Synthesis method of substituted dicyclohexylethylene fluorobenzene compounds

Abstract

The present invention provides a method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds. The substituted dicyclohexylethylene fluorobenzene compounds have a structure shown in formula (I); the synthetic method includes: in a first solvent, 2,3-difluorophenyl ether compounds are subjected to chloromethylation reaction to obtain 2,3-difluorobenzyl chloride compounds; in a second solvent, in the presence of a nickel catalyst and a ligand, 2,3-difluorobenzyl chloride compounds are subjected to Grignard coupling reaction with a Grignard reagent to obtain substituted dicyclohexylethylene fluorobenzene compounds, and the ligand is selected from tetramethylethylenediamine and / or allyl ether. Compared with the existing method, the preferred nickel catalyst of the present invention and the ligand of a specific type can reduce the loading of the nickel catalyst, increase the reaction rate, suppress side reactions, and increase the conversion rate of raw materials, thereby significantly improving the yield and purity of the target product.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds. Background Art

[0002] At present, the common method for synthesizing alkyl dicyclohexylethylene fluorobenzene liquid crystal monomers includes using propyl dicyclohexyl ketone as raw material, preparing aldehyde through two-step ylide reaction and hydrolysis reaction, then reacting with halogenated benzene metal reagent to prepare alcohol, then dehydrating to olefin, and finally hydrogenating to obtain liquid crystal monomer. Its synthesis route is as follows:

[0003]

[0004]

[0005]

[0006] However, the above method has some disadvantages. For example, although the required propyl dicyclohexyl ketone can be purchased directly from the market, the intermediate preparation process to aldehyde is cumbersome and produces a large number of impurities, which is not conducive to product purification. Moreover, the subsequent use of butyl lithium reagent and hydrogenation reaction makes the overall cost of the method relatively high.

[0007] Benzyl chloride can also be directly coupled with a halogenated Grignard reagent to obtain the target product. However, the process often uses palladium acetate, palladium carbon, copper chloride / lithium chloride, cuprous iodide, etc. as catalysts for the reaction (such as European patent application EP2687854A1, Japanese patent application JP2003026612A, and international patent application WO2021191390A1). Although these catalysts can control the occurrence of side reactions during coupling to a certain extent, in general, the yield is less than 80%.

[0008] Therefore, it is of great significance to study and develop a synthesis method with high reaction conversion rate, short process flow and low synthesis cost. Summary of the invention

[0009] The main purpose of the present invention is to provide a method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds to solve the problems of complex process flow, high synthesis cost, low target product generation rate and low purity in the prior art synthesis method of substituted dicyclohexylethylene fluorobenzene compounds.

[0010] In order to achieve the above object, the present invention provides a method for synthesizing a substituted dicyclohexylethylene fluorobenzene compound, wherein the substituted dicyclohexylethylene fluorobenzene compound has a structure shown in formula (I):

[0011]

[0012] Wherein, R1 and R2 are independently selected from C1 to C5 alkyl groups;

[0013] The above-mentioned synthesis method comprises:

[0014] In the first solvent, a 2,3-difluorophenyl ether compound is subjected to a chloromethylation reaction to obtain a 2,3-difluorobenzyl chloride compound. The synthesis route of the 2,3-difluorobenzyl chloride compound is as follows:

[0015]

[0016] In the second solvent, in the presence of a nickel catalyst and a ligand, a 2,3-difluorobenzyl chloride compound and a Grignard reagent undergo a Grignard coupling reaction to obtain a substituted dicyclohexylethylene fluorobenzene compound, wherein the ligand is selected from tetramethylethylenediamine and / or allyl ether. The synthetic route of the substituted dicyclohexylethylene fluorobenzene compound is as follows:

[0017]

[0018] Furthermore, the chloromethylation reaction is carried out under the catalysis of zinc chloride; preferably, the weight ratio of 2,3-difluorophenyl ether compounds to zinc chloride is 100:(10-40); preferably, the chloromethylation reaction system also includes formaldehyde and / or polyformaldehyde, and hydrochloric acid; preferably, the molar ratio of 2,3-difluorophenyl ether compounds to formaldehyde and / or polyformaldehyde is 1:(1.1-2); more preferably, the mass concentration of hydrochloric acid is 30-38wt%; further preferably, the molar ratio of hydrochloric acid with a mass concentration of 36% to 2,3-difluorophenyl ether compounds is (8-15):1.

