A method for synthesizing N-cyclohexyl-2-benzothiazole

Abstract

This invention provides a method for synthesizing N-cyclohexyl-2-benzothiazole, comprising the following steps: reacting cyclohexylamine and 2-halobenzothiazole in an alcohol solvent in the presence of a deacidifying agent at 60-80°C to generate N-cyclohexyl-2-benzothiazole. The method of this invention is simple to operate, uses readily available raw materials, does not use halogen-containing catalysts, has low pollution, and produces products with high purity and yield. It also avoids the use of DMSO as a solvent, thus solving the problem of difficult DMSO recovery and purification.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for synthesizing N-cyclohexyl-2-benzothiazole. Background Technology

[0002] Benzothiazole compounds have been widely used in pesticides, pharmaceuticals, and other fields since their synthesis. Industrially, they are used as rubber accelerators, vulcanizing agents, and dyes for fibers and plastics. In agriculture, they are used as antibacterial agents, insecticides, and fungicides. In medicine, they are used for antiparasitic and anticancer purposes. Modification of benzothiazoles mainly involves introducing different substituents onto the benzene ring and introducing different active groups at the 2-position, with the active group at the 2-position having the greatest impact on its activity.

[0003] Introducing an amino derivative at the 2-position of benzothiazole can give it Schiff base properties, thereby exhibiting a variety of biological activities. When it combines with metal ions through N and S atoms to form heterocyclic metal complexes, it can greatly enhance its antibacterial activity against fungi and bacteria, and can also be used to detect the cytotoxicity of human cancer cells.

[0004] As a benzothiazole compound with an amino derivative introduced at the 2-position, N-cyclohexyl-2-benzothiazole has the following structural formula:

[0005]

[0006] Currently, the main methods for synthesizing N-cyclohexyl-2-benzothiazole are: (1) 2-iodothiocyanate phenyl ester and cyclohexylamine are synthesized into N-cyclohexyl-2-benzothiazole under the catalysis of tetrabutylphosphine bromide; (2) cyclohexyl isothiocyanate and 2-mercaptoaniline are heated in water or dimethyl sulfoxide (DMSO) to synthesize N-cyclohexyl-2-benzothiazole; (3) chlorobenzothiazole and cyclohexylamine are deacidified in DMSO with K2CO3 and CuI as catalyst to synthesize N-cyclohexyl-2-benzothiazole.

[0007] Visekhonuo Kuotsu et al. (An environmentally benign synthesis of Tetrabutylphosphonium tribromide (TBPTB) – a versatile and efficient phasetransfer reagent for organic transformations[J]. Green Chemistry Letters and Reviews, 2021, 14(2): 424-433) used phenyl 2-iodoisothiocyanate and cyclohexylamine in the presence of tetrabutylphosphine bromide to obtain N-cyclohexyl-2-benzothiazole with a yield of 80%. This method has a relatively low yield, and the sources of raw materials and catalysts are not widely available; halogen-containing catalysts are prone to contamination.

[0008] Ritika Sharma et al. (Water-mediated synthesis of benzazole and thioureamotifs by reacting naturally occurring isothiocyanate with amines[J]. Synthetic Communications, 2015, 45: 2106-2114) synthesized N-cyclohexyl-2-benzothiazole by reacting cyclohexyl isothiocyanate with 2-mercaptoaniline at 120 °C for 48 h, with a yield of 56%. This method has a low yield, is complex and time-consuming, and has limited availability of raw materials.

[0009] Stéphanie Toulot et al. (Convenient and Reliable Routes Towards 2-Aminothiazoles: Palladium-Catalyzed versus Copper-Catalyzed Aminations of Halothiazoles[J]. Advanced Synthesis & Catalysis, 2013, 355(16):3263-3272) reacted chlorobenzothiazole with cyclohexylamine in DMSO with K2CO3 deacidification under CuI catalysis to obtain N-cyclohexyl-2-benzothiazole. This method uses DMSO as a solvent, making post-processing and recovery difficult, and the halogen-containing catalyst easily causes environmental pollution.

