Synthesis of cooling agent WS-3

Abstract

The invention provides a synthesis method of a cooling agent WS-3, and particularly, the method comprises the following steps: (1) converting menthol into chlorinated menthol; (2) reacting the chlorinated menthol with magnesium to obtain menthyl magnesium chloride; and (3) reacting the chlorinated menthane magnesium with ethyl isocyanate to form WS-3. The method provides a new synthesis method for synthesizing WS-3, and the method has the advantages of short steps, simple process, high yield, simple purification and post-treatment, low cost, greenness and environmental protection, and can be used for large-scale production.

Description

Technical Field

[0001] The invention relates to the field of chemistry, and in particular to the synthesis of a cooling agent WS-3. Background Art

[0002] Menthyl amide (such as WS-3, W5, G180) is a new type of cooling agent developed by Wilkinson Sword. ) is derived from WS series cooling agents. Among the WS series cooling agents, WS-3 has the strongest cooling effect, stronger taste impact and taste durability. Its cooling effect is 1.5 times that of menthol, and it can be mixed with a variety of cooling agents in the same series. For example, mixing it with WS-5 can improve the shortcomings of the performance of a single cooling agent. Due to the above advantages, WS-3 is an ideal substitute for menthol and is widely used in food, medicine, daily chemicals and tobacco industries.

[0003] Currently, WS-3 is synthesized using menthol as raw material, and there are two main synthetic routes.

[0004] One route is reported in patents CN107954824A and CN1613845A, etc., which converts menthol into chloromenthol, and then introduces a carboxyl group through a Grignard reaction to prepare menthic acid (WS-1).

[0005] It is menthyl chloride, which can then react with ethylamine to prepare the cooling agent WS-3.

[0006] The main problem of this process route is that the reaction efficiency of the Grignard reagent and carbon dioxide gas is not high, and the transportation and use of carbon dioxide gas are inconvenient, which makes the process operation complicated; in addition, the synthetic route is long, resulting in a low overall yield, and thus a high cost. Although the method disclosed in CN 107954824 A has a high yield, there are multiple isomers in the reaction product that are difficult to separate, such as neomenthol acid, etc., and it is difficult to obtain high-purity L-menthol acid, and the production and purification costs are increased.

[0007] Another route is reported in patents CN107721849A, CN103694130A and WO2010019730A1, etc., in which menthol is converted into chloromenthol, and then the chloromenthol is converted into nitrile menthol by sodium cyanide, and then the nitrile group is hydrolyzed in ethanol or acidic hydrolysis and then reacted with ethylamine to generate menthyl amide.

[0008]

[0009] In this process route, highly toxic reagents such as sodium cyanide and diethyl sulfate are required, and the operation of converting nitrile menthol to menthyl amide is complicated and inefficient. The process route usually obtains a new isomer with opposite stereochemistry at the amide (C-1) position, and its application in some fields cannot meet market demand.

[0010] Therefore, there is an urgent need for a method for efficiently synthesizing WS-3 that is short, environmentally friendly, and easy to operate. Summary of the invention

[0011] The purpose of the present invention is to provide a method for efficiently synthesizing WS-3 with a short route, environmental friendliness and convenient operation.

[0012] In a first aspect of the present invention, a method for preparing WS-3 is provided, the method comprising the following reaction steps:

[0013] (1) In an inert solvent, menthol reacts with ZnCl2 to form chloromenthol;

[0014]

[0015] (2) Chloromenthol reacts with Mg in an inert solvent to form menthyl magnesium chloride;

[0016]

[0017] (3) reacting menthyl magnesium chloride with ethyl isocyanate in an inert solvent to form WS-3;

[0018]

[0019] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0020] In step (1), the reaction is carried out in the presence of an acid, preferably, the acid is hydrochloric acid;

[0021] In step (1), the molar ratio of menthol to ZnCl2 in the reaction is 1:(1-8);

[0022] In step (1), the inert solvent is selected from the group consisting of water, or a combination thereof.

[0023] In another preferred embodiment, in the step (1), the reaction temperature of the reaction is 0-90°C; preferably 10-40°C; the reaction time of the reaction is 0.1-20h; preferably 0.8-12h.