[0019] Furthermore, the weight ratio of the first solvent to the 2,3-difluorophenyl ether compound is (3-6):1; preferably, the first solvent is selected from one or more of the group consisting of petroleum ether, cyclohexane, and tetrahydrofuran.

[0020] Furthermore, the temperature of the chloromethylation reaction is 30-70° C., and the time is 18-32 hours.

[0021] Furthermore, the molar ratio of 2,3-difluorobenzyl chloride compound to Grignard reagent is 1:(1-1.5); preferably, the molar ratio of 2,3-difluorobenzyl chloride compound to nickel catalyst is 100:(2-10); preferably, the weight ratio of 2,3-difluorobenzyl chloride compound to ligand is 100:(20-100).

[0022] Furthermore, the nickel-based catalyst is selected from one or more of the group consisting of nickel acetylacetonate, nickel chloride, and bistriphenylphosphine nickel dichloride.

[0023] Furthermore, the temperature of the Grignard coupling reaction is -40 to 30°C, and the time is 1 to 4 hours.

[0024] Furthermore, the above-mentioned synthesis method also includes: using substituted dicyclohexylcarboxylic acid as a raw material, sequentially undergoing esterification reaction, reduction reaction and chlorination reaction to obtain substituted dicyclohexylmethyl chloride; the substituted dicyclohexylmethyl chloride has a structure shown in formula (II):

[0025]

[0026] In a third solvent, metallic magnesium is reacted with substituted dicyclohexylmethyl chloride to obtain a Grignard reagent.

[0027] Furthermore, the molar ratio of metallic magnesium to substituted dicyclohexylmethyl chloride is (1-1.2):1; preferably, the second solvent and the third solvent are independently selected from one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran and xylene.

[0028] Furthermore, the 2,3-difluorobenzyl chloride compound is 4-ethoxy-2,3-difluorobenzyl chloride, the Grignard reagent is propyl dicyclohexylmethyl chloride, and the substituted dicyclohexylethylene fluorobenzene compound is n-propyl cyclohexylethylene 2,3-difluorophenethyl ether.

[0029] The technical scheme of the present invention is applied. The present invention uses 2,3-difluorophenyl ether compounds as raw materials, and obtains 2,3-difluorobenzyl chloride compounds by chloromethylation reaction; under the action of catalysts and ligands, the 2,3-difluorobenzyl chloride compounds and Grignard reagents undergo Grignard coupling reaction to obtain the target product (i.e., substituted dicyclohexylethylene fluorobenzene compounds). On the one hand, compared with the conventional preparation process of liquid crystal monomers, the present invention does not use more expensive raw materials such as phosphonium salts, so the raw material cost is lower, thereby reducing the preparation cost. At the same time, compared with the traditional low-temperature lithiation hydrogenation process, the above-mentioned synthesis process is safer and the synthesis route is shorter. On the other hand, compared with the existing Grignard coupling reaction, the preferred nickel-based catalyst and the specific type of ligand of the present invention are used. The ligand, the nickel-based catalyst and the Grignard reagent form a complex, thereby reducing the loading amount of the nickel-based catalyst. The complex does not need to undergo the β-elimination process of the electrophile during the reaction with the 2,3-difluorobenzyl chloride compound, or can couple to produce a cross-coupling product while forming the complex, thereby increasing the reaction rate, inhibiting the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction between the Grignard reagent and the 2,3-difluorobenzyl chloride compound, thereby reducing side reactions, increasing the conversion rate of the raw materials, and significantly improving the yield and purity of the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0031] Figure 1 shows the mass spectrum of 4-ethoxy-2,3-difluorobenzyl chloride prepared in Example 1 of the present application;

[0032] Figure 2 The hydrogen nuclear magnetic resonance spectrum of 4-ethoxy-2,3-difluorobenzyl chloride prepared in Example 1 of the present application is shown;

[0033] Figure 3 shows the mass spectrum of the target product obtained in Example 1 of the present application;

[0034] Figure 4 The hydrogen nuclear magnetic resonance spectrum of the target product prepared in Example 1 of the present application is shown. DETAILED DESCRIPTION

[0035] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0036] As described in the background technology, the existing synthesis method of substituted dicyclohexylethylene fluorobenzene compounds has the problems of complex process flow, high synthesis cost, low target product yield and low purity. In order to solve the above technical problems, the present application provides a synthesis method of substituted dicyclohexylethylene fluorobenzene compounds, and the substituted dicyclohexylethylene fluorobenzene compounds have the structure shown in formula (I):

