A method for preparing a cooling agent WS-23
By activating DIPPN with hydrochloric acid through anhydrous methanol and combining it with a high-concentration methylamine and ethanol/hexane dual solvent system, the problems of low yield and purity in the synthesis of WS-23 were solved, achieving an efficient and simplified preparation process and a high-purity product.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- KUNSHAN YAXIANG SPICEL CO LTD
- Filing Date
- 2026-01-15
- Publication Date
- 2026-05-15
AI Technical Summary
The existing synthetic route for the cooling agent WS-23 is lengthy, involves numerous side reactions, and is difficult to separate the product, resulting in low yield and low purity, which affects the sensory quality and safety of the product.
DIPPN was activated by passing hydrochloric acid through anhydrous methanol and controlling the system pressure. Combined with a high-concentration methylamine and an ethanol/hexane dual-solvent system, efficient amidation and purification were achieved by controlling the reaction conditions and crystallization process.
The yield and purity of WS-23 were significantly improved, the process steps were simplified, the content of acidic impurities and coloring impurities was reduced, and crystals with moderate particle size and regular morphology were obtained.
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Figure CN121537306B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of cooling agents, specifically to a method for preparing the cooling agent WS-23. Background Technology
[0002] WS-23 (N,2,3-trimethyl-2-isopropylbutyramide), a highly effective and long-lasting synthetic cooling agent, is widely used in food, oral care, e-cigarette liquids, and skincare products. It produces a cooling sensation by activating human cold receptors and, compared to traditional cooling agents like menthol, offers advantages such as a pure cooling sensation, good stability, and virtually no bitterness or irritation. However, the industrial synthesis and purification of WS-23 still face challenges. Existing synthetic routes often involve lengthy steps, numerous side reactions, and difficulties in product separation, easily leading to low product yield and purity, which in turn affects the sensory quality and safety of the final product.
[0003] Patent application CN103274959A discloses a method for synthesizing the cooling agent N,2,3-trimethyl-2-isopropylbutyramide, comprising the following steps: 2,2-isopropylpropionitrile:alcohol:acid gas in a molar ratio of 1:3-5:3-5; 2,2-isopropylpropionitrile, alcohol, and acid are added separately to a 500 mL autoclave, refluxed under stirring, and reacted for 4-10 h. Excess acid gas and alcohol are recovered, the mixture is cooled, washed twice with sodium bicarbonate, extracted with saturated sodium chloride solution, allowed to stand, separated, and dried to obtain 2,3-dimethyl-2-isopropylbutyrate; 2,2-isopropylpropionate:amine:alkaline catalyst in a molar ratio of 1:1.5-5:0.04-0.3; the 2,2-isopropylpropionate, amine, and alkaline catalyst are added separately to a 500 mL autoclave, washed with water, and recrystallized with an organic solvent to obtain the product. This solution improves the conversion rate and simplifies the process to some extent, but its product yield and purity are still insufficient.
[0004] Therefore, there is a need to provide a method for preparing the cooling agent WS-23 to solve the problems existing in the prior art. Summary of the Invention
[0005] In view of this, the present invention provides a method for preparing cooling agent WS-23, which can improve the yield and purity of cooling agent WS-23.
[0006] To achieve the above objectives, the present invention provides a method for preparing the cooling agent WS-23, comprising the following steps:
[0007] Step S1: Add DIPPN and anhydrous methanol to the reactor, mix well, introduce N2, control the temperature, introduce HCl, pressurize and heat, stir the reaction, cool down and depressurize, neutralize, extract, wash, dry, filter, and rotary evaporate to obtain the crude intermediate product.
[0008] Step S2: Transfer the crude intermediate to a reaction vessel, add methylamine / methanol solution, mix well, then introduce N2, heat, stir the reaction, cool down, reduce pressure to recover the solvent, extract, wash, dry, filter, and rotary evaporate to obtain crude WS-23.