[0024] In another preferred embodiment, the step (1) further comprises:

[0025] ZnCl2 is added to an inert solvent, wherein the adding temperature is -50-50°C, preferably -40-30°C, and more preferably -25-5°C.

[0026] In another preferred embodiment, the hydrochloric acid is in liquid form or gaseous form.

[0027] In another preferred embodiment, the molar ratio of hydrochloric acid to ZnCl2 is 1:(0.4-1.8); preferably 1:(0.65-1.4).

[0028] In another preferred embodiment, the step (1) further comprises: separating chloromenthol from the reaction mixture, preferably, the separation is extraction.

[0029] In another preferred embodiment, the recovered liquid of the reaction mixture can be optionally applied to step (1).

[0030] In another preferred embodiment, ZnCl2 is added to concentrated HCl in batches at a temperature of -25-5°C, and after ZnCl2 is dissolved, menthol is added, and the reaction mixture is heated at 30-40°C for 5-9 hours to form chloromenthol.

[0031] In another preferred embodiment, ZnCl2 is added to water at a temperature of -25-30°C (preferably -25-5°C), HCl gas is introduced to saturation, and menthol is added. The reaction mixture is heated at 30-40°C for 5-12 hours to form chloromenthol.

[0032] In another preferred embodiment, the step (1) further comprises: removing the aqueous phase from the reaction mixture after the reaction, washing with saturated NaHCO3 solution, water, and saturated saline in sequence, drying with anhydrous magnesium sulfate, and filtering to obtain colorless liquid chloromenthol.

[0033] In another preferred embodiment, the step (1) further comprises: introducing HCl gas into the removed aqueous phase until saturated, adding menthol, and heating the reaction mixture at 30-40° C. for 0.5-2 h.

[0034] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0035] In step (2), the reaction is carried out in the presence of an initiator, preferably, the initiator is iodine;

[0036] In step (2), the molar ratio of chloromenthol to Mg in the reaction is 1:(0.5-3); preferably, the molar ratio of chloromenthol to Mg in the reaction is 1:1.

[0037] In step (2), the inert solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof.

[0038] In another preferred embodiment, the reaction temperature in step (2) is 30-100°C, preferably 50-80°C; the reaction time of the reaction is 1-8h, preferably 2-6h.

[0039] In another preferred embodiment, the inert solvent in step (2) is anhydrous tetrahydrofuran. In another preferred embodiment, chloromenthol in step (2) is added to the reaction solution in batches.

[0040] In another preferred embodiment, the amount of the first batch of chloromenthol in step (2) is 10-20% of the total amount.

[0041] In another preferred embodiment, the reaction in step (2) is carried out in stages.

[0042] In another preferred embodiment, the first batch of chloromenthol is added into the first stage of the reaction in step (2), the reaction temperature is 60-80° C., and the reaction time is 0.2-0.8 h.

[0043] In another preferred embodiment, in step (2), the second batch of chloromenthol is dissolved in an inert solvent and added to the reaction solution.

[0044] In another preferred embodiment, the temperature of the reaction solution at which the second batch of chloromenthol is added in step (2) is 55-75°C, preferably 55-65°C.

[0045] In another preferred embodiment, in the second stage of the reaction in step (2), a second batch of chloromenthol is added, the reaction temperature is 55-75° C., preferably 55-65° C., and the reaction time is 2-3 h.

[0046] In another preferred embodiment, the step (2) comprises: dissolving chloromenthol in anhydrous tetrahydrofuran, then adding Mg and I2, heating to 65-75°C for reaction for 0.2-0.8 hours, after the reaction is initiated, cooling the reaction solution to 55-65°C, adding the remaining chloromenthol through a constant pressure dropping funnel within 1-2 hours, and continuing the reaction at 55-65°C for 2-3 hours to obtain a menthyl magnesium chloride solution.

[0047] In another preferred embodiment, the step (2) comprises: dissolving chloromenthol in anhydrous tetrahydrofuran, then adding Mg and I2, heating to 65-75°C for reaction for 0.2-0.8 hours, after the reaction is initiated, adding the remaining chloromenthol through a constant pressure dropping funnel within 1-2 hours, and continuing the reaction at 65-75°C for 2-3 hours to obtain a menthyl magnesium chloride solution.

