Menthane amide cooling agent WS-5 and preparation method thereof

Abstract

The invention belongs to the technical field of cooling agent synthesis, and provides a mint amide cooling agent WS-5 and a preparation method thereof. The method comprises the following steps: mixing menthol, pyridine and acetone, and dropwise adding a chloramine reagent solution to obtain menthone; the preparation method comprises the following steps: mixing a tetrahydrofuran solution of menthone with potassium tert-butoxide, and adding p-toluenesulfonyl methyl isocyanide for reaction to obtain nitrile-based menthol; the method comprises the following steps: dissolving nitrile menthol in hydrochloric acid, and reacting to obtain menthic acid; menthic acid, glycine ethyl ester, pyridine and ethyl acetate are mixed, and a condensation reagent solution is added for reaction. According to the preparation method disclosed by the invention, menthol is oxidized into menthone by using a cheap and easily available chloramine reagent; p-methylbenzenesulfonyl methyl isocyanide is used as a nitrile group source, so that the use of a highly toxic reagent is avoided; according to the method, the menthyl formic acid and the glycine ethyl ester are directly condensed, so that the use of high-pollution reagents is avoided while the reaction steps are simplified, the reaction time is shortened, and the production efficiency is improved.

Description

Technical Field

[0001] The invention relates to the technical field of cooling agent synthesis, in particular to a menthamide cooling agent WS-5 and a preparation method thereof. Background Art

[0002] Menthamide is a derivative of the traditional cooling agent menthol. Compared with menthol, it has a stronger cooling effect and stability, so it is widely used in food, medicine, daily chemicals, tobacco and other industries. WS-5 is a representative menthamide cooling agent that can provide a smooth and round cooling effect, mainly affecting the upper part of the mouth and the back of the tongue. The cooling effect of WS-5 is significant and lasting, which can last for half an hour, and it can still maintain the cooling effect at a high temperature of 200°C, which is convenient for high-temperature treatment such as baking in process production. In addition, the product has no peculiar smell, no spicy or irritating feeling, and can achieve a cooling effect when mixed with other flavors without affecting its aroma. In view of the above characteristics, WS-5 has become more and more popular among consumers in recent years.

[0003] At present, the synthesis of WS-5 mainly uses menthol as the raw material to prepare the key intermediate menthyl formic acid, which reacts with dichlorothionyl to generate menthyl formic acid chloride, and then reacts with different amine compounds to obtain the desired WS series cooling agent. The synthesis route is shown below.

[0004]

[0005] At present, menthyl formic acid is mainly prepared by the reaction of menthyl Grignard reagent and carbon dioxide or dry ice. For example, invention patents CN107954824A and CN1613845A report that menthol is converted into chloromenthol, and then a carboxyl group is introduced through a Grignard reaction to prepare menthyl formic acid (WS-1). The main problem of this process route is that the Grignard reaction is difficult to control and there are many by-products. In addition, the route is long, resulting in a low overall yield and a high cost.

[0006] In view of the problems in the above-mentioned process, the improved processes disclosed in the prior art mainly include the following: Patent EP2450337A2 uses menthone as a raw material, first epoxidizes the double bonds in menthone, then uses Lewis acid to catalyze and rearrange it into menthyl formaldehyde, and then oxidizes the menthyl formaldehyde to menthyl formic acid. This method avoids the Grignard reaction that requires anhydrous and oxygen-free operation, and is easy to operate, but the product stereoselectivity is poor and it is difficult to meet market demand. Patent CN117945886A uses menthol as a starting material, first oxidizes to generate menthone, then sequentially generates the corresponding menthyl formaldehyde through Wittig reaction and acidolysis, and finally oxidizes the menthyl formaldehyde to menthyl formic acid. This process requires the use of ferric nitrate as a catalyst and a large amount of oxygen as an oxidant, which poses a safety risk in production. In addition, the use of Wittig reagent also produces a large amount of triphenylphosphine oxide solid waste that is difficult to handle. Patents CN107721849A, CN103694130A, WO2010019730A1 and WO2010019730 reported that the hydroxyl group of menthol was activated, and then converted into nitrile menthol by a nucleophilic substitution reaction of sodium cyanide, and then hydrolyzed to obtain menthyl formic acid. This method has a high yield and is simple to operate, but the method uses highly toxic sodium cyanide, has high safety and environmental protection requirements, and has certain production risks, making it difficult to use for industrial large-scale production.

