CN116332735A

CN116332735A - Synthesis method of substituted dicyclohexyl ethylene fluorobenzene compound

Info

Publication number: CN116332735A
Application number: CN202310326036.8A
Authority: CN
Inventors: 邓友节; 刁伯真; 向榆
Original assignee: Allchemy Co ltd
Current assignee: Allchemy Co ltd
Priority date: 2023-03-29
Filing date: 2023-03-29
Publication date: 2023-06-27

Abstract

The invention provides a synthesis method of a substituted dicyclohexyl ethylene fluorobenzene compound. The substituted dicyclohexyl ethylene fluorobenzene compound has a structure shown in a formula (I); the synthesis method comprises the following steps: in a first solvent, carrying out chloromethylation reaction on the 2, 3-difluorophenyl ether compound to obtain a 2, 3-difluorobenzyl chloride compound; in a second solvent, in the presence of a nickel catalyst and a ligand, the 2, 3-difluorobenzyl chloride compound and a Grignard reagent undergo a Grignard coupling reaction to obtain a substituted dicyclohexyl ethylene fluorobenzene compound, and the ligand is selected from tetramethyl ethylenediamine and/or allyl ether. Compared with the prior art, the nickel-based catalyst and the ligand of the specific type can reduce the loading of the nickel-based catalyst, improve the reaction rate, inhibit side reactions and improve the conversion rate of raw materials, therebyThe yield and purity of the target product are obviously improved.

Description

Synthesis method of substituted dicyclohexyl ethylene fluorobenzene compound

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of a substituted dicyclohexyl ethylene fluorobenzene compound.

Background

The current common method for synthesizing alkyl dicyclohexyl ethylene fluorobenzene liquid crystal monomer comprises the steps of taking propyl dicyclohexyl ketone as a raw material, preparing aldehyde through two-step ylide reaction and hydrolysis reaction, preparing alcohol through reaction with a halobenzene metal reagent, dehydrating to form alkene, and finally hydrogenating to obtain the liquid crystal monomer. The synthetic route is as follows:

however, the above method has some disadvantages, such as the required propyl dicyclohexyl ketone can be directly purchased from the market, but the intermediate preparation to aldehyde has complicated process steps, and the produced impurities are more, which is not beneficial to the purification of the product; moreover, the subsequent need to use butyllithium reagent and hydrogenation makes the overall cost of the process high.

The target product can also be prepared by directly coupling benzyl chloride with a Grignard reagent of a halide, however, palladium acetate, palladium carbon, copper chloride/lithium chloride, cuprous iodide and the like are often used as catalysts for the reaction (such as European patent application EP2687854A1, japanese patent application JP2003026612A and International patent application WO2021191390A 1). Although these catalysts can control the occurrence of side reactions during coupling to some extent, the yield is generally 80% or less.

Therefore, research and development of a synthetic method with high reaction conversion rate, short process flow and low synthetic cost have important significance.

Disclosure of Invention

The invention mainly aims to provide a synthesis method of a substituted dicyclohexyl ethylene fluorobenzene compound, which aims to solve the problems of complex process flow, high synthesis cost, low target product generation rate and low purity of the synthesis method of the substituted dicyclohexyl ethylene fluorobenzene compound in the prior art.

In order to achieve the above object, the present invention provides a method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound having a structure represented by formula (I):

wherein R is ₁ And R is ₂ Are independently selected from C ₁ ～C ₅ Alkyl of (a);

the synthesis method comprises the following steps:

in a first solvent, carrying out chloromethylation reaction on the 2, 3-difluorophenyl ether compound to obtain the 2, 3-difluorobenzyl chloride compound, wherein the synthetic route of the 2, 3-difluorobenzyl chloride compound is as follows:

in a second solvent, in the presence of a nickel catalyst and a ligand, carrying out Grignard coupling reaction on a 2, 3-difluorobenzyl chloride compound and a Grignard reagent to obtain a substituted dicyclohexyl ethylene fluorobenzene compound, wherein the ligand is selected from tetramethyl ethylenediamine and/or allyl ether, and the synthetic route of the substituted dicyclohexyl ethylene fluorobenzene compound is as follows:

further, chloromethylation reaction is carried out under the catalysis of zinc chloride; preferably, the weight ratio of the 2, 3-difluorophenyl ether compound to the zinc chloride is 100 (10-40); preferably, the chloromethylation reaction system also comprises formaldehyde and/or paraformaldehyde and hydrochloric acid; preferably, the mass ratio of the 2, 3-difluorophenyl ether compound to formaldehyde and/or paraformaldehyde is 1 (1.1-2); more preferably, the mass concentration of hydrochloric acid is 30 to 38wt%; it is further preferable that the mass ratio of the hydrochloric acid having a mass concentration of 36% to the 2, 3-difluorophenyl ether compound is (8 to 15): 1.