[0048] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0049] In step (3), the molar ratio of ethyl isocyanate to menthyl magnesium chloride in the reaction is 1:(0.5-3);

[0050] Preferably, the molar ratio of ethyl isocyanate to menthyl magnesium chloride in the reaction is 1:1;

[0051] In step (3), the inert solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof.

[0052] In another preferred embodiment, the reaction temperature in step (3) is 15-50°C, preferably 20-30°C; the reaction time is 1-8h; preferably 2-6h.

[0053] In another preferred embodiment, the mixing of ethyl isocyanate and menthyl magnesium chloride in step (3) is carried out at -40-40°C, preferably -25-30°C.

[0054] In another preferred embodiment, the inert solvent in step (3) is anhydrous tetrahydrofuran.

[0055] In another preferred embodiment, in step (3), ethyl isocyanate is first dissolved in anhydrous tetrahydrofuran and then added dropwise to the anhydrous tetrahydrofuran solution of menthyl magnesium chloride.

[0056] In another preferred embodiment, the dripping time of ethyl isocyanate in step (3) is 1-3 hours.

[0057] In another preferred embodiment, the step (3) further comprises: isolating and purifying WS-3 from the reaction mixture.

[0058] In another preferred embodiment, the step (3) comprises: adding the ethyl isocyanate solution dropwise to the menthyl magnesium chloride solution at -15 to -25°C, completing the addition within 1 to 3 hours, and then reacting at 20 to 30°C for 1 to 3 hours.

[0059] In another preferred embodiment, the step (3) comprises: adding the ethyl isocyanate solution dropwise to the menthyl magnesium chloride solution at 20-30° C., completing the addition within 1-3 hours, and continuing the reaction at 20-30° C. for 1-3 hours.

[0060] In another preferred embodiment, the step (3) comprises: after the reaction is completed, quenching the reaction solution with water, concentrating to remove tetrahydrofuran, extracting the aqueous phase with toluene, combining the toluene phases, washing with water and saturated brine in sequence, concentrating, and recrystallizing the obtained crude product with a mixed solvent of acetone and water to obtain a WS-3 product.

[0061] In a second aspect of the present invention, a method for synthesizing WS-3 is provided, the method comprising the following reaction steps:

[0062] (3) reacting menthyl magnesium chloride with ethyl isocyanate in an inert solvent to form WS-3;

[0063]

[0064] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 This is the gas chromatogram of chloromenthol.

[0066] Figure 2 This is the H NMR spectrum of chloromenthol.

[0067] Figure 3 It is the gas chromatogram of menthyl magnesium chloride (after quenching with 0.1M hydrochloric acid).

[0068] Figure 4 This is the H NMR spectrum of WS-3. DETAILED DESCRIPTION

[0069] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided a method for synthesizing a cooling agent WS-3. The method comprises the following steps: (1) converting menthol into chloromenthol; (2) reacting chloromenthol with magnesium to obtain menthyl magnesium chloride; (3) reacting chloromenthane magnesium with ethyl isocyanate to form WS-3. The method has short steps, simple process, safe operation, environmental friendliness, high yield and purity, and low cost. The present invention was completed on this basis.

[0070] the term

[0071] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0072] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0073] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0074] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0075] The main advantages of the present invention include:

[0076] (1) Short synthesis steps: The method has only three steps, while the current prior art generally has five steps, which greatly shortens the reaction process, reduces the loss of raw materials and the introduction of impurities in the chemical reaction, and also reduces the production and purification costs, which is conducive to industrial scale-up production;

[0077] (2) The raw materials or reactants used in the synthesis method are mainly in liquid or solid form, which is different from carbon dioxide in the prior art, with reduced transportation costs and simple and safe operation; and the highly toxic controlled reagents sodium cyanide and diethyl sulfate in the prior art are replaced with common reagents, which are less toxic, simple in raw materials, and also reduce production costs;

[0078] (3) The WS-3 obtained by the synthesis method has high purity and high reaction yield: the purity of the WS-3 obtained by the method described in this application is higher than 95% under gas chromatography detection, and can be as high as 98% under preferred experimental conditions; the yield of the final product in the reaction described in this application is higher than 70%, and can be as high as 77% under preferred experimental conditions; the overall yield of the reaction is higher than 70%;

[0079] (4) The reaction product can be easily separated: The product obtained by the method described in the present application is mainly WS-3, without interference from isomers of other configurations. The product can be easily separated and purified under the premise of high yield, which greatly reduces the production cost.