[0009] Step S3: Add crude WS-23 to anhydrous ethanol, heat and stir, add hexane and mix evenly, hot filter to obtain a clear solution, cool down, keep warm to crystallize, filter, wash, and vacuum dry to obtain cooling agent WS-23.
[0010] In anhydrous methanol, hydrochloric acid gas is introduced under controlled temperature conditions while the system pressure is controlled, significantly increasing the solubility and effective acidity of hydrochloric acid in methanol. This allows for efficient activation of the nitrile groups in DIPPN under relatively mild bulk acidity. The nitrile nitrogen is first protonated, followed by nucleophilic addition of methanol to the nitrile carbon, generating highly reactive acyl intermediates such as iminomethyl ester hydrochloride. This significantly improves the reactivity of the nitrile group towards subsequent amidation, enabling high conversion at moderate temperatures and reducing dependence on harsh conditions. Furthermore, it effectively suppresses the formation of carboxylic acid byproducts and high-color degradation products, substantially reducing the content of acidic and coloring impurities, and improving the purity of intermediates and the final WS-23. Meanwhile, by neutralizing the system after acid activation, the intermediate exists in the form of neutral hydrophobic molecules, which can selectively enter the organic phase during subsequent extraction. This achieves effective separation of organic intermediates from impurities such as inorganic salts and ammonium chloride in the early stage of the process, providing a cleaner and more controllable raw material system for subsequent amidation and purification steps, thereby improving reaction efficiency, safety and impurity control.
[0011] In this scheme, high concentration of methylamine combined with the aforementioned acyl intermediate obtained by activation with HCl / anhydrous methanol can achieve highly selective generation of WS-23 at moderate temperatures. The reaction time is controllable, the conversion rate is high, the generation of unreacted intermediates and various paraamide impurities is significantly reduced, the impurity profile is simplified, the burden of subsequent purification is reduced, and the purity of WS-23 is improved.
[0012] Ethanol exhibits good solubility for WS-23 at higher temperatures, while hexane, a typical nonpolar solvent, shows a significant decrease in the solubility of WS-23 in the mixed solvent as the hexane ratio increases. Adding hexane while maintaining the system above the dissolution temperature, followed by cooling, helps control the supersaturation of the solution and avoids rapid, large-scale nucleation. Combined with cooling and heat preservation crystallization, the crystals grow slowly from a limited number of nuclei, resulting in crystals of moderate size and regular morphology. Simultaneously, polar and nonpolar impurities tend to dissolve in the ethanol and hexane mother liquors, respectively, and are less likely to enter the crystal lattice. Subsequent washing steps further remove the mother liquor entrained on the crystal surface, thereby improving the purity of WS-23.
[0013] Preferably, in step S1, HCl gas is introduced at 0-10°C and the system pressure is controlled at 3-6 bar, then the temperature is raised to 88-92°C and the reaction is stirred for 4-6 hours.
[0014] Introducing HCl under low temperature and pressure conditions helps to stably control the risk of exothermic reaction and corrosion, and avoids decomposition or darkening of color caused by local high acidity and high temperature.
[0015] Preferably, in step S2, the concentration of methylamine in the methylamine / methanol solution is 30-33 wt%.
[0016] Preferably, in step S2, the heating temperature is 72-78℃; the stirring speed is 500-700 rpm; and the time is 6-8 hours.
[0017] Increasing the temperature can increase the frequency of molecular collisions and the ability to overcome activation energy; combined with stirring, this can accelerate the reaction rate.
[0018] Preferably, in step S2, sodium methoxide is also added when adding the methylamine / methanol solution.
[0019] Sodium methoxide can increase the alkalinity of the system, enhance the nucleophilicity of methylamine, and partially deprotonate methylamine, increasing the proportion of its unprotonated form, putting the amine in a more reactive "free amine" state, accelerating amide bond formation, and shortening the reaction time.
[0020] Preferably, the extractant used in the extraction is ethyl acetate.
