Synthesis method of 2-bromo-5-cyclohexyl-1, 3-dimethylbenzene
Iodized by a multi-step reaction using 2,6-dimethylaniline and iodized reagent, followed by nitrosification and carbo-positive ion rearrangement in an acidic medium, and finally coupled to a cyclohexyl metal halide. , 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with high yield was successfully prepared, solving the problem of synthesis of the intermediate in the prior art, and achieving efficient and stable product preparation.
Patent Information
- Application Number
- CN202411821216.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-11
- Publication Date
- 2025-02-18
AI Technical Summary
The prior art lacks simple and efficient synthetic methods to obtain higher yields of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene, which is the key to the synthesis of thermally activated delayed fluorescence (TADF) material intermediates. question.
By iodinating 2,6-dimethylaniline with iodized reagent at 10-20°C, 4-iodine-2,6-dimethylaniline was obtained, and then nitroscopic reaction was performed in an acidic medium to produce Diazo salt and react with ketone bromide and hydrobromic acid to obtain 2-bromo-5-iodo-1,3-xylene. Finally, 2-bromo- is prepared by coupling reaction with cyclohexyl metal halide. 5-Cyclohexyl-1,3-dimethylbenzene.
This method can efficiently obtain 2-bromo-5-cyclohexyl-1,3-dimethylbenzene in high yields, the intermediate state is stable, suitable for industrial production, and improve the purity and yield of the target product.
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Figure CN119462327A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of organic optoelectronic material synthesis, and in particular to a method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene. Background Art
[0002] Traditional luminescence is fluorescence and phosphorescence, which are the exciton singlet and triplet states returning to the ground state in the form of radiative luminescence, and generally the energy level difference between the lower singlet state and the lower triplet state is relatively large, resulting in the exciton being unable to return to the singlet state once it reaches the triplet state through the intersystem crossing (ISC) process from the singlet state. In order to solve the various problems of traditional fluorescent materials and phosphorescent materials, the recently developed third-generation luminescent materials - thermally activated delayed fluorescence (TADF) materials have attracted much attention. TADF materials avoid the pollution problem caused by heavy metals, and their main luminescence mechanism is: the energy difference between the singlet and triplet states of TADF materials is small, and the small energy difference is conducive to the triplet excitons reaching the singlet state through an effective anti-intersystem crossing process to form singlet excitons, and then produce radiative transition luminescence, achieving 100% exciton utilization.
[0003] 2-Bromo-5-cyclohexyl-1,3-dimethylbenzene is an important intermediate for the synthesis of TADF materials, but its synthesis method is still a blank in the prior art. How to simply synthesize 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a high yield has important practical significance and application value. Summary of the invention
[0004] In order to provide a method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a higher yield, the present application provides a method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene.
[0005] The present application provides a method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene, which adopts the following technical scheme: A method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene comprises the following steps: S1, subjecting 2,6-dimethylaniline and an iodination agent to an iodination reaction at 10-20° C. to obtain a crude 4-iodo-2,6-dimethylaniline product; and post-treating and purifying the crude 4-iodo-2,6-dimethylaniline product to obtain 4-iodo-2,6-dimethylaniline; S2, subjecting the 4-iodo-2,6-dimethylaniline to a nitrosation reaction in an acidic medium to obtain a diazonium salt; S3, reacting the diazonium salt, ketone bromide and hydrobromic acid to obtain a crude 2-bromo-5-iodo-1,3-xylene product; post-treating and purifying the crude 2-bromo-5-iodo-1,3-xylene product to obtain 2-bromo-5-iodo-1,3-xylene; S4, mixing bromocyclohexane, magnesium, iodine and an organic solvent for reaction to obtain a Grignard reagent; refluxing toluene, zinc chloride and the 2-bromo-5-iodo-1,3-dimethylbenzene to separate the water, and then adding the Grignard reagent dropwise to react to obtain a crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; post-treating and purifying the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene to obtain the target product 2-bromo-5-cyclohexyl-1,3-dimethylbenzene.
[0006] By adopting the above technical scheme, the present application uses 2,6-dimethylaniline as a raw material, undergoes halogenation, and then undergoes nitrosation and carbon cation rearrangement to obtain 2-bromo-5-iodo-1,3-dimethylbenzene in high yield, and then couples with cyclohexyl metal halide to prepare the target product 2-bromo-5-cyclohexyl-1,3-dimethylbenzene. The method can obtain the target product in high yield, and at the same time, the intermediates are in a stable state, which is conducive to industrial production.
[0007] In a specific embodiment, in S1, the iodination reaction is specifically as follows: using 2,6-dimethylaniline as a raw material, using elemental iodine as an iodination reagent, using water and dichloromethane as solvents, and carrying out an iodination reaction in the presence of sodium bicarbonate to obtain a crude 4-iodo-2,6-dimethylaniline product.
[0008] By adopting the above technical scheme, due to the low reactivity of molecular iodine, iodide ions are generated by the reaction of elemental iodine and sodium bicarbonate, and iodine is activated as an active substance to perform effective electrophilic substitution, and iodination reaction is selectively performed at the C-4 position of 2,6-dimethylaniline to obtain a crude 4-iodo-2,6-dimethylaniline product; this method has the advantages of fast reaction speed, simple operation, high selectivity, etc.
