A kind of preparation method of alkylcyclohexylbenzidine

Abstract

The invention relates to a preparation method of alkylcyclohexylbenzidine, belonging to the technical field of chemical synthesis. The preparation method comprises the following steps: under the protection of inert gas, compound A is dissolved in a solvent, a palladium catalyst and a ligand are added, and a tetrahydrofuran solution of lithium hexamethyldisilazide is added dropwise to the system for reaction; after the reaction is completed, the reaction is quenched, an organic phase is separated, a hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to a strong acidity, and a solid product is obtained by solid-liquid separation. After the solid product is diluted with tetrahydrofuran, a sodium hydroxide aqueous solution is added dropwise to adjust the pH to a strong alkalinity, and then the alkylcyclohexylbenzidine is obtained by post-treatment and purification. The preparation method of the invention is simple to operate, short in time, high in yield, and conducive to industrial production. The purity of the alkylcyclohexylbenzidine obtained by the preparation method of the invention is not less than 99.9%, and the yield is not less than 78%, that is, both the yield and the purity are relatively high.

Description

Technical Field

[0001] The invention relates to a method for preparing alkylcyclohexylbenzidine, and belongs to the technical field of chemical synthesis. Background Art

[0002] Alkylcyclohexylbenzidine is an important liquid crystal intermediate with a wide range of uses. Its structural formula is as follows: ; Wherein, R1 is any one of n-propyl, n-butyl and n-pentyl; the alkylcyclohexylbenzidine can be applied to liquid crystal displays.

[0003] Alkylcyclohexylbenzidine is an aromatic primary amine compound. Aromatic primary amine compounds are widely present in natural and synthetic substances. Due to their special properties, they are widely used in the synthesis of display materials, spices, dyes, drugs and other substances. In the past, the most commonly used method for synthesizing aromatic primary amine compounds was to prepare aromatic primary amines using the method of catalytic hydrogenation of nitroaromatic hydrocarbons. However, aromatic nitration generally uses high temperature and high pressure violent reaction conditions, so it has high requirements for equipment and is inconvenient to operate. Chinese patent application CN1555921A discovered a transition metal-catalyzed method for preparing aniline from benzene at normal pressure and low temperature using ammonia water as an amine source and hydrogen peroxide as an oxidant, but the conversion rate is low. In recent years, the direct use of ammonia water and ammonia gas as amine sources using transition metal catalysis to prepare aromatic halides into aromatic primary amines has received widespread attention. However, the nucleophilicity of ammonia water or ammonia gas is weak, competing with the resulting aromatic primary amines, resulting in the generation of a large amount of secondary amines or tertiary amines, and ammonia is easy to coordinate with transition metals, resulting in catalyst deactivation by forming inert transition metal-ammine complexes, which may poison the catalyst.

[0004] Chinese patent application CN102050687A discloses a method for preparing aromatic halides into aromatic primary amines in an aqueous system, using ammonia water as an amine source, carbonates, fluorides, phosphates and hydroxides of alkali metals or alkaline earth metals as bases, adding a surfactant, and a ternary system consisting of a copper catalyst, oxalohydrazide and ketone. This method has a complex catalytic system, is not environmentally friendly, has a long reaction time, and is not conducive to industrial production. Summary of the invention

[0005] The invention aims at the deficiencies in the prior art and provides a method for preparing alkylcyclohexylbenzidine. The method has the advantages of simple operation, short time and high yield, and is conducive to industrial production.

[0006] The technical solution of the present invention to solve the above technical problem is as follows: a method for preparing alkylcyclohexylbenzidine, the preparation method comprising:

[0007] S1. Under the protection of inert gas, compound A is dissolved in a solvent, a palladium catalyst and a ligand are added, and a tetrahydrofuran solution of lithium hexamethyldisilazide is added dropwise to the system to react;

[0008] S2. After the reaction of step S1 is completed, the reaction is quenched, the organic phase is separated, and a hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to a strong acidity, and a solid product is obtained by solid-liquid separation. After the solid product is diluted with tetrahydrofuran, a sodium hydroxide aqueous solution is added dropwise to adjust the pH to a strong alkalinity, and then the alkylcyclohexylbenzidine is obtained by post-treatment and purification;

[0009] The compound A is: ;

[0010] The alkylcyclohexylbenzidine is ;

[0011] X is Cl, Br or I; R1 is n-propyl, n-butyl or n-pentyl;

[0012] Furthermore, in step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 10-40°C;

[0013] When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 50-100° C.;

[0014] After the lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise, the temperature in the reaction system was controlled at 60-110° C. for heat preservation reaction.

