CN113603572B - Preparation method of 2, 6-di-tert-butyl-4-bromoanisole - Google Patents
Preparation method of 2, 6-di-tert-butyl-4-bromoanisole Download PDFInfo
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- KKHJQLVAMOKQHO-UHFFFAOYSA-N 5-bromo-1,3-ditert-butyl-2-methoxybenzene Chemical compound COC1=C(C(C)(C)C)C=C(Br)C=C1C(C)(C)C KKHJQLVAMOKQHO-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 31
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 10
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000001273 butane Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000007171 acid catalysis Methods 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000007789 gas Substances 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- -1 tert-butyl carbonium ion Chemical class 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- DKCPKDPYUFEZCP-UHFFFAOYSA-N 2,6-di-tert-butylphenol Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=C1O DKCPKDPYUFEZCP-UHFFFAOYSA-N 0.000 description 3
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- GSMZLBOYBDRGBN-UHFFFAOYSA-N 2-fluoro-2-methylpropane Chemical compound CC(C)(C)F GSMZLBOYBDRGBN-UHFFFAOYSA-N 0.000 description 1
- ANGGPYSFTXVERY-UHFFFAOYSA-N 2-iodo-2-methylpropane Chemical compound CC(C)(C)I ANGGPYSFTXVERY-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical class CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
Abstract
The invention provides a preparation method of 2, 6-di-tert-butyl-4-bromoanisole, which comprises the following steps: adding a tertiary butyl reagent into 4-bromoanisole under acid catalysis to react to obtain 2, 6-di-tertiary butyl-4-bromoanisole. The preparation method of the invention takes the cheap and easily available 4-bromoanisole as the raw material, does not need to use a solvent, can obtain the 2, 6-di-tert-butyl-4-bromoanisole by a one-step method, has the advantages of high production efficiency and low production cost, and has less toxicity of the raw material and auxiliary reagent used in the reaction process, thereby being more friendly to the environment.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a preparation method of 2, 6-di-tert-butyl-4-bromoanisole.
Background
The large-steric-hindrance halogenated aromatic hydrocarbon compound has wide bioactivity, and the compound has wide application in the fields of pesticides, medicines, industrial catalysis and material chemistry.
2, 6-di-tert-butyl-4-bromoanisole is an important intermediate for organic synthesis and chemical medicine, and is a typical halogenated aromatic hydrocarbon compound with large steric hindrance. The existing preparation method of 2, 6-di-tert-butyl-4-bromoanisole mainly takes 2, 6-di-tert-butylphenol as a raw material, bromine is carried out on the para position of the 2, 6-di-tert-butylphenol, and then a methylating agent such as methyl iodide or dimethyl sulfate is used for converting phenolic hydroxyl on the 2, 6-di-tert-butyl into methoxy, or the phenolic hydroxyl on the 2, 6-di-tert-butylphenol is firstly converted into methoxy by methyl iodide or dimethyl sulfate and then bromine is carried out on the para position of the methoxy.
However, the target product can be obtained through two steps of reactions, the production efficiency is low, the cost is high, and reagents with high toxicity such as methyl iodide, dimethyl sulfate, bromine and the like are needed, so that the preparation method is not beneficial to environmental protection.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of 2, 6-di-tert-butyl-4-bromoanisole, which takes cheap and easily available 4-bromoanisole as a raw material, and the 2, 6-di-tert-butyl-4-bromoanisole can be obtained only by a one-step method without using a solvent in the reaction process. The preparation method of 2, 6-di-tert-butyl-4-bromoanisole provided by the invention has the advantages of high production efficiency and low production cost, and all raw materials and auxiliary reagents used in the reaction process have low toxicity and are more environment-friendly.
The invention provides a preparation method of 2, 6-di-tert-butyl-4-bromoanisole, which comprises the following steps: adding a tertiary butyl reagent into 4-bromoanisole under the catalysis of acid to react to obtain the 2, 6-di-tertiary butyl-4-bromoanisole.