[0007] Therefore, there is an urgent need for a method for synthesizing menthyl formic acid with short steps, environmental friendliness, and simple reagents, so as to further efficiently synthesize WS-5 and other menthyl amide cooling agents. Summary of the invention

[0008] The purpose of the present invention is to provide a menthamide cooling agent WS-5 and a preparation method thereof in order to overcome the deficiencies of the prior art, and to solve the problems of complex steps, high cost and high safety risk in the existing synthesis process of menthamide cooling agents.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] The present invention provides a method for preparing menthamide cooling agent WS-5, comprising the following steps:

[0011] 1) mixing menthol, pyridine and acetone to obtain a mixed solution; adding a chloramine reagent solution dropwise to the mixed solution, and continuing the reaction after the addition is completed to obtain menthone;

[0012] 2) mixing a tetrahydrofuran solution of menthone and potassium tert-butoxide, and adding p-toluenesulfonylmethyl isocyanide to the mixture for reaction to obtain nitrile menthol;

[0013] 3) dissolving nitrile menthol in hydrochloric acid and reacting to obtain menthyl formic acid;

[0014] 4) mixing menthyl formic acid, glycine ethyl ester, pyridine and ethyl acetate to obtain a mixed solution, adding a condensation reagent solution to the mixed solution for reaction, and adding hydrochloric acid dropwise to the reaction system to continue the reaction to obtain menthyl amide cooling agent WS-5.

[0015] Preferably, in step 1), the molar ratio of menthol to pyridine is 1:1.2-2.0; the molar mass ratio of menthol to acetone is 1 mol:650-750 g; the chloramine reagent is trichloroisocyanuric acid or dichlorohydantoin; and the molar ratio of chloramine reagent to menthol is 0.4-0.6:1.

[0016] Preferably, in the chloramine reagent solution, the solvent is acetone; the dripping time is 28 to 32 minutes, and the reaction time is 0.5 to 2 hours.

[0017] Preferably, in step 2), the molar ratio of potassium tert-butoxide to menthone is 1.4-1.6:1, and the molar ratio of p-toluenesulfonylmethyl isocyanide to menthone is 1-1.4:1;

[0018] The mixing time is 18 to 25 minutes, and the reaction time is 6 to 10 hours.

[0019] Preferably, in step 3), the mass fraction of the hydrochloric acid is 15-36%, the molar mass ratio of nitrile menthol to hydrochloric acid is 1 mol: 0.4-0.5 kg; and the reaction time is 6-10 h.

[0020] Preferably, in step 4), the molar ratio of menthic acid, glycine ethyl ester and pyridine is 1:1-1.2:3.3-3.7, the molar ratio of menthic acid and condensation reagent is 1:1.3-1.7; the molar mass ratio of menthic acid and ethyl acetate is 1 mol:0.9-1.1 kg;

[0021] The concentration of hydrochloric acid is 0.09-0.11 mol / L, and the volume mass ratio of hydrochloric acid to ethyl acetate is 0.35-0.4 L: 0.9-1.1 kg.

[0022] Preferably, in the condensation reagent solution of step 4), the solvent is ethyl acetate, and the condensation reagent is 1-n-propyl phosphoric anhydride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, Carter's condensation agent or benzotriazole-1-yl-oxytripyrrolidone hexafluorophosphate.

[0023] Preferably, the reaction temperature in step 4) is -2 to 2°C, and the reaction time is 9 to 11 hours; during the addition of hydrochloric acid, the temperature of the reaction system is -2 to 2°C, the hydrochloric acid addition time is 28 to 32 minutes, the temperature for continued reaction is 18 to 22°C, and the reaction time is 5 to 7 hours.

[0024] The invention also provides menthamide cooling agent WS-5 prepared by the preparation method.

[0025] The beneficial effects of the present invention include the following:

[0026] 1) The use of cheap and readily available chloramine reagent can safely and conveniently oxidize menthol to menthone, avoiding the use of other expensive oxidants.

[0027] 2) p-Toluenesulfonylmethyl isocyanide is used as the source of the nitrile group, and the nitrile group is introduced through the Van Leusen reduction nitrilation reaction, avoiding the use of highly toxic reagents such as sodium cyanide.