[0015] Preferably, in step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 20-30° C.;

[0016] When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 60-70° C.;

[0017] After the lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise, the temperature in the reaction system was controlled at 90-100° C. for heat preservation reaction.

[0018] Furthermore, the insulation reaction time is 2 to 10 hours.

[0019] Preferably, the insulation reaction time is 3 to 6 hours.

[0020] Further, the palladium catalyst is at least one of Pd2dba3, palladium acetate, and PdCl2(PhCN)2;

[0021] The ligand is at least one of Xphos, RuPhos and Cy3P.

[0022] Preferably, the palladium catalyst is Pd2dba3, and the ligand is Xphos.

[0023] Furthermore, the solvent is toluene.

[0024] Furthermore, the molar ratio of compound A, palladium catalyst, ligand, and lithium hexamethyldisilazide is 1:(0.01-0.03):(0.02-0.06):(1.0-1.5); the molar ratio of the palladium catalyst and the ligand is 1:(2-2.5).

[0025] Preferably, the molar ratio of the compound A, the palladium catalyst, the ligand, and lithium hexamethyldisilazide is 1:0.02:0.04:1.5; and the molar ratio of the palladium catalyst and the ligand is 1:2.

[0026] Furthermore, in step S2, hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to 1-2; sodium hydroxide aqueous solution is added dropwise to adjust the pH to 13-14.

[0027] Further, the post-processing purification operation is:

[0028] Toluene is added to a system whose pH is adjusted to a strong alkaline state, and an aqueous phase is separated after stratification. The aqueous phase is extracted with toluene and then the obtained organic phases are combined. The organic phase is washed with a sodium chloride aqueous solution until neutral, and the organic phase is dried with anhydrous sodium sulfate and then passed through a neutral alumina column. After the organic phase is passed through the column, the solvent is removed from the organic phase to obtain a solid crude product, and the crude product is recrystallized. The solvent used for the recrystallization is a mixed solvent of petroleum ether and anhydrous ethanol, and the mass ratio of petroleum ether to anhydrous ethanol is (1.9-2.1):1; and finally, the alkylcyclohexylbenzidine is obtained after drying.

[0029] Furthermore, the alkylcyclohexylbenzidine is any one of the following structural formulas:

[0030] .

[0031] The beneficial effects of the present invention are:

[0032] The preparation method of the present invention is simple to operate, short in time, high in yield, and conducive to industrial production. The purity of the alkylcyclohexylbenzidine prepared by the preparation method of the present invention is not less than 99.9% (that is, the alkylcyclohexylbenzidine product that meets the downstream application standards can be directly obtained), and the yield is not less than 78%, that is, the yield and purity are both relatively high.

[0033] In the preparation method of alkylcyclohexylbenzidine of the present invention, lithium hexamethyldisilazide is used as an amine source, and only one-step reaction and hydrochloric acid hydrolysis are required to obtain the target product, the operation is simpler, the conversion rate reaches more than 99%, the crude product has high purity, is easy to purify, and has a high yield. In addition, the reaction conditions of the preparation method of the present invention are easier to control, no harsh reaction conditions are required, and no special equipment is required, which is more suitable for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the GC-MS spectrum of compound A1 in Example 1;

[0035] Figure 2 is the H NMR spectrum of compound A1 in Example 1;

[0036] Figure 3 for Figure 2 H NMR spectrum with chemical shift of 0.8-2.6;

[0037] Figure 4 for Figure 2 H NMR spectrum with chemical shift of 7.2-7.6;

[0038] Figure 5 is the NMR carbon spectrum of compound A1 in Example 1;

[0039] Figure 6 is the GC-MS spectrum of 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) in Example 1;

[0040] Figure 7 is the H NMR spectrum of 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) in Example 1;

[0041] Figure 8 for Figure 7 H NMR spectrum with chemical shift of 0.6-2.7;

[0042] Fig. 9 for Figure 7 H NMR spectrum with chemical shift of 4.6-7.8;

[0043] Fig.10 is the C NMR spectrum of 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) in Example 1;

