Preparation method of N-(2-methylcyclohexyl)-2, 3, 4, 5, 6-pentafluorobenzamide, atomized liquid and atomization device
By reacting pentafluorobenzoic acid, alkaline substances, and 2-methylcyclohexylamine in an organic solvent and then processing them, the synthesis problem of high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide in the prior art has been solved, providing a high-purity, low-cost preparation method suitable for electronic atomization devices.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HG INNOVATION LTD
- Filing Date
- 2025-12-18
- Publication Date
- 2026-05-12
AI Technical Summary
Existing technologies cannot effectively synthesize high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, and pose safety hazards, high energy consumption, and high costs.
N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide with a purity greater than or equal to 99% was obtained by reacting pentafluorobenzoic acid, an alkaline substance and 2-methylcyclohexylamine in an organic solvent, adding a condensing agent and then condensing.
The preparation of high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide was achieved under mild reaction conditions, low cost, simple operation, and high yield, making it suitable for electronic atomization devices.
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Figure CN122010756A_ABST
Abstract
Description
Technical Field
[0001] This application belongs to the field of sweetener technology, specifically relating to the preparation method, atomizing liquid and atomizing device of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. Background Technology
[0002] An electronic atomizing device is a device that atomizes a liquid into an aerosol through heating or other methods. Sweeteners are an important component of the liquid, which can optimize the taste and enhance the user experience.
[0003] Currently, the main sweeteners used as components of e-liquids include neotame, sucralose, neohesperidin dihydrochalcone (NHDC), and steviol glycosides (GSG). These sweeteners were developed for food and beverage applications and have significant drawbacks in their use in electronic atomization devices. For example, neotame is prone to decomposition and developing a bitter taste, while sucralose and NHDC are prone to causing core burn-in.
[0004] N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, as a synthetic sweetener, has low purity obtained by existing preparation methods, and poses significant safety hazards, high energy consumption, and high cost. Summary of the Invention
[0005] The technical problem to be solved by this application is to provide a method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, an atomizing liquid and an atomizing device, so as to improve the problem that the existing technology cannot effectively synthesize high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0006] To address the aforementioned problems, this application provides the following technical solution: This application discloses a method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, comprising: Pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine were added to an organic solvent to obtain a first mixture. A condensing agent is added to the first mixture to carry out a condensation reaction to obtain the crude target product. The crude target product is added to the second mixture and filtered to obtain the first purified product; The first purified product was dissolved in ethanol, decolorized with activated carbon, and then hot-filtered to obtain a filtrate. Water was added to the filtrate to precipitate a solid, which was then filtered to obtain a filter residue. The filter residue was dried to obtain N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, wherein the purity of the N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide was greater than or equal to 99%.
[0007] Furthermore, in the preparation method, the alkaline substance includes at least one selected from triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, and sodium carbonate; and / or The condensing agent comprises at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, Carter's condensing agent, and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate; and / or The organic solvent includes at least one of ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide.
[0008] Further, in the first mixture, the molar ratio of pentafluorobenzoic acid to 2-methylcyclohexylamine is 1:(1~1.2); and / or The molar ratio of pentafluorobenzoic acid to the condensing agent is 1:(1~1.2); and / or The molar ratio of pentafluorobenzoic acid to the alkaline substance is 1:(1.2~1.5).
[0009] Furthermore, in the preparation method, the ratio of the amount of pentafluorobenzoic acid (mol) to the volume of the organic solvent (mL) in the first mixture is 1 / 8 to 1 / 3 mol / mL.
[0010] Further, in the preparation method, the condensation reaction to obtain the crude target product includes: The reaction product of the condensation reaction is washed with water to obtain a washing solution, which is then subjected to extraction, drying and vacuum concentration in sequence to obtain the crude target product.
[0011] Furthermore, in the preparation method, the extractant in the extraction process includes ethyl acetate; and / or The drying process employs a desiccant, which includes at least one of anhydrous Na2SO4 and anhydrous magnesium sulfate.
[0012] Furthermore, in the preparation method, the second mixture comprises ethyl acetate and petroleum ether.
[0013] Furthermore, in the preparation method, the volume ratio of ethyl acetate to petroleum ether in the second mixture is 1:(5~10).
[0014] This application also proposes an atomizing liquid comprising an active substance and a sweetener, wherein the sweetener comprises N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide prepared as described above.