[0010] Therefore, existing methods for synthesizing N-cyclohexyl-2-benzothiazole suffer from problems such as low yield, limited availability of raw materials and catalysts, environmental pollution caused by catalysts, complex operation, and difficulties in solvent post-processing and recovery. There is a need in this field for a simple and environmentally friendly method for synthesizing N-cyclohexyl-2-benzothiazole. Summary of the Invention

[0011] To address the shortcomings of the aforementioned synthetic methods, this invention provides a novel method for synthesizing N-cyclohexyl-2-benzothiazole. This method uses cyclohexylamine and 2-halobenzothiazole as raw materials, employs an alcohol solvent, and directly synthesizes the target product at 60-80°C. The method of this invention is simple to operate, uses readily available raw materials, does not use halogen-containing catalysts, has low pollution levels, and produces products with high purity and yield. Furthermore, it does not use DMSO as a solvent, thus solving the problem of difficult DMSO recovery and purification.

[0012] Specifically, the method for synthesizing N-cyclohexyl-2-benzothiazole according to the present invention includes the following steps:

[0013] Cyclohexylamine and 2-halobenzothiazole are reacted in an alcohol solvent at 60-80°C in the presence of a deacidifying agent to generate N-cyclohexyl-2-benzothiazole.

[0014] In one or more embodiments, the deacidifying agent is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0015] In one or more embodiments, the alcohol solvent is a low-boiling-point alcohol solvent, preferably with a boiling point ≤120°C.

[0016] In one or more embodiments, the alcohol solvent is selected from C1-C4 alcohols, such as one or more of ethanol, n-propanol, isopropanol and n-butanol, preferably ethanol.

[0017] In one or more embodiments, the 2-halobenzothiazole is selected from one or more of 2-chlorobenzothiazole, 2-bromobenzothiazole and 2-iodobenzothiazole, preferably 2-chlorobenzothiazole.

[0018] In one or more embodiments, the reaction temperature is 70-75°C.

[0019] In one or more implementations, the reaction time is 4-8 hours.

[0020] In one or more embodiments, the molar ratio of cyclohexylamine to 2-halobenzothiazole is (1-1.5):1.

[0021] In one or more embodiments, the molar ratio of cyclohexylamine to 2-halobenzothiazole is (1-1.2):1.

[0022] In one or more embodiments, the molar ratio of the deacidifying agent to 2-halobenzothiazole is (1-3):1.

[0023] In one or more embodiments, the amount of alcohol solvent used is 3 to 8 times the total mass of cyclohexylamine and 2-halobenzothiazole.

[0024] In one or more embodiments, the method comprises: heating a mixture of cyclohexylamine, a deacidifying agent, and an alcohol solvent to 60-80°C, and then adding 2-halobenzothiazole dropwise to react at 60-80°C.

[0025] In one or more embodiments, the dropping rate of 2-halobenzothiazole is ≤0.2 mol / h.

[0026] In one or more embodiments, the dropping rate of 2-halobenzothiazole is ≤0.1 mol / h.

[0027] In one or more embodiments, the dropping rate of 2-halobenzothiazole is 0.05-0.1 mol / h.

[0028] In one or more embodiments, the method further includes: after the reaction is complete, filtering off the inorganic salts in the reaction system while it is still hot, then cooling the solution to room temperature after recovering the solvent under reduced pressure, and filtering the filter cake after washing and drying to obtain N-cyclohexyl-2-benzothiazole. Detailed Implementation

[0029] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0030] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0031] In this document, the terms “contains,” “includes,” “containing,” and similar terms encompass the meanings of “basically composed of” and “composed of.” For example, when this document discloses “A contains B and C,” the statement “A is composed of B and C” should be considered as having been disclosed in this document.

[0032] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0033] Unless otherwise specified, percentages refer to mass percentages and proportions refer to mass ratios in this article.

[0034] In this document, when describing embodiments or examples, it should be understood that it is not intended to limit the invention to those embodiments or examples. Rather, all alternatives, modifications, and equivalents of the methods and materials described herein are covered within the scope defined by the claims.

