A process for the preparation of 2-cyclohexyl-5-methylphenol

Abstract

The application provides a preparation method of 2-cyclohexyl-5-methylphenol and relates to the technical field of medicine synthesis. The preparation method of 2-cyclohexyl-5-methylphenol comprises the following steps: taking 4-methyl salicylic acid as raw material, and sequentially performing methylation, decarboxylation halogenation, coupling with halogenated cyclohexane and hydrolysis reaction to obtain 2-cyclohexyl-5-methylphenol. The 2-cyclohexyl-5-methylphenol synthesized by the method has high purity and high yield, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine synthesis, in particular to a preparation method of 2-cyclohexyl-5-methylphenol. BACKGROUND

[0002] 2-cyclohexyl-5-methylphenol is an important chemical raw material and a key intermediate of various medicines. At present, the synthesis routes of 2-cyclohexyl-5-methylphenol include:

[0003] Route 1: Patents DE598298 and US2054270 report that m-cresol is used as a raw material to couple with cyclohexene, and then the compound A, i.e. 2-cyclohexyl-5-methylphenol, is obtained through multiple purifications. The obvious disadvantage of this kind of invention is that it is difficult to purify the mixed product after coupling, and the yield is not reported in the literature.

[0004]

[0005] Route 2: Patent DE61544 reports that m-cresol is used as a raw material to couple with cyclohexanol. This route also has the technical problem that the product is mixed and difficult to purify, and the yield is not reported, which is not suitable for industrialization.

[0006]

[0007] Therefore, the existing method for preparing 2-cyclohexyl-5-methylphenol has the technical problems of low product purity and difficulty in purification, which hinders its industrial production. Therefore, it is urgent for those skilled in the art to develop a preparation method of 2-cyclohexyl-5-methylphenol with high purity to adapt to industrial production. SUMMARY

[0008] (I) Technical problems to be solved

[0009] In view of the deficiencies of the prior art, the present application provides a preparation method of 2-cyclohexyl-5-methylphenol, which solves the technical problems of low product purity and difficulty in purification of the existing method for preparing 2-cyclohexyl-5-methylphenol.

[0010] (II) Technical solutions

[0011] To achieve the above object, the present application is implemented by the following technical solutions:

[0012] In a first aspect, the present application provides a preparation method of 2-cyclohexyl-5-methylphenol, which uses 4-methylsalicylic acid as a raw material and sequentially undergoes methylation, decarboxylation halogenation, coupling with halogenated cyclohexane and hydrolysis reaction to obtain 2-cyclohexyl-5-methylphenol, i.e. compound A;

[0013] The synthesis route of the 2-cyclohexyl-5-methylphenol is as follows:

[0014]

[0015] X is one of Br, CI, 1 0

[0016] Preferably, the preparation method comprises the following steps:

[0017] S1, using 4-methyl salicylic acid as raw material, reacting with methylating agent under the action of acid binding agent to obtain compound 1;

[0018] S2, the compound 1 is added to a solvent and halogenated reagent, and decarboxylation halogenation is carried out under the action of a catalyst to obtain compound 2;

[0019] S3, the compound 2 is coupled with halogenated cyclohexane under the action of a catalyst under alkaline conditions to obtain compound 3;

[0020] S4, the compound 3 is subjected to hydrolysis reduction reaction under acidic conditions to obtain 2-cyclohexyl-5-methyl phenol.

[0021] Preferably, S1 specifically comprises the following steps: mixing 4-methyl salicylic acid, solvent, acid binding agent, stirring uniformly, adding methylating agent dropwise, controlling temperature reaction, extraction, concentration, cooling and crystallization, filtration, and drying to obtain compound 1, and the mass ratio of 4-methyl salicylic acid to acid binding agent is 1:1-4, preferably 1:1-2.

[0022] Preferably, the preparation method satisfies at least one of the following conditions:

[0023] The solvent is selected from one of water, ethyl acetate, dichloromethane, and preferably water;

[0024] The acid binding agent is selected from one of triethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate, and preferably triethylamine;

[0025] The mass ratio of 4-methyl salicylic acid to methylating agent is 1:2-8, and preferably 1:2-4;

[0026] The methylating agent is selected from one of dimethyl sulfate, dimethyl carbonate, and trimethyl phosphate, and preferably dimethyl sulfate;

[0027] The temperature of the temperature-controlled reaction is 0-80℃, and preferably 35-50℃.