[0044] Fig.11 for Fig.10 The NMR carbon spectrum with chemical shifts of 14.0-44.0;

[0045] Fig.12 for Fig.10 The chemical shift of the carbon NMR spectrum is 112.0-150.0. DETAILED DESCRIPTION

[0046] In order to make the above-mentioned purpose, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0048] A method for preparing alkylcyclohexylbenzidine, the preparation method comprising:

[0049] S1. Under the protection of inert gas, compound A is dissolved in a solvent, a palladium catalyst and a ligand are added, and a tetrahydrofuran solution of lithium hexamethyldisilazide is added dropwise to the system to react;

[0050] S2. After the reaction of step S1 is completed, the reaction is quenched, the organic phase is separated, and a hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to a strong acidity, and a solid product is obtained by solid-liquid separation. After the solid product is diluted with tetrahydrofuran, a sodium hydroxide aqueous solution is added dropwise to adjust the pH to a strong alkalinity, and then the alkylcyclohexylbenzidine is obtained by post-treatment and purification;

[0051] The compound A is: ;

[0052] The alkylcyclohexylbenzidine is ;

[0053] X is Cl, Br or I; R1 is n-propyl, n-butyl or n-pentyl;

[0054] The reaction process of the alkylcyclohexylbenzidine preparation method is as follows:

[0055] .

[0056] Specifically, in step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 10-40°C;

[0057] When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 50-100° C.;

[0058] After the lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise, the temperature in the reaction system was controlled at 60-110° C. for heat preservation reaction.

[0059] Preferably, in step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 20-30° C.;

[0060] When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 60-70° C.;

[0061] After the lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise, the temperature in the reaction system was controlled at 90-100° C. for heat preservation reaction.

[0062] Specifically, the insulation reaction time is 2 to 10 hours.

[0063] Preferably, the insulation reaction time is 3 to 6 hours.

[0064] Specifically, the palladium catalyst is at least one of Pd2dba3, palladium acetate, and PdCl2(PhCN)2;

[0065] The ligand is at least one of Xphos, RuPhos and Cy3P.

[0066] Preferably, the palladium catalyst is Pd2dba3, and the ligand is Xphos.

[0067] Specifically, the solvent is toluene.

[0068] Specifically, the molar ratio of the compound A, the palladium catalyst, the ligand, and lithium hexamethyldisilazide is 1:(0.01-0.03):(0.02-0.06):(1.0-1.5); the molar ratio of the palladium catalyst and the ligand is 1:(2-2.5).

[0069] Preferably, the molar ratio of the compound A, the palladium catalyst, the ligand, and lithium hexamethyldisilazide is 1:0.02:0.04:1.5; and the molar ratio of the palladium catalyst and the ligand is 1:2.

[0070] Specifically, in step S2, hydrochloric acid solution (aqueous solution of hydrochloric acid with a mass concentration of 10%) is added dropwise to the organic phase to adjust the pH to 1-2; and sodium hydroxide aqueous solution (aqueous solution of sodium hydroxide with a mass concentration of 5-10%) is added dropwise to adjust the pH to 13-14.

[0071] Specifically, the post-processing purification operation is:

[0072] Toluene is added to a system whose pH is adjusted to strong alkalinity, and an aqueous phase is separated after stratification. The aqueous phase is extracted with toluene and then the obtained organic phases are combined. The organic phase is washed with a sodium chloride aqueous solution (10% mass concentration) until neutral. The organic phase is dried with anhydrous sodium sulfate and then passed through a neutral alumina column. After the column is completed, the organic phase is dehydrated to obtain a solid crude product, and the crude product is recrystallized. The solvent used for the recrystallization is a mixed solvent of petroleum ether and anhydrous ethanol, and the mass ratio of petroleum ether to anhydrous ethanol is (1.9-2.1):1. Finally, the alkylcyclohexylbenzidine is obtained after drying.

[0073] More specifically, during the recrystallization operation, the mass ratio of the crude product to the mixed solvent is 1:(7-9); the recrystallization operation is performed by the freeze crystallization method, and the specific method is: the crude product is added to the mixed solvent and heated under reflux until it is completely dissolved, and then cooled to -25 to -15°C and filtered.

[0074] Furthermore, the alkylcyclohexylbenzidine is any one of the following structural formulas:

[0075] .