[0035] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0036] The inventors have solved the problem of difficult DMSO recovery and purification by using alcohol solvents instead of DMSO and without using halogen-containing catalysts, and the resulting N-cyclohexyl-2-benzothiazole can be synthesized directly at 60-80℃. This also reduces pollution, simplifies and facilitates operation, and improves the content and yield of the finished product.

[0037] This invention discovers that alcohol solvents are suitable for the synthesis of N-cyclohexyl-2-benzothiazole from the reaction of cyclohexylamine and 2-halobenzothiazole, achieving a high yield. The alcohol solvents suitable for this invention are preferably low-boiling-point solvents, especially those with a boiling point ≤120℃, to facilitate solvent recovery after the reaction. Suitable alcohol solvents include ethanol, n-propanol, isopropanol, and n-butanol. In a preferred embodiment, this invention uses ethanol as the solvent, which is beneficial for improving purity and yield. If DMSO is used as the solvent, the product has high solubility in DMSO, making it difficult to precipitate the product by evaporating the solvent, resulting in a less pure product and requiring high-temperature distillation, which is cumbersome.

[0038] In this invention, the amount of alcohol solvent used can be 3-8 times the total mass of cyclohexylamine and 2-halobenzothiazole. In a preferred embodiment, the amount of alcohol solvent used is 4-6 times, for example, 4.5 times, 5 times, or 5.5 times the total mass of cyclohexylamine and 2-halobenzothiazole.

[0039] The 2-halobenzothiazoles suitable for use in this invention include 2-chlorobenzothiazole, 2-bromobenzothiazole, and 2-iodobenzothiazole. Preferably, 2-chlorobenzothiazole is used, which is advantageous for reducing costs and facilitating scale-up production.

[0040] In this invention, the molar ratio of cyclohexylamine to 2-halobenzothiazole can be (1-1.5):1. Preferably, the molar ratio of cyclohexylamine to 2-halobenzothiazole is (1-1.2):1, for example, 1.05:1, 1.1:1, or 1.15:1, which is beneficial for improving purity and yield.

[0041] The deacidifying agent suitable for use in this invention can be any basic compound capable of neutralizing the hydrogen halides produced in the reaction. Preferably, the deacidifying agent is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Compared to using sodium hydroxide or potassium hydroxide as the deacidifying agent, using sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate as the deacidifying agent can reduce the by-product 2-ethoxybenzothiazole. In some embodiments, the deacidifying agent is sodium carbonate and / or potassium carbonate, which is beneficial for reducing the amount of deacidifying agent used and the amount of bubbles generated. In some embodiments, the deacidifying agent is sodium bicarbonate and / or potassium bicarbonate, which is beneficial for increasing the yield.

[0042] In this invention, the amount of deacidifying agent used is sufficient to neutralize the hydrogen halide produced in the reaction. Typically, the molar ratio of the deacidifying agent to 2-halobenzothiazole is (1-3):1. For example, when sodium carbonate and / or potassium carbonate are used as the deacidifying agent, the molar ratio of the deacidifying agent to 2-halobenzothiazole can be (1-2):1, preferably (1-1.5):1, such as 1:1, 1.1:1, 1.2:1; when sodium bicarbonate and / or potassium bicarbonate are used as the deacidifying agent, the molar ratio of the deacidifying agent to 2-halobenzothiazole can be (2-3):1, such as 2:1, 2.1:1, 2.2:1, 2.5:1.

[0043] In some embodiments, the molar ratio of cyclohexylamine, 2-halobenzothiazole, and deacidifying agent is (1-1.2):1:(1-1.5), and the amount of alcohol solvent used is 4-6 times the total mass of cyclohexylamine and 2-halobenzothiazole.

[0044] In this invention, the reaction temperature can be 60-80℃. Temperatures above 80℃ result in lower reaction yields and purity. Preferably, the reaction temperature is 70-75℃, which helps reduce side reactions and improves reaction yield and purity. The reaction time can be 4-8 hours, for example, 4.5 hours, 5 hours, 5.5 hours, 6 hours, or 7 hours. Reaction times below 4 hours result in incomplete reactions.