[0028] 3) Directly condensing menthyl formic acid and glycine ethyl ester simplifies the reaction steps while avoiding the safety and environmental impacts caused by highly polluting reagents, shortens the reaction time, and improves production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the H NMR spectrum of the menthone of Example 1;

[0030] Figure 2 is the mass spectrum of menthone in Example 1;

[0031] Figure 3 is the H NMR spectrum of the nitrile menthol of Example 1;

[0032] Figure 4 is the H NMR spectrum of the menthic acid of Example 1;

[0033] Figure 5 is the H NMR spectrum of WS-5 of Example 1;

[0034] Figure 6 This is the mass spectrum of WS-5 of Example 1. DETAILED DESCRIPTION

[0035] The present invention provides a method for preparing menthamide cooling agent WS-5, comprising the following steps:

[0036] 1) mixing menthol (compound 1), pyridine and acetone to obtain a mixed solution; adding a chloramine reagent solution dropwise to the mixed solution, and continuing the reaction after the addition is completed to obtain menthone (compound 2);

[0037] 2) mixing a tetrahydrofuran solution of menthone and potassium tert-butoxide, and adding p-toluenesulfonylmethyl isocyanide to the mixture for reaction to obtain nitrile menthol (compound 3);

[0038] 3) dissolving nitrile menthol in hydrochloric acid and reacting to obtain menthic acid (compound 4);

[0039] 4) mixing menthyl formic acid, glycine ethyl ester, pyridine and ethyl acetate to obtain a mixed solution, adding a condensation reagent solution to the mixed solution for reaction, and adding hydrochloric acid dropwise to the reaction system to continue the reaction to obtain menthyl amide cooling agent WS-5.

[0040] The synthetic route of the menthamide cooling agent WS-5 of the present invention is as follows:

[0041]

[0042] In the present invention, the molar ratio of menthol and pyridine in step 1) is preferably 1:1.2-2.0, more preferably 1:1.4-1.7, and more preferably 1:1.5-1.6; the molar mass ratio of menthol and acetone is preferably 1 mol:650-750g, more preferably 1 mol:680-720g, and more preferably 1 mol:690-700g; the chloramine reagent is preferably trichloroisocyanuric acid or dichlorohydantoin; the molar ratio of chloramine reagent and menthol is preferably 0.4-0.6:1, more preferably 0.45-0.55:1, and more preferably 0.5:1.

[0043] In the present invention, in the chloramine reagent solution, the solvent is preferably acetone; the dropwise addition time is preferably 28 to 32 minutes, more preferably 29 to 31 minutes, and more preferably 30 minutes; the reaction time is preferably 0.5 to 2 hours, and more preferably 1 to 1.5 hours.

[0044] In the present invention, the mixed solution obtained by the reaction in step 1) is sequentially subjected to solid-liquid separation, filtrate concentration, extraction, washing and drying to obtain menthol; the solid-liquid separation is carried out by suction filtration, the insoluble solids are removed by suction filtration, the filtrate is concentrated to remove the acetone solvent, and the reagent used for extraction is preferably methyl tert-butyl ether, ether or ethyl acetate; the reagent used for washing is preferably hydrochloric acid, sodium hydroxide solution and saturated salt solution in sequence, the concentration of hydrochloric acid is preferably 0.8-1.2 mol / L, more preferably 1 mol / L; the concentration of sodium hydroxide solution is preferably 3.8-4.2 mol / L, more preferably 4 mol / L, and the salt solution is preferably sodium chloride solution; the reagent used for drying is preferably anhydrous sodium sulfate.

[0045] In the present invention, the molar ratio of potassium tert-butoxide to menthone in step 2) is preferably 1.4-1.6:1, more preferably 1.45-1.55:1, more preferably 1.5:1, and the molar ratio of p-toluenesulfonylmethyl isocyanide to menthone is preferably 1-1.4:1, more preferably 1.1-1.3:1, more preferably 1.2:1;

[0046] The mixing time is preferably 18 to 25 minutes, more preferably 20 to 22 minutes; the reaction time is preferably 6 to 10 hours, more preferably 7 to 9 hours, and more preferably 8 hours.

[0047] In the present invention, a saturated aqueous solution of ammonium chloride is added to the reaction product obtained by the reaction in step 2), the aqueous phase is extracted, the organic extracts are combined, dried, filtered, and purified by reduced pressure distillation to obtain nitrile menthol; the reagent used for extracting the aqueous phase is preferably methyl tert-butyl ether, and the reagent used for drying is preferably anhydrous sodium sulfate.

[0048] In the present invention, the mass fraction of the hydrochloric acid in step 3) is preferably 15-36%, more preferably 18-30%, and more preferably 20-25%; the molar mass ratio of nitrile menthol to hydrochloric acid is preferably 1 mol: 0.4-0.5 kg, and more preferably 1 mol: 0.44-0.45 kg; the reaction time is preferably 6-10 h, more preferably 7-9 h, and more preferably 8 h.