[0021] Ethyl acetate has good solubility in this type of organic matter and low solubility in inorganic salts, which can effectively separate organic matter from salt impurities, thereby improving product purity.
[0022] Preferably, in step S3, the heating temperature is 52-56°C; and the temperature when adding hexane is 50-52°C.
[0023] Preferably, in step S3, the temperature for heat preservation and crystallization is 0-5℃, and the time is 60-90 min.
[0024] Preferably, in step S3, the vacuum drying temperature is 40-50℃ and the time is 4-6 hours.
[0025] Preferably, the cooling agent WS-23 comprises the following raw materials in parts by weight:
[0026] 10-30 parts DIPPN, 18-24 parts HCl, 30-90 parts anhydrous ethanol and 40-120 parts hexane.
[0027] The cooling agent WS-23 prepared using the above-mentioned parts by weight of raw materials has a high yield and high purity.
[0028] The above-described technical solution of the present invention has at least the following beneficial effects:
[0029] 1. By activating DIPPN in anhydrous methanol with hydrochloric acid and controlling the system pressure, the reactivity of the nitrile group to the subsequent amidation direction was significantly improved. The generation of carboxylic acid byproducts and high-color degradation products was effectively inhibited, the content of acidic impurities and coloring impurities was greatly reduced, and the purity of intermediates and final WS-23 was improved.
[0030] 2. High concentration of methylamine provides a sufficient nucleophilic amine source, which can efficiently attack acyl intermediates such as imine methyl ester formed in the previous step, significantly reducing the generation of unreacted intermediates and various paraamide impurities, simplifying the impurity spectrum, reducing the burden of subsequent purification, and promoting the improvement of WS-23 purity.
[0031] 3. By using a dual solvent system of ethanol and hexane and controlling the process, the supersaturation of the solution can be controlled, avoiding massive instantaneous nucleation and thus obtaining crystals with moderate particle size and regular morphology. Simultaneously, polar and non-polar impurities tend to dissolve in the mother liquor of ethanol and hexane, respectively, and are less likely to enter the crystal lattice, thereby improving the purity of WS-23. Attached Figure Description
[0032] Figure 1 The chromatogram is of WS-23 prepared in Example 1 of this invention. Detailed Implementation
[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. The described embodiments are some embodiments of the present invention, and all other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.
[0034] Example 1
[0035] 20 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 30 mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced and the reactor temperature was controlled at 5 °C. HCl gas was introduced at this temperature and the system pressure was controlled at 3 bar. The total amount of HCl introduced was 21 g. Then the temperature was raised to 88 °C and the reaction was stirred at 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 atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0036] The crude intermediate was transferred to a reaction vessel, and 60 mL of a 31 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 75 °C. The mixture 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. 100 mL of deionized water was added to the residue for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.
[0037] Add crude WS-23 to 60g of anhydrous ethanol, heat to 52℃, stir until completely dissolved, add 80g of hexane while maintaining the temperature at 50℃ and mix well, hot filter to obtain a clear solution, cool to 0℃ at a rate of 1℃ / min, keep warm to crystallize for 70min, collect the crystals by suction filtration, wash, and vacuum dry at 45℃ for 6h to obtain the cooling agent WS-23.
[0038] Example 2
[0039] Add 30g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 35mL of anhydrous methanol to the reaction vessel, mix well, introduce N2, control the vessel temperature at 0℃, introduce HCl gas at this temperature, control the system pressure at 5 bar, and introduce a total of 24g of HCl. Then raise the temperature to 92℃ and stir the reaction at 600rpm for 6h. After the reaction is completed, slowly cool down to room temperature, slowly depressurize to atmospheric pressure, neutralize to pH 7-8, extract three times with ethyl acetate, combine the organic phases, wash with deionized water, dry, filter, and rotary evaporate to obtain the crude intermediate.
[0040] The crude intermediate was transferred to a reaction vessel, and 65 mL of a 33 wt% methylamine / methanol solution and 0.9 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 72 °C. The mixture 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. 100 mL of deionized water was added to the residue for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.