[0037]

[0038] Wherein, R1 and R2 independently include but are not limited to C1-C5 alkyl;

[0039] The above-mentioned synthesis method comprises:

[0040] In the first solvent, a 2,3-difluorophenyl ether compound is subjected to a chloromethylation reaction to obtain a 2,3-difluorobenzyl chloride compound. The synthesis route of the 2,3-difluorobenzyl chloride compound is as follows:

[0041]

[0042] In the second solvent, in the presence of a nickel catalyst and a ligand, a 2,3-difluorobenzyl chloride compound and a Grignard reagent undergo a Grignard coupling reaction to obtain a substituted dicyclohexylethylene fluorobenzene compound, wherein the ligand includes but is not limited to tetramethylethylenediamine and / or allyl ether. The synthetic route of the substituted dicyclohexylethylene fluorobenzene compound is as follows:

[0043]

[0044] The present invention uses 2,3-difluorophenyl ether compounds as raw materials, and uses chloromethylation reaction to obtain 2,3-difluorobenzyl chloride compounds; under the action of a catalyst and a ligand, the 2,3-difluorobenzyl chloride compounds and Grignard reagents undergo a Grignard coupling reaction to obtain a target product (i.e., a substituted dicyclohexylethylene fluorobenzene compound). On the one hand, compared to the conventional preparation process of liquid crystal monomers, the present invention does not use more expensive raw materials such as phosphonium salts, so the raw material cost is lower, thereby reducing the preparation cost. At the same time, compared to the traditional low-temperature lithiation hydrogenation process, the above-mentioned synthesis process is safer and the synthesis route is shorter. On the other hand, compared with the existing Grignard coupling reaction, the preferred nickel-based catalyst and the specific type of ligand of the present invention are used. The ligand, the nickel-based catalyst and the Grignard reagent form a complex, thereby reducing the loading amount of the nickel-based catalyst. The complex does not need to undergo the β-elimination process of the electrophile during the reaction with the 2,3-difluorobenzyl chloride compound, or can couple to produce a cross-coupling product while forming the complex, thereby increasing the reaction rate, inhibiting the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction between the Grignard reagent and the 2,3-difluorobenzyl chloride compound, thereby reducing side reactions, increasing the conversion rate of the raw materials, and significantly improving the yield and purity of the target product.

[0045] In order to increase the reaction rate of the chloromethylation reaction and improve the generation rate of 2,3-difluorobenzyl chloride compounds, in a preferred embodiment, the chloromethylation reaction is carried out under the catalysis of zinc chloride.

[0046] In order to further increase the reaction rate of the chloromethylation reaction and further increase the generation rate of 2,3-difluorobenzyl chloride compounds, preferably, the weight ratio of 2,3-difluorophenyl ether compounds to zinc chloride is 100:(10-40).

[0047] In a preferred embodiment, the chloromethylation reaction system also includes formaldehyde and / or paraformaldehyde, and hydrochloric acid. Formaldehyde and / or paraformaldehyde and hydrochloric acid can be used as chloromethylation reagents to react and generate 2,3-difluorobenzyl chloride compounds.

[0048] In order to improve the conversion rate of raw materials and the production rate of 2,3-difluorobenzyl chloride compounds and provide more sufficient raw materials for the subsequent Grignard coupling reaction, preferably, the molar ratio of 2,3-difluorophenyl ether compounds to formaldehyde and / or polyformaldehyde is 1:(1.1-2).

[0049] In order to further improve the conversion rate of raw materials and further improve the production rate of 2,3-difluorobenzyl chloride compounds, more preferably, the mass concentration of hydrochloric acid is 30-38wt%; further preferably, the molar ratio of hydrochloric acid with a mass concentration of 36% to 2,3-difluorophenyl ether compounds is (8-15):1.

[0050] In a preferred embodiment, the weight ratio of the first solvent to the 2,3-difluorophenyl ether compound is (3-6): 1. The weight ratio of the first solvent to the 2,3-difluorophenyl ether compound includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the compatibility of the 2,3-difluorophenyl ether compound with the first solvent, thereby improving the reaction efficiency of the chloromethylation reaction, thereby improving the generation rate of 2,3-difluorobenzyl chloride compounds; and at the same time, it is beneficial to inhibit the occurrence of side reactions, thereby improving the purity of 2,3-difluorobenzyl chloride compounds.