[0015] This application also proposes an atomizing device, including an atomizer, wherein the liquid storage chamber of the atomizer is filled with the atomizing liquid as described above.
[0016] Compared with the prior art, the embodiments of this application have the following advantages: In this embodiment, the method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide involves first adding pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine to an organic solvent, then adding a condensing agent. The reaction yields the crude target product of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. After filtration in a second mixture, the product is dissolved in ethanol, decolorized with activated carbon, and then hot-filtered. Water is added to the filtrate to precipitate the solid. After filtration and drying of the filter residue, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide with a purity greater than or equal to 99% can be obtained. Alternatively, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide can be synthesized from pentafluorobenzoic acid and 2-methylcyclohexylamine in an organic solvent using mild reaction conditions, which are friendly to operators and the environment, and are low in cost, simple to operate, and have high yield and high purity. Therefore, the method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in this application effectively solves the problem that existing technologies cannot effectively synthesize high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0017] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and do not limit this application. Attached Figure Description
[0018] Figure 1 This is a flowchart of the preparation method of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in the embodiments of this application; Figure 2 This is the HPLC detection chromatogram of the target product in Example 1; Figure 3 This is a TGA image of the target product in Example 1; Figure 4This is a gas chromatogram of the refined target product in Example 1; Figure 5 This is the mass spectrum of the target product in Example 1 at RT 29.024 min; Figure 6 This is the mass spectrum of the target product in Example 1 at RT 31.225 min; Figure 7 This is a diagram of the heating wire after the core paste test of each atomizing liquid in Test Example 7. Detailed Implementation
[0019] To make the above-mentioned objectives, features and advantages of this application more apparent and understandable, the application will be further described in detail below with reference to the accompanying drawings and specific embodiments.
[0020] The terms "first" and "second" in the specification and claims of this application may explicitly or implicitly include one or more of the features. In the description of this application, unless otherwise stated, "multiple" means two or more. Furthermore, "and / or" in the specification and claims indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.
[0021] The inventors discovered that sweeteners in the prior art are developed for food and beverage applications and are not suitable for electronic atomization devices; the inventors also discovered that N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, as a synthetic sweetener, has significant safety hazards in its existing preparation methods, and is energy-intensive and costly.
[0022] For example, the reaction of pentafluorobenzoyl chloride with 2-methylcyclohexylamine in related technologies is highly irritating and toxic, which can easily cause harm to operators and is detrimental to environmental and personnel safety. Another related technology uses a catalytic condensation method of pentafluorobenzoamide with 2-methylcyclohexylamine, which uses easily hydrolyzable chlorides, which are prone to corroding equipment, and requires high temperature and high pressure reactions, posing safety hazards. In addition, the purification step uses vacuum distillation, which is energy-intensive and costly.
[0023] In response to the above problems, such as Figure 1 As shown in the embodiments of this application, a method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide is provided, including steps 101 to 104.
[0024] Step 101: Add pentafluorobenzoic acid, an alkaline substance and 2-methylcyclohexylamine to an organic solvent to obtain a first mixture.
[0025] In this step, pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine are added to an organic solvent and mixed evenly to obtain the first mixture mentioned above, so that the subsequent condensing agent can catalyze the reaction between pentafluorobenzoic acid and 2-methylcyclohexylamine.
[0026] Step 102: Add a condensing agent to the first mixture and carry out a condensation reaction to obtain the crude target product.
[0027] In this step, a condensing agent is added to the first mixture and mixed by stirring, which catalyzes the condensation of pentafluorobenzoic acid and 2-methylcyclohexylamine to form N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. After returning to room temperature, the mixture is further mixed by stirring for 2-4 hours to complete the condensation reaction and obtain the crude product containing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0028] Step 103: Add the crude target product to the second mixture and filter to obtain the first purified product.
[0029] In this step, the condensation reaction product of pentafluorobenzoic acid and 2-methylcyclohexylamine is added to the second mixture for purification. The mixture is stirred at room temperature for 2-10 hours. Then, the residue is filtered and dried to achieve the preliminary purification of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide and obtain the first purified product.
[0030] Step 103: Dissolve the first purified product in ethanol, decolorize with activated carbon, and then perform hot filtration to obtain a filtrate. Add water to the filtrate to precipitate a solid, then filter to obtain a filter residue. Dry the filter residue to obtain N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, wherein the purity of the N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide is greater than or equal to 99%.