[0028] Preferably, S2 specifically comprises the following steps: nitrogen protection, mixing compound 1, halogenated reagent, catalyst, and solvent, stirring uniformly, warming reaction, sodium thiosulfate quenching, dichloromethane extraction, water washing, and concentrating organic layer to obtain compound 2.

[0029] Preferably, the preparation method satisfies at least one of the following conditions:

[0030] The solvent is selected from one of acetonitrile, tetrahydrofuran, ethyl acetate, preferably acetonitrile;

[0031] The halogenated reagent is selected from one of tetrabutylammonium tribromide, tetrabutylammonium trichloride, tetrabutylammonium triiodide, preferably tetrabutylammonium tribromide;

[0032] The mass ratio of the compound 1 to the halogenated reagent is 1:1-4, preferably 1:1-2.5;

[0033] The catalyst is selected from one of potassium phosphate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, preferably potassium phosphate;

[0034] The mass ratio of the compound 1 to the catalyst is 1:1-3, preferably 1:1-2;

[0035] The temperature of the temperature-increasing reaction is 80-150℃, preferably 80-125℃.

[0036] Preferably, the S3 specifically comprises the following steps: under nitrogen protection, compound 2, solvent, base, catalyst are added, the temperature is lowered, halocyclohexane is added, after the reaction is completed, ammonium chloride aqueous solution is added for quenching, ethyl acetate is extracted, the organic layer is concentrated, and compound 3 is obtained.

[0037] Preferably, the preparation method satisfies at least one of the following conditions:

[0038] The solvent is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, preferably tetrahydrofuran;

[0039] The base is selected from one of N,N,N',N'-tetramethyl ethylenediamine, triethylamine, N,N-dimethylaniline, preferably N,N,N',N'-tetramethyl ethylenediamine;

[0040] The mass ratio of the compound 2 to the base is 1:1-3, preferably 1:1.5;

[0041] The catalyst is selected from one of magnesium-iron chloride mixture, zinc-zinc chloride mixture, magnesium-zinc chloride mixture, preferably magnesium-iron chloride mixture, wherein the mass ratio of each component in the mixture is 1:1;

[0042] The mass ratio of the compound 2 to the catalyst is 1:1-4, preferably 1:1-2;

[0043] The lowering of the temperature refers to lowering the temperature to-5-20℃, preferably 0-10℃;

[0044] The halogenated cyclohexane is selected from one of bromocyclohexane, chlorocyclohexane, iodocyclohexane, and preferably is bromocyclohexane;

[0045] The mass ratio of the compound 2 to the halogenated cyclohexane is 1:1-4, and preferably is 1:1.2-2.

[0046] Preferably, the S4 specifically comprises the following steps: taking the compound 3, a solvent, an acidifying agent, reacting at T1, after the reaction, quenching with an aqueous base, washing with acid, washing with water, concentrating the solvent, crystallizing at T2, filtering, and drying to obtain the 2-cyclohexyl-5-methylphenol.

[0047] In the S4, the solvent is selected from one of water, dichloromethane, and acetonitrile, and preferably is dichloromethane.

[0048] In the S4, the acidifying agent is selected from one of boron trichloride, boron tribromide, and 35% hydrobromic acid, and preferably is boron tribromide.

[0049] In the S4, the mass ratio of the compound 3 to the acidifying agent is 1:2-5, and preferably is 1:2-4.

[0050] The quenching with the aqueous base comprises quenching with a 1M aqueous sodium hydroxide solution, and the washing with acid comprises washing with a 1M aqueous hydrochloric acid solution.

[0051] In the S4, T1 is -15-15℃, and preferably is -10-5℃.

[0052] In the S4, T2 is -5-20℃, and preferably is -5-5℃.

[0053] In a second aspect, the present application provides a 2-cyclohexyl-5-methylphenol prepared by the preparation method of the 2-cyclohexyl-5-methylphenol according to the first aspect, and a structural formula of the 2-cyclohexyl-5-methylphenol is as follows:

[0054]

[0055] (III) Beneficial Effects

[0056] The present application provides a preparation method of 2-cyclohexyl-5-methylphenol. Compared with the prior art, the present application has the following beneficial effects:

[0057] The present application takes 4-methyl salicylic acid as a raw material, and obtains 2-cyclohexyl-5-methylphenol, i.e., compound A, through methylation, decarboxylation halogenation, coupling with halogenated cyclohexane, and reduction. Compared with the prior art, the 2-cyclohexyl-5-methylphenol synthesized by the present application has high purity and high yield, and is suitable for industrial production. The present application has broad prospects and industrial application value. DETAILED DESCRIPTION

[0058] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application are described clearly and completely. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0059] The technical solutions in the embodiments of the present application solve the technical problem of low product purity and difficulty in purification in the prior art method for preparing 2-cyclohexyl-5-methylphenol.