[0051] In order to further improve the compatibility of 2,3-difluorophenyl ether compounds with the first solvent, further improve the reaction efficiency of the chloromethylation reaction, and at the same time to further suppress the occurrence of side reactions and further improve the purity of 2,3-difluorobenzyl chloride compounds, preferably, the first solvent includes but is not limited to one or more of the group consisting of petroleum ether, cyclohexane, and tetrahydrofuran.

[0052] In a preferred embodiment, the temperature of the chloromethylation reaction is 30 to 70° C., and the time is 18 to 32 hours. The temperature and time of the chloromethylation reaction include but are not limited to the above ranges. Limiting them within the above ranges is conducive to suppressing the occurrence of side reactions, thereby facilitating the improvement of the conversion rate of raw materials during the chloromethylation reaction, thereby facilitating the improvement of the yield and purity of 2,3-difluorobenzyl chloride compounds, and creating conditions for subsequent reactions.

[0053] In a preferred embodiment, the molar ratio of the 2,3-difluorobenzyl chloride compound to the Grignard reagent is 1:(1-1.5). The molar ratio of the 2,3-difluorobenzyl chloride compound to the Grignard reagent includes but is not limited to the above range, and limiting it within the above range is beneficial to improving the conversion rate of the reaction raw materials and the generation rate of the target product.

[0054] In a preferred embodiment, the molar ratio of 2,3-difluorobenzyl chloride compound to nickel catalyst is 100:(2-10); preferably, the weight ratio of 2,3-difluorobenzyl chloride compound to ligand is 100:(20-100). The molar ratio of 2,3-difluorobenzyl chloride compound to nickel catalyst includes but is not limited to the above range, and limiting it within the above range is beneficial to improving the catalytic efficiency of nickel catalyst, thereby improving the yield of target product. The weight ratio of 2,3-difluorobenzyl chloride compounds to ligands includes but is not limited to the above range. Limiting it within the above range is conducive to increasing the amount of complexes formed by ligands, nickel-based catalysts and Grignard reagents, thereby reducing the loading of nickel-based catalysts. The complex does not need to undergo the β-elimination of electrophiles during the reaction with 2,3-difluorobenzyl chloride compounds, or can couple to produce cross-coupling products while forming the complex, thereby increasing the reaction rate, inhibiting the self-coupling reaction of Grignard reagents and the Grignard exchange reaction between Grignard reagents and 2,3-difluorobenzyl chloride compounds, thereby reducing side reactions and increasing the yield of the target product. In short, compared with other ranges, limiting the amount of 2,3-difluorobenzyl chloride compounds, nickel-based catalysts and ligands within the above range is conducive to exerting the synergistic effect of nickel-based catalysts and ligands, and is conducive to improving the conversion rate of raw materials, thereby increasing the yield of the target product and reducing the synthesis cost.

[0055] In a preferred embodiment, the nickel catalyst includes, but is not limited to, one or more of the group consisting of nickel acetylacetonate, nickel chloride, and bistriphenylphosphine nickel dichloride. Compared with other types of nickel catalysts, the use of the above preferred types of nickel catalysts is conducive to further exerting the synergistic effect of the nickel catalyst and the ligand, thereby further improving the yield of the target product.

[0056] In a preferred embodiment, the temperature of the Grignard coupling reaction is -40 to 30°C, and the time is 1 to 4 hours. The temperature and time of the Grignard coupling reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to suppressing the occurrence of side reactions in the process, and is conducive to improving the conversion rate of raw materials, thereby helping to improve the generation rate of the target product.

[0057] In a preferred embodiment, the above-mentioned synthesis method further comprises: using substituted dicyclohexylcarboxylic acid as a raw material, sequentially undergoing esterification reaction, reduction reaction and chlorination reaction to obtain substituted dicyclohexylmethyl chloride; the substituted dicyclohexylmethyl chloride has a structure shown in formula (II): In a third solvent, metallic magnesium is reacted with substituted dicyclohexylmethyl chloride to obtain a Grignard reagent.