Further, 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, tetrahydrofuran.

Further, the chloromethylation reaction temperature is 30-70 ℃ and the time is 18-32 h.

Further, the mass ratio of the 2, 3-difluorobenzyl chloride compound to the Grignard reagent is 1 (1-1.5); preferably, the mass ratio of the 2, 3-difluorobenzyl chloride compound to the nickel catalyst is 100 (2-10); preferably, the weight ratio of the 2, 3-difluorobenzyl chloride compound to the ligand is 100 (20-100).

Further, the nickel-based catalyst is selected from one or more of the group consisting of nickel acetylacetonate, nickel chloride, and bis-triphenylphosphine nickel dichloride.

Further, the temperature of the Grignard coupling reaction is-40-30 ℃ and the time is 1-4 h.

Further, the above synthesis method further comprises: taking substituted dicyclohexyl formic acid as a raw material, and sequentially carrying out esterification reaction, reduction reaction and chlorination reaction to obtain substituted dicyclohexyl methyl chloride; the substituted dicyclohexylmethyl chloride has a structure shown in a formula (II):

reacting magnesium metal with substituted dicyclohexyl methyl chloride in a third solvent to obtain the Grignard reagent.

Further, the mass ratio of the metal magnesium to the substance substituted for dicyclohexyl methyl chloride is (1-1.2): 1; preferably, the second solvent and the third solvent are each independently selected from one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, xylene.

Further, 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.

By applying the technical scheme of the invention, the 2, 3-difluorobenzyl chloride compound is obtained by using the 2, 3-difluorophenyl ether compound as a raw material and utilizing chloromethylation reaction; under the action of a catalyst and a ligand, the 2, 3-difluorobenzyl chloride compound and a Grignard reagent undergo a Grignard coupling reaction to obtain a target product (namely the substituted dicyclohexylethylene fluorobenzene compound). On one hand, compared with the conventional preparation process of the liquid crystal monomer, the preparation method does not use expensive raw materials such as phosphine salt and the like, so that the cost of the raw materials is lower, thereby being capable of reducing the preparation cost, and meanwhile, compared with the traditional low-temperature lithiation hydrogenation process, the synthesis process is higher in safety and shorter in synthesis route. On the other hand, compared with the existing Grignard coupling reaction, the preferred nickel-based catalyst and the ligand of a specific type are adopted, and the ligand, the nickel-based catalyst and the Grignard reagent form a complex, so that the load of the nickel-based catalyst can be reduced, the complex does not need to undergo the process of eliminating beta of an electrophile in the reaction process of the complex and the 2, 3-difluorobenzyl chloride compound, or the complex can be formed and coupled to produce a cross-coupled product, so that the reaction rate can be improved, the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction of the Grignard reagent and the 2, 3-difluorobenzyl chloride compound can be inhibited, the side reaction can be reduced, the conversion rate of raw materials can be improved, and the yield and purity of a target product can be remarkably improved.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. In the drawings:

FIG. 1 shows a mass spectrum of 4-ethoxy-2, 3-difluorobenzyl chloride prepared in example 1 of the present application;

FIG. 2 shows the nuclear magnetic resonance hydrogen spectrum of 4-ethoxy-2, 3-difluorobenzyl chloride prepared in example 1 of the present application;

FIG. 3 shows a mass spectrum of the target product produced in example 1 of the present application;

FIG. 4 shows a hydrogen nuclear magnetic resonance spectrum of the target product produced in example 1 of the present application.

Detailed Description

It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present invention will be described in detail with reference to examples.