[0060] The technical solutions in the embodiments of the present application solve the technical problem of low product purity and difficulty in purification in the prior art method for preparing 2-cyclohexyl-5-methylphenol.

[0061] At present, the synthesis route of 2-cyclohexyl-5-methylphenol also includes: Journal of the American Chemical Society, 1943, vol. 65, p. 1240, reports that m-cresol is used as a raw material to couple with cyclohexanone, and then the target product is obtained by reduction. In the invention, the coupling yield of m-cresol with cyclohexanone is only 14%, and the reduction requires noble metal palladium or platinum, which is not conducive to industrialization.

[0062]

[0063] It is found that the existing invention route for preparing compound A not only has the technical problems of low product purity and difficulty in purification, but also has the technical problem of using noble metal to increase cost. The use of noble metal is high in cost and also causes the above-mentioned method to be difficult to industrialize. Therefore, it is urgent to develop a preparation method of compound A with high purity and good yield, which does not include noble metal reagent, so as to adapt to industrial production.

[0064] In order to better understand the above technical solutions, the above technical solutions will be described in detail in combination with specific embodiments.

[0065] Example 1

[0066] The embodiment provides a preparation method of 2-cyclohexyl-5-methylphenol, which specifically comprises the following steps:

[0067]

[0068] S1, synthesis of compound 1

[0069] Into a 500 mL flask, add compound 1 (90.1 g, 0.5 mol), tetrabutylammonium bromide (241, 0.5 mol), potassium phosphate (106.2 g, 0.5 mol) and 500 mL acetonitrile, and stir to dissolve. Heat to 100°C and react for 4 h. Cool to room temperature, add 200 mL of a sodium thiosulfate solution to quench, extract with 500 mL of dichloromethane, wash the organic layer with 200 mL of water, and concentrate to dryness to obtain compound 2 as an oil, 95.5 g, in a yield of 95% and with a purity of 99.2%.

[0070] S2, synthesis of compound 2

[0071] Into a 500 mL flask, add compound 1 (90.1 g, 0.5 mol), tetrabutylammonium bromide (241, 0.5 mol), potassium phosphate (106.2 g, 0.5 mol) and 500 mL acetonitrile, and stir to dissolve. Heat to 100°C and react for 4 h. Cool to room temperature, add 200 mL of a sodium thiosulfate solution to quench, extract with 500 mL of dichloromethane, wash the organic layer with 200 mL of water, and concentrate to dryness to obtain compound 2 as an oil, 95.5 g, in a yield of 95% and with a purity of 99.2%.

[0072] S3, synthesis of compound 3

[0073] Into a 500 mL flask, add compound 1 (90.1 g, 0.5 mol), tetrabutylammonium bromide (241, 0.5 mol), potassium phosphate (106.2 g, 0.5 mol) and 500 mL acetonitrile, and stir to dissolve. Heat to 100°C and react for 4 h. Cool to room temperature, add 200 mL of a sodium thiosulfate solution to quench, extract with 500 mL of dichloromethane, wash the organic layer with 200 mL of water, and concentrate to dryness to obtain compound 2 as an oil, 95.5 g, in a yield of 95% and with a purity of 99.2%.

[0074] S4, synthesis of compound A

[0075] Into a 500 mL flask, add compound 1 (90.1 g, 0.5 mol), tetrabutylammonium bromide (241, 0.5 mol), potassium phosphate (106.2 g, 0.5 mol) and 500 mL acetonitrile, and stir to dissolve. Heat to 100°C and react for 4 h. Cool to room temperature, add 200 mL of a sodium thiosulfate solution to quench, extract with 500 mL of dichloromethane, wash the organic layer with 200 mL of water, and concentrate to dryness to obtain compound 2 as an oil, 95.5 g, in a yield of 95% and with a purity of 99.2%.

[0076] Example 2

[0077] The embodiment provides a preparation method of 2-cyclohexyl-5-methylphenol, and specifically comprises the following steps.