[0045] In this invention, it is preferable to first heat the mixture of cyclohexylamine, deacidifying agent, and alcohol solvent to 60-80°C, and then add 2-halobenzothiazole to react at 60-80°C. Heating other materials to the reaction temperature first, and then adding 2-halobenzothiazole, helps to avoid the formation of byproducts such as 2-ethoxybenzothiazole. In this invention, it is preferable to control the addition rate of 2-halobenzothiazole to avoid excessive side reactions caused by excessively rapid addition. For example, 2-halobenzothiazole can be added dropwise, preferably at a rate ≤0.2 mol / h, more preferably ≤0.1 mol / h, for example, 0.05-0.1 mol / h, which can effectively reduce the occurrence of side reactions. Preferably, after adding 2-halobenzothiazole, the reaction continues for 4-5 hours to ensure complete reaction.

[0046] In some embodiments, a mixture of cyclohexylamine, a deacidifying agent, and an alcohol solvent is first heated to 60-80°C, preferably 70-75°C, and then 2-halobenzothiazole is added dropwise at a rate of ≤0.2 mol / h, preferably ≤0.1 mol / h to carry out the reaction of the present invention.

[0047] After the reaction is complete, the inorganic salts in the reaction system can be filtered off while hot. The solution is then cooled to room temperature after most of the solvent has been recovered under reduced pressure. The filtered solution is then washed and dried to obtain the N-cyclohexyl-2-benzothiazole product. Washing with ethanol and water is acceptable.

[0048] The present invention has the following advantages over the prior art:

[0049] (1) The operation is simpler and more convenient;

[0050] (2) Low-boiling-point alcohols are used as solvents, making recovery easy and purification simple;

[0051] (3) It does not involve halogen catalysts, resulting in less pollution;

[0052] (4) High content and yield of finished product.

[0053] The present invention will be described below by way of specific embodiments. It should be understood that these embodiments are merely illustrative and are not intended to limit the scope of the invention. The methods, reagents, and materials used in the embodiments are conventional methods, reagents, and materials in the art, unless otherwise stated. The raw material compounds in the embodiments are all commercially available.

[0054] Example 1

[0055] 10.9 g of cyclohexylamine, 150 g of ethanol, and 11.7 g of sodium carbonate were added to a four-necked flask. The mixture was heated to approximately 75 °C, and 16.6 g of 2-chlorobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-chlorobenzothiazole reaction was complete. The inorganic salts were filtered off while the mixture was still hot. The solution was then cooled to room temperature after most of the solvent was recovered under reduced pressure. After filtration, the solution was washed once with ice-cold ethanol and once with water, and then dried. The purity of the N-cyclohexyl-2-benzothiazole product was 99.2%, and the yield was 90.8%.

[0056] Example 2

[0057] 10.9 g of cyclohexylamine, 130 g of ethanol, and 11.7 g of sodium carbonate were added to a four-necked flask. The mixture was heated to approximately 75 °C, and 16.6 g of 2-chlorobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-chlorobenzothiazole reaction was complete. The inorganic salts were filtered while hot. The solution was then cooled to room temperature after most of the solvent was recovered under reduced pressure. After filtration, the solution was washed once with ice-cold ethanol and once with water, and then dried. The purity of the N-cyclohexyl-2-benzothiazole product was 98.9%, and the yield was 90.1%.

[0058] Example 3

[0059] 10.9 g of cyclohexylamine, 150 g of isopropanol, and 11.7 g of sodium carbonate were added to a four-necked flask. The mixture was heated to approximately 75°C, and 16.6 g of 2-chlorobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-chlorobenzothiazole reaction was complete. The inorganic salts were filtered off while the mixture was still hot. The solution was then cooled to room temperature after most of the solvent was recovered under reduced pressure. After filtration, the solution was washed once with ice-cold ethanol and once with water, and then dried. The N-cyclohexyl-2-benzothiazole product had a purity of 98.8% and a yield of 88.5%.

[0060] Example 4

[0061] 10.9 g of cyclohexylamine, 150 g of n-butanol, and 11.7 g of sodium carbonate were added to a four-necked flask. The mixture was heated to approximately 75°C, and 16.6 g of 2-chlorobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-chlorobenzothiazole reaction was complete. The inorganic salts were filtered off while the mixture was still hot. The solution was then cooled to room temperature after most of the solvent was recovered under reduced pressure. After filtration, the solution was washed once with ice-cold ethanol and once with water, and then dried. The N-cyclohexyl-2-benzothiazole product had a purity of 98.5% and a yield of 84.8%.