[0009] In a specific embodiment, the molar ratio of the 2,6-dimethylaniline, iodine and sodium bicarbonate is 1:1-1.1:1-3; and the iodine is added in multiple times.
[0010] By adopting the above technical scheme, the batch addition of iodine has the advantages of easy metering and easy operation, and can react more thoroughly with sodium bicarbonate, thereby improving the utilization rate of raw materials; at the same time, by optimizing 2,6-dimethylaniline, iodine and sodium bicarbonate, the purity and yield of the obtained product 4-iodo-2,6-dimethylaniline can be improved.
[0011] In a specific possible implementation scheme, in S1, the specific process of the post-treatment purification is: adding a saturated aqueous sodium bisulfite solution to the crude 4-iodo-2,6-dimethylaniline and then adding dichloromethane, passing through diatomaceous earth, and allowing the layers to stand to separate the upper aqueous phase and the lower organic phase; the organic phase is washed with a saturated sodium chloride solution and concentrated to obtain the 4-iodo-2,6-dimethylaniline.
[0012] By adopting the above technical solution, after dichloromethane is extracted, diatomaceous earth is used to assist filtration, so that the aqueous phase and the organic phase are clearly separated, and the organic phase is then subjected to saturated sodium chloride to remove the excess sodium bicarbonate and the remaining small amount of water dissolved in the system, which is beneficial to the subsequent concentration and purification of the organic phase. The entire post-treatment process is reasonably set up, simple to operate, and reduces the occurrence of side reactions.
[0013] In a specific embodiment, in S2, the molar ratio of 4-iodo-2,6-dimethylaniline to sodium nitrite is 1:1-1.1:2-3.
[0014] By adopting the above technical scheme, when 4-iodo-2,6-dimethylaniline is nitrosated in the present application, an N-nitroso derivative is first generated, and then isomerization occurs in an acidic medium, and intramolecular rearrangement is performed to obtain a C-nitroso derivative; at the same time, the purity and yield of the obtained product can be improved by optimizing the molar ratio of 4-iodo-2,6-dimethylaniline and sodium nitrite.
[0015] In a specific embodiment, in S2, the acid source in the acidic medium is fluoroboric acid, concentrated sulfuric acid, concentrated nitric acid or concentrated hydrochloric acid; when the nitrosation reaction occurs, the acid source is added first and then sodium nitrate.
[0016] By adopting the above technical solution, the acid source is first added to ensure that the reaction solution remains strongly acidic during the entire nitrosation process, providing H + , which is conducive to the smooth generation of N-nitroso compounds and the complete reaction; at the same time, the acid source participates in the subsequent reaction, carbon cation rearrangement occurs, and finally a high yield of diazonium salt is obtained.
[0017] In a specific embodiment, in S3, the molar ratio of the diazonium salt, ketone bromide and hydrobromic acid is 1:0.1-0.5:4-8.
[0018] By adopting the above technical scheme, the ratio of diazonium salt, ketone bromide and hydrobromic acid is optimized, so that the reaction is more efficient and sufficient, and the yield and purity of the obtained 2-bromo-5-iodo-1,3-xylene are higher.
[0019] In a specific possible implementation scheme, in S3, the specific process of the post-treatment purification is: adding petroleum ether to the crude 2-bromo-5-iodo-1,3-xylene to extract, passing through diatomaceous earth, then washing with a saturated aqueous sodium bisulfite solution, drying over anhydrous sodium sulfate, passing through silica gel, washing the obtained filter cake with petroleum ether, and concentrating the obtained organic layer to obtain the 2-bromo-5-iodo-1,3-xylene.
[0020] By adopting the above technical scheme, petroleum ether interacts with impurities in the crude 2-bromo-5-iodo-1,3-xylene product to dissolve the impurities from the crude 2-bromo-5-iodo-1,3-xylene product. After filtering through diatomaceous earth, the petroleum ether is separated from the impurity components to obtain an extract with higher purity. Then, saturated sodium sulfite and anhydrous sodium sulfate are used to remove water remaining in the crude 2-bromo-5-iodo-1,3-xylene product to reduce the water solubility of the organic phase, and the viscous solid is recrystallized using a petroleum ether solvent to make the reaction product have a higher purity.
[0021] In a specific embodiment, in S4, the molar ratio of 2-bromo-5-iodo-1,3-xylene, bromocyclohexane, magnesium and zinc chloride is 1:3-3.5:3.1-3.7:1-2.
[0022] By adopting the above technical scheme, cyclohexyl bromide and magnesium are used as raw materials, and in the presence of an initiator iodine, a Grignard reagent is reacted in an organic solvent, and the obtained Grignard reagent is subjected to a transfer metalation reaction with zinc chloride to obtain an organic zinc reagent. The organic zinc reagent has better reaction activity than a palladium reagent and a nickel reagent, and the organic zinc reagent is subjected to a carbon-carbon bond coupling reaction with 2-bromo-5-iodo-1,3-xylene to generate a target product 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; and the yield and purity of the obtained product can be improved by optimizing the molar ratio of 2-bromo-5-iodo-1,3-xylene, cyclohexyl bromide, magnesium and zinc chloride.