[0078]

[0079] S1, synthesis of compound 1

[0080] 4-methyl salicylic acid (76.1 g, 0.5 mol), potassium carbonate (138.2 g, 1.0 mol) are added into 500 mL of ethyl acetate, stirred, slowly drop dimethyl sulfate (252.3 g, 2.0 mol), after drop, the temperature is controlled to be 50 DEG C, reaction is carried out for 7 h, 300 mL of water is added, stirring is carried out for 30 min, the organic layer is separated, part of solvent is concentrated, the temperature is lowered to-5 DEG C, crystallization is carried out, filtration is carried out, and oven drying is carried out, to obtain compound 1, 85.6 g, the yield is 95%, and the purity is 99.2%.

[0081] S2, synthesis of compound 2

[0082] Under nitrogen protection, compound 1 (90.1 g, 0.5 mol), tetrabutylammonium iodide (311.6, 0.5 mol), sodium phosphate (164 g, 1.0 mol) and 800 mL of tetrahydrofuran are sequentially added into a reaction bottle, the temperature is raised to 125 DEG C, reaction is carried out for 2 h, the temperature is lowered to room temperature, 400 mL of sodium thiosulfate solution is added for quenching, 500 mL of dichloromethane is extracted, the organic layer is washed with 300 mL*2 water, and concentration is carried out to dryness, to obtain oily compound 2, 116.6 g, the yield is 94%, and the purity is 99.0%.

[0083] S3, synthesis of compound 3

[0084] Under nitrogen protection, compound 2 (124 g, 0.5 mol), magnesium powder (24 g, 1.0 mol), zinc chloride (136 g, 1.0 mol), 600 mL of 2-methyl tetrahydrofuran and DMA (15.9 g, 0.75 mol) are sequentially added into a reaction bottle, stirring is carried out, the temperature is lowered to 0 DEG C, iodocyclohexane (126 g, 0.6 mol) is added, the temperature is controlled to be 10 DEG C, reaction is carried out for 2.5 h, 200 mL of ammonium chloride aqueous solution is added for quenching, 200 mL*2 of ethyl acetate is extracted, the organic layers are combined, and concentration is carried out to dryness, to obtain oily compound 3, 86.8 g, the yield is 85%, and the purity is 99.4%.

[0085] S4, synthesis of compound A

[0086] Into a reaction flask, compound 3 (102.2 g, 0.5 mol), 400 mL acetonitrile, boron trichloride (176 g, 1.5 mol) were added successively, stirred to dissolve, temperature was controlled at 5 °C, stirred for 5 h, after reaction, 1 M sodium hydroxide solution was added dropwise for quenching, 1 M hydrochloric acid solution was used to adjust pH to 4, 600 mL dichloromethane was added, the organic layer was separated, the organic layer was washed with water, part of the solvent was concentrated, the temperature was lowered to 0 °C, crystallization was performed, filtration was performed, and drying was performed to obtain solid compound A, i.e. 2-cyclohexyl-5-methylphenol, 89.4 g, yield 94%, purity 99.2%.

[0087] Example 3

[0088] The embodiment provides a preparation method of 2-cyclohexyl-5-methylphenol, which specifically comprises the following steps.

[0089]

[0090] S1, synthesis of compound 1

[0091] 4-methylsalicylic acid (76.1 g, 0.5 mol) and sodium carbonate (106 g, 1.0 mol) were added into 400 mL dichloromethane, stirred, and trimethyl phosphate (210 g, 1.5 mol) was slowly added dropwise, after dropwise addition, the temperature was controlled at 40 °C, reaction was performed for 5 h, 500 mL water was added, stirring was performed for 30 min, the organic layer was separated, part of the solvent was concentrated, the temperature was lowered to 0 °C, crystallization was performed, filtration was performed, and drying was performed to obtain compound 1, 86.5 g, yield 96%, purity 99.0%.

[0092] S2, synthesis of compound 2

[0093] Under nitrogen protection, compound 1 (90.1 g, 0.5 mol), tetrabutylammonium chloride (435, 1.25 mol), potassium hydrogen phosphate (136.2 g, 1.0 mol) and 1000 mL ethyl acetate were added successively into a reaction flask, the temperature was raised to 80 °C, reaction was performed for 6 h, the temperature was lowered to room temperature, 400 mL sodium thiosulfate solution was added for quenching, the organic layer was separated, the organic layer was washed with 400 mL*2 water, and concentration was performed to dryness to obtain oily compound 2, 72.1 g, yield 92%, purity 99.2%.