As described in the background art, the existing synthesis method of the substituted dicyclohexyl ethylene fluorobenzene compound has the problems of complex process flow, high synthesis cost, low yield of target products and low purity. In order to solve the technical problems, the application provides a synthesis method of a substituted dicyclohexyl ethylene fluorobenzene compound, wherein the substituted dicyclohexyl ethylene fluorobenzene compound has a structure shown in a formula (I):

wherein R is ₁ And R is ₂ Each independently include but are not limited to C ₁ ～C ₅ Alkyl of (a);

the synthesis method comprises the following steps:

in a second solvent, in the presence of a nickel catalyst and a ligand, carrying out Grignard coupling reaction on the 2, 3-difluorobenzyl chloride compound and a Grignard reagent to obtain a substituted dicyclohexyl ethylene fluorobenzene compound, wherein the ligand comprises but is not limited to tetramethyl ethylenediamine and/or allyl ether, and the synthetic route of the substituted dicyclohexyl ethylene fluorobenzene compound is as follows:

the invention takes 2, 3-difluorophenyl ether compounds as raw materials and obtains 2, 3-difluorobenzyl chloride compounds by chloromethylation reaction; under the action of a catalyst and a ligand, the 2, 3-difluorobenzyl chloride compound and a Grignard reagent undergo a Grignard coupling reaction to obtain a target product (namely the substituted dicyclohexylethylene fluorobenzene compound). On one hand, compared with the conventional preparation process of the liquid crystal monomer, the preparation method does not use expensive raw materials such as phosphine salt and the like, so that the cost of the raw materials is lower, thereby being capable of reducing the preparation cost, and meanwhile, compared with the traditional low-temperature lithiation hydrogenation process, the synthesis process is higher in safety and shorter in synthesis route. On the other hand, compared with the existing Grignard coupling reaction, the preferred nickel-based catalyst and the ligand of a specific type are adopted, and the ligand, the nickel-based catalyst and the Grignard reagent form a complex, so that the load of the nickel-based catalyst can be reduced, the complex does not need to undergo the process of eliminating beta of an electrophile in the reaction process of the complex and the 2, 3-difluorobenzyl chloride compound, or the complex can be formed and coupled to produce a cross-coupled product, so that the reaction rate can be improved, the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction of the Grignard reagent and the 2, 3-difluorobenzyl chloride compound can be inhibited, the side reaction can be reduced, the conversion rate of raw materials can be improved, and the yield and purity of a target product can be remarkably improved.

In order to increase the reaction rate of the chloromethylation reaction and increase the rate of formation of 2, 3-difluorobenzyl chloride, in a preferred embodiment the chloromethylation reaction is carried out under the catalysis of zinc chloride.

In order to further increase the reaction rate of chloromethylation and further increase the production rate of 2, 3-difluorobenzyl chloride compound, the weight ratio of 2, 3-difluorophenyl ether compound to zinc chloride is preferably 100 (10 to 40).

In a preferred embodiment, the chloromethylation system also comprises formaldehyde and/or paraformaldehyde, and hydrochloric acid. Formaldehyde and/or paraformaldehyde and hydrochloric acid can be used as chloromethylation reagents, so that 2, 3-difluorobenzyl chloride compounds are generated by reaction.

In order to increase the conversion rate of the raw materials and increase the generation rate of the 2, 3-difluorobenzyl chloride compound, more sufficient raw materials are provided for the subsequent Grignard coupling reaction, preferably, the mass ratio of the 2, 3-difluorophenyl ether compound to formaldehyde and/or paraformaldehyde is 1 (1.1-2).

In order to further improve the conversion rate of the raw materials and further improve the generation rate of the 2, 3-difluorobenzyl chloride compound, more preferably, the mass concentration of the hydrochloric acid is 30-38 wt%; it is further preferable that the mass ratio of the hydrochloric acid having a mass concentration of 36% to the 2, 3-difluorophenyl ether compound is (8 to 15): 1.

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 comprises but is not limited to the range, and the weight ratio is limited to the range, so that the compatibility of the 2, 3-difluorophenyl ether compound and the first solvent is improved, the reaction efficiency of chloromethylation reaction is improved, and the generation rate of the 2, 3-difluorobenzyl chloride compound is improved; simultaneously, the method is favorable for inhibiting side reactions, thereby being favorable for improving the purity of the 2, 3-difluorobenzyl chloride compounds.