[0031] In this step, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, after the first purification treatment, is added to anhydrous ethanol and heated to dissolve at 40℃~60℃. Then, it is decolorized with activated carbon, hot filtered, and the filtrate is added with water to precipitate a white solid. After filtration, the filtrate is dried to complete the second purification treatment, obtaining pure N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide with a purity greater than or equal to 99%.
[0032] The method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in this application involves the synthesis of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide by reacting pentafluorobenzoic acid with 2-methylcyclohexylamine in an organic solvent through the action of an alkaline substance and a condensing agent. The reaction conditions are mild, friendly to operators and the environment, and the method is low in cost, simple to operate, has high yield, and high purity.
[0033] Therefore, the preparation method of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in the embodiments of this application can effectively solve the problem that the prior art cannot effectively synthesize high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0034] In this embodiment, the reaction equation for the condensation reaction of pentafluorobenzoic acid with 2-methylcyclohexylamine to form N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide is as follows:
[0035] In some embodiments, the molar ratio of pentafluorobenzoic acid to 2-methylcyclohexylamine in the first mixture is 1:(1~1.2), which allows them to effectively react and generate N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide.
[0036] In some embodiments, the molar ratio of pentafluorobenzoic acid to 2-methylcyclohexylamine in the first mixture is one of 1:1, 1:1.1, 1:1.2, or any two of them.
[0037] In some embodiments, in step 101 above, pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine can be added sequentially to an organic solvent at 0-20°C with stirring. In some embodiments, the alkaline substance includes at least one of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, and sodium carbonate, which can provide an alkaline environment for the condensation reaction between pentafluorobenzoic acid and 2-methylcyclohexylamine.
[0038] In some embodiments, the molar ratio of the above-mentioned pentafluorobenzoic acid to the basic substance is 1:(1.2~1.5), which can effectively provide a basic environment for the condensation reaction between pentafluorobenzoic acid and 2-methylcyclohexylamine, thereby promoting the reaction.
[0039] In some embodiments, the molar ratio of pentafluorobenzoic acid to the alkaline substance can be one of 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any combination thereof.
[0040] In some embodiments, the organic solvents mentioned above include at least one of ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide, which can not only dissolve pentafluorobenzoic acid and 2-methylcyclohexylamine well, but also do not participate in the condensation reaction and are easy to remove in post-processing.
[0041] In some embodiments, the ratio of the amount of pentafluorobenzoic acid (mol) to the volume of the organic solvent (mL) in the first mixture is 1 / 8 to 1 / 3 mol / mL, which can effectively dissolve the reaction substances and facilitate post-processing removal.
[0042] In some embodiments, the ratio between the amount of pentafluorobenzoic acid (mol) and the volume of the organic solvent (mL) in the first mixture can be one of 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or any two of them.
[0043] In some embodiments, in step 102 above, the condensing agent includes at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), Carter's condensing agent (BOP), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), which can effectively catalyze the condensation reaction between pentafluorobenzoic acid and N-(2-methylcyclohexyl).
[0044] In some embodiments, in step 102 above, the condensing agent is added to the first mixture at a molar ratio of pentafluorobenzoic acid to condensing agent of 1:(1~1.2), which can effectively catalyze the condensation reaction between pentafluorobenzoic acid and 2-methylcyclohexylamine, and also avoid condensing agent residue.
[0045] In some embodiments, in step 102 above, the condensing agent may be added to the first mixture according to one or any two of the following molar ratios of pentafluorobenzoic acid to condensing agent: 1:1, 1:1.1, 1:1.2.
[0046] In some embodiments, step 102 above, performing a condensation reaction to obtain the crude target product, includes: washing the reaction product of the condensation reaction with water to obtain a washing liquid, and then subjecting the washing liquid to extraction, drying and vacuum concentration in sequence to obtain the crude target product.
[0047] In this embodiment, after the condensation reaction between pentafluorobenzoic acid and 2-methylcyclohexylamine is completed, an appropriate amount of water is added for washing, followed by separation. The aqueous phase is extracted with an extractant, and the organic phases are combined. The mixture is then washed with water and saturated NaCl aqueous solution, followed by further separation. The organic phase is then dried with anhydrous Na2SO4, anhydrous magnesium sulfate, and other drying agents. Finally, the mixture is concentrated under reduced pressure to obtain crude N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzoamide with a purity of 85%~95%.