[0094] S3, synthesis of compound 3

[0095] Under nitrogen protection, compound 2 (78.3g, 0.5mol), zinc powder (39g, 0.6mol), zinc chloride (81.8g, 0.6mol), 300mL of ether, TEA (60.7g, 0.6mol) were sequentially added into a reaction bottle, and stirred to be cooled to 0°C, chlorocyclohexane (89g, 0.75mol) was added, the temperature was controlled at 0°C, the reaction was carried out for 6h, 300mL of ammonium chloride aqueous solution was added for quenching, 300mL of ethyl acetate was used for extraction, the organic layers were combined, and concentrated to dryness to obtain oily compound 3, 84.7g, the yield was 83%, and the purity was 98.7%.

[0096] S4, synthesis of compound A

[0097] Compound 3 (102.2g, 0.5mol), 500mL of water, 35% hydrobromic acid solution (462.3g, 2.0mol) were sequentially added into a reaction bottle, and stirred to be dissolved, the temperature was controlled at 0°C, and stirred for 4h, after the reaction was completed, 1M sodium hydroxide solution was added dropwise for quenching, 1M hydrochloric acid solution was used for adjusting pH to 4, 600mL of dichloromethane was added, the organic layer was separated, the organic layer was washed with water, part of the solvent was concentrated, and cooled to 5°C for crystallization, filtration and drying to obtain solid compound A, i.e., 2-cyclohexyl-5-methylphenol, 89.6g, the yield was 94.2%, and the purity was 98.5%.

[0098] Compared with the prior art, the method has the following beneficial effects:

[0099] The method has the advantages that raw materials are easy to obtain, the method is environmentally friendly, a noble metal is not used, 2-cyclohexyl-5-methylphenol prepared by the method has good purity, high yield and low cost, and the method is suitable for industrial production.

[0100] It should be noted that, in the present document, relational terms such as first and second and the like can be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by "comprises... a" does not, without more constraints, exclude the presence of additional identical elements in the process, method, article, or apparatus that comprises the element.

[0101] The above examples are only used to illustrate the technical solutions of the present application, but not limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can be modified, or some technical features can be replaced equivalently; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

[0102] The present application is described by the above examples to illustrate the detailed process flow of the present application, but the present application is not limited to the above detailed process flow, i.e. it does not mean that the present application must rely on the above detailed process flow to be implemented. Those skilled in the art should understand that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for preparing 2-cyclohexyl-5-methylphenol, characterized in that, Using 4-methylsalicylic acid as a raw material, methylation, decarboxylation and halogenation, coupling with halocyclohexane and hydrolysis were carried out sequentially to obtain 2-cyclohexyl-5-methylphenol, namely compound A; The synthetic route for 2-cyclohexyl-5-methylphenol is as follows: ； The preparation method includes the following steps: S1. Using 4-methylsalicylic acid as a raw material, under the action of an acid-binding agent, it reacts with a methylating agent to obtain compound 1; S2. Compound 1 and the halogenating agent are added to a solvent and decarboxylated and halogenated under the action of a catalyst to obtain compound 2; S3. Compound 2 is coupled with halocyclohexane under alkaline conditions and with the action of a catalyst to obtain compound 3. S4. Compound 3 undergoes a hydrolysis-reduction reaction under acidic conditions to yield 2-cyclohexyl-5-methylphenol; The S2 specifically includes the following steps: nitrogen protection, mixing compound 1, halogenating reagent, catalyst and solvent, stirring evenly, heating to react, quenching with sodium thiosulfate, extraction with dichloromethane, washing with water, concentrating the organic layer to obtain compound 2. In S2, the halogenating agent is selected from one of tetrabutylammonium tribromide, tetrabutylammonium trichloride, and tetrabutylammonium triiodide; In S2, the catalyst is selected from one of potassium phosphate, sodium phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate. In S3, the base is selected from one of N,N,N',N'-tetramethylethylenediamine, triethylamine, and N,N-dimethylaniline; In S3, the catalyst is selected from one of the following: a magnesium-ferric chloride mixture, a zinc-zinc chloride mixture, and a magnesium-zinc chloride mixture.

2. The preparation method according to claim 1, characterized in that, The S1 specifically includes the following steps: mixing 4-methylsalicylic acid, solvent, and acid-binding agent, stirring evenly, adding methylating reagent dropwise, reacting under controlled temperature, extracting, concentrating, cooling to crystallize, filtering, and drying to obtain compound 1, wherein the molar ratio of 4-methylsalicylic acid to acid-binding agent is 1:1-4.