The preparation method as described above, wherein the tertiary-butylating reagent is selected from one of isobutylene, tertiary-butanol or halogenated tertiary-butane.
The preparation method as described above, wherein the molar ratio of the 4-bromoanisole to the tertiary butylating reagent is 1: (2-4).
The preparation method as described above, wherein the acid is at least one selected from sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and aluminum trichloride.
The preparation method as described above, wherein the molar ratio of the acid to the 4-bromoanisole is (0.03 to 1): 1.
The preparation method as described above, wherein the temperature of the reaction is 0 to 80 ℃.
The preparation method, wherein the reaction time is 2-6 h.
The preparation method further comprises the steps of separating and purifying the reaction system, wherein the separating and purifying steps comprise:
adding deionized water into the reaction system, and separating to obtain an organic phase;
adding a crystallization solvent into the organic phase, stirring, continuously stirring at 0-10 ℃ for 2-6h after solid is separated out, and carrying out suction filtration and drying to obtain the 2, 6-di-tert-butyl-4-bromoanisole.
The preparation method comprises the step of preparing the crystal solvent from one or more of methanol, ethanol, isopropanol, ethyl acetate, n-heptane, toluene and methyl tertiary butyl ether.
The preparation method as described above, wherein the ratio of the mass of the crystallization solvent to the mass of the theoretical product is (0.5-10): 1.
The preparation method of 2, 6-di-tert-butyl-4-bromoanisole takes the cheap and easily obtained 4-bromoanisole as the raw material, does not need to use a solvent in the reaction process, can obtain the 2, 6-di-tert-butyl-4-bromoanisole by a one-step method, has the advantages of high production efficiency and low production cost, has less toxicity of the raw material and auxiliary reagent used in the reaction process, is more environment-friendly, and is beneficial to being applied to industrial production.
Drawings
FIG. 1 shows the preparation of 2, 6-di-tert-butyl-4-bromoanisole according to example 1 of the present invention 1 HNMR diagram.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a preparation method of 2, 6-di-tert-butyl-4-bromoanisole, which comprises the following steps: adding a tertiary butyl reagent into 4-bromoanisole under the catalysis of acid to react to obtain 2, 6-di-tertiary butyl-4-bromoanisole.
The preparation method can be represented by the following reaction formula:
the reaction is essentially Friedel-crafts alkylation reaction, firstly, under the catalysis of acid, a tert-butyl carbonium ion intermediate is formed by a tert-butyl reagent, the tert-butyl carbonium ion intermediate is used as an electrophile to carry out electrophilic substitution reaction with raw material 4-bromoanisole, methoxy and bromine are o-para-position positioning groups, but the activating capacity of methoxy to benzene ring is stronger than that of bromine to benzene ring, so that two tert-butyl groups are generated at the ortho position of methoxy, and 2, 6-di-tert-butyl-4-bromoanisole is obtained.
The preparation method of the invention takes the cheap and easily available 4-bromoanisole as the raw material, does not need to use a solvent in the reaction process, can obtain the 2, 6-di-tert-butyl-4-bromoanisole by a one-step method, has the advantages of high production efficiency and low production cost, has less toxicity of the raw material and auxiliary reagent used in the reaction process, is more friendly to the environment and is beneficial to being applied to industrial production.
In a specific embodiment, the tertiary butyl reagent used in the reaction is selected from one of isobutylene, tertiary butanol or halogenated tertiary butane.
Wherein the halogenated tert-butane may be fluoro tert-butane, chloro tert-butane, bromo tert-butane, iodo tert-butane, etc.
The tertiary butyl reagent can generate tertiary butyl carbonium ions after acid catalysis, and can smoothly perform electrophilic substitution reaction with 4-bromoanisole to obtain 2, 6-di-tertiary butyl-4-bromoanisole.
