step of the reaction is purified has little impact on the subsequent condensation reaction. Therefore, intermediates obtained using this route can be directly used in the next step of the reaction without purification, simplifying the process. Furthermore, the study found that compared to traditional clotrimazole preparation routes, the route described in this invention significantly improves the yield and purity of clotrimazole, and also significantly reduces the residual amount of (2-chlorophenyl)diphenylmethanol, resulting in a substantial improvement in the quality of the clotrimazole product.

[0013] More specifically, (2-chlorophenyl)diphenylmethanol is esterified with sulfonyl chloride to obtain an intermediate ((2-chlorophenyl)diphenylmethanesulfonate), and the intermediate is condensed with imidazole to obtain clotrimazole.

[0014] More specifically, after (2-chlorophenyl)diphenylmethanol undergoes an esterification reaction with sulfonyl chloride, imidazole is added to the esterified material, followed by a condensation reaction to obtain clotrimazole.

[0015] In some embodiments, the esterification reaction of (2-chlorophenyl)diphenylmethanol with sulfonyl chloride to obtain the intermediate is carried out at a temperature of 10–40°C, preferably 30–40°C. This reaction condition results in higher reactivity, a faster reaction rate, and a higher yield.

[0016] In some embodiments, when (2-chlorophenyl)diphenylmethanol is subjected to an esterification reaction with sulfonyl chloride to obtain an intermediate, the sulfonyl chloride is added dropwise to a solution of (2-chlorophenyl)diphenylmethanol. Specifically, the temperature during the dropwise addition of sulfonyl chloride is -20 to 10°C, preferably 0 to 10°C.

[0017] In some embodiments, R is methyl or ethyl, preferably ethyl. Studies have shown that when R is methyl or ethyl, especially ethyl, the reaction yield is higher; after purification, clotrimazole has higher purity and less residual (2-chlorophenyl)diphenylmethanol.

[0018] In some embodiments, when (2-chlorophenyl)diphenylmethanol undergoes an esterification reaction with sulfonyl chloride to obtain an intermediate, an acid-binding agent is added. Specifically, the acid-binding agent is triethylamine, N,N-diisopropylethylamine, or pyridine. Triethylamine is preferred. This promotes the forward reaction and increases the reaction yield.

[0019] In some embodiments, the molar ratio of (2-chlorophenyl)diphenylmethanol to sulfonyl chloride is 1:1 to 3. Preferably, it is 1:1.5 to 2.

[0020] In some embodiments, the amount of imidazole used is 3 to 10 times the molar amount of (2-chlorophenyl)diphenylmethanol, preferably 3 to 5 times.

[0021] In some embodiments, the purification process of clotrimazole after reaction is as follows: the reacted material is cooled and stirred to crystallize, the filtered solid is pulped with a mixture of acetonitrile and acetone at 40-50°C, cooled, filtered, and dried.

[0022] In one or more embodiments, the temperature for cooling and stirring to induce crystallization is -20 to 20°C, preferably -5 to 10°C.

[0023] In one or more embodiments, the volume ratio of acetonitrile to acetone is 1:0.9 to 1.1.

[0024] The beneficial effects of this invention are as follows:

[0025] (1) In this invention, after reacting sulfonyl chloride with (2-chlorophenyl)diphenylmethanol, no purification is required. Imidazole can be added directly to carry out the next reaction. Therefore, a one-pot preparation method can be achieved, which is more economical.

[0026] (2) The intermediate made by the present invention of sulfonyl chloride and (2-chlorophenyl)diphenylmethanol is (2-chlorophenyl)diphenylmethanesulfonate, which has higher stability, can avoid the generation of unstable chlorinated intermediates, and makes impurity control more convenient.

[0027] (3) In the preparation of the intermediate, the present invention uses sulfonyl chloride to react with (2-chlorophenyl)diphenylmethanol, which avoids the use of aluminum trichloride or thionyl chloride for heating, making it environmentally friendly and a green process.

[0028] (4) The preparation method provided by the present invention does not require nitrogen protection, and the reaction can be completed under normal conditions. The conditions are mild and easy to industrialize.

[0029] (5) The preparation method provided by the present invention does not require high-temperature distillation, column chromatography separation, or seed crystal addition. After the reaction is completed, the product can be filtered, pulped and washed to obtain high-purity clotrimazole. Attached Figure Description

[0030] 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.