In order to further increase the compatibility of the 2, 3-difluorophenyl ether compound with the first solvent, further increase the reaction efficiency of the chloromethylation reaction, and simultaneously to further suppress the occurrence of side reactions, further increase the purity of the 2, 3-difluorobenzyl chloride compound, preferably, the first solvent includes one or more of petroleum ether, cyclohexane, tetrahydrofuran, but not limited thereto.

In a preferred embodiment, the chloromethylation reaction is carried out at a temperature of from 30 to 70℃for a period of from 18 to 32 hours. The chloromethylation reaction temperature and time include but are not limited to the above ranges, and the limitation of the above ranges is beneficial to inhibiting the occurrence of side reactions, thereby being beneficial to improving the conversion rate of raw materials in the chloromethylation reaction process, being beneficial to improving the yield and purity of 2, 3-difluorobenzyl chloride compounds and creating conditions for subsequent reactions.

In a preferred embodiment, the mass ratio of 2, 3-difluorobenzyl chloride compound to grignard reagent is 1 (1-1.5). The mass ratio of the 2, 3-difluorobenzyl chloride compound to the Grignard reagent includes but is not limited to the above range, and the limitation of the mass ratio in the above range is beneficial to improving the conversion rate of the reaction raw materials and the yield of the target product.

In a preferred embodiment, the mass ratio of the 2, 3-difluorobenzyl chloride compound to the nickel catalyst is 100 (2-10); preferably, the weight ratio of the 2, 3-difluorobenzyl chloride compound to the ligand is 100 (20-100). The mass ratio of the 2, 3-difluorobenzyl chloride compound to the nickel catalyst includes, but is not limited to, the above range, and limiting the mass ratio to the above range is advantageous for improving the catalytic efficiency of the nickel catalyst, thereby being advantageous for improving the yield of the target product. The weight ratio of the 2, 3-difluorobenzyl chloride compound to the ligand comprises but is not limited to the range, and the weight ratio is limited to the range, so that the yield of a complex formed by the ligand, the nickel catalyst and the Grignard reagent is favorably improved, the load of the nickel catalyst is favorably reduced, the complex and the 2, 3-difluorobenzyl chloride compound do not need to undergo the process of eliminating beta of an electrophile or can be coupled to produce a cross-coupling product while forming the complex in the reaction process, the reaction rate is favorably improved, the self-coupling reaction of the Grignard reagent and the Grignard exchange reaction of the Grignard reagent and the 2, 3-difluorobenzyl chloride compound are favorably inhibited, the side reaction is favorably reduced, and the yield of a target product is favorably improved. In short, compared with other ranges, the use amount of the 2, 3-difluorobenzyl chloride compound, the nickel catalyst and the ligand is limited in the above ranges, which is favorable for exerting the synergistic effect of the nickel catalyst and the ligand and improving the conversion rate of raw materials, thereby being favorable for improving the generation rate of target products and reducing the synthesis cost.

In a preferred embodiment, the nickel-based catalyst includes, but is not limited to, one or more of the group consisting of nickel acetylacetonate, nickel chloride, bis triphenylphosphine nickel dichloride. Compared with other types of nickel catalysts, the nickel catalyst of the preferred type is favorable for further playing the synergistic effect of the nickel catalyst and the ligand, thereby being favorable for further improving the generation rate of target products.

In a preferred embodiment, the temperature of the Grignard coupling reaction is from-40 to 30℃for a period of from 1 to 4 hours. The temperature and time of the grignard coupling reaction include but are not limited to the above ranges, and limiting the temperature and time to the above ranges is beneficial to inhibiting the occurrence of side reactions in the process, and is beneficial to improving the conversion rate of raw materials, thereby being beneficial to improving the generation rate of target products.

In a preferred embodiment, the above synthesis method further comprises: taking substituted dicyclohexyl formic acid as a raw material, and sequentially carrying out esterification reaction, reduction reaction and chlorination reaction to obtain substituted dicyclohexyl methyl chloride; the substituted dicyclohexylmethyl chloride has a structure represented by formula (II):

Under the acidic condition, the substituted dicyclohexyl formic acid and alcohol are subjected to esterification reaction to obtain an esterification product substituted dicyclohexyl formic acid ester; reducing the esterification product by sodium borohydride to obtain a reduced product substituted dicyclohexyl methanol; under the condition that organic alkali is used as an acid binding agent, the reduction product and a chlorinating agent undergo a chlorination reaction to obtain substituted dicyclohexyl methyl chloride; reacting magnesium metal with substituted dicyclohexyl methyl chloride in a third solvent to obtain the Grignard reagent.