[0049] In the present invention, the reaction product obtained by the reaction in step 3) is sequentially subjected to vacuum filtration, filtrate extraction, organic phase combination, drying, filtration, and concentration to obtain menthic acid; the purpose of vacuum filtration is to remove the solid precipitated in the solution, the reagent used for filtrate extraction is preferably methyl tert-butyl ether, and the reagent used for drying is preferably anhydrous sodium sulfate.

[0050] In the present invention, the molar ratio of menthic acid, glycine ethyl ester and pyridine in step 4) is preferably 1:1-1.2:3.3-3.7, more preferably 1:1.05-1.15:3.4-3.6, more preferably 1:1.1:3.5; the molar ratio of menthic acid and condensation reagent is preferably 1:1.3-1.7, more preferably 1:

[0051] 1.4 to 1.6, more preferably 1:1.5; the molar mass ratio of menthic acid to ethyl acetate is preferably 1 mol:0.9 to 1.1 kg, more preferably 1 mol:0.95 to 1.05 kg, more preferably 1 mol:1 kg;

[0052] The concentration of hydrochloric acid is preferably 0.09-0.11 mol / L, more preferably 0.095-0.105 mol / L, more preferably 0.1 mol / L, and the volume mass ratio of hydrochloric acid to ethyl acetate is preferably 0.35-0.4 L:0.9-1.1 kg, more preferably 0.37-0.38 L:0.95-1.05 kg, more preferably 0.375 L:1 kg.

[0053] In the condensation reagent solution of step 4) of the present invention, the solvent is preferably ethyl acetate, and the condensation reagent is preferably 1-n-propyl phosphoric anhydride (T3P), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), Carter's condensation agent (BOP) or benzotriazole-1-yl-oxytripyrrolidone hexafluorophosphate (PyBOP).

[0054] In the present invention, the T3P condensing agent has the following advantages: (1) low toxicity (LD50>2000 mg / kg); (2) good stability and can be stored for a long time; (3) easy operation (preparation of an organic solvent solution with a mass fraction of 50%, such as EtOAc, DMF or MeCN as a common solvent); (4) water-soluble by-products can be easily extracted into water.

[0055] In the present invention, the temperature of the reaction in step 4) is preferably -2 to 2°C, more preferably -1 to 1°C, and more preferably 0°C; the reaction time is preferably 9 to 11h, more preferably 9.5 to 10.5h, and more preferably 10h; the temperature of the reaction system during the dropwise addition of hydrochloric acid is preferably -2 to 2°C, more preferably -1 to 1°C, and more preferably 0°C; the time for dropwise addition of hydrochloric acid is preferably 28 to 32min, more preferably 29 to 31min, and more preferably 30min; the temperature for continued reaction is preferably 18 to 22°C, more preferably 19 to 21°C, and more preferably 20°C; the time for continued reaction is preferably 5 to 7h, more preferably 5.5 to 6.5h, and more preferably 6h.

[0056] In the present invention, after the step 4) continues to react, the aqueous phase is removed, the organic phase is washed, dried, filtered, concentrated, and recrystallized to obtain the menthamide cooling agent WS-5; the reagent for washing the organic phase is preferably water, the drying reagent is preferably anhydrous sodium sulfate, the solvent used for recrystallization is preferably a mixed solvent of acetone and water, and the volume ratio of acetone to water is preferably 1:1.5-2.5, more preferably 1:1.8-2.2, and more preferably 1:2.

[0057] The invention also provides menthamide cooling agent WS-5 prepared by the preparation method.

[0058] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0059] Example 1

[0060] At room temperature, 1.0 mol of menthol and 1.5 mol of pyridine were dissolved in 700 g of acetone, and then trichloroisocyanuric acid solution (0.45 mol of trichloroisocyanuric acid was dissolved in 900 g of acetone) was added dropwise to the above solution using a constant pressure dropping funnel, and the dropping time was 30 min. After the dropping was completed, the reaction was continued for 1.0 h. The reaction solution was filtered with a sand funnel and a water pump (vacuum degree was 0.2 atm) to remove the insoluble solids, and the filtrate was concentrated under reduced pressure with a rotary evaporator (vacuum degree was 0.2 atm) to remove the acetone solvent. The residue was extracted with 700 g of methyl tert-butyl ether, and washed with 1 mol / L hydrochloric acid twice (200 mL each time), 4 mol / L NaOH solution (200 mL) once, and saturated sodium chloride solution (250 mL) once, dried over anhydrous MgSO4, filtered, and concentrated to obtain colorless liquid menthone (141.9 g, 0.92 mol, yield 92%). Menthone NMR data: 1 HNMR (CDCl3, 400MHz) δ2.26-2.37 (m, 1H), 1.81-2.16 (m, 6H), 1.28-1.47 (m, 2H), 1.00 (d, J = 6.3Hz, 3H), 0.90 (d, J = 6.8Hz, 3H), 0.84 (d, J = 6.8Hz, 3H). [Me] + (EI): m / z = 154.2.