[0048] In some embodiments, the extractant in the above extraction process includes ethyl acetate. By using ethyl acetate as the extractant, it can be separated from water into layers, and as a fragrance material, it can be added to the atomized liquid without introducing impurities.
[0049] In one embodiment, the second mixture comprises ethyl acetate and petroleum ether, which can effectively remove impurities from the reaction product to obtain N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide with a purity of 98%~99%.
[0050] In some embodiments, the volume ratio of ethyl acetate to petroleum ether in the second mixture is 1:(5~10), which can more effectively remove impurities from the condensation reaction product of pentafluorobenzoic acid and 2-methylcyclohexylamine.
[0051] In some embodiments, the volume ratio of ethyl acetate to petroleum ether in the second mixture can be one or any two of the following: 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.
[0052] In some embodiments, the mass (g) of the reaction product N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide to the volume (mL) of the second mixture is 1:(3~10), which can effectively utilize the second mixture to dissolve the reaction product N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, which has been purified.
[0053] In some embodiments, in step 104 above, the mass (g) of the first purified N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide to the volume (mL) of anhydrous ethanol is in the ratio of 1:(2~4), which can effectively dissolve the first purified N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0054] This application also proposes an atomizing liquid comprising an active substance and a sweetener, the sweetener comprising N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide prepared as described above.
[0055] Among them, the application of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide as a sweetener in electronic atomization devices results in a pure sweet taste, more puffs, no burnt core, and no bitterness.
[0056] This application discloses an atomizing device, which includes an atomizer, wherein the liquid storage chamber of the atomizer is filled with the atomizing liquid as described above.
[0057] This application provides a mouth-sucking product, comprising an active substance and a sweetener, the sweetener including N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide prepared by the method described above; the mouth-sucking product may be, for example, a mouth-sucking pouch, a mouth-sucking tablet, or a mouth-dissolving film.
[0058] For the above-mentioned atomizing liquid, atomizing device, and oral product embodiments, they include N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide and can achieve the same technical effect. To avoid repetition, they will not be described again here. For relevant details, please refer to the description of the N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide embodiments.
[0059] To make the inventive objectives, technical solutions, and beneficial effects of this application clearer, the application is further described below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application.
[0060] (1) HPLC detection: The chromatographic column was SB-C18 4μm 4.6×25mm; the detection wavelength was 210nm; the mobile phase A was pure water and B was acetonitrile; the flow rate was 0.8mL / min; and the column temperature was 30℃. Elution should be performed according to the gradient in the table below:
[0061] (2) Sensory evaluation of the atomizing liquid; Twenty testers used the same model of electronic atomizing device containing atomizing liquid. They scored the device on four aspects: sweetness, sweetness sensation, sweetness intensity on the tongue, sweetness blending, comfort, and reliability. The average score was used as the total score. The evaluation dimensions were as follows: sweetness (1-10 points, higher score means higher sweetness); sweetness sensation (1-10 points, better sweetness means higher score); sweetness intensity on the tongue (1-10 points, higher score means lower sweetness); sweetness blending (1-10 points, better blending means higher score); and comfort (1-10 points, better comfort during inhalation means higher score).
[0062] Example 1 (1) In an ice bath at 0°C, with stirring, add the basic substances triethylamine (6.07 g, 6 mmol, 1.2 eq) and 2-methylcyclohexylamine (6.23 g, 5.5 mmol, 1.1 eq) to ethyl acetate (53 mL, 5 vol) in which pentafluorobenzoic acid (10.60 g, 5 mmol, 1.0 eq) is dissolved, and then add the condensing agent HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea) (20.91 g, 5.5 mmol, 1.1 eq), after returning to room temperature, continue stirring for 4 h, add water (50 mL) to wash and separate the phases. Extract the aqueous phase with ethyl acetate (30 mL), then combine the organic phases, wash with water (50 mL), then wash with saturated NaCl aqueous solution (50 mL) and separate the phases. Dry the organic phase with anhydrous Na2SO4, and then concentrate under reduced pressure to dryness to obtain the crude target product. The mass of the crude target product was 14.74 g, the HPLC purity was 95.50%, and the yield was 96%.