In a preferred embodiment, the ratio of the amount of magnesium metal to the amount of the substance substituted for dicyclohexylmethyl chloride is (1 to 1.2): 1. The mass ratio of the magnesium metal to the substituted dicyclohexyl methyl chloride comprises but is not limited to the above range, and the conversion rate of the substituted dicyclohexyl methyl chloride is improved by limiting the mass ratio to the above range, so that the yield of the Grignard reagent is improved, and sufficient raw materials are provided for the Grignard coupling reaction.

The second solvent and the third solvent may be any organic solvent commonly used in the art. In a preferred embodiment, the second solvent and the third solvent each independently include, but are not limited to, one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, xylene.

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 dicyclohexylethylenefluorobenzene compound is n-propyl cyclohexylethylene 2, 3-difluorophenethyl ether. The synthesis method provided by the application is particularly suitable for synthesizing the n-propyl cyclohexyl ethylene 2, 3-difluorophenethyl ether.

The present application is described in further detail below in conjunction with specific embodiments, which should not be construed as limiting the scope of the claims.

Example 1

A synthetic method of a substituted dicyclohexyl ethylene fluorobenzene compound comprises the following steps:

(1) Chloromethylation reaction

The synthetic route for this reaction is as follows:

into a 500mL three-necked flask, 31.6g (0.2 mol) of 2, 3-difluorophenetole, 9g (0.3 mol) of paraformaldehyde and 3.5g of ZnCl were charged ₂ 304g of 36% strength by mass concentrated hydrochloric acid (3 mol) and 150mL of cyclohexane as the first solvent. Under the stirring condition, the reaction system is heated to 60 ℃ and continuously reacts for 24 hours to obtain the product. The reaction system is cooled to room temperature, 250mL of water and 100mL of cyclohexane are added for dilution, the mixture is stirred for 15min and then is kept stand for liquid separation, an organic layer and a water layer are obtained, wherein the organic layer is washed to be neutral by water, 5g of silica gel column chromatography is adopted, 50mL of cyclohexane is used for flushing the column, the organic layer is concentrated to be basically concentrated to be dry, 38.5g of product is obtained, and 200mL of toluene is adopted for completely dissolving the product for standby. Calculated, the theoretical yield of 4-ethoxy-2, 3-difluorobenzyl chloride was 41.3g,the yield thereof was found to be 93.22%. A toluene solution of 38.5g (0.186 mol) of 4-ethoxy-2, 3-difluorobenzyl chloride was prepared for further use. FIG. 1 is a mass spectrum of the prepared 4-ethoxy-2, 3-difluorobenzyl chloride, and FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the 4-ethoxy-2, 3-difluorobenzyl chloride.

(2) Synthesis of grignard reagents

The synthetic route for this reaction is as follows:

4.9g (0.204 mol) of magnesium turnings and 10mL of tetrahydrofuran are added into a 500mL three-port bottle, nitrogen is adopted for replacement for 5 times, a reaction system is heated to 65 ℃, 1 particle of iodine is added into the reaction system, 10mL of initiator is dropwise added, wherein the initiator consists of 50g (0.206 mol) of propyl dicyclohexylmethyl chloride and 250mL of third solvent tetrahydrofuran, the temperature is controlled to be 55-60 ℃ after initiation, the rest solution is dropwise added, and the temperature is kept at 60 ℃ for 2 hours after the completion of dropwise addition, so as to obtain the Grignard reagent.

