Preparation method of cooling agent WS-23

Abstract

The invention provides a preparation method of a cooling agent WS-23, and belongs to the technical field of cooling agents, and the preparation method comprises the following steps: S1, adding DIPPN and absolute methanol into a reaction kettle, uniformly mixing, introducing N2, controlling the temperature, introducing Hcl, pressurizing and heating, stirring to react, cooling and releasing pressure, neutralizing, extracting, washing, drying, filtering, and performing rotary evaporation to obtain an intermediate crude product; step S2, preparing a WS-23 crude product; and S3, adding the WS-23 crude product into absolute ethyl alcohol, heating and stirring, adding hexane, uniformly mixing, carrying out hot filtration to obtain a clear solution, cooling, carrying out heat preservation crystallization, carrying out suction filtration, washing, and carrying out vacuum drying to obtain the cooling agent WS-23. According to the method, the yield and the purity of the cooling agent WS-23 can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cooling agents, in particular to a preparation method of a cooling agent WS-23. BACKGROUND

[0002] As a kind of efficient, long-lasting synthetic cooling ingredients, cooling agent WS-23 (N, 2, 3-trimethyl-2-isopropyl butyric amide) has been widely used in food, oral care, electronic cigarette liquid and skin care products, etc. It produces a cooling sensation by activating the human cold receptor, and compared with traditional cooling agents such as menthol, it has the advantages of pure cooling, good stability, almost no bitterness and irritation. However, the industrial synthesis and purification process of WS-23 still faces challenges. The existing synthesis route is often long in steps, has more side reactions, and the product separation is difficult, which easily leads to low yield and low purity of the product, thereby affecting the sensory quality and safety of the final product.

[0003] The patent application file with publication number CN103274959A discloses a synthesis method of cooling agent N, 2, 3-trimethyl-2-isopropyl butyric amide, which comprises the following steps: according to the molar ratio of 2, 2-isopropyl propionitrile: alcohol: acid is 1:3-5:3-5, 2, 2-isopropyl propionitrile, alcohol and acid are added into 500 mL autoclave respectively, reflux under stirring, reaction for 4-10 h, recover excess acid gas and alcohol, cool, wash with sodium bicarbonate twice, extract with saturated sodium chloride solution, stand, separate, dry to obtain 2, 3-dimethyl-2-isopropyl butyrate; according to the molar ratio of 2, 3-dimethyl-2-isopropyl butyrate: amine: basic catalyst is 1:1.5-5:0.04-0.3, the 2, 2-isopropyl propionitrile, amine: basic catalyst are added into 500 mL autoclave respectively, washed with water, added with organic solvent for recrystallization to obtain the product. This scheme improves the conversion rate to some extent and simplifies the process steps, but the product yield and purity are still insufficient.

[0004] Therefore, it is necessary to provide a preparation method of cooling agent WS-23 to solve the problems existing in the prior art. SUMMARY

[0005] Therefore, the present application provides a preparation method of cooling agent WS-23, which can improve the yield and purity of cooling agent WS-23.

[0006] To achieve the above-mentioned purpose, the present application provides a preparation method of cooling agent WS-23, which comprises the following steps: Step S1, adding DIPPN and anhydrous methanol into a reaction kettle, mixing uniformly, introducing N2, controlling temperature, introducing Hcl, increasing pressure and temperature, stirring and reacting, reducing temperature and pressure, neutralizing, extracting, washing, drying, filtering, and rotary evaporating to obtain an intermediate crude product; Step S2, the intermediate crude product is transferred into a reaction kettle, methylamine / methanol solution is added, after mixing, N2 is introduced, temperature is raised, stirring reaction is carried out, temperature is lowered, solvent is recovered under reduced pressure, extraction is carried out, washing is carried out, drying is carried out, filtration is carried out, and rotary evaporation is carried out to obtain WS-23 crude product; Step S3, the WS-23 crude product is added into anhydrous ethanol, heated and stirred, hexane is added and mixed uniformly, hot filtration is carried out to obtain a clear solution, temperature is lowered and cooled, temperature is kept, filtration is carried out, washing is carried out, vacuum drying is carried out, and the cooling agent WS-23 is obtained.