[0080] The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0081] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0082] Step 1: Synthesis of chloromenthol

[0083]

[0084] Example 1

[0085] Under ice-water cooling, ZnCl2 (505g, 3.71mol) was added in batches to concentrated HCl (36.5%, 366mL, 4.36mol). After ZnCl2 was completely dissolved, menthol (193g, 1.24mol) was added. The ice-water bath was removed and the reaction mixture was heated at 35°C for 7h. The aqueous phase was directly separated and washed with saturated NaHCO3 solution (100mL), water (100mL), and saturated brine (100mL) in turn, dried over anhydrous magnesium sulfate, and filtered to obtain colorless liquid chloromenthol (205.2g, 95% yield). The hydrogen spectrum is shown in Figure 2 shown.

[0086] 1 H NMR (400MHz, CDCl3): δ3.77(td,J=11.0,4.2Hz,1H),2.33(septd,J=7.0,2.9Hz,1H),2.25-2.17(m,1H),1.77-1.64 (m,2H),1.48-1.31(m,3H),1.10-0.82(m,3H),0.92(d,J=7.3Hz,3H),0.91(d,J=5.8Hz,3H),0.76(d,J=7.3Hz,3H).

[0087] The purity of chloromenthol was detected by gas chromatography. The specific chromatographic conditions are shown in Table 1 below:

[0088] Table 1 Gas chromatography analysis conditions of chloromenthol

[0089]

[0090]

[0091] The gas chromatogram analysis results are shown in Table 2 below. Figure 1 As shown, the purity of chloromenthol obtained was 89.6%.

[0092] Table 2 Gas chromatography purity results of chloromenthol

[0093]

[0094] Example 2

[0095] Under ice-water cooling, ZnCl2 (350 g, 2.57 mol) was added to water (150 g), HCl gas (77 g) was introduced until saturated, and menthol (84 g, 0.54 mol) was added. The ice-water bath was removed, and the reaction mixture was heated at 25°C for 3.5 h. The aqueous phase was directly separated, and the organic phase was washed with saturated NaHCO3 solution (100 mL), water (100 mL), and saturated brine (100 mL) in turn, dried over anhydrous magnesium sulfate, and filtered to obtain colorless liquid chloromenthol (90.1 g, 96% yield, gas chromatography purity 93.2%).

[0096] The experimental results show that the reaction temperature is lowered and the reaction conditions are further optimized, and the purity of the reaction product, chloromenthol, can be further increased to about 93%.

[0097] Example 3

[0098] At -20°C, ZnCl2 (350 g, 2.57 mol) was added to water (150 g), HCl gas (100 g) was introduced until saturated, and menthol (84 g, 0.54 mol) was added. The reaction mixture was heated at 25°C for 1.0 h. The aqueous phase was directly separated, and the organic phase was washed with saturated NaHCO3 solution (100 mL), water (100 mL), and saturated brine (100 mL) in sequence, dried over anhydrous magnesium sulfate, and filtered to obtain colorless liquid chloromenthol (91.3 g, 97% yield, gas chromatography purity 94.1%).

[0099] The experimental results show that lowering the temperature of the HCl aeration process can increase the aeration volume of hydrogen chloride, significantly improving the reaction rate, thereby shortening the reaction time and reducing the reaction time consumption, which is helpful for industrial production. In addition, after the reaction time is shortened, the reaction can be applied to flow processes.

[0100] Example 4

[0101] At -20°C, HCl gas (100 g) was introduced into the aqueous phase in Example 3 until saturated, and menthol (84 g, 0.54 mol) was added. The reaction mixture was heated at 25°C for 1.0 h. The aqueous phase was directly separated and washed with saturated NaHCO3 solution (100 mL), water (100 mL), and saturated brine (100 mL) in sequence, dried over anhydrous magnesium sulfate, and filtered to obtain colorless liquid chloromenthol (90.8 g, 97% yield, gas chromatography purity 94.0%).