[0023] In a specific possible implementation scheme, in S4, the specific process of the post-treatment purification is: cooling the crude 2-bromo-5-cyclohexyl-1,3-dimethylbenzene to room temperature, controlling the temperature below 10°C, adding dilute hydrochloric acid to adjust the acidity, and then adding ethyl acetate for extraction, passing the organic layer through diatomaceous earth, and washing with saturated sodium bisulfite aqueous solution to obtain the organic layer, and then concentrating and distilling to obtain the target product.
[0024] By adopting the above technical scheme, the crude 2-bromo-5-cyclohexyl-1,3-dimethylbenzene is added to an acidic aqueous solution to quench the reaction, and then extracted with ethyl acetate, filtered with diatomaceous earth to remove the catalyst, and then dried with saturated sodium bisulfite, and distilled after drying to purify the target product.
[0025] In summary, this application has the following beneficial technical effects: 1. The present application uses 2,6-dimethylaniline as a raw material, undergoes halogenation, and then undergoes nitrosation and carbon cation rearrangement to obtain 2-bromo-5-iodo-1,3-dimethylbenzene in high yield, and then couples it with cyclohexyl metal halide to prepare the target product 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; this method can obtain the target product in high yield, and at the same time, the intermediates are in a stable state, which is conducive to industrial production; 2. In the present application, when the nitrosation reaction occurs, the acid source is first added to ensure that the reaction solution remains strongly acidic during the entire nitrosation process, providing H + , which is conducive to the smooth generation of N-nitroso compounds and the complete reaction; at the same time, the acid source participates in the subsequent reaction, the carbon cation rearrangement occurs, and finally a high yield of diazonium salt is obtained; 3. The present application controls the parameters of each process step during the process, thereby improving the utilization rate of raw materials, reducing the occurrence of side reactions, and facilitating subsequent separation and purification; at the same time, the purity of the intermediate products is improved by purifying the intermediate products by multiple means, so that the final product has the advantages of high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene prepared in Example 1 of the present application.
[0027] Figure 2 This is the HPLC spectrum of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene prepared in Example 1 of the present application. DETAILED DESCRIPTION
[0028] The present application is further described in detail below through examples.
[0029] All raw materials in the examples are commercially available. Example 1
[0030] This embodiment discloses a method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene, comprising the following steps: S1, in a reaction kettle, add 451g of 2,6-dimethylaniline, 625.3g of sodium bicarbonate, 1.8L of dichloromethane and deionized water, add iodine in batches, add 98g each time, add in 10 times, each time with an interval of 1h, control the temperature at 10-20°C, after adding, keep warm for reaction; take samples, monitor by HPLC, at this time, the reaction is completed to obtain crude 4-iodo-2,6-dimethylaniline (the remaining iodine of the raw material 2,6-dimethylaniline 0.5%, which means the reaction is over); the crude 4-iodo-2,6-dimethylaniline was transferred to a 10L bottle, 1.1L saturated sodium bisulfite solution was added dropwise to produce bubbles and become viscous, then 1.5L dichloromethane was added, and the mixture was passed through diatomaceous earth and allowed to stand for stratification. The lower aqueous phase was separated, and the organic phase was washed three times with 2L saturated sodium chloride aqueous solution until the aqueous layer became clear, the aqueous layer was discarded, and the organic layer was concentrated to obtain 919.57g of 4-iodo-2,6-dimethylaniline with a purity of 98.9%; The reaction equation in S1 is as follows: ; S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate were mixed, and 1632g of 50% pure fluoroboric acid was added dropwise at 15-20°C. After the addition was complete, the mixture was stirred for 20min, cooled to 0°C, and 269.64g of sodium nitrite aqueous solution was added dropwise. After the addition was complete, the mixture was kept warm for 1h and filtered to obtain 1212g of diazonium salt as a white solid; The reaction equation in S2 is as follows: ; S3, in a 10L three-necked flask, mix 600g DMF, 165.74g cuprous bromide and 3898g hydrobromic acid, heat to 40°C, add diazonium salt in portions, 121.2g each time, add in 10 portions, 1h interval between each addition, keep warm for 1h after addition; take samples, monitor by GCMS, the reaction is completed at this time to obtain crude 2-bromo-5-iodo-1,3-xylene (main peak 82.84%, indicating the end of the reaction); pour the crude 2-bromo-5-iodo-1,3-xylene into 10L ice water, add 8L petroleum ether for extraction, separate the lower aqueous phase, retain the organic layer, pass the aqueous phase through diatomaceous earth, retain the organic layer, discard the aqueous layer, and separate the two organic layer liquids. The organic layers were combined, 3 L of saturated sodium bisulfite aqueous solution was added to the combined organic layer for washing twice, and the mixture was dried over anhydrous sodium sulfate, and passed through silica gel. The filtrate was passed through a chromatography column, specifically: 300 g of 100-200 mesh column chromatography silica gel