[0061] At room temperature, 1.07 mol of solid potassium tert-butoxide was added to a vigorously stirred (stirring rate of 800 rpm) menthone tetrahydrofuran solution (0.713 mol of menthone dissolved in 770 g of tetrahydrofuran), and after stirring for 20 min, 0.86 mol of solid p-toluenesulfonylmethyl isocyanide was added to the above solution. After reacting at room temperature for 8 h, a saturated NH4Cl aqueous solution was added to the reaction mixture, and the aqueous phase was extracted 3 times with methyl tert-butyl ether (500 mL of methyl tert-butyl ether each time). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reduced pressure distillation (heating temperature of 150°C, pressure of 5.5 kPa) to obtain colorless nitrile menthol (100.2 g, 0.61 mol, yield 85%). NMR data of nitrile menthol: 1 H NMR (600MHz, CDCl3): δ2.35 (dt, J = 3.6, 12.0Hz, 1H), 2.12-2.18 (m, 1H), 2.07-2.12 (m, 1H), 1.73-1.79 (m, 1H), 1.67-1 .71(m,1H),1.30-1.45(m,3H),0.86-1.03(m,2H),0.96(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H),0.82(d,J=6.6Hz,3H).

[0062] At room temperature, 0.50 mol of nitrile menthol was dissolved in 220 g of hydrochloric acid with a mass fraction of 18%, and heated to reflux at 120°C for 10 h. The reaction mixture was cooled to room temperature, and the solid precipitated in the solution was removed by vacuum filtration (vacuum degree of 0.2 atm), and the filtrate was extracted with methyl tert-butyl ether for 3 times (200 mL of methyl tert-butyl ether was used each time), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain white solid menthyl formic acid (88.5 g, 0.48 mol, yield 96%). NMR data of menthyl formic acid: 1 H NMR (400MHz, CDCl3) δ2.34-2.27(m,1H),1.92(dq,J=12.7,1.4Hz,1H),1.72(dddd,J=24.8,12.6,5.5,2.9Hz,3H),1.51(tt,J=12.8,3.7Hz,1H) ,1.37(tdd,J=11.2,6.4,3.3Hz,1H),1.27-1.17(m,1H),1.11-0.95(m,2H),0.92(d,J=6.8Hz,3H),0.91(d,J=6.4Hz,3H),0.81(d,J=6.8Hz,3H).

[0063] 0.4 mol of menthyl formic acid, 0.44 mol of glycine ethyl ester, 1.4 mol of pyridine and 400 g of ethyl acetate were mixed to obtain a mixed solution. At 0°C, T3P solution (0.6 mol of T3P dissolved in 190.9 g of ethyl acetate) was added to the mixed solution and kept at 0°C for 10 h. At 0°C, 150 mL of 0.1 mol / L hydrochloric acid was added dropwise to the reaction solution within 30 min. The mixture was stirred at 20°C (at a rate of 500 rpm) for 6 h. The aqueous phase was separated and the organic phase was washed with water 3 times (150 mL each time), dried with anhydrous Na2SO4, filtered and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (the volume ratio of acetone to water in the mixed solvent was 1:2) to obtain a white solid WS-5 (93.7 g, 0.35 mol, yield 87%, gas chromatography purity 98.2%). WS-5 NMR data: 1H NMR (CDCl3, 400MHz) δ5.97 (t, J = 5.2 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.04 (d, J = 5.2 Hz, 2H), 2.10 (td, J = 11.6Hz,3.4Hz),1.81(dq,J=12.7Hz,2.3Hz,1H),1.65-1.77(m,3H),1.54(tt,J=11.5Hz,2.9Hz,1H),1 .31-1.42(m,1H),1.29(t,J=7.2Hz,3H),1.23(q,J=12.3Hz,1H),1.02(qd,J=12.7Hz,2.9Hz,1H),0.96 (qd,J=11.6Hz,3.2Hz,1H),0.90(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H),0.79(d,J=6.9Hz,3H);[M+H] + (HR-ESI): m / z = 270.2066.