[0063] (2) The crude target product (14.74 g) was added to a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:8 (73.7 mL, 5 vol), stirred at room temperature for 5 h, filtered, and the first purified product was obtained; the mass of the first purified product was 13.56 g, the HPLC purity was 98.52%, and the yield was 92%.
[0064] (3) The first purified product (13.56 g) was dissolved in anhydrous ethanol (40.7 mL, 3 vol), heated to 45 °C to dissolve, and then activated carbon (1.4 g, 10% m / m) was added and stirred for 1 h. After hot filtration, pure water (135.6 mL, 10 vol) was added dropwise to the filtrate while stirring. After a large amount of white solid precipitated, the filter cake was collected by filtration and dried in a vacuum drying oven at 40~60 °C for 8 h to obtain the target product, purified N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0065] The tested product yielded 12.61g of refined target product, with an HPLC purity of 99.50% and a yield of 93%.
[0066] The HPLC test results of the target product in Example 1 are shown in Table 2 and 3 respectively. Figure 2 As shown, since this compound is a racemic mixture, it has two chiral centers and exhibits two peaks in the liquid phase.
[0067] Table 2
[0068] The target product in Example 1 was subjected to TGA analysis, and the results are as follows: Figure 3As shown in the figure. The results show that the compound is almost completely volatilized at 255°C, which is 35°C lower than the boiling point of glycerol (290°C), so it can be completely atomized in an electronic atomizing device.
[0069] The target product in Example 1 was analyzed by GCMS, and the gas chromatography results are shown in Table 3. Figure 4 As shown, the mass spectrometry results are as follows: Figures 5-6 As shown.
[0070] Table 3
[0071] Figure 4 In Table 3, peaks 1 and 4 are components of the compound N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, totaling 99.745%.
[0072] The mass spectrometry showed m / z=307.1, which is consistent with the molecular weight of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, confirming that the target product is indeed N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0073] Example 2 (1) In a 0°C ice bath, with stirring, add the basic substances N,N-diisopropylethylamine (6.07 g, 6 mmol, 1.2 eq) and 2-methylcyclohexylamine (6.79 g, 6.0 mmol, 1.2 eq) to tetrahydrofuran (64 mL, 6 vol) in which pentafluorobenzoic acid (10.60 g, 5 mmol, 1.0 eq) is dissolved, followed by the addition of the condensing agent HBTU (benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate) (22.76 g, 6 vol). 0 mmol, 1.2 eq), after returning to room temperature, continue stirring for 4 h, add water (50 mL) to wash and separate the phases, extract the aqueous phase with ethyl acetate (30 mL), then combine the organic phases, wash with water (50 mL), then wash with saturated NaCl aqueous solution (50 mL) and separate the phases, dry the organic phase with anhydrous Na2SO4, and then concentrate under reduced pressure to dryness to obtain the crude target product; the mass of the crude target product was tested to be 14.85 g, the HPLC purity was 95.25%, and the yield was 97%.
[0074] (2) The crude target product (14.85 g) was added to a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:9 (104.0 mL, 7 vol), stirred at room temperature for 5 h, filtered, and the first purified product was obtained; the mass of the first purified product was 13.36 g, the HPLC purity was 98.62%, and the yield was 90%.
[0075] (3) The first purified product (13.36 g) was dissolved in anhydrous ethanol (40.1 mL, 3 vol), heated to 45 °C to dissolve, and then activated carbon (1.3 g, 10% m / m) was added and stirred for 1 h. After hot filtration, purified water (133.6 mL, 10 vol) was added dropwise to the filtrate while stirring. After a large amount of white solid precipitated, the product was filtered, the filter cake was collected, and dried in a vacuum drying oven at 40~60 °C for 8 h to obtain the target product, purified N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. The mass of the target product was 12.29 g, the HPLC purity was 99.52%, and the yield was 92%.
[0076] Example 3 (1) In an ice bath at 0℃, with stirring, add sodium bicarbonate (5.04 g, 6 mmol, 1.2 eq) and 2-methylcyclohexylamine (6.23 g, 5.5 mmol, 1.1 eq) to N,N-dimethylformamide (64 mL, 6 vol) in which pentafluorobenzoic acid (10.60 g, 5 mmol, 1.0 eq) is dissolved. Then add the condensing agent BOP (Carter's condensing agent) (24.32 g, 5.5 mmol, 1.1 eq). After restoring to room temperature, continue stirring for 3 h. Wash with water (50 mL) and separate the liquid. Extract the aqueous phase with ethyl acetate (30 mL). Then combine the organic phases, wash with water (50 mL), wash with saturated NaCl aqueous solution (50 mL) and separate the liquid. Dry the organic phase with anhydrous Na2SO4 and concentrate under reduced pressure to dryness to obtain the crude target product. The mass of the crude target product was 14.43 g, the HPLC purity was 95.12%, and the yield was 94%.