[0076] Example 1

[0077] S1. In a 500mL three-necked flask protected by N2, add compound A1 38.5g (0.1mol), Pd2dba 31.83g (0.002mol), Xphos 1.91g (0.004mol) and toluene 192.5g in sequence, stir and dissolve at room temperature, raise the temperature, and add 133.7g (0.15mol) of lithium hexamethyldisilazide tetrahydrofuran solution to the three-necked flask using a dropping funnel at 60-70℃. After the addition is completed, raise the temperature and keep it at 90-100℃ for 3 hours.

[0078] S2. Slowly drop 192.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Drop 115.5g of 10% hydrochloric acid into the organic phase for hydrolysis, adjust the pH to 1-2, produce a large amount of solids, and filter. Dilute the filter cake with 250g of tetrahydrofuran and adjust the pH to 14 with 5% NaOH aqueous solution. The solids gradually dissolve completely. Add 170g of toluene to extract, separate the aqueous phase and then extract the aqueous phase with 85g of toluene. After combining the organic phases, wash with 10% sodium chloride aqueous solution until neutral, and then add anhydrous sodium sulfate to the organic phase to dry and remove water. After drying, filter and pass the filtrate through a neutral alumina column. After passing through the column, the solvent was removed under reduced pressure. 123.7 g of petroleum ether and 61.9 g of anhydrous ethanol were added to the dried solid and heated to reflux until it was completely dissolved. The mixture was cooled to an internal temperature of -25 to -20°C and filtered. The filter cake was rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine, with a GC purity of 99.9% and a yield of 88.7%.

[0079] The GC-MS spectrum of compound A1 is as follows Figure 1 As shown, the NMR spectrum is Figure 2-Figure 5 As shown, the conditions for NMR spectrum determination are: 1 H-NMR (400MHz, Chloroform-d).

[0080] The GC-MS spectrum of 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine is as follows Figure 6 As shown, the NMR spectrum is Figure 7-Figure 12 As shown, the conditions for NMR spectrum determination are: 1 H-NMR (400 MHz, DMSO-d).

[0081] The structural formula of compound A1 is: ;

[0082] The structural formula of 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine is .

[0083] Example 2

[0084] S1. In a 500mL three-necked flask protected by N2, add compound A2 35.7g (0.1mol), Pd2dba 31.83g (0.002mol), Xphos 1.91g (0.004mol) and toluene 178.5g in sequence, stir and dissolve at room temperature, raise the temperature, and add 133.7g (0.15mol) of lithium hexamethyldisilazide tetrahydrofuran solution to the three-necked flask using a dropping funnel at 60-70℃. After the addition is completed, raise the temperature and keep it at 90-100℃ for 3 hours.

[0085] S2. Slowly drop 178.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Drop 107.1g of 10% hydrochloric acid into the organic phase for hydrolysis, adjust the pH to 1-2, produce a large amount of solids, and filter. Dilute the filter cake with 237g of tetrahydrofuran and adjust the pH to 14 with 5% NaOH aqueous solution. The solid gradually dissolves completely. Add 160g of toluene to extract, separate the aqueous phase and then extract the aqueous phase with 80g of toluene. After combining the organic phases, wash with 10% sodium chloride aqueous solution until neutral, and then add anhydrous sodium sulfate to the organic phase to dry and remove water. After drying, filter and pass the filtrate through a neutral alumina column. After passing through the column, the solvent was removed under reduced pressure. 123.7 g of petroleum ether and 61.9 g of anhydrous ethanol were added to the dried solid and heated to reflux until it was completely dissolved. The mixture was cooled to an internal temperature of -20 to -15°C and filtered. The filter cake was rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-propyl-cyclohexyl)-biphenyl-4-amine, with a GC purity of 99.9% and a yield of 78.5%.

[0086] The structural formula of compound A2 is: ;

[0087] The structural formula of 4'-(4-propyl-cyclohexyl)-biphenyl-4-amine is: .

[0088] Example 3

[0089] S1. In a 500mL three-necked flask protected by N2, add 38.5g (0.1mol) of compound A1, 0.003mol of palladium acetate, 0.006mol of RuPhos and 192.5g of toluene in sequence, stir and dissolve at room temperature, raise the temperature, and add 133.7g (0.15mol) of lithium hexamethyldisilazide tetrahydrofuran solution to the three-necked flask using a dropping funnel at 60-70°C. After the addition is completed, raise the temperature and keep it at 90-100°C for 10 hours.