[0007] In anhydrous methanol, hydrochloric acid is introduced, and the solubility and effective acidity of hydrochloric acid in methanol are significantly improved, thereby realizing efficient activation of the nitrile group in DIPPN under a relatively mild bulk phase acidity. The nitrile group nitrogen is first protonated, and then methanol undergoes nucleophilic addition to the nitrile carbon to generate high-activity acyl intermediates such as imidic acid methyl ester hydrochloride. On the one hand, the reaction activity of the nitrile group to the subsequent amidation direction is significantly improved, so that the subsequent reaction can be realized at medium temperature with high conversion, reducing the dependence on harsh conditions; on the other hand, the generation of carboxylic acid by-products and high-color degradation products is effectively inhibited, greatly reducing the content of acidic impurities and coloring impurities, and improving the purity of the intermediate and the final WS-23. At the same time, by neutralizing the system after the acidic activation, the intermediate exists in the form of a neutral hydrophobic molecule, which can selectively enter the organic phase in the subsequent extraction, realizing the effective separation of organic intermediates and inorganic salts, ammonium chloride and other impurities at an early stage of the process, providing a cleaner and controllable raw material system for the subsequent amidation and refining steps, thereby improving the reaction efficiency, safety and impurity control.

[0008] In the present scheme, high-concentration methylamine is combined with the acyl intermediate obtained by the aforementioned Hcl / anhydrous methanol activation, which can realize the high-selectivity generation of WS-23 at medium temperature, with controllable reaction time and high conversion, significantly reducing the generation of unreacted intermediates and various by-product amides, simplifying the impurity spectrum, reducing the burden of subsequent refining, and promoting the purity improvement of WS-23.

[0009] Ethanol has good solubility for WS-23 at relatively high temperatures, while hexane is a typical non-polar anti-solvent. With the increase of the proportion of hexane, the solubility of the mixed solvent for WS-23 decreases significantly. By adding hexane while keeping the system at a temperature higher than the solubility temperature, and then cooling, it is beneficial to control the supersaturation of the solution and avoid a large number of instantaneous nucleation. Combined with cooling and temperature holding crystallization, the crystals grow slowly from a limited number of crystal nuclei, thereby obtaining crystals with moderate particle size and regular morphology. At the same time, polar and non-polar impurities tend to dissolve in ethanol and hexane-rich mother liquor, respectively, and are not easy to enter the crystal lattice. The subsequent washing step further elutes the entrained mother liquor on the surface of the crystals, thereby realizing the purity improvement of WS-23.

[0010] Preferably, in step S1, the temperature of temperature control is 0-10℃; the pressure of pressure control is 3-6bar; the temperature of temperature increase is 88-92℃; and the time of stirring reaction is 4-6h.

[0011] Under the conditions of low temperature and pressure, the introduction of HCl can smoothly control the risk of exothermic and corrosion, and avoid decomposition or color deepening caused by local high acidity and high temperature.

[0012] Preferably, in step S2, the concentration of methylamine in the methylamine / methanol solution is 30-33wt%.

[0013] Preferably, in step S2, the temperature of temperature increase is 72-78℃; the speed of stirring reaction is 500-700rpm; and the time is 6-8h.

[0014] The increase of temperature can improve the molecular collision frequency and the ability to overcome activation energy, and the stirring can accelerate the reaction rate.

[0015] Preferably, in step S2, sodium methoxide is also added when the methylamine / methanol solution is added.

[0016] Sodium methoxide can improve the basicity of the system and enhance the nucleophilicity of methylamine. In addition, sodium methoxide can partially deprotonate methylamine, increase the proportion of its unprotonated form, make the amine in a more active "free amine" state, accelerate the formation of amide bond, and shorten the reaction time.

[0017] Preferably, the extractant used in the extraction is ethyl acetate.

[0018] Ethyl acetate has good solubility for such organisms and low solubility for inorganic salts, which can effectively separate the organisms and salt impurities, thereby improving the purity of the product.

[0019] Preferably, in step S3, the temperature of heating is 52-56℃; and the temperature when hexane is added is 50-52℃.

[0020] Preferably, in step S3, the temperature of heat preservation crystallization is 0-5℃, and the time is 60-90min.

[0021] Preferably, in step S3, the temperature of vacuum drying is 40-50℃, and the time is 4-6h.

[0022] Preferably, the cooling agent WS-23 comprises the following raw materials in weight parts: DIPPN 10-30 parts, HCl 18-24 parts, anhydrous ethanol 30-90 parts, and hexane 40-120 parts.

[0023] The cooling agent WS-23 prepared by using the above weight parts of raw materials has high yield and high purity.