[0031] Figure 1 The liquid chromatogram of clotrimazole prepared in Comparative Example 1 of this invention;

[0032] Figure 2 for Figure 1 A magnified view of a portion of the image;

[0033] Figure 3 The liquid chromatogram of clotrimazole prepared in Example 1 of this invention;

[0034] Figure 4 for Figure 3 A magnified view of a portion of the image;

[0035] Figure 5 The liquid chromatogram of clotrimazole prepared in Example 2 of this invention;

[0036] Figure 6 for Figure 5 A magnified view of a portion of the image. Detailed Implementation

[0037] 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.

[0038] Comparative Example 1: Preparation of Clotrimazole using Conventional Methods

[0039] Add 500 mL of toluene and 100 g of (2-chlorophenyl)diphenylmethanol to a 1 L three-necked flask, stir to dissolve, then add 5 mL of LDM and 10 g of thionyl chloride. Heat to 61 °C to initiate the reaction. After initiation, begin dropwise addition of 91 g of thionyl chloride, controlling the temperature to not exceed 65 °C. Maintain the temperature at 63 °C and stir for 2 h. After the reaction is complete, heat to 92 °C and begin atmospheric distillation. After no obvious fraction is obtained, continue distillation for 2 h. Cool to 32 °C and collect 130 mL of the fraction by vacuum distillation. Heat to 44 °C and collect 390 mL of the fraction by vacuum distillation. Cool the residue to 25 °C to obtain a (2-chlorophenyl)diphenylchloromethane toluene solution.

[0040] Under nitrogen protection, 35g of imidazole was added, followed by dropwise addition of 51mL of triethylamine, with the temperature controlled below 35℃. After the addition was complete, the mixture was stirred at 25℃ for 1 hour, and then at 45℃ for 2 hours. After the reaction was complete, 330g of 10% NaHCO3 was added at room temperature. After stirring for 0.5 hours, the mixture was separated, washed three times with 300mL of purified water, and once with 300mL of saturated saline. The mixture was then distilled under reduced pressure at 60℃ until no obvious fraction was observed. 200mL of isopropanol was added to the residue. The mixture was heated to 70℃, stirred to dissolve, and 5g of activated carbon was added. The mixture was kept warm and stirred for 0.5 hours, then hot-filtered. The filtrate was cooled to 0℃, a small amount of seed crystals was added, and the mixture was kept warm and stirred for 12 hours. The mixture was filtered and dried under blast air for 6 hours to obtain 57.5g of clotrimazole. Yield: 49.2%, Purity (HPLC%): 95.661%, (2-chlorophenyl)diphenylmethanol: 2.579%. Figures 1-2 As shown.

[0041] Example 1: Preparation of Clotrimazole using this method

[0042] Add 500 mL of acetonitrile and 100 g of (2-chlorophenyl)diphenylmethanol to a 1 L three-necked flask, stir and cool to -10 °C, add 56 g of triethylamine, and add 62.3 g of methanesulfonyl chloride dropwise while stirring and controlling the temperature at 5 °C. After the addition is complete, react at 35 °C for 3 h.

[0043] Add 116 g of imidazole to the above solution and stir at 35 °C for 5 h. After the reaction is complete, cool to 5 °C and stir to crystallize for 3 h. Filter and wash twice with 500 mL of water. The filter cake is slurried in 500 mL of acetonitrile-acetone (1:1 v / v) at 45 °C for 1 h, cooled to room temperature, filtered, and dried by forced air for 6 h to obtain 90.4 g. Yield: 77.3%. Purity (HPLC%): 99.917%, (2-chlorophenyl)diphenylmethanol: 0.021%, etc. Figures 3-4 As shown.

[0044] Example 2: Preparation of Clotrimazole using this method

[0045] Add 250 mL of tetrahydrofuran and 50 g of (2-chlorophenyl)diphenylmethanol to a 500 mL three-necked flask, stir and cool to -10 °C, add 28.2 g of triethylamine, and add 35 g of ethylsulfonyl chloride dropwise at 0 °C while stirring. After the addition is complete, react at 35 °C for 4 h.

[0046] Add 58.1 g of imidazole to the above solution and stir at 36 °C for 6 h. After the reaction is complete, cool to 0 °C and stir to crystallize for 3 h. Filter and wash twice with 250 mL of water. The filter cake is slurried in 250 mL of acetonitrile-acetone (1:1 v / v) at 46 °C for 1 h, cooled to room temperature, filtered, and dried by forced air for 6 h to obtain 47.8 g. Yield: 81.7%. Purity (HPLC%): 99.979%. (2-chlorophenyl)diphenylmethanol: Not detected. Figures 5-6 As shown.