[0090] S2. Slowly drop 192.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Drop 115.5g of 10% hydrochloric acid into the organic phase for hydrolysis, adjust the pH to 1-2, produce a large amount of solids, and filter. Dilute the filter cake with 250g of tetrahydrofuran and adjust the pH to 14 with 5% NaOH aqueous solution. The solids gradually dissolve completely. Add 170g of toluene to extract, separate the aqueous phase and then extract the aqueous phase with 85g of toluene. After combining the organic phases, wash with 10% sodium chloride aqueous solution until neutral, and then add anhydrous sodium sulfate to the organic phase to dry and remove water. After drying, filter and pass the filtrate through a neutral alumina column. After passing through the column, the solvent was removed under reduced pressure. The dried solid was added with 123.7 g of petroleum ether and 61.9 g of anhydrous ethanol and heated under reflux until it was completely dissolved. The solid was cooled to an internal temperature of -25 to -20 ° C and filtered. The filter cake was rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine.

[0091] In this example, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.9% and the yield is 85.5%.

[0092] Example 4

[0093] S1. In a 500mL three-necked flask protected by N2, add compound A1 38.5g (0.1mol), PdCl2(PhCN)2 0.001mol, RuPhos 1.91g 0.0025mol and toluene 192.5g in sequence, stir and dissolve at room temperature, raise the temperature, and add 89.13g (0.10mol) of lithium hexamethyldisilazide tetrahydrofuran solution into the three-necked flask using a dropping funnel at 60-70℃. After the addition is completed, raise the temperature and keep it at 90-100℃ for 6 hours.

[0094] S2. Slowly drop 192.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Drop 115.5g of 10% hydrochloric acid into the organic phase for hydrolysis, adjust the pH to 1-2, produce a large amount of solids, and filter. Dilute the filter cake with 250g of tetrahydrofuran and adjust the pH to 14 with 5% NaOH aqueous solution. The solids gradually dissolve completely. Add 170g of toluene to extract, separate the aqueous phase and then extract the aqueous phase with 85g of toluene. After combining the organic phases, wash with 10% sodium chloride aqueous solution until neutral, and then add anhydrous sodium sulfate to the organic phase to dry and remove water. After drying, filter and pass the filtrate through a neutral alumina column. After passing through the column, the solvent is removed under reduced pressure. The dried solid is added with 123.7 g petroleum ether and 61.9 g anhydrous ethanol and heated to reflux until it is completely dissolved. The mixture is cooled to an internal temperature of -25 to -20°C and filtered. The filter cake is rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine.

[0095] In this example, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.9% and the yield is 87.3%.

[0096] Example 5

[0097] S1. In a 500mL three-necked flask protected by N2, add compound A1 38.5g (0.1mol), Pd2dba 31.83g (0.002mol), Cy3P 0.004mol and toluene 192.5g in sequence, stir and dissolve at room temperature, raise the temperature, and add 133.7g (0.15mol) of lithium hexamethyldisilazide tetrahydrofuran solution to the three-necked flask using a dropping funnel at 60-70℃. After the addition is completed, raise the temperature and keep it at 100-110℃ for 2 hours.

[0098] S2. Slowly drop 192.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Drop 115.5g of 10% hydrochloric acid into the organic phase for hydrolysis, adjust the pH to 1-2, produce a large amount of solids, and filter. Dilute the filter cake with 250g of tetrahydrofuran and adjust the pH to 14 with 5% NaOH aqueous solution. The solids gradually dissolve completely. Add 170g of toluene to extract, separate the aqueous phase and then extract the aqueous phase with 85g of toluene. After combining the organic phases, wash with 10% sodium chloride aqueous solution until neutral, and then add anhydrous sodium sulfate to the organic phase to dry and remove water. After drying, filter and pass the filtrate through a neutral alumina column. After passing through the column, the solvent is removed under reduced pressure. The dried solid is added with 123.7 g petroleum ether and 61.9 g anhydrous ethanol and heated to reflux until it is completely dissolved. The mixture is cooled to an internal temperature of -25 to -20°C and filtered. The filter cake is rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine.

[0099] In this example, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.9% and the yield is 86.9%.

[0100] Comparative Example 1

[0101] 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) was prepared by the same method as in Example 1, except that tetrahydrofuran was used as the solvent for the preparation, and in step S1, a lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise at room temperature, and then the reaction was kept warm at 70° C. under reflux.