[0024] The above technical solutions of the present application at least include the following beneficial effects: 1. By activating DIPPN in anhydrous methanol, passing in hydrochloric acid, and controlling the system pressure, the reaction activity of the nitrile group to the subsequent amide direction is significantly improved, and the generation of carboxylic acid by-products and high-color degradation products is effectively inhibited, greatly reducing the content of acidic impurities and coloring impurities, and improving the purity of the intermediate and the final WS-23.

[0025] 2. High-concentration methylamine provides sufficient nucleophilic amine source, which can efficiently attack the acyl intermediates such as imine acid methyl ester formed in the previous step, significantly reducing the generation of unreacted intermediates and various by-product amides, simplifying the impurity spectrum, reducing the burden of subsequent purification, and promoting the purity improvement of WS-23.

[0026] 3. By using a double-solvent system of ethanol and hexane and process control, the supersaturation of the solution can be controlled to avoid a large amount of nucleation at once, thereby obtaining crystals with moderate particle size and regular morphology. At the same time, polar and non-polar impurities tend to dissolve in the mother liquor of ethanol and hexane, respectively, and are not easy to enter the crystal lattice, thereby achieving the improvement of the purity of WS-23. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The chromatogram of WS-23 prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be described clearly and completely below in combination with the embodiments of the present application. The described embodiments are part of the embodiments of the present application, and all other embodiments obtained by those of ordinary skill in the art based on the described embodiments of the present application belong to the scope of protection of the present application.

[0029] Example 1 Into a reaction kettle, 20 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 30 mL of anhydrous methanol were added, mixed uniformly, N2 was passed in, the kettle temperature was controlled at 5°C, 21 g of HCl was passed in, the pressure was maintained at 3 bar, the temperature was raised to 88°C, and the stirring speed was 700 rpm. The reaction was carried out for 5 h, then the temperature was slowly lowered to room temperature, the pressure was slowly released to normal pressure, and neutralized to pH 7-8. Ethyl acetate was used for extraction 3 times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.

[0030] The intermediate crude product was transferred into a reaction kettle, 60 mL of a 31 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added, after uniform mixing, N2was introduced, the temperature was raised to 75°C, and the reaction was stirred at 600 rpm for 7 h. After the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure. Deionized water was added to the residue to dilute it, and the mixture was extracted with ethyl acetate three times. The organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain WS-23 crude product.

[0031] The WS-23 crude product was added to 60 g of anhydrous ethanol, heated to 52°C, and stirred until completely dissolved. 80 g of hexane was added while maintaining the temperature at 50°C, and the mixture was uniformly mixed and filtered while hot to obtain a clear solution. The solution was cooled to 0°C at a rate of 1°C / min, and the crystals were collected by suction filtration after crystallization for 70 min. The crystals were washed and dried under vacuum at 45°C for 6 h to obtain the cooling agent WS-23.

[0032] Example 2 A reaction kettle was charged with 30 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 35 mL of anhydrous methanol, and the mixture was uniformly mixed and introduced with N2. The kettle temperature was controlled at 0°C, 24 g of HCl was introduced, the pressure was maintained at 5 bar, the temperature was raised to 92°C, and the reaction was stirred at 600 rpm for 6 h. After the reaction was completed, the temperature was slowly lowered to room temperature, and the pressure was slowly released to normal pressure. The mixture was neutralized to a pH of 7-8, extracted with ethyl acetate three times, and the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the intermediate crude product.

[0033] The intermediate crude product was transferred into a reaction kettle, 65 mL of a 33 wt% methylamine / methanol solution and 0.9 g of sodium methoxide were added, after uniform mixing, N2was introduced, the temperature was raised to 72°C, and the reaction was stirred at 500 rpm for 8 h. After the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure. Deionized water was added to the residue to dilute it, and the mixture was extracted with ethyl acetate three times. The organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain WS-23 crude product.

[0034] The WS-23 crude product was added to 90 g of anhydrous ethanol, heated to 56°C, and stirred until completely dissolved. 120 g of hexane was added while maintaining the temperature at 50°C, and the mixture was uniformly mixed and filtered while hot to obtain a clear solution. The solution was cooled to 5°C at a rate of 0.5°C / min, and the crystals were collected by suction filtration after crystallization for 90 min. The crystals were washed and dried under vacuum at 40°C for 6 h to obtain the cooling agent WS-23.