[0064] The NMR hydrogen spectrum of the menthone in Example 1 is as follows Figure 1 As shown, the mass spectrum of the menthone in Example 1 is as shown Figure 2 As shown, the nuclear magnetic hydrogen spectrum of the nitrile menthol of Example 1 is as follows Figure 3 As shown, the NMR hydrogen spectrum of the menthyl formic acid in Example 1 is as follows Figure 4 As shown, the nuclear magnetic hydrogen spectrum of WS-5 of Example 1 is as follows Figure 5 As shown, the mass spectrum of WS-5 of Example 1 is as shown Figure 6 shown.

[0065] Example 2

[0066] At room temperature, 10.0 mol of menthol and 15.0 mol of pyridine were dissolved in 7 kg of acetone, and then a dichlorohydantoin solution (4.5 mol of dichlorohydantoin dissolved in 7.0 kg of acetone) was added dropwise to the above solution using a constant pressure dropping funnel, and the dropping time was 30 min. After the dropping was completed, the reaction was continued for 1.0 h. The reaction solution was filtered with a sand funnel and a water pump (vacuum degree was 0.2 atm) to remove the insoluble solids, and the filtrate was concentrated under reduced pressure with a rotary evaporator (vacuum degree was 0.2 atm) to remove the acetone solvent. The residue was extracted with 7.0 kg of methyl tert-butyl ether, and washed with 1 mol / L hydrochloric acid twice (2.0 L each time), 4 mol / L NaOH solution (2.0 L) once, and saturated sodium chloride solution (2.5 L) once, dried with anhydrous MgSO4, filtered, and concentrated to obtain colorless liquid menthone (1.34 kg, 8.7 mol, yield 87%).

[0067] At room temperature, 10.7 mol of solid potassium tert-butoxide was added to a vigorously stirred (stirring rate of 800 rpm) menthone tetrahydrofuran solution (7.13 mol of menthone dissolved in 7.7 kg of tetrahydrofuran), and after stirring for 20 min, 8.6 mol of solid p-toluenesulfonylmethyl isocyanide was added to the above solution. After reacting at room temperature for 8 h, a saturated NH4Cl aqueous solution was added to the reaction mixture, and the aqueous phase was extracted 3 times with methyl tert-butyl ether (5.0 L of methyl tert-butyl ether each time). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reduced pressure distillation (heating temperature of 150°C, pressure of 5.5 kPa) to obtain colorless nitrile menthol (1.013 kg, 6.13 mol, yield 86%).

[0068] At room temperature, 5.0 mol of nitrile menthol was dissolved in 2.2 kg of hydrochloric acid with a mass fraction of 18%, and heated under reflux at 120°C for 10 h. The reaction mixture was cooled to room temperature, and the solid precipitated in the solution was removed by vacuum filtration (vacuum degree of 0.2 atm), and the filtrate was extracted with methyl tert-butyl ether for 3 times (2.0 L of methyl tert-butyl ether was used each time), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain white solid menthyl formic acid (879.0 g, 4.77 mol, yield 95%).

[0069] 4.0 mol of menthyl formic acid, 4.4 mol of glycine ethyl ester, 14.0 mol of pyridine and 4.0 kg of ethyl acetate were mixed to obtain a mixed solution. T3P solution (6.0 mol of T3P dissolved in 1.91 kg of ethyl acetate) was added to the mixed solution at 0°C and kept at 0°C for 10 hours. 1.5 L of 0.1 mol / L hydrochloric acid was added dropwise to the reaction solution at 0°C within 30 minutes. The mixture was stirred at 20°C (at a rate of 500 rpm) for 6 hours. The aqueous phase was separated and the organic phase was washed with water 3 times (1.5 L each time), dried with anhydrous Na2SO4, filtered and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (the volume ratio of acetone to water in the mixed solvent was 1:2) to obtain a white solid WS-5 (959.0 g, 3.56 mol, yield 89%, gas chromatography purity 98.4%).

[0070] Example 3

[0071] At room temperature, 1.0 mol of menthol and 1.4 mol of pyridine were dissolved in 680 g of acetone, and then trichloroisocyanuric acid solution (0.4 mol of trichloroisocyanuric acid was dissolved in 860 g of acetone) was added dropwise to the above solution using a constant pressure dropping funnel, and the dropping time was 29 min. After the dropping was completed, the reaction was continued for 1.0 h. The reaction solution was filtered with a sand funnel and a water pump (vacuum degree was 0.2 atm) to remove the insoluble solids, and the filtrate was concentrated under reduced pressure with a rotary evaporator (vacuum degree was 0.2 atm) to remove the acetone solvent. The obtained residue was extracted with 670 g of methyl tert-butyl ether, and washed with 1 mol / L hydrochloric acid twice (200 mL each time), 4 mol / L NaOH solution (200 mL) once, and saturated sodium chloride solution (250 mL) once, dried over anhydrous MgSO4, filtered, and concentrated to obtain colorless liquid menthone (128.0 g, 0.83 mol, yield 83%).