[0102] In this comparative example 1, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 93.0% and the yield is 61.2%.

[0103] During the experiment of Comparative Example 1, after the reaction was quenched, the organic phase was tested and it was found that a portion of the reaction intermediates were reduced to compound A1, resulting in lower product purity and yield.

[0104] In addition, in this comparative example 1, tetrahydrofuran is used as a solvent, which will produce a large amount of triple-effect wastewater containing tetrahydrofuran. When the hexamethyldisilazide lithium tetrahydrofuran solution is added dropwise at room temperature, the reaction is slow, and there is a large amount of unreacted lithium reagent. The subsequent sudden temperature rise will easily cause charging problems in the reaction system, which will bring safety hazards to the production and preparation process. However, the present invention uses toluene as a solvent to avoid the generation of a large amount of triple-effect wastewater, which is more conducive to environmental protection; when the hexamethyldisilazide lithium tetrahydrofuran solution is added dropwise at 60-70°C, a rapid reaction will occur during the addition process, and the subsequent temperature rise will be used for insulation reaction, so that the reaction is complete and the product conversion rate is improved.

[0105] Comparative Example 2

[0106] The same method as in Example 1 was used to prepare 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a), except that methanol was used for deprotection in step S2. The specific operation was as follows:

[0107] S1. In a 500mL three-necked flask protected by N2, add compound A1 38.5g (0.1mol), Pd2dba 31.83g (0.002mol), Xphos 1.91g (0.004mol) and toluene 192.5g in sequence, stir and dissolve at room temperature, raise the temperature, and add 133.7g (0.15mol) of lithium hexamethyldisilazide tetrahydrofuran solution to the three-necked flask using a dropping funnel at 60-70℃. After the addition is completed, raise the temperature and keep it at 90-100℃ for 3 hours.

[0108] S2. Slowly drop 192.5g of saturated sodium sulfate aqueous solution into the reaction solution to quench and separate the aqueous phase. Add methanol to the organic phase, heat to 65~70℃ and stir for 4h. After insulation, the reaction system is washed with 10% sodium chloride aqueous solution until neutral, and anhydrous sodium sulfate is added to the organic phase to dry and remove water. After drying, filter, and the filtrate is passed through a neutral alumina column. After passing through the column, the solvent is removed under reduced pressure. After drying, 123.7g of petroleum ether and 61.9g of anhydrous ethanol are added to the solid, heated to reflux until completely dissolved, cooled to an internal temperature of -25~-20℃, and filtered. The filter cake is rinsed with petroleum ether at the same temperature and dried to obtain the 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine.

[0109] In this comparative example 2, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 88.7% and the yield is 56.7%.

[0110] In the experimental process of Comparative Example 2, after the reaction was quenched, the organic phase was taken and deprotected using methanol at reflux temperature. Tracking tests showed that deprotection could be completed in 4 hours, but the purity was low, some large unknown impurities were generated, and the product state was poor during post-processing.

[0111] Comparative Example 3

[0112] 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) was prepared by the same method as in Example 1, except that in step S2, the amount of hydrochloric acid added to the organic phase was reduced to adjust the pH to 3-4.

[0113] In this comparative example 3, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.8%, and the yield is 81.3%.

[0114] From the comparison of the data of Comparative Example 3 and Example 1, it can be seen that if the amount of hydrochloric acid added in step S2 is reduced, the reaction of step S2 will be incomplete, thereby reducing the product yield.

[0115] Comparative Example 4

[0116] 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) was prepared by the same method as in Example 1, except that the amount of Xphos added in step S1 was 0.002 mol, so that the molar ratio of the palladium catalyst to the ligand was 1:1.

[0117] In this comparative example 4, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.8%, and the yield is 72.6%.

[0118] From the comparison of the data of Comparative Example 4 and Example 1, it can be seen that if the amount of ligand used is reduced, the catalytic reaction effect will be deteriorated and the product yield will be reduced.

[0119] Comparative Example 5

[0120] 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) was prepared by the same method as in Example 1, except that in step S2, the mass ratio of petroleum ether to anhydrous ethanol in the solvent used for recrystallization was 1:1, that is, the amount of petroleum ether added was 92.8 g, and the amount of anhydrous ethanol added was 92.8 g.