[0035] Example 3 Into a reactor, 10 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 20 mL of anhydrous methanol were added, mixed uniformly, N2 was introduced, the temperature of the reactor was controlled at 10°C, 18 g of HCl was introduced, the pressure was maintained at 4 bar, the temperature was raised to 90°C, the reaction was stirred at a speed of 800 rpm for 4 h, after the reaction was completed, the temperature was slowly lowered to room temperature, the pressure was slowly released to normal pressure, neutralized to pH 7-8, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate product.

[0036] The crude intermediate product was transferred into a reactor, 50 mL of a 30 wt% methylamine / methanol solution and 0.6 g of sodium methoxide were added, mixed uniformly, N2 was introduced, the temperature was raised to 78°C, the reaction was stirred at a speed of 650 rpm for 6 h, after the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure; 100 mL of deionized water was added to the residue to dilute, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.

[0037] The crude WS-23 product was added to 30 g of anhydrous ethanol, heated to 54°C, stirred until completely dissolved, 40 g of hexane was added while maintaining the temperature at 52°C, mixed uniformly, and hot filtered to obtain a clear solution, cooled to 0°C at a rate of 2°C / min, and incubated for crystallization for 75 min, the crystals were collected by suction filtration, washed, and vacuum dried at 50°C for 4 h to obtain the cooling agent WS-23.

[0038] Example 4 Into a reactor, 20 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25 mL of anhydrous methanol were added, mixed uniformly, N2 was introduced, the temperature of the reactor was controlled at 0°C, 21 g of HCl was introduced, the pressure was maintained at 5 bar, the temperature was raised to 92°C, the reaction was stirred at a speed of 650 rpm for 5.5 h, after the reaction was completed, the temperature was slowly lowered to room temperature, the pressure was slowly released to normal pressure, neutralized to pH 7-8, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate product.

[0039] The crude intermediate product was transferred into a reactor, 55 mL of a 33 wt% methylamine / methanol solution and 0.8 g of sodium methoxide were added, mixed uniformly, N2 was introduced, the temperature was raised to 72°C, the reaction was stirred at a speed of 600 rpm for 6.5 h, after the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure; 100 mL of deionized water was added to the residue to dilute, extracted with ethyl acetate for 3 times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.

[0040] WS-23 crude product was added into 60 g anhydrous ethanol, heated to 56 ℃, stirred until completely dissolved, 80 g hexane was added under the condition of keeping the temperature at 55 ℃, mixed uniformly, filtered hot to obtain a clear solution, cooled to 0 ℃ at a rate of 1.5 ℃ / min, kept crystallization for 80 min, the crystals were collected by suction filtration, washed, and dried under vacuum at 45 ℃ for 5 h to obtain the coolant WS-23.

[0041] Example 5 A reaction kettle was charged with 10 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25 mL of anhydrous methanol, mixed uniformly, N2 was introduced, the kettle temperature was controlled at 5 ℃, 18 g of HCl was introduced, the pressure was maintained at 5 bar, the temperature was raised to 88 ℃, and the reaction was stirred at a speed of 750 rpm for 4.5 h. After the reaction was completed, the temperature was slowly lowered to room temperature, and the pressure was slowly released to normal pressure. Neutralization was performed to a pH of 7-8, extraction was performed with ethyl acetate three times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate product.

[0042] The crude intermediate product was transferred into a reaction kettle, 50 mL of a 31 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added, mixed uniformly, N2 was introduced, the temperature was raised to 72 ℃, and the reaction was stirred at a speed of 700 rpm for 6 h. After the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure; 100 mL of deionized water was added to the residue to dilute it, extraction was performed with ethyl acetate three times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.

[0043] The crude WS-23 product was added into 30 g anhydrous ethanol, heated to 56 ℃, stirred until completely dissolved, 40 g hexane was added under the condition of keeping the temperature at 50 ℃, mixed uniformly, filtered hot to obtain a clear solution, cooled to 5 ℃ at a rate of 0.5 ℃ / min, kept crystallization for 90 min, the crystals were collected by suction filtration, washed, and dried under vacuum at 40 ℃ for 6 h to obtain the coolant WS-23.

[0044] Example 6 A reaction kettle was charged with 30 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 30 mL of anhydrous methanol, mixed uniformly, N2 was introduced, the kettle temperature was controlled at 10 ℃, 24 g of HCl was introduced, the pressure was maintained at 4 bar, the temperature was raised to 90 ℃, and the reaction was stirred at a speed of 700 rpm for 5 h. After the reaction was completed, the temperature was slowly lowered to room temperature, and the pressure was slowly released to normal pressure. Neutralization was performed to a pH of 7-8, extraction was performed with ethyl acetate three times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate product.