(3) Grignard coupling reaction

The synthetic route of the grignard coupling reaction is as follows:

at room temperature, the prepared toluene solution of 38.5g (0.186 mol) of 4-ethoxy-2, 3-difluorobenzyl chloride is added into another 500mL three-necked flask, 0.96g (0.0037 mol) of nickel acetylacetonate and 18.23g (0.186 mol) of allyl ether are added, the reaction system is cooled to-35 to-30 ℃ after 5 times of nitrogen substitution, the prepared Grignard reagent is added dropwise, and the temperature is kept for 1h after the dropwise addition. The reaction solution and 90g of dilute hydrochloric acid with the mass concentration of 17% are subjected to acidification and hydrolysis, and in a mixed system obtained by acidification and hydrolysis, 100mL of water is used for washing an organic layer once, then 100mL of sodium bicarbonate solution with the mass concentration of 1% is used for alkaline washing once, and finally 100mL of water is used for washing three times to neutrality. The washed organic layer was concentrated to give 66.2g of crude white product with a theoretical yield of 72.9g and a yield of the desired product of 90.8%. Fig. 3 and 4 show a mass spectrum and a nuclear magnetic resonance hydrogen spectrum of the obtained target product, respectively, and the target product was confirmed to be n-propylcyclohexylethylene 2, 3-difluorophenethyl ether.

Example 2

The difference from example 1 is that: in the Grignard coupling reaction process, tetramethyl ethylenediamine is used as a ligand to replace allyl ether in the example 1, and the weight ratio of 4-ethoxy-2, 3-difluoro benzyl chloride to tetramethyl ethylenediamine is 100:80. The remaining steps were the same as in example 1.

Example 3

The difference from example 1 is that: the mass ratio of 4-ethoxy-2, 3-difluorobenzyl chloride to allyl ether was 5:1. The remaining steps were the same as in example 1.

Example 4

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the allyl ether is 1:1. The remaining steps were the same as in example 1.

Example 5

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the allyl ether is 1:1.5. The remaining steps were the same as in example 1.

Example 6

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the nickel acetylacetonate is 100:10.

Example 7

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the nickel acetylacetonate is 100:20.

Example 8

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the grignard reagent was 1:1.5.

Example 9

The difference from example 1 is that: the mass ratio of the 4-ethoxy-2, 3-difluorobenzyl chloride to the grignard reagent was 1:2.

Example 10

The difference from example 1 is that: the temperature of the Grignard coupling reaction was-40℃for 4 hours.

Example 11

The difference from example 1 is that: the temperature of the Grignard coupling reaction was 30℃for 2 hours.

Example 12

The difference from example 1 is that: the temperature of the Grignard coupling reaction was 50℃for 2 hours.

Example 13

The difference from example 1 is that: in the chloromethylation reaction process, the weight ratio of the 2, 3-difluorophenetole to the zinc chloride is 100:10; the mass ratio of 2, 3-difluorophenetole to paraformaldehyde is 1:1.1.

Example 14

The difference from example 1 is that: in the chloromethylation reaction process, the weight ratio of the 2, 3-difluorophenetole to the zinc chloride is 100:40; the mass ratio of 2, 3-difluorophenetole to paraformaldehyde is 1:2.

Example 15

The difference from example 1 is that: in the chloromethylation reaction process, the weight ratio of the 2, 3-difluorophenetole to the zinc chloride is 100:1; the mass ratio of 2, 3-difluorophenetole to paraformaldehyde is 1:0.8.

Example 16

The difference from example 1 is that: in the chloromethylation reaction process, the first solvent is petroleum ether, and the weight ratio of petroleum ether to 2, 3-difluorophenetole is 3:1.

Example 17

The difference from example 1 is that: in the chloromethylation reaction process, the first solvent is tetrahydrofuran, and the weight ratio of the tetrahydrofuran to the 2, 3-difluorophenetole is 6:1.

Example 18

The difference from example 1 is that: in the chloromethylation reaction process, the weight ratio of the first solvent to the 2, 3-difluorophenetole is 8:1.

Example 19

The difference from example 1 is that: chloromethylation was carried out at 30℃for 32h.

Example 20

The difference from example 1 is that: the chloromethylation reaction was carried out at a temperature of 70℃for 18h.

Example 21

The difference from example 1 is that: the chloromethylation reaction was carried out at 25℃for the same time as in example 1.

Comparative example 1

The difference from example 1 is that: no allyl ether was added during the grignard coupling reaction. The remaining steps were the same as in example 1.

Comparative example 2

The difference from example 1 is that: copper chloride is used as a catalyst in the Grignard coupling reaction process to replace the nickel acetylacetonate in example 1.

Comparative example 3

The difference from example 1 is that: palladium acetate is used as a catalyst in the grignard coupling reaction process to replace the nickel acetylacetonate in example 1.