It will be appreciated that since it is desirable to form two tertiary butyl groups ortho to the methoxy group of the 4-bromoanisole compound, the amount of material controlling the tertiary butylating reagent is at least twice the amount of 4-bromoanisole material.
In general, when the molar ratio of 4-bromoanisole to tertiary butylating reagent is 1: and (2-4), the complete conversion of the substrate is facilitated, and excessive raw materials are not wasted.
Further, when the tertiary butylating reagent is isobutylene, the isobutylene and the 4-bromoanisole are respectively in a gas phase and a liquid phase, and the two phases are in a heterogeneous state, so that the difficulty of the reaction is increased, and the mole ratio of the 4-bromoanisole to the isobutylene is 1: (3-4) so that more isobutene can be contacted and reacted with 4-bromoanisole to promote the reaction.
The choice of the acid catalyst in the acid catalysis is not particularly limited in the invention, so long as the catalyst can promote the tertiary butyl reagent to form a tertiary butyl carbocation intermediate and is conducive to undergoing Friedel-crafts alkylation with 4-bromoanisole.
Specifically, the acid used for preparing the 2, 6-di-tert-butyl-4-bromoanisole can be a protonic acid and/or a Lewis acid, including but not limited to at least one of sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and aluminum trichloride.
In the actual reaction process, an acid matching the reactivity of the tertiary butyl reagent may be selected as a catalyst depending on the reactivity of the tertiary butyl reagent.
Further, the molar ratio of the acid to the 4-bromoanisole is (0.03-1): 1, and in the molar ratio range, the acid can play a good role in catalysis, and the 4-bromoanisole and the tertiary butyl reagent can be promoted to smoothly carry out Friedel-crafts alkylation reaction.
Further, the reaction temperature of 4-bromoanisole and the tertiary butyl reagent is 0 to 80℃and, specifically, the reaction temperature may be different in the above-mentioned range depending on the reactivity of the tertiary butyl reagent used.
When the tertiary butyl reagent is halogenated tertiary butane, the reaction activity is higher, and the 4-bromoanisole and the halogenated tertiary butane can complete the reaction at 0-30 ℃;
when the tertiary butyl reagent is tertiary butyl alcohol, the reaction activity is moderate, and the 4-bromoanisole and the tertiary butyl alcohol can complete the reaction at 30-50 ℃;
when the tertiary butyl reagent is isobutene, the isobutene and the 4-bromoanisole are respectively in two phases of gas phase and liquid phase, the reaction activity is low, the reaction can be completed only by heating, and the reaction of the 4-bromoanisole and the isobutene can be carried out at 50-80 ℃.
In general, the progress of the reaction of 4-bromoanisole with the tertiary butylating reagent can be monitored using methods common in the art, including but not limited to Thin Layer Chromatography (TLC), gas Chromatography (GC), high Performance Liquid Chromatography (HPLC), nuclear magnetic resonance spectroscopy (NMR), and the like.
The monitoring of the reaction by any one of the monitoring means can find that the reaction can be completed when 4-bromoanisole reacts with the tertiary butyl reagent for 2 to 6 hours.
After the reaction is completed, the reaction system is also required to be separated and purified so as to obtain the pure 2, 6-di-tert-butyl-4-bromoanisole.
Specifically, the separation and purification comprises the following steps:
s1: adding deionized water into the reaction system, and separating to obtain an organic phase;
s2: adding a crystallization solvent into the organic phase, stirring, continuously stirring for 4 hours at the temperature of between 0 and 10 ℃ after solid is separated out, and obtaining the 2, 6-di-tert-butyl-4-bromoanisole after suction filtration and drying.
Furthermore, in the step S1, after the reaction is finished, the temperature of the reaction system is not required to be reduced, and deionized water is added at the original temperature of the reaction, so that the deionized water can better dissolve water-soluble impurities in the reaction system.