[0102] The experimental results show that the aqueous phase obtained after the reaction treatment can be used as the reaction mother liquor and continued to be recycled to obtain the target product, namely chloromenthol, and the reaction yield and purity do not change significantly. The recycling of the reaction mother liquor reduces the generation of three reaction wastes and is environmentally friendly.

[0103] Example 5

[0104] At room temperature, ZnCl2 (350g, 2.57mol) was added to water (150g), HCl gas (36g) was introduced until saturated, and menthol (84g, 0.54mol) was added. The reaction mixture was heated at 25°C for 10.0h. The aqueous phase was directly separated and washed with saturated NaHCO3 solution (100mL), water (100mL), and saturated brine (100mL) in sequence, dried over anhydrous magnesium sulfate, and filtered to obtain colorless liquid chloromenthol (83.0g, 88.4% yield, gas chromatography purity 73.4%).

[0105] The experimental results show that increasing the temperature at which ZnCl2 is added to water reduces the amount of hydrogen chloride dissolved, slows down the reaction rate, and also reduces the reaction purity to a certain extent.

[0106] Step 2: Synthesis of Menthyl Magnesium Chloride Solution

[0107]

[0108] Example 6

[0109] Dissolve chloromenthol (30g, 0.17mol) in anhydrous tetrahydrofuran (90mL), then add Mg chips (27.8g, 1.14mol) and I2 (2.18g, 8.6mmol), and heat to 70℃ for 0.5 hours. After the reaction is initiated, cool the reaction solution to 60℃, add the remaining chloromenthol (170g, 0.98mol, dissolved in 680mL anhydrous tetrahydrofuran) through a constant pressure dropping funnel, and add dropwise within 1.5 hours, and continue to react at 60℃ for 2.5 hours to obtain a menthyl magnesium chloride solution. Take a small amount of sample solution, quench it with 0.1M hydrochloric acid, and analyze the gas phase. The content of menthyl magnesium chloride in the liquid phase is 82.4%.

[0110] The content of menthyl magnesium chloride was detected by gas chromatography. The specific chromatographic conditions are shown in Table 3 below:

[0111] Table 3 Gas chromatography analysis conditions for the content of menthyl magnesium chloride

[0112]

[0113] Gas chromatogram Figure 3 The analysis results are shown in Table 4 below, and the purity of the menthyl magnesium chloride is 82.351%.

[0114] Table 4 Gas chromatography purity analysis results of menthyl magnesium chloride

[0115]

[0116] Example 7

[0117] Menthyl chloride (30g, 0.17mol) was dissolved in anhydrous tetrahydrofuran (90mL), and then Mg chips (27.8g, 1.14mol) and I2 (2.18g, 8.6mmol) were added, and the mixture was heated to 70°C for 0.5 hours. After the reaction was initiated, the remaining menthyl chloride (170g, dissolved in 680mL anhydrous tetrahydrofuran) was added dropwise through a constant pressure dropping funnel within 1.5 hours, and the reaction was continued at 70°C for 2.5 hours to obtain a menthyl magnesium chloride solution. A small amount of the sample solution was taken and quenched with 0.1M hydrochloric acid and then analyzed by gas phase. The content of menthyl magnesium chloride in the liquid phase was 72.0%.

[0118] The experimental results show that lowering the reaction temperature after the reaction is initiated increases the product content of the Grignard reaction and is beneficial to improving the yield of the reaction.

[0119] Step 3: Synthesis of WS-3

[0120]

[0121] Example 8

[0122] At -20°C, ethyl isocyanate solution (8.1 g, 114 mmol, dissolved in 40 mL of anhydrous tetrahydrofuran) was added dropwise to the solution of menthyl magnesium chloride in Example 6 (one tenth of the supernatant of the Grignard reagent obtained in Example 6), and the addition was completed within 2.0 hours. The cooling device was removed, the reaction solution was naturally warmed to room temperature, and the reaction was continued for 1.0 hour. The reaction solution was quenched with water (50 mL), concentrated to remove tetrahydrofuran, the aqueous phase was extracted with toluene (50 mL x 3), the toluene phases were combined, washed with water (50 mL) and saturated brine (50 mL) in turn, and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (volume ratio, acetone: water = 1:2) to obtain WS-3 product (18.6 g, 88.07 mmol, two-step yield 76.9%, gas chromatography purity 98.2%). The hydrogen spectrum is shown as follows Figure 4 shown.