The yields of 4-ethoxy-2, 3-difluorobenzyl chloride and the yields of the desired product (i.e., n-propylcyclohexylethylene 2, 3-difluorophenethyl ether) produced in all of the above examples and comparative examples of the present application are summarized in table 1.

TABLE 1

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

as is apparent from comparison between examples 1 and 2 and comparative examples 1 and 2, compared with the conventional grignard coupling reaction, the preferred nickel-based catalyst and the ligand of the specific type according to the present invention are used to form a complex with the nickel-based catalyst and the grignard reagent, so that the loading amount of the nickel-based catalyst can be reduced, the complex does not need to undergo the process of eliminating beta of an electrophile or can be coupled to produce a cross-coupled product while forming the complex during the reaction with the 2, 3-difluorobenzyl chloride compound, thereby improving the reaction rate, inhibiting the self-coupling reaction of the grignard reagent and the grignard exchange reaction of the grignard reagent and the 2, 3-difluorobenzyl chloride compound, thereby reducing side reactions, improving the conversion rate of raw materials, and significantly improving the yield and purity of the target product.

Comparing examples 1, 3 to 5, it is known that the mass ratio of 4-ethoxy-2, 3-difluorobenzyl chloride to allyl ether includes, but is not limited to, the preferred ranges of the present application, and the preferred ranges of the present application are limited to the advantages of the ligand and the nickel catalyst that more effectively form a complex with the grignard reagent, the advantages of reducing the loading of the nickel catalyst, generating cross-coupled products without beta elimination or simultaneous coupling of electrophiles, improving the reaction rate, and inhibiting the grignard exchange of the grignard reagent with the benzyl chloride, thereby controlling the side reaction of the self-coupling of the benzyl chloride, and thus improving the yield of the target product.

Comparing examples 1, 6 and 7, it is understood that the mass ratio of 4-ethoxy-2, 3-difluorobenzyl chloride to nickel acetylacetonate includes, but is not limited to, the preferred ranges of the present application, and limiting the mass ratio to the preferred ranges of the present application is advantageous for improving the catalytic efficiency of the nickel-based catalyst, thereby being advantageous for improving the yield of the target product.

Comparing examples 1, 8 and 9, it is understood that the mass ratio of 4-ethoxy-2, 3-difluorobenzyl chloride to grignard reagent includes, but is not limited to, the preferred ranges of the present application, and that limiting the mass ratio to the preferred ranges of the present application is advantageous for increasing the conversion of the reaction raw materials and for increasing the yield of the target product.

As can be seen from comparing examples 1, 10 to 12, the temperature and time of the grignard coupling reaction include, but are not limited to, the preferred ranges of the present application, and limiting the same to the preferred ranges of the present application is advantageous for suppressing the occurrence of side reactions in the process, for improving the conversion rate of the raw materials, and thus for improving the yield of the target product.

Comparing examples 1, 13 to 15, it can be seen that the weight ratio of 2, 3-difluorophenetole to zinc chloride includes, but is not limited to, the preferred ranges of the present application, and limiting it to the preferred ranges of the present application is advantageous for further increasing the reaction rate of chloromethylation reaction; the mass ratio of the 2, 3-difluorophenetole to the paraformaldehyde comprises but is not limited to the preferred range of the application, and the mass ratio is limited to the preferred range of the application, so that the conversion rate of raw materials is improved, the generation rate of 4-ethoxy-2, 3-difluorobenzyl chloride is improved, and more sufficient raw materials are provided for the subsequent Grignard coupling reaction.

Comparing examples 1, 16 to 18, it is known that the use of the first solvent of the preferred type and limiting the amount of the first solvent within the preferred range of the present application is advantageous for further improving the compatibility of the 2, 3-difluorophenyl ether compound with the first solvent, and for further improving the reaction efficiency of the chloromethylation reaction, thereby being advantageous for improving the yield of the 2, 3-difluorobenzyl chloride compound; meanwhile, the occurrence of side reaction is further restrained, so that the purity of the 2, 3-difluorobenzyl chloride compound is further improved.