In the step S2, the organic phase is not required to be cooled after liquid separation, a crystallization solvent is added into the organic phase for stirring, the process is a crystallization process, after solid precipitation is found by stirring, the organic phase solution is controlled to be continuously stirred for 2-6 hours at the temperature of 0-10 ℃, and the 2, 6-di-tert-butyl-4-bromoanisole product can be rapidly and completely precipitated.
HPLC detection shows that the purity of the 2, 6-di-tert-butyl-4-bromoanisole obtained after crystallization can reach more than 98 percent.
Specifically, the crystallization solvent can be one or more selected from methanol, ethanol, isopropanol, ethyl acetate, n-heptane, toluene and methyl tertiary butyl ether. The 2, 6-di-tert-butyl-4-bromoanisole obtained by adopting the solvent for crystallization has higher purity.
The inventor researches and discovers that when the ratio of the mass of the crystallization solvent to the mass of the theoretical product is (0.5-10): 1, the purified 2, 6-di-tert-butyl-4-bromoanisole has higher purity and yield. The theoretical product mass refers to the mass of the obtained 2, 6-di-tert-butyl-4-bromoanisole when the reaction yield is 100%.
Specifically, the reaction system may be crystallized by selecting an appropriate amount of the crystallization solvent within the above-defined mass ratio range depending on the solubility of the crystallization solvent to 2, 6-di-t-butyl-4-bromoanisole.
The method for preparing 2, 6-di-tert-butyl-4-bromoanisole provided by the present invention will be described in detail with reference to specific examples.
In the examples below, unless otherwise indicated, all experimental procedures referred to are those commonly used in the art and all starting materials referred to as well as auxiliary reagents used in the reaction process may be prepared by commercially available or conventional methods.
Example 1
The preparation process of the 2, 6-di-tert-butyl-4-bromoanisole in this example can be represented by the following reaction scheme:
the preparation method comprises the following steps:
1. at room temperature, 186g (1 mol) of 4-bromoanisole and 5g (with the concentration of 98 percent and 0.05 mol) of concentrated sulfuric acid are firstly added into a flask to be stirred, then isobutene gas is introduced into the flask to completely replace air in the flask, after replacement is completed, the temperature of a reaction system is raised to 55-65 ℃ under the stirring state, 168g (3 mol) of isobutene gas is continuously introduced into the reaction system after the temperature is raised, and the reaction is continued for 2 hours at 55-65 ℃;
after 2 hours of reaction, sampling, detecting that the 4-bromoanisole raw material is completely reacted through HPLC, and judging that the reaction is finished;
2. adding 100g of deionized water into a reaction system at 55-65 ℃, stirring for 10min, standing for separating liquid, and collecting an organic phase;
3. 300mL of ethanol (237 g) is added into the organic phase at 55-65 ℃ for stirring, solid precipitation is started after 30min, the organic phase solution is slowly cooled to 0 ℃ for 4h after 3 h, the solid precipitation is complete, 259g of 2, 6-di-tert-butyl-4-bromoanisole is obtained after suction filtration and drying, and the yield is 87%.
FIG. 1 shows the preparation of 2, 6-di-tert-butyl-4-bromoanisole according to example 1 of the present invention 1 H NMR chart As shown in FIG. 1, 2, 6-Di-tert-butyl-4-bromoanisole obtained in example 1 was obtained by 1 H NMR was characterized as follows:
1 H NMR(400MHz,CDCl 3 )δ7.33(s,2H),3.66(s,3H),1.40(s,18H).
example 2
The preparation process of the 2, 6-di-tert-butyl-4-bromoanisole in this example can be represented by the following reaction scheme:
the preparation method comprises the following steps:
1. at room temperature, 186g (1 mol) of 4-bromoanisole and 200g (with the concentration of 98 percent and 2 mol) of concentrated sulfuric acid are firstly added into a flask, stirred and mixed uniformly, then the reaction system is heated to 35-45 ℃, 185g (2.5 mol) of tertiary butanol is added into a mixed solution of 4-bromoanisole and concentrated sulfuric acid dropwise at the temperature, and the reaction is continued for 2 hours at 35-45 ℃ after the dropwise addition is completed;
after 2 hours of reaction, sampling, detecting that the 4-bromoanisole raw material is completely reacted through HPLC, and judging that the reaction is finished;
2. adding 100g of deionized water into a reaction system at 55-65 ℃, stirring for 10min, standing for separating liquid, and collecting an organic phase;
3. adding 300mL of ethanol (237 g) into the organic phase at 55-65 ℃ for stirring, starting to precipitate solids after 30min, slowly cooling the organic phase solution to 0 ℃ for about 3 hours, continuing stirring for 4h, completely precipitating the solids, and obtaining 241g of solid product after suction filtration and drying;
warp yarn 1 H NMR confirmed that the obtained solid product was 2, 6-di-t-butyl-4-bromoanisole, and the yield was 81%.
Example 3
The preparation process of the 2, 6-di-tert-butyl-4-bromoanisole in this example can be represented by the following reaction scheme:
the preparation method comprises the following steps:
1. 186g (1 mol) of 4-bromoanisole and 6.6g (0.05 mol) of powdery aluminum trichloride are added into a flask at room temperature to be stirred, then the air in the flask is completely replaced by nitrogen, after replacement is completed, the reaction system is cooled to 0-5 ℃ under the stirring state, 232g (2.5 mol) of tert-butyl chloride is continuously added into the reaction system at the temperature of 0-5 ℃ after the cooling is completed, and the reaction is continuously carried out for 5 hours at the temperature of 0-5 ℃ after the dropping is completed;
after the reaction is carried out for 5 hours, sampling is carried out, the reaction of the 4-bromoanisole raw material is detected to be complete through HPLC, and the end of the reaction is judged;
2. adding 100g of deionized water into a reaction system at 55-65 ℃, stirring for 10min, standing for separating liquid, and collecting an organic phase;
3. adding 300mL of ethanol (237 g) into the organic phase at 55-65 ℃ for stirring, starting to precipitate solids after 30min, slowly cooling the organic phase solution to 0 ℃ for about 3 hours, continuing stirring for 4h, completely precipitating the solids, and obtaining 250g of solid product after suction filtration and drying;
by passing through 1 H NMR confirmed that the obtained solid product was 2, 6-di-t-butyl-4-bromoanisole, and the yield was 84%.
Example 4
The preparation process of the 2, 6-di-tert-butyl-4-bromoanisole in this example can be represented by the following reaction scheme:
the preparation method comprises the following steps:
1. at room temperature, 186g (1 mol) of 4-bromoanisole, 6.6g (0.05 mol) of powdery aluminum trichloride and 8.6g (0.05 mol) of p-toluenesulfonic acid (p-TSA) are firstly added into a flask and stirred, then isobutene gas is introduced into the flask to completely replace air in the flask, after replacement is completed, the reaction system is heated to 55-65 ℃ under the stirring state, 168g (3 mol) of isobutene gas is continuously introduced into the reaction system after the heating is completed, and the reaction is continued for 2 hours at 55-65 ℃;
after 2 hours of reaction, sampling, detecting that the 4-bromoanisole raw material is completely reacted through HPLC, and judging that the reaction is finished;
2. adding 100g of deionized water into a reaction system at 55-65 ℃, stirring for 10min, standing for separating liquid, and collecting an organic phase;
3. adding 300mL of ethanol (237 g) into the organic phase at 55-65 ℃ for stirring, starting to precipitate solids after 30min, slowly cooling the organic phase solution to 0 ℃ for about 3 hours, continuously stirring for 4 hours to precipitate solids completely, and obtaining 259g of solid product after suction filtration and drying;
by passing through 1 H NMR confirmed that the obtained solid product was 2, 6-di-t-butyl-4-bromoanisole, and the yield was 87%.