[0058] Under acidic conditions, substituted dicyclohexylcarboxylic acid is subjected to an esterification reaction with alcohol to obtain an esterification product, substituted dicyclohexylcarboxylic acid ester; sodium borohydride is used to cause the esterification product to undergo a reduction reaction to obtain a reduced product, substituted dicyclohexylmethanol; under the condition that an organic base is used as an acid-binding agent, the reduced product is subjected to a chlorination reaction with a chlorination reagent to obtain a substituted dicyclohexylmethyl chloride; in a third solvent, metallic magnesium is reacted with the substituted dicyclohexylmethyl chloride to obtain a Grignard reagent.

[0059] In a preferred embodiment, the molar ratio of magnesium metal to substituted dicyclohexylmethyl chloride is (1-1.2): 1. The molar ratio of magnesium metal to substituted dicyclohexylmethyl chloride includes but is not limited to the above range, and limiting it within the above range is beneficial to improving the conversion rate of substituted dicyclohexylmethyl chloride, thereby improving the generation rate of Grignard reagent and providing sufficient raw materials for Grignard coupling reaction.

[0060] The second solvent and the third solvent in the present application can be organic solvents commonly used in the art. In a preferred embodiment, the second solvent and the third solvent independently include but are not limited to one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, and xylene.

[0061] In a preferred embodiment, the 2,3-difluorobenzyl chloride compound is 4-ethoxy-2,3-difluorobenzyl chloride, the Grignard reagent is propyl dicyclohexylmethyl chloride, and the substituted dicyclohexylethylene fluorobenzene compound is n-propyl cyclohexylethylene 2,3-difluorophenethyl ether. The above-mentioned synthesis method provided in the present application is particularly suitable for synthesizing n-propyl cyclohexylethylene 2,3-difluorophenethyl ether.

[0062] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0063] Example 1

[0064] A method for synthesizing a substituted dicyclohexylethylene fluorobenzene compound comprises:

[0065] (1) Chloromethylation reaction

[0066] The synthetic route of the reaction is as follows:

[0067]

[0068] 31.6g (0.2mol) 2,3-difluorophenyl ether, 9g (0.3mol) paraformaldehyde, 3.5g ZnCl2, 304g concentrated hydrochloric acid (3mol) with a mass concentration of 36% and 150mL first solvent cyclohexane were added to a 500mL three-necked flask. Under stirring conditions, the reaction system was heated to 60°C and the reaction was continued for 24h to obtain the product. The reaction system was cooled to room temperature, 250mL water and 100mL cyclohexane were added for dilution, and the mixture was allowed to stand for separation after stirring for 15min to obtain an organic layer and an aqueous layer, wherein the organic layer was washed with water to neutrality, 5g silica gel column chromatography was used, and 50mL cyclohexane was used to flush the column, and the organic layer was concentrated to basically dry to obtain 38.5g of product, and 200mL toluene was used to dissolve the product completely for standby use. It was calculated that the theoretical yield of 4-ethoxy-2,3-difluorobenzyl chloride was 41.3g, and the yield was 93.22%. Prepare a toluene solution of 38.5 g (0.186 mol) of 4-ethoxy-2,3-difluorobenzyl chloride for later use. Figure 1 is the mass spectrum of the obtained 4-ethoxy-2,3-difluorobenzyl chloride, Figure 2 This is the H NMR spectrum of 4-ethoxy-2,3-difluorobenzyl chloride.

[0069] (2) Synthesis of Grignard reagent

[0070] The synthetic route of the reaction is as follows:

[0071]

[0072] Add 4.9g (0.204mol) of magnesium chips and 10mL of tetrahydrofuran into a 500mL three-necked flask, replace with nitrogen 5 times, heat the reaction system to 65°C, add 1 grain of iodine to the reaction system and drop 10mL of initiator, wherein the initiator is composed of 50g (0.206mol) of propyldicyclohexylmethyl chloride and 250mL of the third solvent tetrahydrofuran, control the temperature at 55-60°C after initiation, drop the remaining solution, and keep it at 60°C for 2h after the addition is completed to obtain a Grignard reagent.