3. The preparation method according to claim 2, characterized in that, The mass ratio of 4-methylsalicylic acid to the acid-binding agent is 1:1-2.

4. The preparation method according to claim 2, characterized in that, The preparation method satisfies at least one of the following conditions: In S1, the solvent is selected from water, ethyl acetate, and dichloromethane. In S1, the acid-binding agent is selected from one of triethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate; In S1, the molar ratio of 4-methylsalicylic acid to the methylating agent is 1:2-8; In S1, the methylating agent is selected from dimethyl sulfate and trimethyl phosphate; In S1, the temperature of the temperature-controlled reaction is 0-80℃.

5. The preparation method according to claim 4, characterized in that, The preparation method satisfies the following conditions: In step S1, the solvent is water; the acid-binding agent is triethylamine; the mass ratio of 4-methylsalicylic acid to the methylating agent is 1:2-4; the methylating agent is dimethyl sulfate; and the temperature of the temperature-controlled reaction is 35-50℃.

6. The preparation method according to claim 1, characterized in that, The preparation method satisfies at least one of the following conditions: In S2, the solvent is selected from one of acetonitrile, tetrahydrofuran, and ethyl acetate; In S2, the molar ratio of compound 1 to the halogenating reagent is 1:1-4; In S2, the mass ratio of compound 1 to catalyst is 1:1-3; In S2, the temperature of the heating reaction is 80-150℃.

7. The preparation method according to claim 6, characterized in that, The preparation method satisfies the following conditions: In S2, the solvent is acetonitrile; the halogenating agent is tetrabutylammonium tribromide; the mass ratio of compound 1 to the halogenating agent is 1:1-2.5; the catalyst is potassium phosphate; the mass ratio of compound 1 to the catalyst is 1:1-2; and the temperature for the heating reaction is 80-125℃.

8. The preparation method according to claim 1, characterized in that, The S3 process specifically includes the following steps: under nitrogen protection, compound 2, solvent, alkali, and catalyst are added, the temperature is lowered, halocyclohexane is added, after the reaction is complete, ammonium chloride aqueous solution is added to quench the reaction, ethyl acetate is used for extraction, the organic layer is concentrated, and compound 3 is obtained.

9. The preparation method according to claim 8, characterized in that, The preparation method satisfies at least one of the following conditions: In S3, the solvent is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; In S3, the molar ratio of compound 2 to the base is 1:1-3; In S3, the catalyst is selected from one of magnesium-ferric chloride mixture, zinc-zinc chloride mixture, and magnesium-zinc chloride mixture, wherein the mass ratio of each component in the mixture is 1:1; In S3, the mass ratio of compound 2 to catalyst is 1:1-4; In S3, cooling refers to lowering the temperature to -5 to 20°C; In S3, the halocyclohexane is selected from one of bromocyclohexane, chlorocyclohexane, and iodocyclohexane; In S3, the mass ratio of compound 2 to halocyclohexane is 1:1-4.

10. The preparation method according to claim 9, characterized in that, The preparation method satisfies the following conditions: In S3, the solvent is tetrahydrofuran; the mass ratio of compound 2 to the base is 1:1.5; the mass ratio of compound 2 to the catalyst is 1:1-2; cooling refers to lowering the temperature to 0-10℃; the halocyclohexane is bromocyclohexane; the mass ratio of compound 2 to halocyclohexane is 1:1.2-2.

11. The preparation method according to claim 1, characterized in that, S4 specifically includes the following steps: take compound 3, solvent, and acidifying reagent, react at temperature T1, after the reaction is complete, quench with alkaline water, wash with acid, wash with water, concentrate part of the solvent, crystallize at temperature T2, filter, dry, and obtain 2-cyclohexyl-5-methylphenol. In step S4, the solvent is selected from water, dichloromethane, and acetonitrile. In S4, the acidifying agent is selected from boron trichloride, boron tribromide, and 35% hydrobromic acid. In step S4, the mass ratio of compound 3 to the acidifying reagent is 1:2-5; The alkaline quenching includes quenching with a 1M sodium hydroxide aqueous solution, and the acid washing includes washing with a 1M hydrochloric acid aqueous solution. In S4, T1 is -15 to 15°C; In S4, T2 is -5 to 20°C.

12. The preparation method according to claim 11, characterized in that, The following conditions must be met: In S4, the solvent is dichloromethane; the acidifying agent is boron tribromide; the mass ratio of compound 3 to the acidifying agent is 1:2-4; T1 is -10 to 5℃; T2 is -5 to 5℃.

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