[0041] Add crude WS-23 to 90g of anhydrous ethanol, heat to 56℃, stir until completely dissolved, add 120g of hexane while maintaining the temperature at 50℃ and mix well, hot filter to obtain a clear solution, cool to 5℃ at a rate of 0.5℃ / min, keep warm to crystallize for 90min, collect the crystals by suction filtration, wash, and vacuum dry at 40℃ for 6h to obtain the cooling agent WS-23.
[0042] Example 3
[0043] 10g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 20mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced and the reactor temperature was controlled at 10℃. HCl gas was introduced at this temperature and the system pressure was controlled at 4 bar. The total amount of HCl introduced was 18g. Then the temperature was raised to 90℃ and the reaction was stirred at 800rpm for 4h. After the reaction was completed, the temperature was slowly lowered to room temperature and the pressure was slowly released to atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0044] The crude intermediate was transferred to a reaction vessel, and 50 mL of a 30 wt% methylamine / methanol solution and 0.6 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 78 °C. The mixture was stirred at 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 for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain crude WS-23.
[0045] Add crude WS-23 to 30g of anhydrous ethanol, heat to 54℃, stir until completely dissolved, add 40g of hexane while maintaining the temperature at 52℃ and mix well, hot filter to obtain a clear solution, cool to 0℃ at a rate of 2℃ / min, keep warm to crystallize for 75min, collect the crystals by suction filtration, wash, and vacuum dry at 50℃ for 4h to obtain the cooling agent WS-23.
[0046] Example 4
[0047] 20g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced to control the reactor temperature at 0℃. HCl gas was then introduced at this temperature, and the system pressure was controlled at 5 bar. The total amount of HCl introduced was 21g. The temperature was then raised to 92℃ and the reaction was stirred at 650rpm for 5.5h. After the reaction was completed, the temperature was slowly lowered to room temperature, and the pressure was slowly released to atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0048] The crude intermediate was transferred to a reaction vessel, and 55 mL of a 33 wt% methylamine / methanol solution and 0.8 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 72 °C. The mixture was stirred at 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 for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain crude WS-23.
[0049] Add crude WS-23 to 60g of anhydrous ethanol, heat to 56℃, stir until completely dissolved, add 80g of hexane while maintaining the temperature at 55℃ and mix well, hot filter to obtain a clear solution, cool to 0℃ at a rate of 1.5℃ / min, keep warm to crystallize for 80min, collect the crystals by suction filtration, wash, and vacuum dry at 45℃ for 5h to obtain the cooling agent WS-23.
[0050] Example 5
[0051] 10 g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25 mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced and the reactor temperature was controlled at 5 °C. HCl gas was introduced at this temperature and the system pressure was controlled at 5 bar. The total amount of HCl introduced was 18 g. The temperature was then raised to 88 °C and the reaction was stirred at 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 atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0052] The crude intermediate was transferred to a reaction vessel, and 50 mL of a 31 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 72 °C. The mixture was stirred at 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 for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.
[0053] Add crude WS-23 to 30g of anhydrous ethanol, heat to 56℃, stir until completely dissolved, add 40g of hexane while maintaining the temperature at 50℃ and mix well, hot filter to obtain a clear solution, cool to 5℃ at a rate of 0.5℃ / min, keep warm to crystallize for 90min, collect the crystals by suction filtration, wash, and vacuum dry at 40℃ for 6h to obtain the cooling agent WS-23.
[0054] Example 6
[0055] Add 30g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 30mL of anhydrous methanol to the reactor, mix well, introduce N2, control the reactor temperature at 10℃, introduce HCl gas at this temperature, control the system pressure at 4 bar, and introduce a total of 24g of HCl. Then raise the temperature to 90℃ and stir the reaction at 700rpm for 5h. After the reaction is completed, slowly cool down to room temperature, slowly depressurize to atmospheric pressure, neutralize to pH 7-8, extract three times with ethyl acetate, combine the organic phases, wash with deionized water, dry, filter, and rotary evaporate to obtain the crude intermediate.