[0045] The intermediate crude product was transferred into a reaction kettle, 65 mL of a 32 wt% methylamine / methanol solution and 0.8 g of sodium methoxide were added, after uniform mixing, N2was introduced, the temperature was raised to 78°C, and the reaction was stirred at 500 rpm for 8 h. After the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure. Deionized water was added to the residue to dilute it, and the mixture was extracted with ethyl acetate three times. The organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain WS-23 crude product.

[0046] The WS-23 crude product was added to 90 g of anhydrous ethanol, heated to 52°C, and stirred until completely dissolved. While maintaining the temperature at 50°C, 120 g of hexane was added and mixed uniformly. The mixture was filtered while hot to obtain a clear solution. The solution was cooled to 0°C at a rate of 2°C / min, and the crystals were collected by suction filtration after being crystallized for 60 min. The crystals were washed and dried under vacuum at 50°C for 4 h to obtain the cooling agent WS-23.

[0047] Example 7 A reaction kettle was charged with 20 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25 mL of anhydrous methanol, mixed uniformly, and N2was introduced. The kettle temperature was controlled at 5°C, 21 g of HCl was introduced, the pressure was maintained at 3 bar, the temperature was raised to 88°C, and the reaction was stirred at 650 rpm for 6 h. After the reaction was completed, the temperature was slowly lowered to room temperature, and the pressure was slowly released to normal pressure. The mixture was neutralized to a pH of 7-8, extracted with ethyl acetate three times, and the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain the intermediate crude product.

[0048] The intermediate crude product was transferred into a reaction kettle, 55 mL of a 30 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added, after uniform mixing, N2was introduced, the temperature was raised to 75°C, and the reaction was stirred at 600 rpm for 7 h. After the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure. Deionized water was added to the residue to dilute it, and the mixture was extracted with ethyl acetate three times. The organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain WS-23 crude product.

[0049] The WS-23 crude product was added to 60 g of anhydrous ethanol, heated to 55°C, and stirred until completely dissolved. While maintaining the temperature at 55°C, 120 g of hexane was added and mixed uniformly. The mixture was filtered while hot to obtain a clear solution. The solution was cooled to 2°C at a rate of 1°C / min, and the crystals were collected by suction filtration after being crystallized for 75 min. The crystals were washed and dried under vacuum at 45°C for 5.5 h to obtain the cooling agent WS-23.

[0050] Example 8 Into a reaction kettle, 20 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25 mL of anhydrous methanol were added and mixed uniformly, N2 was introduced, the kettle temperature was controlled at 5 ℃, 21 g of HCl was introduced, the pressure was maintained at 3 bar, the temperature was raised to 88 ℃, the reaction was stirred at a speed of 650 rpm for 6 h, after the reaction was completed, the temperature was slowly lowered to room temperature, the pressure was slowly released to normal pressure, and neutralization was performed to a pH of 7-8, and then extraction was performed with ethyl acetate three times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain a crude intermediate product.

[0051] The crude intermediate product was transferred into a reaction kettle, 55 mL of a 30 wt% methylamine / methanol solution was added, mixed uniformly, N2 was introduced, the temperature was raised to 75 ℃, and the reaction was stirred at a speed of 600 rpm for 7 h, after the reaction was completed, the temperature was lowered to room temperature, and the methylamine / methanol solvent was recovered under reduced pressure; 100 mL of deionized water was added to the residue for dilution, extraction was performed with ethyl acetate three times, the organic phase was combined and washed with deionized water, dried, filtered, and rotary evaporated to obtain a crude WS-23 product.

[0052] The crude WS-23 product was added to 60 g of anhydrous ethanol, heated to 55 ℃, stirred until completely dissolved, and then 120 g of hexane was added while maintaining the temperature at 55 ℃, mixed uniformly, and hot filtered to obtain a clear solution, cooled to 2 ℃ at a rate of 1 ℃ / min, and crystallized for 75 min, the crystals were collected by suction filtration, washed, and vacuum dried at 45 ℃ for 5.5 h to obtain the cooling agent WS-23.

[0053] The present application also carried out comparative examples and related tests.

[0054] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is only that in step S1, after the introduction of HCl, the temperature raising and stirring reaction is performed under normal pressure, and the other compositions and preparation methods are the same as those of Example 1, and the cooling agent WS-23 is prepared.