was installed in a 1 m high column (inner diameter 0.1 m), DCM was used as an eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain a red oily substance; the red oily substance was distilled at an internal temperature of 116 ° C and a top temperature of 80 ° C to obtain a colorless and transparent oily 2-bromo-5-iodo-1,3-xylene with a yield of 81% and a purity of 98.2%; The reaction equation in S3 is as follows: ; S4, 115.56g of bromocyclohexane was mixed with 800ml of tetrahydrofuran to form a mixed solution, 19.47g of magnesium chips, 0.15g of iodine, 100ml of tetrahydrofuran and 12.84g of bromocyclohexane were added to a 1L three-necked flask, and the reaction system was heated with a hair dryer. When the color of the system changed from red to white, the heating was stopped. When the temperature was cooled to 50°C, the mixed solution was added dropwise, and the temperature was maintained at 50°C. After the addition was completed, the system was heated to 70°C and kept warm for 3h. The reaction solution The mixture was cooled to room temperature to obtain a Grignard reagent; 300 ml of toluene, 48.69 g of zinc chloride and 74 g of 2-bromo-5-iodo-1,3-xylene were added to a 500 L three-necked flask, the mixture was refluxed and water was separated, and the mixture was transferred to a 3 L three-necked flask under nitrogen protection, the temperature was lowered to 0°C, and the Grignard reagent was added dropwise. After the addition was completed, the mixture was kept at 0°C for 30 min, nitrogen was replaced, 0.4 g of palladium dichloride was added, the temperature was raised to 75°C for reaction, and GCMS was used for monitoring. At this time, the reaction was completed to obtain 2-bromo-5-iodo-1,3-xylene. The crude product of cyclohexyl-1,3-dimethylbenzene was cooled to room temperature, and the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene was poured into 1L of ice water, the temperature was controlled below 10°C, dilute hydrochloric acid was added to adjust the acidity, and then 300ml of ethyl acetate was added for extraction, the organic layer was passed through diatomaceous earth, and washed twice with 200ml of saturated sodium sulfite aqueous solution, and dried with anhydrous sodium sulfate, and passed through silica gel. The filtrate was passed through a chromatography column, specifically: 100-2 300 g of silica gel for column chromatography with 00 mesh was used, DCM was used as eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain an oily substance; the oily substance was distilled at an internal temperature of 146°C and a top temperature of 122°C to obtain 49 g of a light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 78% and a purity of 98.9%. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 1 As shown, its HPLC spectrum is as Figure 2 As shown; The reaction equation in S4 is as follows: .
[0031] Example 2 This embodiment is basically the same as embodiment 1, except that: in S1, 451 g of 2,6-dimethylaniline, 312.7 g of sodium bicarbonate, 1.8 L of dichloromethane and deionized water were added to the reaction kettle, and iodine was added in portions, 94.2 g each time, and added in 10 portions, each time with an interval of 1 hour, and the temperature was controlled at 10-20° C. After the addition was completed, the reaction was kept warm; sampling was performed and monitored by HPLC, and the reaction was completed at this time to obtain a crude product of 4-iodo-2,6-dimethylaniline (original The crude 4-iodo-2,6-dimethylaniline was transferred to a 10L bottle, 1.1L saturated sodium bisulfite solution was added dropwise to produce bubbles and thicken, then 1.5L dichloromethane was added, and the mixture was passed through diatomaceous earth and allowed to stand for stratification. The lower aqueous phase was separated, and the organic phase was washed three times with 2L saturated sodium chloride aqueous solution until the aqueous layer became clear. The aqueous layer was discarded, and the organic layer was concentrated to obtain 458.63g of 4-iodo-2,6-dimethylaniline with a purity of 96.5%.
[0032] Finally, after four steps of reaction, 44.4 g of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a purity of 98.2% and a yield of 69.9% was obtained.
[0033] Example 3 This embodiment is basically the same as embodiment 1, except that: in S1, 451 g of 2,6-dimethylaniline, 938 g of sodium bicarbonate, 1.8 L of dichloromethane and deionized water were added to the reaction kettle, and iodine was added in batches, 103.6 g each time, and added in 10 times, each time with an interval of 1 hour, and the temperature was controlled at 10-20° C. After the addition was completed, the reaction was kept warm; sampling was taken and monitored by HPLC, and the reaction was completed at this time to obtain a crude 4-iodo-2,6-dimethylaniline (raw material The reaction was completed with 0.5% of 2,6-dimethylaniline remaining); the crude 4-iodo-2,6-dimethylaniline was transferred to a 10L bottle, 1.1L of saturated sodium bisulfite solution was added dropwise until bubbles appeared and the solution became viscous, then 1.5L of dichloromethane was added, and the solution was passed through diatomaceous earth and allowed to stand for stratification. The lower aqueous phase was separated, and the organic phase was washed three times with 2L of saturated sodium chloride aqueous solution until the aqueous layer became clear. The aqueous layer was discarded, and the organic layer was concentrated to obtain 924.32g of 4-iodo-2,6-dimethylaniline with a purity of 98.5%.
[0034] Finally, after four steps of reaction, 47.3 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 74.5% and a purity of 97.2% was obtained.