[0072] At room temperature, 1.03 mol of solid potassium tert-butoxide was added to a vigorously stirred (stirring rate of 800 rpm) menthone tetrahydrofuran solution (0.713 mol of menthone dissolved in 770 g of tetrahydrofuran), and after stirring for 20 min, 0.78 mol of solid p-toluenesulfonylmethyl isocyanide was added to the above solution. After reacting at room temperature for 7 h, a saturated NH4Cl aqueous solution was added to the reaction mixture, and the aqueous phase was extracted 3 times with methyl tert-butyl ether (500 mL of methyl tert-butyl ether each time). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reduced pressure distillation (heating temperature of 150°C, pressure of 5.5 kPa) to obtain colorless nitrile menthol (99.0 g, 0.60 mol, yield 84%).

[0073] At room temperature, 0.50 mol of nitrile menthol was dissolved in 200 g of hydrochloric acid with a mass fraction of 20%, and heated to reflux at 120°C for 8 h. The reaction mixture was cooled to room temperature, and the solid precipitated in the solution was removed by vacuum filtration (vacuum degree of 0.2 atm), and the filtrate was extracted with methyl tert-butyl ether for 3 times (200 mL of methyl tert-butyl ether was used each time), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain white solid menthyl formic acid (86.6 g, 0.47 mol, yield 94%).

[0074] 0.4 mol of menthyl formic acid, 0.42 mol of glycine ethyl ester, 1.36 mol of pyridine and 400 g of ethyl acetate were mixed to obtain a mixed solution. T3P solution (0.56 mol of T3P dissolved in 178.2 g of ethyl acetate) was added to the mixed solution at 1°C and kept at 1°C for 10.5 h. 148 mL of 0.095 mol / L hydrochloric acid was added dropwise to the reaction solution at 1°C and the addition was completed within 29 min. The mixture was stirred at 19°C (at a rate of 500 rpm) for 5.5 h. The aqueous phase was separated and the organic phase was washed with water 3 times (150 mL each time), dried with anhydrous Na2SO4, filtered and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (the volume ratio of acetone to water in the mixed solvent was 1:2) to obtain a white solid WS-5 (93.7 g, 0.35 mol, yield 87%, gas chromatography purity 98.2%).

[0075] Example 4

[0076] At room temperature, 1.0 mol of menthol and 1.7 mol of pyridine were dissolved in 720 g of acetone, and then a dichlorohydantoin solution (0.5 mol of dichlorohydantoin was dissolved in 950 g of acetone) was added dropwise to the above solution using a constant pressure dropping funnel, and the dropping time was 31 min. After the dropping was completed, the reaction was continued for 1.2 h. The reaction solution was filtered with a sand funnel and a water pump (vacuum degree was 0.2 atm) to remove the insoluble solids, and the filtrate was concentrated under reduced pressure with a rotary evaporator (vacuum degree was 0.2 atm) to remove the acetone solvent. The residue was extracted with 740 g of methyl tert-butyl ether, and washed with 1 mol / L hydrochloric acid twice (200 mL each time), 4 mol / L NaOH solution (200 mL) once, and saturated sodium chloride solution (250 mL) once, dried over anhydrous MgSO4, filtered, and concentrated to obtain colorless liquid menthone (135.7 g, 0.88 mol, yield 88%).

[0077] At room temperature, 1.01 mol of solid potassium tert-butoxide was added to a vigorously stirred (stirring rate of 800 rpm) menthone tetrahydrofuran solution (0.713 mol of menthone dissolved in 770 g of tetrahydrofuran), and after stirring for 22 min, 0.93 mol of solid p-toluenesulfonylmethyl isocyanide was added to the above solution. After reacting at room temperature for 9 h, a saturated NH4Cl aqueous solution was added to the reaction mixture, and the aqueous phase was extracted 3 times with methyl tert-butyl ether (500 mL of methyl tert-butyl ether each time). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reduced pressure distillation (heating temperature of 150°C, pressure of 5.5 kPa) to obtain colorless nitrile menthol (96.6 g, 0.58 mol, yield 82%).

[0078] At room temperature, 0.50 mol of nitrile menthol was dissolved in 230 g of hydrochloric acid with a mass fraction of 15%, and heated under reflux at 120°C for 9 h. The reaction mixture was cooled to room temperature, and the solid precipitated in the solution was removed by vacuum filtration (vacuum degree of 0.2 atm), and the filtrate was extracted with methyl tert-butyl ether for 3 times (200 mL of methyl tert-butyl ether was used each time), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain white solid menthyl formic acid (84.8 g, 0.46 mol, yield 92%).