Comparing examples 1, 19 to 21, it is understood that the temperature and time of chloromethylation reaction include, but are not limited to, the preferred ranges of the present application, and limiting the temperature and time to the preferred ranges of the present application is advantageous for suppressing the occurrence of side reactions, thereby being advantageous for improving the conversion rate of raw materials during chloromethylation reaction, thereby being advantageous for improving the yield and purity of 2, 3-difluorobenzyl chloride compound, and providing conditions for subsequent reactions.

It should be noted that the terms "first," "second," and the like in the description and in the claims of the present application are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the application described herein are, for example, capable of operation in sequences other than those described herein.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. The synthesis method of the substituted dicyclohexyl ethylene fluorobenzene compound is characterized in that the substituted dicyclohexyl ethylene fluorobenzene compound has a structure shown in a formula (I):

the synthesis method comprises the following steps:

in a first solvent, carrying out chloromethylation reaction on a 2, 3-difluorophenyl ether compound to obtain a 2, 3-difluorobenzyl chloride compound, wherein the synthetic route of the 2, 3-difluorobenzyl chloride compound is as follows:

in a second solvent, in the presence of a nickel catalyst and a ligand, carrying out Grignard coupling reaction on the 2, 3-difluorobenzyl chloride compound and a Grignard reagent to obtain the substituted dicyclohexyl ethylene fluorobenzene compound, wherein the ligand is selected from tetramethyl ethylenediamine and/or allyl ether, and the synthetic route of the substituted dicyclohexyl ethylene fluorobenzene compound is as follows:

2. the method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 1, wherein the chloromethylation reaction is performed under the catalysis of zinc chloride; preferably, the weight ratio of the 2, 3-difluorophenyl ether compound to the zinc chloride is 100 (10-40);

preferably, the chloromethylation reaction system also comprises formaldehyde and/or paraformaldehyde and hydrochloric acid; preferably, the mass ratio of the 2, 3-difluorophenyl ether compound to the formaldehyde and/or paraformaldehyde is 1 (1.1-2);

more preferably, the mass concentration of the hydrochloric acid is 30-38 wt%; further preferably, the mass ratio of the hydrochloric acid having a mass concentration of 36% to the 2, 3-difluorophenyl ether compound is (8-15): 1.

3. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 1 or 2, wherein 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, tetrahydrofuran.

4. The method for synthesizing a substituted dicyclohexylethylenefluorobenzene compound according to any one of claims 1 to 3, wherein the chloromethylation reaction is carried out at a temperature of 30 to 70 ℃ for 18 to 32 hours.

5. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 4, wherein the mass ratio of the 2, 3-difluorobenzyl chloride compound to the grignard reagent is 1 (1-1.5); preferably, the mass ratio of the 2, 3-difluorobenzyl chloride compound to the nickel catalyst is 100 (2-10); preferably, the weight ratio of the 2, 3-difluorobenzyl chloride compound to the ligand is 100 (20-100).

6. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 5, wherein the nickel-based catalyst is one or more selected from the group consisting of nickel acetylacetonate, nickel chloride and bis (triphenylphosphine) nickel dichloride.

7. The method for synthesizing a substituted dicyclohexylethylene fluorobenzene compound according to any one of claims 1 to 6, wherein the temperature of the grignard coupling reaction is-40 to 30 ℃ for 1 to 4 hours.

8. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 1, further comprising:

taking substituted dicyclohexyl formic acid as a raw material, and sequentially carrying out esterification reaction, reduction reaction and chlorination reaction to obtain substituted dicyclohexyl methyl chloride; the substituted dicyclohexylmethyl chloride has a structure shown in a formula (II):

reacting magnesium metal with the substituted dicyclohexylmethyl chloride in a third solvent to obtain the grignard reagent.

9. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 8, wherein the ratio of the amount of the magnesium metal to the amount of the substituted dicyclohexyl methyl chloride is (1-1.2): 1; preferably, the second solvent and the third solvent are each independently selected from one or more of the group consisting of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, xylene.

10. The method for synthesizing a substituted dicyclohexyl ethylenefluorobenzene compound according to claim 1, wherein the 2, 3-difluorobenzyl chloride compound is 4-ethoxy-2, 3-difluorobenzyl chloride, the grignard reagent is propyl dicyclohexylmethyl chloride, and the substituted dicyclohexyl ethylenefluorobenzene compound is n-propyl cyclohexylethylene 2, 3-difluorophenethyl ether.