[0056] The crude intermediate was transferred to a reaction vessel, and 65 mL of a 32 wt% methylamine / methanol solution and 0.8 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 78 °C. The mixture 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. 100 mL of deionized water was added to the residue for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude WS-23 product.
[0057] Add crude WS-23 to 90g of anhydrous ethanol, heat to 52℃, stir until completely dissolved, add 120g of hexane while maintaining the temperature at 50℃ and mix well, hot filter to obtain a clear solution, cool to 0℃ at a rate of 2℃ / min, keep warm to crystallize for 60min, collect the crystals by suction filtration, wash, and vacuum dry at 50℃ for 4h to obtain the cooling agent WS-23.
[0058] Example 7
[0059] 20g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced and the reactor temperature was controlled at 5℃. HCl gas was introduced at this temperature and the system pressure was controlled at 3 bar. The total amount of HCl introduced was 21g. Then the temperature was raised to 88℃ and the reaction was stirred at 650rpm for 6h. After the reaction was completed, the temperature was slowly lowered to room temperature and the pressure was slowly released to atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0060] The crude intermediate was transferred to a reaction vessel, and 55 mL of a 30 wt% methylamine / methanol solution and 0.7 g of sodium methoxide were added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 75 °C. The mixture 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. 100 mL of deionized water was added to the residue for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain crude WS-23.
[0061] Add crude WS-23 to 60g of anhydrous ethanol, heat to 55℃, stir until completely dissolved, add 120g of hexane while maintaining the temperature at 55℃ and mix well, hot filter to obtain a clear solution, cool to 2℃ at a rate of 1℃ / min, keep warm to crystallize for 75min, collect the crystals by suction filtration, wash, and vacuum dry at 45℃ for 5.5h to obtain the cooling agent WS-23.
[0062] Example 8
[0063] 20g of DIPPN (2-isopropyl-2,3-dimethylbutyronitrile) and 25mL of anhydrous methanol were added to the reactor and mixed thoroughly. N2 was introduced and the reactor temperature was controlled at 5℃. HCl gas was introduced at this temperature and the system pressure was controlled at 3 bar. The total amount of HCl introduced was 21g. Then the temperature was raised to 88℃ and the reaction was stirred at 650rpm for 6h. After the reaction was completed, the temperature was slowly lowered to room temperature and the pressure was slowly released to atmospheric pressure. The pH was neutralized to 7-8. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain the crude intermediate.
[0064] The crude intermediate was transferred to a reaction vessel, and 55 mL of a 30 wt% methylamine / methanol solution was added. After mixing thoroughly, N2 was introduced, and the temperature was raised to 75 °C. The mixture 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. 100 mL of deionized water was added to the residue for dilution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with deionized water, dried, filtered, and rotary evaporated to obtain crude WS-23.
[0065] Add crude WS-23 to 60g of anhydrous ethanol, heat to 55℃, stir until completely dissolved, add 120g of hexane while maintaining the temperature at 55℃ and mix well, hot filter to obtain a clear solution, cool to 2℃ at a rate of 1℃ / min, keep warm to crystallize for 75min, collect the crystals by suction filtration, wash, and vacuum dry at 45℃ for 5.5h to obtain the cooling agent WS-23.
[0066] The present invention also includes comparative examples and related experiments.
[0067] Comparative Example 1
[0068] The only difference between Comparative Example 1 and Example 1 is that in step S1, after introducing HCl, the reaction is carried out under normal pressure with heating and stirring. The other components and preparation methods are the same as in Example 1, and the cooling agent WS-23 is prepared.
[0069] Comparative Example 2
[0070] The difference between Comparative Example 2 and Example 1 is that in step S3, only anhydrous ethanol was used and hexane was not added. The other components and preparation methods were the same as in Example 1, and the cooling agent WS-23 was prepared.