[0035] Example 4 This embodiment is basically the same as embodiment 1, except that: in S1, 451 g of 2,6-dimethylaniline, 156.4 g of sodium bicarbonate, 1.8 L of dichloromethane and deionized water were added to the reaction kettle, and iodine was added in batches, 188.4 g each time, and added in 10 times, each time with an interval of 1 hour, and the temperature was controlled at 10-20° C. After the addition was completed, the reaction was kept warm; sampling was performed and monitored by HPLC. At this time, the reaction was completed to obtain a crude product of 4-iodo-2,6-dimethylaniline (original The crude 4-iodo-2,6-dimethylaniline was transferred to a 10L bottle, 1.1L saturated sodium bisulfite solution was added dropwise to produce bubbles and the solution became viscous, then 1.5L dichloromethane was added, the solution was passed through diatomaceous earth, and the layers were separated. The lower aqueous phase was separated, and the organic phase was washed three times with 2L saturated sodium chloride aqueous solution until the aqueous layer became clear. The aqueous layer was discarded, and the organic layer was concentrated to obtain 236.34g of 4-iodo-2,6-dimethylaniline with a purity of 97.6%.
[0036] Finally, after four steps of reaction, 39.4 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 62.1% and a purity of 95.3% was obtained.
[0037] Example 5 This embodiment is basically the same as embodiment 1, except that: S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate are mixed, and 1632g of fluoroboric acid is added dropwise at 15-20°C. After the addition is complete, stir for 20min, cool to 0°C, and add 256.8g of sodium nitrite aqueous solution dropwise. After the addition is complete, keep warm for 1h and filter to obtain 1034g of white borate solid.
[0038] Finally, after four steps of reaction, 47.7 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 75.1% and a purity of 98.1% was obtained.
[0039] Example 6 This embodiment is basically the same as embodiment 1, except that: S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate are mixed, and 1632g of fluoroboric acid is added dropwise at 15-20°C. After the addition is complete, stir for 20min, cool to 0°C, and add 282.5g of sodium nitrite aqueous solution dropwise. After the addition is complete, keep warm for 1h and filter to obtain 1193g of white borate solid.
[0040] Finally, after four steps of reaction, 48 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 75.6% and a purity of 98.3% was obtained.
[0041] Example 7 This embodiment is basically the same as embodiment 1, except that: S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate are mixed, and 1632g of fluoroboric acid is added dropwise at 15-20°C. After the addition is complete, stir for 20min, cool to 0°C, and add 513.6g of sodium nitrite aqueous solution dropwise. After the addition is complete, keep warm for 1h and filter to obtain 1150g of white borate solid.
[0042] Finally, after four steps of reaction, 41.4 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 65.2% and a purity of 97.1% was obtained.
[0043] Example 8 This embodiment is basically the same as embodiment 1, except that: S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate are mixed, and 269.64g of sodium nitrite aqueous solution is added at 0°C. After the addition is complete, stirring is performed for 20min. 1632g of fluoroboric acid is added at 15-20°C. After the addition is complete, the mixture is kept warm for 1h and filtered to obtain 1042g of white borate solid.
[0044] Finally, after four steps of reaction, 44.7 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 70.4% and a purity of 93.9% was obtained.
[0045] Example 9 This embodiment is basically the same as embodiment 1, except that, S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate were mixed, and 269.64g of sodium nitrite aqueous solution was added at 0°C. After the addition was completed, stirring was performed for 20min. 652.8g of fluoroboric acid was added at 15-20°C. After the addition was completed, the mixture was kept warm for 1h and filtered to obtain 1065g of white borate solid.
[0046] Finally, after four steps of reaction, 44.8 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 70.6% and a purity of 97.5% was obtained.
[0047] Example 10 This embodiment is basically the same as embodiment 1, except that, S2, in a 10L three-necked flask, 919.57g of 4-iodo-2,6-dimethylaniline and 4000g of ethyl acetate are mixed, and then 269.64g of sodium nitrite aqueous solution is added at 0°C. After the addition is completed, stirring is performed for 20min. 1632g of concentrated hydrochloric acid with a purity of 50% is added at 15-20°C. After the addition is completed, the mixture is kept warm for 1h and filtered to obtain 1001g of chlorate.
[0048] Finally, after four steps of reaction, 41.8 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 65.9% and a purity of 91.1% was obtained.
[0049] Embodiment 11 This embodiment is basically the same as embodiment 1, except that: S3, in a 10L three-necked flask, 600g DMF, 55.25g cuprous bromide and 2599g hydrobromic acid are mixed, the temperature is raised to 40°C, and borate is added in portions, 121.2g each time, and added in 10 portions, each time with an interval of 1h. After the addition is completed, the reaction is kept warm for 1h; sampling is performed and monitored by GCMS. At this time, the reaction is completed to obtain a crude product of 2-bromo-5-iodo-1,3-xylene; the crude product of 2-bromo-5-iodo-1,3-xylene is poured into 10L ice water, extracted with 8L petroleum ether, the lower aqueous phase is separated, the organic layer is retained, the aqueous phase is passed through diatomaceous earth, the organic layer is retained, the aqueous layer is discarded, and the two organic layers are separated. The liquid layers were combined, 3 L of saturated sodium bisulfite aqueous solution was added to the combined organic layer, washed twice, and dried with anhydrous sodium sulfate, and passed through silica gel. The filtrate was passed through a chromatography column, specifically: 300 g of 100-200 mesh column chromatography silica gel was installed in a 1 m high column (inner diameter 0.1 m), DCM was used as an eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain a red oily substance; the red oily substance was distilled at an internal temperature of 116 ° C and a top temperature of 80 ° C to obtain a colorless and transparent oily 2-bromo-5-iodo-1,3-xylene with a yield of 77% and a purity of 97.1%; Finally, after four steps of reaction, 46.5 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 73.2% and a purity of 98.1% was obtained.