[0123] 1H NMR (400MHz, CDCl3): δ5.43(brs,1H),3.27~3.31(m,2H),1.92~1.98(m,1H)1.66~1.78(m,4H),1.51~1.52(m,1H),1.31~1.43(m, 1H), 1.25~1.28(m,1H), 1.11~1.15(t,J=7.2Hz,3H), 0.93~1.02(m,2H), 0.88~0.91(t,J=6.0Hz,6H), 0.77~0.78(d,J=7.2Hz,3H).

[0124] Example 9

[0125] At room temperature, ethyl isocyanate solution (8.1 g, 114 mmol, dissolved in 40 mL of anhydrous tetrahydrofuran) was added dropwise to the solution of menthyl magnesium chloride in Example 6 (one tenth of the supernatant of the Grignard reagent obtained in Example 6), and the addition was completed within 2.0 hours, and the reaction was continued at room temperature for 2 hours. The reaction solution was quenched with water (50 mL), concentrated to remove tetrahydrofuran, and the aqueous phase was extracted with toluene (50 mL x 3). The toluene phases were combined, washed with water (50 mL) and saturated brine (50 mL) in turn, and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (volume ratio, acetone: water = 1: 2) to obtain WS-3 product (13.6 g, 64.40 mmol, yield 56.2%, gas chromatography purity 78.3%).

[0126] The experimental results show that lowering the temperature during the dropwise addition and mixing of the reactants is more conducive to the reaction, and the reaction yield and product purity are significantly improved.

[0127] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing WS-3, characterized in that: The method comprises the following reaction steps: (1) In an inert solvent, menthol reacts with ZnCl2 to form chloromenthol; (2) Chloromenthol reacts with Mg in an inert solvent to form menthyl magnesium chloride; (3) reacting menthyl magnesium chloride with ethyl isocyanate in an inert solvent to form WS-3; 2. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: In step (1), the reaction is carried out in the presence of an acid, preferably, the acid is hydrochloric acid; In step (1), the molar ratio of menthol to ZnCl2 in the reaction is 1:(1-8); In step (1), the inert solvent is selected from the group consisting of water, or a combination thereof.

3. The method according to claim 2, characterized in that In the step (1), the reaction temperature is 0-90°C, preferably 10-40°C; the reaction time is 0.1-20h, preferably 0.8-12h.

4. The method according to claim 2, characterized in that The step (1) further includes: ZnCl2 is added to an inert solvent, wherein the adding temperature is -50-50°C, preferably -40-30°C, and more preferably -25-5°C.

5. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: In step (2), the reaction is carried out in the presence of an initiator, preferably, the initiator is iodine; In step (2), the molar ratio of chloromenthol to Mg in the reaction is 1:(0.5-3); In step (2), the inert solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof.

6. The method according to claim 2, characterized in that The reaction temperature in step (2) is 30-100°C, preferably 50-80°C; The reaction time of the reaction is 1-8h; preferably 2-6h.

7. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: In step (3), the molar ratio of ethyl isocyanate to menthyl magnesium chloride in the reaction is 1:(0.5-3); In step (3), the inert solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof.

8. The method according to claim 7, characterized in that The reaction temperature in step (3) is 15-50°C, preferably 20-30°C; the reaction time is 1-8h, preferably 2-6h.

9. The method according to claim 7, characterized in that In the step (3), the mixing of ethyl isocyanate and menthyl magnesium chloride is carried out at -40-40°C, preferably -25-30°C.

10. A method for preparing WS-3, characterized in that: The method comprises the following reaction steps: (3) reacting menthyl magnesium chloride with ethyl isocyanate in an inert solvent to form WS-3;

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