[0077] (2) The crude target product (14.43 g) was added to a mixture of ethyl acetate and petroleum ether (V:V=1:7, 86.6 mL, 6 vol), stirred at room temperature for 5 h, filtered, and the first purified product was obtained; the mass of the first purified product was 13.28 g, the HPLC purity was 98.62%, and the yield was 92%.
[0078] (3) The first purified product (13.28 g) was dissolved in ethanol (39.8 mL, 3 vol) and heated to 45 °C to dissolve. Then activated carbon (1.3 g, 10% m / m) was added and stirred for 1 h. After hot filtration, pure water (132.8 mL, 10 vol) was added dropwise to the filtrate while stirring. After a large amount of white solid precipitated, the product was filtered and the filter cake was collected. The product was dried in a vacuum drying oven at 40~60 °C for 8 h to obtain the target product, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. The mass of the target product was 12.08 g, the HPLC purity was 99.51%, and the yield was 91%.
[0079] Test Example 1 Take 0.2g of the monomeric sweetener neotame, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide and sucralose respectively and dissolve them in 99.8g of mixed solvent (PG to VG mass ratio = 6:4). Mix them evenly to prepare atomized liquids W1, W2 and W3 containing 2‰ sweetness. Sensory evaluation tests were conducted on the above-mentioned atomizing liquids, and the results are shown in Table 4.
[0080] Table 4
[0081] As shown in Table 2 above, and as indicated in Table 4, neotame has the highest sweetness, a good sweetness profile, a certain burst of sweetness, and a long-lasting sweetness that can be clearly perceived after exhalation. N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide has a significantly higher sweetness than sucralose, approximately 80% of that of neotame, a certain burst of sweetness, but the sweetness dissipates quickly and there is no obvious sweetness. Sucralose has the weakest sweetness, significantly weaker than neotame and N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, and has a strong astringent and dry taste.
[0082] Test Example 2 Sweetener neotame, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, and sucralose were mixed evenly according to the following mass percentages: propylene glycol 37.7%, glycerol 40%, nicotine benzoate 2%, WS-23 5%, sweetener addition 0.2%, and lemon flavoring 15% to prepare atomized liquids W4, W5, and W6. Sensory evaluation tests were conducted on the above-mentioned atomizing liquids, and the results are shown in Table 5.
[0083] Table 5
[0084] As shown in Table 2, neotame has the highest sweetness and is relatively uniform overall; its sweetness can be perceived after exhalation. N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide is slightly less sweet than neotame; it is sweet upon entry but not perceived after exhalation, and it provides good support for the aroma. Triclosan has the weakest sweetness, significantly weaker than neotame and N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, and it does not provide sufficient support for the aroma.
[0085] Test Example 3 Take the sweeteners neotame, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, sucralose in propylene glycol 37.7%, glycerol 40%, and nicotine respectively. The following are the mass percentages of benzoate 2%, WS-23 5%, sweetener 0.2%, and watermelon flavor 15%, mixed evenly to prepare atomized liquids W7, W8, and W9; Sensory evaluation tests were conducted on the above-mentioned atomizing liquids, and the results are shown in Table 6.
[0086] Table 6
[0087] As shown in Table 6, neotame has the highest sweetness, with the sweetness concentrated in the later stages, leaving a sweet aftertaste upon exhalation, but its aroma is slightly insufficient; N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide has a sweetness of about 80% of neotame, with the sweetness concentrated in the middle stages, leaving no sweet aftertaste upon exhalation, and its aroma is better and clearer; sucralose has the weakest sweetness, very weak, significantly weaker than neotame and N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, with moderate sweetness, but it is significantly insufficient in supporting the aroma.