[0050] Example 12 This embodiment is basically the same as embodiment 1, except that: S3, in a 10L three-necked flask, 600g DMF, 276.25g cuprous bromide and 5198g hydrobromic acid are mixed, the temperature is raised to 40°C, borate is added in portions, 121.2g each time, and the addition is divided into 10 portions, each time with an interval of 1h. After the addition is completed, the reaction is kept warm for 1h; sampling is taken and monitored by GCMS. At this time, the reaction is completed to obtain a crude product of 2-bromo-5-iodo-1,3-xylene; the crude product of 2-bromo-5-iodo-1,3-xylene is poured into 10L ice water, extracted with 8L petroleum ether, the lower aqueous phase is separated, the organic layer is retained, the aqueous phase is passed through diatomaceous earth, the organic layer is retained, the aqueous layer is discarded, and the two organic layers are separated. The liquid layers were combined, 3 L of saturated sodium bisulfite aqueous solution was added to the combined organic layer, washed twice, and dried with anhydrous sodium sulfate, and passed through silica gel. The filtrate was passed through a chromatography column, specifically: 300 g of 100-200 mesh column chromatography silica gel was installed in a 1 m high column (inner diameter 0.1 m), DCM was used as an eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain a red oily substance; the red oily substance was distilled at an internal temperature of 116 ° C and a top temperature of 80 ° C to obtain a colorless and transparent oily 2-bromo-5-iodo-1,3-xylene with a yield of 75% and a purity of 96.3%; Finally, after four steps of reaction, 44.7 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 70.4% and a purity of 97.7% was obtained.
[0051] Embodiment 13 This embodiment is basically the same as embodiment 1, except that: S3, in a 10L three-necked flask, 600g DMF, 552.5g cuprous bromide and 1299.5g hydrobromic acid are mixed, the temperature is raised to 40°C, and borate is added in portions, 121.2g each time, and added in 10 portions, each time with an interval of 1h. After the addition is completed, the reaction is kept warm for 1h; sampling is performed and monitored by GCMS. At this time, the reaction is completed to obtain a crude product of 2-bromo-5-iodo-1,3-xylene; the crude product of 2-bromo-5-iodo-1,3-xylene is poured into 10L ice water, extracted with 8L petroleum ether, the lower aqueous phase is separated, the organic layer is retained, the aqueous phase is passed through diatomaceous earth, the organic layer is retained, the aqueous layer is discarded, and the two organic layers are separated. The organic layer liquids were combined, 3 L of saturated sodium bisulfite aqueous solution was added to the combined organic layer, washed twice, and dried with anhydrous sodium sulfate, and passed through silica gel. The obtained filtrate was passed through a chromatography column, specifically: 300 g of 100-200 mesh column chromatography silica gel was installed in a 1 m high column (inner diameter 0.1 m), DCM was used as an eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the obtained filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain a red oily substance; the red oily substance was distilled at an internal temperature of 116 ° C and a top temperature of 80 ° C to obtain a colorless and transparent oily 2-bromo-5-iodo-1,3-xylene with a yield of 71% and a purity of 96.3%; Finally, after four steps of reaction, 42.2 g of light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 66.5% and a purity of 96.2% was obtained.
[0052] Embodiment 14 This embodiment is substantially the same as embodiment 1, except that: S4, 105.06 g of bromocyclohexane is mixed with 800 ml of tetrahydrofuran to form a mixed solution, 17.75 g of magnesium chips, 0.15 g of iodine, 100 ml of tetrahydrofuran and 11.67 g of bromocyclohexane are added to a 1 L three-necked flask, and the reaction system is heated with a hair dryer. When the color of the system changes from red to white, heating is stopped. When the temperature is cooled to 50° C., the mixed solution is added dropwise, and the temperature is maintained at 50° C. After the addition is completed, The system was heated to 70°C and kept warm for 3h, and the reaction solution was cooled to room temperature to obtain the Grignard reagent; 300ml toluene, 32.46g zinc chloride and 74g 2-bromo-5-iodo-1,3-xylene were added to a 500L three-necked flask, and the water was refluxed and transferred to a 3L three-necked flask under nitrogen protection, and the temperature was lowered to 0°C, and the Grignard reagent was added dropwise. After the addition was completed, the system was kept warm at 0°C for 30min, nitrogen was replaced, 0.4g palladium dichloride was added, and the temperature was raised to 75°C for reaction, and GCMS was used for monitoring. At this time, the reaction is completed to obtain a crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; cool to room temperature, pour the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene into 1L of ice water, control the temperature below 10°C, add dilute hydrochloric acid to adjust the acidity, and then add 300ml of ethyl acetate for extraction, pass the organic layer through diatomaceous earth, and wash twice with 200ml of saturated sodium sulfite aqueous solution, and dry with anhydrous sodium sulfate, pass through silica gel, and pass the obtained filtrate through a chromatography column, specifically: on a column with a height of 1m (inner diameter 0 .1m) was filled with 300g of 100-200 mesh column chromatography silica gel, DCM was used as eluent, the amount of eluent was 2L, the flow rate was 1ml / s, the filter cake was washed with 0.5L of petroleum ether, all the eluent was collected, and then concentrated to obtain an oily substance; the oily substance was distilled at an internal temperature of 146°C and a top temperature of 122°C to obtain 36g of a light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 72% and a purity of 98.1%.