[0071] Performance testing
[0072] The yield and purity of the cooling agent WS-23 samples prepared in Examples 1-8 and Comparative Examples 1-2 were tested. Three samples were taken for each example and comparative example, and the average value of the test results was taken. The test results are shown in Table 1.
[0073] Table 1
[0074]
[0075] As shown in Table 1 above, the yield and purity of the cooling agent WS-23 prepared in Comparative Example 1 decreased significantly compared with that in Example 1. This indicates that maintaining a certain pressure during the activation process of DIPPN in HCl / anhydrous methanol is beneficial to improving the solubility and effective acidity of hydrochloric acid in methanol, thereby enhancing the activation efficiency of nitrile groups and promoting the effective conversion of subsequent amidation, thus reducing the content of impurities generated by side reactions and improving the yield and purity of WS-23. Compared with Example 1, the yield and purity of the cooling agent WS-23 prepared in Comparative Example 2 also decreased to some extent. This indicates that using an ethanol / hexane dual solvent system and adding an antisolvent at a temperature higher than the dissolution temperature during recrystallization is beneficial to controlling the supersaturation of the system and avoiding a large amount of instantaneous nucleation, thereby reducing impurity entrainment, improving crystal quality and recovery rate, and further improving the purity of WS-23.
[0076] The difference between Example 8 and Example 7 is that sodium methoxide was not added in Example 8 for the preparation of crude WS-23. The lack of alkali to neutralize residual acid and activate ester / imide groups resulted in slower and incomplete aminolysis, leading to a decrease in yield and purity. This indicates that the weak base catalysis of sodium methoxide is beneficial for neutralizing residual acid and improving the effective nucleophilicity of methylamine. At the same time, it promotes the conversion of active intermediates to the target amide product, thereby accelerating the amidation process and reducing the content of unreacted intermediates and byproducts, thus improving the yield and purity of WS-23.
[0077] The above are preferred embodiments of the present invention. Those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing a cooling agent WS-23, characterized in that, Includes the following steps: Step S1: Add DIPPN and anhydrous methanol to the reaction vessel, mix well, introduce N2, control the temperature, introduce HCl, pressurize and heat, stir the reaction, cool down and depressurize, neutralize, extract, wash, dry, filter, and rotary evaporate to obtain the crude intermediate product. Step S2: Transfer the crude intermediate to a reaction vessel, add methylamine / methanol solution and sodium methoxide, mix well, then introduce N2, heat to 72-78℃, stir the reaction, cool down, reduce pressure to recover the solvent, extract, wash, dry, filter, and rotary evaporate to obtain crude WS-23. Step S3: Add crude WS-23 to anhydrous ethanol, heat and stir, add hexane and mix well, hot filter to obtain a clear solution, cool down, keep warm to crystallize, filter, wash, and vacuum dry to obtain cooling agent WS-23; In step S1, the temperature is controlled at 0-10℃; the pressure is applied at 3-6 bar; and the temperature is raised to 88-92℃. The preparation method of the cooling agent WS-23 includes the following raw materials in parts by weight: 10-30 parts DIPPN, 18-24 parts HCl, 30-90 parts anhydrous ethanol and 40-120 parts hexane.
2. The preparation method of the cooling agent WS-23 according to claim 1, characterized in that, In step S1, the stirring reaction time is 4-6 hours.
3. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In step S2, the concentration of methylamine in the methylamine / methanol solution is 30-33 wt%.
4. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In step S2, the stirring reaction speed is 500-700 rpm and the time is 6-8 hours.
5. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, The extraction solvent used is ethyl acetate.
6. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In step S3, the heating temperature is 52-56℃; the temperature when adding hexane is 50-52℃.
7. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In step S3, the temperature for heat preservation and crystallization is 0-5℃, and the time is 60-90min.
8. The method for preparing the cooling agent WS-23 according to claim 1, characterized in that, In step S3, the vacuum drying temperature is 40-50℃ and the time is 4-6 hours.