[0121] In this comparative example 5, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 99.7% and the yield is 68.7%.

[0122] Comparative Example 6

[0123] 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) was prepared by the same method as in Example 1, except that in step S2, the mass ratio of petroleum ether to anhydrous ethanol in the solvent used for recrystallization was 3:1, that is, the amount of petroleum ether added was 139.2 g, and the amount of anhydrous ethanol added was 46.4 g.

[0124] In this comparative example 6, the GC purity of the obtained 4'-(4-pentyl-cyclohexyl)-biphenyl-4-amine (1a) is 93.4% and the yield is 87.6%.

[0125] From the comparison of the experimental data of Comparative Examples 5 and 6 with Example 1, it can be seen that the use of the mixed solvent defined in the present invention for recrystallization purification operation is more conducive to obtaining the target product of alkylcyclohexylbenzidine with high purity and high yield.

[0126] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0127] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing alkylcyclohexylbenzidine, characterized in that: The preparation method is: S1. Under the protection of inert gas, compound A is dissolved in a solvent, a palladium catalyst and a ligand are added, and a tetrahydrofuran solution of lithium hexamethyldisilazide is added dropwise to the system to react; S2. After the reaction of step S1 is completed, the reaction is quenched, the organic phase is separated, and a hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to a strong acidity, and a solid product is obtained by solid-liquid separation. After the solid product is diluted with tetrahydrofuran, a sodium hydroxide aqueous solution is added dropwise to adjust the pH to a strong alkalinity, and then the alkylcyclohexylbenzidine is obtained by post-treatment and purification; The compound A is: ; The alkylcyclohexylbenzidine is ; X is Cl, Br or I; R1 is n-propyl, n-butyl or n-pentyl; In step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 10-40°C; When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 50-100° C.; After the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise, the temperature in the reaction system is controlled to be 60-110° C. and the reaction is carried out at a temperature-insulating state; The palladium catalyst is at least one of Pd2dba3, palladium acetate, and PdCl2(PhCN)2; the ligand is at least one of Xphos, RuPhos, and Cy3P; The post-processing purification operation is: Toluene is added to a system whose pH is adjusted to a strong alkaline state, and an aqueous phase is separated after stratification. The aqueous phase is extracted with toluene and then the obtained organic phases are combined. The organic phase is washed with a sodium chloride aqueous solution until neutral, and the organic phase is dried with anhydrous sodium sulfate and then passed through a neutral alumina column. After the organic phase is passed through the column, the solvent is removed from the organic phase to obtain a solid crude product, and the crude product is recrystallized. The solvent used for the recrystallization is a mixed solvent of petroleum ether and anhydrous ethanol, and the mass ratio of petroleum ether to anhydrous ethanol is (1.9-2.1):1; and finally, the alkylcyclohexylbenzidine is obtained after drying.

2. The method for preparing an alkylcyclohexylbenzidine according to claim 1, characterized in that: In step S1, when the palladium catalyst and the ligand are added, the temperature in the system is 20-30°C; When the lithium hexamethyldisilazide tetrahydrofuran solution is added dropwise into the reaction system, the temperature in the reaction system is 60-70° C.; After the lithium hexamethyldisilazide tetrahydrofuran solution was added dropwise, the temperature in the reaction system was controlled at 90-100° C. for heat preservation reaction.

3. The method for preparing an alkylcyclohexylbenzidine according to claim 1, characterized in that: The insulation reaction time is 2 to 10 hours.

4. The method for preparing an alkylcyclohexylbenzidine according to claim 1, characterized in that: The solvent is toluene.

5. The method for preparing alkylcyclohexylbenzidine according to claim 1, characterized in that: The molar ratio of the compound A, the palladium catalyst, the ligand, and lithium hexamethyldisilazide is 1:(0.01-0.03):(0.02-0.06):(1.0-1.5); the molar ratio of the palladium catalyst and the ligand is 1:(2-2.5).

6. The method for preparing alkylcyclohexylbenzidine according to claim 1, characterized in that: In step S2, hydrochloric acid solution is added dropwise to the organic phase to adjust the pH to 1-2; sodium hydroxide aqueous solution is added dropwise to adjust the pH to 13-14.

7. The method for preparing alkylcyclohexylbenzidine according to claim 1, characterized in that: The alkylcyclohexylbenzidine is any one of the following structural formulas: 。

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