[0055] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that in step S3, only anhydrous ethanol is used without the addition of hexane, and the other compositions and preparation methods are the same as those of Example 1, and the cooling agent WS-23 is prepared.

[0056] Performance detection test The cooling agent WS-23 samples prepared in Examples 1-8 and Comparative Examples 1-2 were tested for yield and purity, three samples were taken for each example and comparative example, and the test results were averaged, and the test results are shown in Table 1.

[0057] Table 1

[0058] From the above Table 1, the yield and purity of the cooling agent WS-23 prepared in Comparative Example 1 are both greatly decreased compared with Example 1, indicating that maintaining a certain pressure during the HCl / anhydrous methanol activation of DIPPN is beneficial to improve the solubility and effective acidity of hydrochloric acid in methanol, thereby improving the activation efficiency of nitrile group and promoting the effective conversion of subsequent amidation, thereby reducing the impurity content generated by side reactions and improving the yield and purity of WS-23; the yield and purity of the cooling agent WS-23 prepared in Comparative Example 2 also have a certain degree of decrease compared with Example 1, indicating that using the ethanol / hexane double solvent system and adding anti-solvent at a temperature higher than the dissolution temperature during the recrystallization process is beneficial to control the supersaturation of the system and avoid a large amount of instantaneous nucleation, thereby reducing the impurity entrainment, improving the crystal quality and recovery rate, and further improving the purity of WS-23.

[0059] The difference between Example 8 and Example 7 is that sodium methoxide is not added for the preparation of WS-23 crude product in Example 8, which lacks the neutralization of residual acid by base and the activation of ester / imide group, resulting in slow and incomplete aminolysis, and thus leading to the decrease of yield and purity, indicating that the weak base catalysis of sodium methoxide is beneficial to neutralize the residual acid and improve the effective nucleophilicity of methylamine, and at the same time, promote the conversion of active intermediate to target amide product, thereby accelerating the amidation process and reducing the content of unreacted intermediate and by-product, and improving the yield and purity of WS-23.

[0060] The above is the preferred embodiment of the present application, and those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing a cooling agent WS-23, characterized by, The method comprises the following steps: Step S1, adding DIPPN and anhydrous methanol into a reaction kettle, mixing uniformly, passing in N2, controlling temperature, passing in HCl, pressurizing and heating, stirring and reacting, cooling and depressurizing, neutralizing, extracting, washing, drying, filtering, and rotary evaporation to obtain an intermediate crude product; Step S2, transferring the intermediate crude product into a reaction kettle, adding a methylamine / methanol solution, mixing uniformly, passing in N2, heating, stirring and reacting, cooling, recovering the solvent under reduced pressure, extracting, washing, drying, filtering, rotary evaporation to obtain WS-23 crude product; Step S3, adding the WS-23 crude product into anhydrous ethanol, heating and stirring, adding hexane, mixing uniformly, hot filtering to obtain a clear solution, cooling, temperature-holding crystallization, suction filtration, washing, vacuum drying to obtain the cooling agent WS-23.

2. The preparation method of the cooling agent WS-23 according to claim 1, characterized in that, In the step S1, the temperature for temperature control is 0-10℃; the pressure for pressurization is 3-6bar; the temperature for heating is 88-92℃; and the stirring and reaction time is 4-6h.

3. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In the step S2, the methylamine concentration of the methylamine / methanol solution is 30-33wt%.

4. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In the step S2, the temperature for heating is 72-78℃; the stirring speed is 500-700rpm; and the time is 6-8h.

5. The preparation method of the cooling agent WS-23 according to claim 1, characterized in that, In the step S2, sodium methoxide is also added when the methylamine / methanol solution is added.

6. The method of claim 1, wherein the WS-23 is prepared by the process of claim 1. The extractant used in the extraction is ethyl acetate.

7. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In the step S3, the heating temperature is 52-56℃; and the temperature when hexane is added is 50-52℃.

8. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In the step S3, the temperature for temperature-holding crystallization is 0-5℃, and the time is 60-90min.

9. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In the step S3, the temperature for vacuum drying is 40-50℃, and the time is 4-6h.

10. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, The cooling agent WS-23 comprises the following raw materials in weight parts: DIPPN 10-30 parts, HCl 18-24 parts, anhydrous ethanol 30-90 parts, and hexane 40-120 parts.

Images