[0079] 0.4 mol of menthic acid, 0.46 mol of glycine ethyl ester, 1.44 mol of pyridine and 400 g of ethyl acetate were mixed to obtain a mixed solution. T3P solution (0.64 mol of T3P dissolved in 203.6 g of ethyl acetate) was added to the mixed solution at -1°C and kept at -1°C for 9.5 h. 152 mL of 0.105 mol / L hydrochloric acid was added dropwise to the reaction solution at -1°C within 31 min. The mixture was stirred at 21°C (at a rate of 500 rpm) for 6.5 h. The aqueous phase was separated and the organic phase was washed with water 3 times (150 mL each time), dried with anhydrous Na2SO4, filtered and concentrated. The crude product was recrystallized with a mixed solvent of acetone and water (in the mixed solvent, the volume ratio of acetone to water was 1:2) to obtain a white solid WS-5 (98.1 g, 0.36 mol, yield 91%, gas chromatography purity 98.5%).

[0080] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing menthamide cooling agent WS-5, characterized in that: The following steps are included: 1) mixing menthol, pyridine and acetone to obtain a mixed solution; adding a chloramine reagent solution dropwise to the mixed solution, and continuing the reaction after the addition is completed to obtain menthone; 2) mixing a tetrahydrofuran solution of menthone and potassium tert-butoxide, and adding p-methylbenzenesulfonylmethyl isocyanide to the mixture for reaction to obtain nitrile menthol; 3) dissolving nitrile menthol in hydrochloric acid and reacting to obtain menthic acid; 4) mixing menthyl formic acid, glycine ethyl ester, pyridine and ethyl acetate to obtain a mixed solution, adding a condensation reagent solution to the mixed solution for reaction, and adding hydrochloric acid dropwise to the reaction system to continue the reaction to obtain menthyl amide cooling agent WS-5.

2. The preparation method according to claim 1, characterized in that: Step 1) The molar ratio of menthol to pyridine is 1:1.2-2.0; the molar mass ratio of menthol to acetone is 1 mol:650-750 g; the chloramine reagent is trichloroisocyanuric acid or dichlorohydantoin; and the molar ratio of chloramine reagent to menthol is 0.4-0.6:

1.

3. The preparation method according to claim 1 or 2, characterized in that: In the chloramine reagent solution, the solvent is acetone; the dropwise addition time is 28 to 32 minutes, and the reaction time is 0.5 to 2 hours.

4. The preparation method according to claim 3, characterized in that: Step 2) the molar ratio of potassium tert-butoxide to menthone is 1.4-1.6:1, and the molar ratio of p-toluenesulfonylmethyl isocyanide to menthone is 1-1.4:1; The mixing time is 18 to 25 minutes, and the reaction time is 6 to 10 hours.

5. The preparation method according to claim 1 or 4, characterized in that: Step 3) The mass fraction of the hydrochloric acid is 15-36%, the molar mass ratio of nitrile menthol to hydrochloric acid is 1 mol: 0.4-0.5 kg; and the reaction time is 6-10 hours.

6. The preparation method according to claim 5, characterized in that: Step 4) The molar ratio of menthic acid, glycine ethyl ester and pyridine is 1:1-1.2:3.3-3.7, the molar ratio of menthic acid and condensation reagent is 1:1.3-1.7; the molar mass ratio of menthic acid and ethyl acetate is 1 mol:0.9-1.1 kg; The concentration of hydrochloric acid is 0.09-0.11 mol / L, and the volume mass ratio of hydrochloric acid to ethyl acetate is 0.35-0.4 L: 0.9-1.1 kg.

7. The preparation method according to claim 6, characterized in that: In step 4), the solvent of the condensation reagent solution is ethyl acetate, and the condensation reagent is 1-n-propyl phosphoric anhydride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, Carter's condensation agent or benzotriazole-1-yl-oxytripyrrolidone hexafluorophosphate.

8. The preparation method according to claim 1 or 7, characterized in that: Step 4) The reaction temperature is -2 to 2°C, and the reaction time is 9 to 11 hours; during the addition of hydrochloric acid, the temperature of the reaction system is -2 to 2°C, the hydrochloric acid addition time is 28 to 32 minutes, the continued reaction temperature is 18 to 22°C, and the continued reaction time is 5 to 7 hours.

9. Menthamide cooling agent WS-5 prepared by the preparation method according to any one of claims 1 to 8.

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