[0073] (3) Grignard coupling reaction

[0074] The synthetic route of the Grignard coupling reaction is as follows:

[0075]

[0076] At room temperature, add the prepared 38.5g (0.186mol) toluene solution of 4-ethoxy-2,3-difluorobenzyl chloride to another 500mL three-necked flask, add 0.96g (0.0037mol) nickel acetylacetonate and 18.23g (0.186mol) allyl ether, replace with nitrogen 5 times, cool the reaction system to -35~-30℃, add the above prepared Grignard reagent dropwise, and keep warm for 1h after the addition. The reaction solution is acidified and hydrolyzed in 90g of 17% dilute hydrochloric acid. In the mixed system obtained by acidification and hydrolysis, the organic layer is first washed once with 100mL water, then washed once with 100mL sodium bicarbonate solution with a mass concentration of 1%, and finally washed three times with 100mL water until neutral. The washed organic layer is concentrated to obtain 66.2g of white crude product, with a theoretical yield of 72.9g and a yield of 90.8% of the target product. Figure 3 and Figure 4 The mass spectrum and hydrogen nuclear magnetic resonance spectrum of the obtained target product are respectively, confirming that the target product is n-propylcyclohexylethylidene 2,3-difluorophenethyl ether.

[0077] Example 2

[0078] The difference from Example 1 is that during the Grignard coupling reaction, tetramethylethylenediamine is used as a ligand instead of the allyl ether in Example 1, and the weight ratio of 4-ethoxy-2,3-difluorobenzyl chloride to tetramethylethylenediamine is 100:80. The remaining steps are the same as in Example 1.

[0079] Example 3

[0080] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to allyl ether is 5:1. The remaining steps are the same as in Example 1.

[0081] Example 4

[0082] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to allyl ether is 1:1. The remaining steps are the same as in Example 1.

[0083] Example 5

[0084] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to allyl ether is 1:1.5. The remaining steps are the same as in Example 1.

[0085] Example 6

[0086] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to nickel acetylacetonate is 100:10.

[0087] Example 7

[0088] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to nickel acetylacetonate is 100:20.

[0089] Example 8

[0090] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to the Grignard reagent is 1:1.5.

[0091] Example 9

[0092] The difference from Example 1 is that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to the Grignard reagent is 1:2.

[0093] Example 10

[0094] The difference from Example 1 is that the temperature of the Grignard coupling reaction is -40°C and the time is 4 hours.

[0095] Embodiment 11

[0096] The difference from Example 1 is that the temperature of the Grignard coupling reaction is 30° C. and the time is 2 h.

[0097] Example 12

[0098] The difference from Example 1 is that the temperature of the Grignard coupling reaction is 50° C. and the time is 2 h.

[0099] Embodiment 13

[0100] The difference from Example 1 is that during the chloromethylation reaction, the weight ratio of 2,3-difluorophenethyl ether to zinc chloride is 100:10; and the molar ratio of 2,3-difluorophenethyl ether to paraformaldehyde is 1:1.1.

[0101] Embodiment 14

[0102] The difference from Example 1 is that during the chloromethylation reaction, the weight ratio of 2,3-difluorophenethyl ether to zinc chloride is 100:40; and the molar ratio of 2,3-difluorophenethyl ether to paraformaldehyde is 1:2.

[0103] Embodiment 15

[0104] The difference from Example 1 is that during the chloromethylation reaction, the weight ratio of 2,3-difluorophenethyl ether to zinc chloride is 100:1; and the molar ratio of 2,3-difluorophenethyl ether to paraformaldehyde is 1:0.8.

[0105] Example 16

[0106] The difference from Example 1 is that during the chloromethylation reaction, the first solvent is petroleum ether, and the weight ratio of petroleum ether to 2,3-difluorophenethyl ether is 3:1.

[0107] Embodiment 17

[0108] The difference from Example 1 is that during the chloromethylation reaction, the first solvent is tetrahydrofuran, and the weight ratio of tetrahydrofuran to 2,3-difluorophenethyl ether is 6:1.

[0109] Embodiment 18

[0110] The difference from Example 1 is that during the chloromethylation reaction, the weight ratio of the first solvent to 2,3-difluorophenethyl ether is 8:1.

[0111] Embodiment 19

[0112] The difference from Example 1 is that the temperature of the chloromethylation reaction is 30° C. and the time is 32 h.

[0113] Embodiment 20

[0114] The difference from Example 1 is that the temperature of the chloromethylation reaction is 70° C. and the time is 18 h.

[0115] Embodiment 21

[0116] The difference from Example 1 is that the temperature of the chloromethylation reaction is 25° C. and the time is the same as that of Example 1.

[0117] Comparative Example 1

[0118] The difference from Example 1 is that no allyl ether is added during the Grignard coupling reaction. The remaining steps are the same as in Example 1.