[0047] Table 1 shows a comparison of the yield, purity, and impurity data for Comparative Example 1 and Examples 1-2.

[0048] Table 1 Comparison of data from Comparative Example 1 and Examples 1-2

[0049]

[0050] Table 1 shows that Examples 1 and 2, using sulfonate esters as intermediates followed by a condensation reaction, significantly improved the yield and purity of clotrimazole, increasing it to over 99.9%, while significantly reducing the residual amount of (2-chlorophenyl)diphenylmethanol. Furthermore, a comparison between Examples 1 and 2 demonstrates that using ethylsulfonyl chloride as an intermediate further enhances the yield and purity of clotrimazole obtained via this reaction route, with virtually no residual (2-chlorophenyl)diphenylmethanol, thereby further improving the quality of clotrimazole as a pharmaceutical product.

[0051] 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 process for the preparation of clotrimazole, characterized by, This includes steps using (2-chlorophenyl)diphenylmethanol as a starting material according to the following reaction route; Wherein, R is methyl, ethyl or trifluoromethyl.

2. The method for preparing clotrimazole as described in claim 1, characterized in that, After esterification of (2-chlorophenyl)diphenylmethanol with sulfonyl chloride, imidazole is added to the esterified material and a condensation reaction is carried out to obtain clotrimazole.

3. The method for preparing clotrimazole as described in claim 1, characterized in that, The esterification reaction of (2-chlorophenyl)diphenylmethanol with sulfonyl chloride to obtain the intermediate is carried out at a temperature of 10~40℃.

4. The process for preparing clotrimazole according to claim 3, wherein the solvent is ethanol. The esterification reaction of (2-chlorophenyl)diphenylmethanol with sulfonyl chloride to obtain the intermediate is carried out at a temperature of 30~40℃.

5. The method for preparing clotrimazole as described in claim 1, characterized in that, When (2-chlorophenyl)diphenylmethanol is esterified with sulfonyl chloride to obtain an intermediate, sulfonyl chloride is added dropwise to a solution of (2-chlorophenyl)diphenylmethanol.

6. The method for preparing clotrimazole as described in claim 5, characterized in that, The temperature during the dropwise addition of sulfonyl chloride is -20~10℃.

7. The method for preparing clotrimazole as described in claim 5, characterized in that, The temperature during the dropwise addition of sulfonyl chloride is 0~10℃.

8. The method for preparing clotrimazole as described in claim 1, characterized in that, R is methyl or ethyl.

9. The method for preparing clotrimazole as described in claim 1, characterized in that, When (2-chlorophenyl)diphenylmethanol is esterified with sulfonyl chloride to obtain an intermediate, an acid-binding agent is added.

10. The method for preparing clotrimazole as described in claim 9, characterized in that, The acid-binding agent is triethylamine, N,N-diisopropylethylamine, or pyridine.

11. The method for preparing clotrimazole as described in claim 1, characterized in that, The molar ratio of (2-chlorophenyl)diphenylmethanol to sulfonyl chloride is 1:1~3.

12. The method for preparing clotrimazole as described in claim 11, characterized in that, The molar ratio of (2-chlorophenyl)diphenylmethanol to sulfonyl chloride is 1:1.5~2.

13. The method for preparing clotrimazole as described in claim 1, characterized in that, The amount of imidazole used is 3 to 10 times the molar amount of (2-chlorophenyl)diphenylmethanol.

14. The method for preparing clotrimazole as described in claim 13, characterized in that, The amount of imidazole used is 3 to 5 times the molar amount of (2-chlorophenyl)diphenylmethanol.

15. The method for preparing clotrimazole as described in claim 1, characterized in that, The purification process of clotrimazole after reaction is as follows: the reaction material is cooled and stirred to precipitate crystals, and the filtered solid is pulped with a mixture of acetonitrile and acetone at 40~50℃, cooled, filtered, and dried.

16. The method for preparing clotrimazole as described in claim 15, characterized in that, The temperature for cooling and stirring to induce crystallization is -20~20℃.

17. The method for preparing clotrimazole as described in claim 15, characterized in that, The temperature for cooling and stirring to induce crystallization is -5~10℃.

18. The method for preparing clotrimazole as described in claim 15, characterized in that, The volume ratio of acetonitrile to acetone is 1:0.9~1.1.

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