[0053] Embodiment 15 This embodiment is substantially the same as embodiment 1, except that: S4, 122.56 g of bromocyclohexane is mixed with 800 ml of tetrahydrofuran to form a mixed solution, 21.19 g of magnesium chips, 0.15 g of iodine, 100 ml of tetrahydrofuran and 13.62 g of bromocyclohexane are added to a 1 L three-necked flask, and the reaction system is heated with a hair dryer. When the color of the system changes from red to white, heating is stopped. When the temperature is cooled to 50° C., the mixed solution is added dropwise, and the temperature is maintained at 50° C. After the addition is completed, The system was heated to 70°C and kept warm for 3h, and the reaction solution was cooled to room temperature to obtain the Grignard reagent; 300ml toluene, 64.92g zinc chloride and 74g 2-bromo-5-iodo-1,3-xylene were added to a 500L three-necked flask, and the water was refluxed and transferred to a 3L three-necked flask under nitrogen protection, and the temperature was lowered to 0°C, and the Grignard reagent was added dropwise. After the addition was completed, the system was kept warm at 0°C for 30min, nitrogen was replaced, 0.4g palladium dichloride was added, and the temperature was raised to 75°C for reaction, and GCMS was used for monitoring. At this time, the reaction is completed to obtain a crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; cool to room temperature, pour the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene into 1L of ice water, control the temperature below 10°C, add dilute hydrochloric acid to adjust the acidity, and then add 300ml of ethyl acetate for extraction, pass the organic layer through diatomaceous earth, and wash twice with 200ml of saturated sodium sulfite aqueous solution, and dry with anhydrous sodium sulfate, pass through silica gel, and pass the obtained filtrate through a chromatography column, specifically: on a column with a height of 1m (inner diameter 0 .1m) was filled with 300g of 100-200 mesh column chromatography silica gel, DCM was used as eluent, the amount of eluent was 2L, the flow rate was 1ml / s, the filter cake was washed with 0.5L of petroleum ether, all the eluent was collected, and then concentrated to obtain an oily substance; the oily substance was distilled at an internal temperature of 146°C and a top temperature of 122°C to obtain 37g of a light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 74% and a purity of 98.4%.
[0054] Example 16 This embodiment is substantially the same as embodiment 1, except that: S4, 70.04 g of bromocyclohexane is mixed with 800 ml of tetrahydrofuran to form a mixed solution, 11.45 g of magnesium chips, 0.15 g of iodine, 100 ml of tetrahydrofuran and 7.78 g of bromocyclohexane are added to a 1L three-necked flask, and the reaction system is heated with a hair dryer. When the color of the system changes from red to white, heating is stopped. When the temperature is cooled to 50°C, the mixed solution is added dropwise, and the temperature is maintained at 50°C. After the addition is completed, the system is heated to a temperature of 100°C. The temperature was raised to 70°C and kept warm for 3 hours. The reaction solution was cooled to room temperature to obtain the Grignard reagent. In a 500L three-necked flask, 300ml of toluene, 97.38g of zinc chloride and 74g of 2-bromo-5-iodo-1,3-xylene were added to reflux and separate the water. Under nitrogen protection, the mixture was transferred to a 3L three-necked flask, cooled to 0°C, and the Grignard reagent was added dropwise. After the addition was completed, the mixture was kept warm at 0°C for 30 minutes, replaced with nitrogen, and 0.4g of palladium dichloride was added. The temperature was raised to 75°C for reaction. The reaction was monitored by GCMS. The reaction was completed to obtain a crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; the mixture was cooled to room temperature, and the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene was poured into 1L of ice water, the temperature was controlled below 10°C, dilute hydrochloric acid was added to adjust the acidity, and then 300ml of ethyl acetate was added for extraction, the organic layer was passed through diatomaceous earth, and washed twice with 200ml of saturated sodium sulfite aqueous solution, and dried with anhydrous sodium sulfate, and passed through silica gel. The filtrate was passed through a chromatography column, specifically: a column with a height of 1m (inner diameter of 0.1 m) was filled with 300 g of 100-200 mesh column chromatography silica gel, DCM was used as the eluent, the amount of the eluent was 2 L, the flow rate was 1 ml / s, the filter cake was washed with 0.5 L of petroleum ether, all the eluent was collected, and then concentrated to obtain an oily substance; the oily substance was distilled at an internal temperature of 146° C. and a top temperature of 122° C. to obtain 32.5 g of a light yellow oily liquid 2-bromo-5-cyclohexyl-1,3-dimethylbenzene with a yield of 65% and a purity of 95.6%.