[0062] Example 5

[0063] 10.9 g of cyclohexylamine, 150 g of ethanol, and 17.0 g of sodium bicarbonate were added to a four-necked flask. The mixture was heated to approximately 75°C, and 16.6 g of 2-chlorobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-chlorobenzothiazole reaction was complete. The inorganic salts were filtered off while hot. After recovering most of the solvent under reduced pressure, the solution was cooled to room temperature and filtered. The filter cake was washed once with ice-cold ethanol and once with water, and then dried. The N-cyclohexyl-2-benzothiazole product had a purity of 98.8% and a yield of 91.3%.

[0064] Example 6

[0065] 10.9 g of cyclohexylamine, 150 g of ethanol, and 11.7 g of sodium carbonate were added to a four-necked flask. The mixture was heated to approximately 75 °C, and 21.4 g of 2-bromobenzothiazole was slowly added dropwise over 1 hour. After the addition was completed, the mixture was kept at this temperature for 5 hours until the 2-bromobenzothiazole reaction was complete. The inorganic salts were filtered off while the mixture was still hot. The solution was then cooled to room temperature after most of the solvent was recovered under reduced pressure. After filtration, the solution was washed once with ice-cold ethanol and once with water, and then dried. The N-cyclohexyl-2-benzothiazole product had a purity of 97.3% and a yield of 86.6%.

Claims

1. A method for synthesizing N-cyclohexyl-2-benzothiazole, characterized in that, The method includes: Cyclohexylamine and 2-halobenzothiazole are reacted in an alcohol solvent at 70-75°C in the presence of a deacidifying agent to generate N-cyclohexyl-2-benzothiazole. The 2-halobenzothiazole is selected from one or more of 2-chlorobenzothiazole, 2-bromobenzothiazole and 2-iodobenzothiazole; The deacidifying agent is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The alcohol solvent is selected from C1-C4 alcohols; The boiling point of the alcohol solvent is ≤120℃.

2. The method as described in claim 1, characterized in that, The alcohol solvent is selected from one or more of ethanol, n-propanol, isopropanol, and n-butanol.

3. The method as described in claim 1, characterized in that, The alcohol solvent is ethanol.

4. The method as described in claim 1, characterized in that, The 2-halobenzothiazole is 2-chlorobenzothiazole.

5. The method as described in claim 1, characterized in that, The reaction time is 4-8 hours.

6. The method as described in claim 1, characterized in that, The molar ratio of cyclohexylamine to 2-halobenzothiazole is (1-1.5):

1.

7. The method as described in claim 1, characterized in that, The molar ratio of cyclohexylamine to 2-halobenzothiazole is (1-1.2):

1.

8. The method as described in claim 1, characterized in that, The molar ratio of the deacidifying agent to 2-halobenzothiazole is (1-3):

1.

9. The method as described in claim 1, characterized in that, The amount of the alcohol solvent used is 3-8 times the total mass of cyclohexylamine and 2-halobenzothiazole.

10. The method as described in claim 1, characterized in that, The method includes heating a mixture of cyclohexylamine, a deacidifying agent, and an alcohol solvent to 60-80°C, and then adding 2-halobenzothiazole dropwise to react at 60-80°C.

11. The method as described in claim 10, characterized in that, The dropping rate of 2-halobenzothiazole is ≤0.2 mol / h.

12. The method as described in claim 10, characterized in that, The dropping rate of 2-halobenzothiazole is ≤0.1 mol / h.

13. The method as described in claim 10, characterized in that, The dropping rate of 2-halobenzothiazole is 0.05-0.1 mol / h.

14. The method as described in claim 1, characterized in that, The method further includes: after the reaction is complete, filtering off the inorganic salts in the reaction system while it is still hot, then cooling the solution to room temperature after recovering the solvent under reduced pressure, filtering, and washing and drying the filter cake to obtain N-cyclohexyl-2-benzothiazole.

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