[0088] Test Example 4 18 mL of each of the above-mentioned atomizing liquids W1 to W9 were injected into the electronic atomizing device. First, the atomizer was used to inhale the liquid, followed by manual inhalation to assess for bitterness or burnt coil. If burnt coil was detected, the atomizer was stopped. With the heating element resistance of the electronic atomizing device at 0.8 Ω and the output power at 25 W, 50 puffs were taken with the atomizer, followed by 5 manual checks, up to a total of 1100 puffs. The results were then analyzed to determine if the atomized aerosol exhibited burnt coil or bitterness. The test results are shown in Table 7 below. Figure 7 : Table 7
[0089] From Table 7 above and Figure 7 It is known that atomizing fluids containing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide are less likely to cause bitterness or wicking compared to those containing neotame or sucralose. This is because N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide has a lower boiling point, allowing it to atomize completely along with the atomizing fluid, leaving minimal residue on the wick and reducing carbon buildup. This extends the lifespan of the heating wire and decreases the probability of bitterness or wicking during inhalation.
[0090] In summary, the preparation method of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in this application involves first adding pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine to an organic solvent, then adding a condensing agent. The reaction yields the crude target product of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide. After filtration in a second mixture, the product is dissolved in ethanol, decolorized with activated carbon, hot-filtered, and water is added to the filtrate to precipitate the solid. After filtration and drying of the filter residue, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide with a purity greater than or equal to 99% can be obtained. Alternatively, N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide can be synthesized from pentafluorobenzoic acid and 2-methylcyclohexylamine in an organic solvent using mild reaction conditions, which are friendly to operators and the environment, and are low in cost, simple to operate, and have high yield and high purity. Therefore, the method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in this application effectively solves the problem of existing technologies being unable to effectively synthesize high-purity N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide.
[0091] Although preferred embodiments of the present application have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the embodiments of the present application.
[0092] The preparation method, atomizing liquid, and atomizing device of N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide provided in this application have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.
Claims
1. A method for preparing N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, characterized in that, include: Pentafluorobenzoic acid, an alkaline substance, and 2-methylcyclohexylamine were added to an organic solvent to obtain a first mixture. A condensing agent is added to the first mixture to carry out a condensation reaction to obtain the crude target product. The crude target product is added to the second mixture and filtered to obtain the first purified product; The first purified product was dissolved in ethanol, decolorized with activated carbon, and then hot-filtered to obtain a filtrate. Water was added to the filtrate to precipitate a solid, which was then filtered to obtain a filter residue. The filter residue was dried to obtain N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide, wherein the purity of the N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide was greater than or equal to 99%.
2. The preparation method according to claim 1, characterized in that, The alkaline substance includes at least one of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, and sodium carbonate; and / or The condensing agent comprises at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, Carter's condensing agent, and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate; and / or The organic solvent includes at least one of ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide.
3. The preparation method according to claim 1, characterized in that, In the first mixture, the molar ratio of pentafluorobenzoic acid to 2-methylcyclohexylamine is 1:(1~1.2); and / or The molar ratio of pentafluorobenzoic acid to the condensing agent is 1:(1~1.2); and / or The molar ratio of pentafluorobenzoic acid to the alkaline substance is 1:(1.2~1.5).
4. The preparation method according to claim 1, characterized in that, In the first mixture, the ratio between the amount of pentafluorobenzoic acid and the volume of the organic solvent is 1 / 8 to 1 / 3 mol / mL.
5. The preparation method according to claim 1, characterized in that, The condensation reaction to obtain the target crude product includes: The reaction product of the condensation reaction is washed with water to obtain a washing solution, which is then subjected to extraction, drying and vacuum concentration in sequence to obtain the crude target product.
6. The preparation method according to claim 5, characterized in that, The extractant used in the extraction process includes ethyl acetate; and / or The drying process employs a desiccant, which includes at least one of anhydrous Na2SO4 and anhydrous magnesium sulfate.
7. The preparation method according to any one of claims 1 to 6, characterized in that, The second mixture comprises ethyl acetate and petroleum ether.
8. The preparation method according to claim 7, characterized in that, The volume ratio of ethyl acetate to petroleum ether in the second mixture is 1:(5~10).
9. An atomizing fluid, characterized in that, It includes an active substance and a sweetener, wherein the sweetener includes N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluorobenzamide prepared by the preparation method according to any one of claims 1 to 8.
10. An atomizing device, wherein, It includes an atomizer, the liquid reservoir of which stores the atomizing liquid as described in claim 9.