[0055] In the present application, when the nitrosation reaction occurs in S2, the acid source is first added to ensure that the reaction solution remains strongly acidic during the entire nitrosation process, providing H+, which is conducive to the smooth generation of N-nitroso compounds and a complete reaction; at the same time, the acid source participates in the subsequent reaction, carbon cation rearrangement occurs, and a high-yield diazonium salt is obtained, thereby improving the yield and purity of the target product.
[0056] The present application controls the molar ratio of reactants in each process step during the process, thereby improving the utilization rate of raw materials, reducing the occurrence of side reactions, and facilitating subsequent separation and purification; at the same time, the purity of the intermediate products is improved by purifying the intermediate products by multiple means, so that the final product has the advantages of high yield and high purity.
[0057] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.
Claims
1. A method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene, characterized in that: The following steps are involved: S1, subjecting 2,6-dimethylaniline and an iodination agent to an iodination reaction at 10-20° C. to obtain a crude 4-iodo-2,6-dimethylaniline product; and post-treating and purifying the crude 4-iodo-2,6-dimethylaniline product to obtain 4-iodo-2,6-dimethylaniline; S2, subjecting the 4-iodo-2,6-dimethylaniline to a nitrosation reaction in an acidic medium to obtain a diazonium salt; S3, reacting the diazonium salt, ketone bromide and hydrobromic acid to obtain a crude 2-bromo-5-iodo-1,3-xylene product; post-treating and purifying the crude 2-bromo-5-iodo-1,3-xylene product to obtain 2-bromo-5-iodo-1,3-xylene; S4, mixing bromocyclohexane, magnesium, iodine and an organic solvent for reaction to obtain a Grignard reagent; refluxing toluene, zinc chloride and the 2-bromo-5-iodo-1,3-dimethylbenzene to separate the water, and then adding the Grignard reagent dropwise to react to obtain a crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene; post-treating and purifying the crude product of 2-bromo-5-cyclohexyl-1,3-dimethylbenzene to obtain the target product 2-bromo-5-cyclohexyl-1,3-dimethylbenzene.
2. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S1, the iodination reaction is specifically as follows: using 2,6-dimethylaniline as a raw material, using elemental iodine as an iodination reagent, using water and dichloromethane as solvents, and carrying out an iodination reaction in the presence of sodium bicarbonate to obtain a crude 4-iodo-2,6-dimethylaniline product.
3. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 2, characterized in that: The molar ratio of the 2,6-dimethylaniline, iodine and sodium bicarbonate is 1:1-1.1:1-3; the iodine is added in multiple times.
4. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S1, the specific process of the post-treatment purification is: adding a saturated aqueous sodium bisulfite solution to the crude 4-iodo-2,6-dimethylaniline and then adding dichloromethane, passing through diatomaceous earth, and allowing the mixture to stand for stratification to separate an upper aqueous phase and a lower organic phase; washing the organic phase with a saturated sodium chloride solution and concentrating the organic phase to obtain the 4-iodo-2,6-dimethylaniline.
5. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S2, the molar ratio of 4-iodo-2,6-dimethylaniline to sodium nitrite is 1:1-1.
1.
6. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S2, the acid source in the acidic medium is fluoroboric acid, concentrated sulfuric acid, concentrated nitric acid or concentrated hydrochloric acid; when the nitrosation reaction occurs, the acid source is added first and then sodium nitrate.
7. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S3, the molar ratio of the diazonium salt, ketone bromide and hydrobromic acid is 1:0.1-0.5:4-8.
8. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S3, the specific process of the post-treatment purification is: adding petroleum ether to the crude 2-bromo-5-iodo-1,3-xylene for extraction, passing through diatomaceous earth, washing with a saturated aqueous sodium bisulfite solution, drying with anhydrous sodium sulfate, passing through silica gel, washing the obtained filter cake with petroleum ether, and concentrating the obtained organic layer to obtain the 2-bromo-5-iodo-1,3-xylene.
9. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S4, the molar ratio of 2-bromo-5-iodo-1,3-dimethylbenzene, cyclohexyl bromide, magnesium and zinc chloride is 1:3-3.5:3.1-3.7:1-2.
10. The method for synthesizing 2-bromo-5-cyclohexyl-1,3-dimethylbenzene according to claim 1, characterized in that: In S4, the specific process of the post-treatment purification is: cooling the crude 2-bromo-5-cyclohexyl-1,3-dimethylbenzene to room temperature, controlling the temperature below 10°C, adding dilute hydrochloric acid to adjust the acidity, and then adding ethyl acetate for extraction, passing the organic layer through diatomaceous earth, and washing with saturated sodium bisulfite aqueous solution to obtain the organic layer, and then concentrating and distilling to obtain the target product.