Example 5
The preparation process of the 2, 6-di-tert-butyl-4-bromophenyl ether of this example can be represented by the following reaction scheme:
the preparation method comprises the following steps:
1. at room temperature, 186g (1 mol) of 4-bromoanisole and 5g (with the concentration of 98 percent and 0.05 mol) of concentrated sulfuric acid are firstly added into a flask to be stirred, then isobutene gas is introduced into the flask to completely replace air in the flask, after replacement is completed, the temperature of a reaction system is raised to 55-65 ℃ under the stirring state, 168g (3 mol) of isobutene gas is continuously introduced into the reaction system after the temperature is raised, and the reaction is continued for 2 hours at 55-65 ℃;
after 2 hours of reaction, sampling, detecting that the 4-bromoanisole raw material is completely reacted through HPLC, and judging that the reaction is finished;
2. adding 100g of deionized water into a reaction system at 55-65 ℃, stirring for 10min, standing for separating liquid, and collecting an organic phase;
3. 150mL of ethyl acetate (135 g) is added into the organic phase at 55-65 ℃ for stirring, then 750mL of n-heptane (513 g) is added dropwise, the system is slowly cooled to 0 ℃ for about 3 hours, stirring is continued for 4 hours, solid is completely separated out, and 240g of solid product is obtained after suction filtration and drying;
by passing through 1 H NMR confirmed that the obtained solid product was 2, 6-di-t-butyl-4-bromoanisole, and the yield was 80%.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (3)
1. The preparation method of the 2, 6-di-tert-butyl-4-bromoanisole is characterized by comprising the following steps: adding a tertiary butyl reagent into 4-bromoanisole under the catalysis of acid to react, and separating and purifying a reaction system, wherein the separation and purification comprises the following steps:
adding deionized water into the reaction system, and separating to obtain an organic phase;
adding a crystallization solvent into the organic phase, stirring, continuously stirring at 0-10 ℃ for 2-6 hours after solid is separated out, and carrying out suction filtration and drying to obtain the 2, 6-di-tert-butyl-4-bromoanisole;
wherein the molar ratio of the 4-bromoanisole to the tertiary butyl reagent is 1: (2-4);
the acid is at least one selected from sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid;
the molar ratio of the acid to the 4-bromoanisole is (0.03-1): 1;
the temperature of the reaction is 0-80 ℃;
the ratio of the mass of the crystallization solvent to the theoretical product mass is (0.5-10): 1;
the crystallization solvent is one or more selected from methanol, ethanol, isopropanol, ethyl acetate, n-heptane, toluene and methyl tertiary butyl ether.
2. The method according to claim 1, wherein the tertiary-butylating reagent is one selected from the group consisting of isobutylene, tertiary-butanol and halogenated tertiary-butane.
3. The process according to any one of claims 1 to 2, wherein the reaction time is 2 to 6 hours.
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| CN1762944A (en) * | 2005-09-28 | 2006-04-26 | 茂名学院 | 2-tertiary-butyl hydroquinone preparation method |
| CN101333153A (en) * | 2008-06-30 | 2008-12-31 | 寿光富康制药有限公司 | Preparation of m-bromoanisole |
| CN112876342A (en) * | 2021-02-08 | 2021-06-01 | 杉杉新材料（衢州）有限公司 | Preparation method of 2, 5-di-tert-butyl-p-xylylene ether |
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| CN1762944A (en) * | 2005-09-28 | 2006-04-26 | 茂名学院 | 2-tertiary-butyl hydroquinone preparation method |
| CN101333153A (en) * | 2008-06-30 | 2008-12-31 | 寿光富康制药有限公司 | Preparation of m-bromoanisole |
| CN112876342A (en) * | 2021-02-08 | 2021-06-01 | 杉杉新材料（衢州）有限公司 | Preparation method of 2, 5-di-tert-butyl-p-xylylene ether |
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