[0119] Comparative Example 2

[0120] The difference from Example 1 is that cupric chloride is used as a catalyst in the Grignard coupling reaction process, replacing the nickel acetylacetonate in Example 1.

[0121] Comparative Example 3

[0122] The difference from Example 1 is that palladium acetate is used as a catalyst in the Grignard coupling reaction process, replacing the nickel acetylacetonate in Example 1.

[0123] The yields of 4-ethoxy-2,3-difluorobenzyl chloride and the target product (i.e., n-propylcyclohexylethylidene 2,3-difluorophenethyl ether) obtained in all the above examples and comparative examples of the present application are summarized in Table 1.

[0124] Table 1

[0125]

[0126]

[0127] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0128] By comparing Examples 1 and 2 and Comparative Examples 1 and 2, it can be seen that compared with the existing Grignard coupling reaction, the preferred nickel-based catalyst and the specific type of ligand of the present invention are used. The ligand, the nickel-based catalyst and the Grignard reagent form a complex, thereby reducing the loading amount of the nickel-based catalyst. The complex does not need to undergo the β-elimination process of the electrophile during the reaction with the 2,3-difluorobenzyl chloride compound, or can couple to produce a cross-coupling product while forming the complex, thereby increasing the reaction rate, inhibiting the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction between the Grignard reagent and the 2,3-difluorobenzyl chloride compound, thereby reducing side reactions, improving the conversion rate of the raw materials, and significantly improving the yield and purity of the target product.

[0129] By comparing Examples 1, 3 to 5, it can be seen that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to allyl ether includes but is not limited to the preferred range of the present application. Limiting it within the preferred range of the present application is beneficial to the advantage that the ligand and the nickel catalyst form a complex with the Grignard reagent more effectively, is beneficial to reducing the loading amount of the nickel-based catalyst, and does not require β-elimination or simultaneous coupling of the electrophile to produce a cross-coupling product, which is beneficial to increasing the reaction rate, and is beneficial to inhibiting the self-coupling of the Grignard reagent and the Grignard exchange between the Grignard reagent and the benzyl chloride, thereby controlling the side reaction of the self-coupling of the benzyl chloride, thereby helping to increase the yield of the target product.

[0130] By comparing Examples 1, 6 and 7, it can be seen that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to nickel acetylacetonate includes but is not limited to the preferred range of the present application. Limiting it within the preferred range of the present application is beneficial to improving the catalytic efficiency of the nickel-based catalyst, thereby helping to improve the generation rate of the target product.

[0131] By comparing Examples 1, 8 and 9, it can be seen that the molar ratio of 4-ethoxy-2,3-difluorobenzyl chloride to the Grignard reagent includes but is not limited to the preferred range of the present application. Limiting it within the preferred range of the present application is beneficial to improving the conversion rate of the reaction raw materials and the generation rate of the target product.

[0132] By comparing Examples 1, 10 to 12, it can be seen that the temperature and time of the Grignard coupling reaction include but are not limited to the preferred range of the present application. Limiting them within the preferred range of the present application is beneficial to suppressing the occurrence of side reactions in the process, and is beneficial to improving the conversion rate of raw materials, thereby helping to improve the generation rate of the target product.

[0133] By comparing Examples 1 and 13 to 15, it can be seen that the weight ratio of 2,3-difluorophenethyl ether to zinc chloride includes but is not limited to the preferred range of the present application, and limiting it within the preferred range of the present application is beneficial to further improve the reaction rate of the chloromethylation reaction; the amount of substance ratio of 2,3-difluorophenethyl ether to polyformaldehyde includes but is not limited to the preferred range of the present application, and limiting it within the preferred range of the present application is beneficial to improve the conversion rate of the raw materials, and at the same time is beneficial to increase the generation rate of 4-ethoxy-2,3-difluorobenzyl chloride, providing more sufficient raw materials for the subsequent Grignard coupling reaction.

[0134] By comparing Examples 1 and 16 to 18, it can be seen that the use of the first solvent of the preferred type of the present application and limiting its usage range within the preferred range of the present application is beneficial to further improve the compatibility of 2,3-difluorophenyl ether compounds with the first solvent, and is beneficial to further improve the reaction efficiency of the chloromethylation reaction, thereby helping to increase the generation rate of 2,3-difluorobenzyl chloride compounds; at the same time, it is beneficial to further inhibit the occurrence of side reactions, thereby helping to further improve the purity of 2,3-difluorobenzyl chloride compounds.

[0135] Comparing Examples 1, 19 to 21, it can be seen that the temperature and time of the chloromethylation reaction include but are not limited to the preferred range of the present application. Limiting it within the preferred range of the present application is beneficial to suppressing the occurrence of side reactions, thereby helping to improve the conversion rate of raw materials during the chloromethylation reaction, thereby helping to improve the yield and purity of 2,3-difluorobenzyl chloride compounds, creating conditions for subsequent reactions.

[0136] It should be noted that the terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence. It should be understood that the terms used in this way can be interchangeable where appropriate, so that the embodiments of the present application described herein can be implemented in an order other than those described herein, for example.

[0137] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds, characterized in that: The substituted dicyclohexylethylene fluorobenzene compound has a structure shown in formula (I): Wherein, R1 and R2 are independently selected from C1 to C5 alkyl groups; The synthesis method comprises: In a first solvent, a 2,3-difluorophenyl ether compound is subjected to a chloromethylation reaction to obtain a 2,3-difluorobenzyl chloride compound. The synthesis route of the 2,3-difluorobenzyl chloride compound is as follows: In the second solvent, in the presence of nickel acetylacetone catalyst and ligand, the 2,3-difluorobenzyl chloride compound and the Grignard reagent undergo a Grignard coupling reaction to obtain the substituted dicyclohexylethylidene fluorobenzene compound, wherein the ligand is selected from tetramethylethylenediamine and / or allyl ether, and the synthesis route of the substituted dicyclohexylethylidene fluorobenzene compound is as follows:

2. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The chloromethylation reaction is carried out under the catalysis of zinc chloride.

3. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 2, characterized in that: The weight ratio of the 2,3-difluorophenyl ether compound to the zinc chloride is 100:(10-40).

4. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The chloromethylation reaction system also includes formaldehyde and / or paraformaldehyde, and hydrochloric acid.

5. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 4, characterized in that: The molar ratio of the 2,3-difluorophenyl ether compound to the formaldehyde and / or the paraformaldehyde is 1:(1.1-2).

6. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 4, characterized in that: The mass concentration of the hydrochloric acid is 30-38wt%.

7. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 6, characterized in that: The molar ratio of the hydrochloric acid with a mass concentration of 36% to the 2,3-difluorophenyl ether compound is (8-15):

1.

8. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The weight ratio of the first solvent to the 2,3-difluorophenyl ether compound is (3-6):

1.

9. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 8, characterized in that: The first solvent is selected from one or more of the group consisting of petroleum ether, cyclohexane, and tetrahydrofuran.

10. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to any one of claims 1 to 9, characterized in that: The temperature of the chloromethylation reaction is 30-70° C. and the time is 18-32 hours.

11. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 10, characterized in that: The molar ratio of the 2,3-difluorobenzyl chloride compound to the Grignard reagent is 1:(1-1.5).

12. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 10, characterized in that: The molar ratio of the 2,3-difluorobenzyl chloride compound to the nickel acetylacetonate catalyst is 100:(2-10).

13. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 10, characterized in that: The weight ratio of the 2,3-difluorobenzyl chloride compound to the ligand is 100:(20-100).

14. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The temperature of the Grignard coupling reaction is -40 to 30°C, and the time is 1 to 4 hours.

15. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The synthesis method also includes: Substituted dicyclohexylcarboxylic acid is used as a raw material, and esterification reaction, reduction reaction and chlorination reaction are carried out in sequence to obtain substituted dicyclohexylmethyl chloride; the substituted dicyclohexylmethyl chloride has a structure shown in formula (II): In a third solvent, metallic magnesium is reacted with the substituted biscyclohexylmethyl chloride to obtain the Grignard reagent.

16. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 15, characterized in that: The molar ratio of the metallic magnesium to the substituted dicyclohexylmethyl chloride is (1-1.2):

1.

17. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 15, characterized in that: The second solvent and the third solvent are independently selected from one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, and xylene.

18. The method for synthesizing substituted dicyclohexylethylene fluorobenzene compounds according to claim 1, characterized in that: The 2,3-difluorobenzyl chloride compound is 4-ethoxy-2,3-difluorobenzyl chloride, the Grignard reagent is propyl dicyclohexylmethyl chloride, and the substituted dicyclohexylethylene fluorobenzene compound is n-propyl cyclohexylethylene 2,3-difluorophenethyl ether.

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