CN112745202A - Preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof - Google Patents
Preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof Download PDFInfo
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Abstract
The invention provides a preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof, which comprises the following steps: reacting aromatic aldehyde, secondary amine and Lewis acid in a solvent, adding a 2, 6-disubstituted phenol solution, and continuously reacting to obtain a reaction solution; the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and the derivatives thereof are obtained after washing the reaction liquid and separating the organic layer.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of 4-phenyl methylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-ketone and derivatives thereof.
Background
The 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and its derivatives can be used in medicine, environmental protection, chemical industry and other fields, wherein the medicine field is mainly used as a cyclooxygenase inhibitor, applied to antibacterial and anti-inflammatory drugs, the environmental protection field can be used for sewage treatment, and the chemical industry can be used as a polymerization inhibitor for styrene and other unsaturated compounds. The preparation method in the prior art comprises the steps of firstly obtaining Mannich base through Mannich reaction on 2, 6-di-tert-butylphenol, benzaldehyde and derivatives thereof and secondary amine, and then decomposing the Mannich base to prepare the catalyst. The disadvantages of the conventional mannich reaction are: the reaction condition is that the reaction is carried out for 24-48 hours at the temperature of 120-150 ℃, the energy consumption is high, and due to the fact that the reaction time is long, corresponding byproducts are more, nitrogen gas is introduced for protection in long-time high-temperature reaction, a large amount of high-boiling-point impurities are still generated, and the requirement on later-stage purification is very high. The secondary amine in the reactant is generally low in boiling point, volatile and low in recovery rate, and can escape together with nitrogen when nitrogen is introduced to protect the reaction, and a tail gas absorption device is also required to be connected to absorb vaporized secondary amine, and even the vaporized secondary amine needs to be supplemented because the secondary amine is excessively volatile, so that the conversion rate of the 2, 6-di-tert-butylphenol is improved. The Mannich base generated by the reaction must be decomposed under the conditions of acid anhydride, acyl chloride or high temperature to remove secondary amine, so as to generate the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one. Considering that high-temperature reaction may generate high-boiling-point impurities, the addition of acid anhydride or acid chloride at low temperature is generally adopted to promote the reaction, but under the conditions of acid anhydride and acid chloride, excessive and removed secondary amine can generate amide, which is not beneficial to recycling the secondary amine.
Mannich reactions generally do not require the addition of a catalyst, but for the reaction of the invention based on phenol, the reaction rate can be increased under acidic conditions. The inorganic acid (sulfuric acid, hydrochloric acid, phosphoric acid, etc.) can also be used for catalysis, but hydrochloric acid and sulfuric acid can only be used after dilution, and the diluted system contains a large amount of water, so that the reaction is more harmful, and phosphoric acid is not diluted, but the catalytic effect is very little. Organic acid catalysts (such as p-toluenesulfonic acid, benzoic acid, L-proline and the like) which are reported recently are required in large amount and are not easy to remove after the reaction is finished.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof.
In order to achieve the above objects and other objects, the present invention includes the following technical solutions: the invention provides a preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-ketone and derivatives thereof, which comprises the following steps:
reacting aromatic aldehyde, secondary amine and Lewis acid in a solvent, adding a 2, 6-disubstituted phenol solution, and continuously reacting to obtain a reaction solution; washing the reaction liquid to separate an organic layer to obtain the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof, wherein the structural formula of the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof is as follows:
wherein R is1Is any one of methyl, ethyl, isopropyl and tert-butyl, R2Is any one of phenyl, 4-chlorophenyl, 4-bromophenyl, 3-chlorophenyl, 3-bromophenyl, 2-chlorophenyl, 2-bromophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 1-naphthyl and 2-naphthyl.
In one embodiment, the aromatic aldehyde is any one of benzaldehyde, o-bromobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde, p-methoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, p-methylbenzaldehyde, o-cyanobenzaldehyde, m-cyanobenzaldehyde, p-cyanobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-nitrobenzaldehyde, 1-naphthaldehyde, and 2-naphthaldehyde.
In one embodiment, the aromatic aldehyde is any one of benzaldehyde, p-bromobenzaldehyde, p-chlorobenzaldehyde, m-bromobenzaldehyde, m-chlorobenzaldehyde, p-methoxybenzaldehyde, m-methoxybenzaldehyde, 3, 4-dimethylbenzaldehyde, p-methylbenzaldehyde, p-cyanobenzaldehyde, p-nitrobenzaldehyde and 1-naphthaldehyde.
In one embodiment, the 2, 6-disubstituted phenol is any one of 2, 6-di-tert-butylphenol, 2, 6-dimethylphenol, 2, 6-diethylphenol and 2, 6-diisopropylphenol.
In one embodiment, the secondary amine is any one of piperidine, tetrahydropyrrole, morpholine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, and di-n-butylamine.
In one embodiment, the lewis acid is any one of zinc chloride, aluminum chloride, ferric chloride, ferrous chloride, and boron trifluoride diethyl etherate.
In one embodiment, the molar ratio of the 2, 6-disubstituted phenol, the aromatic aldehyde and the secondary amine is (0.9-1.1): (1-1.2): (1-1.2).
In one embodiment, the molar ratio of the Lewis acid to the 2, 6-disubstituted phenol is from 0.01 to 0.05.
In one embodiment, the molar yield of the method is 70-80%.
In one embodiment, the reaction is a heated reflux water diversion reaction.
In one embodiment, the total reaction time of the method is 6-10 hours.
In one embodiment, the reaction temperature is 90-100 ℃.
In one embodiment, the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and its derivatives further comprise purification processes of concentration and recrystallization.
In one embodiment, the concentration is vacuum distillation concentration, and the vacuum distillation temperature is 80-100 ℃.
In one embodiment, the washing detergent is one or more of diluted hydrochloric acid, water and saturated saline.
In one embodiment, the recrystallization solvent is a mixture of ethyl acetate and n-hexane.
In one embodiment, the solvent is any one of toluene, 1, 2-dichloroethane, xylene, and ethyl acetate.
In one embodiment, the solvent in the 2, 6-disubstituted phenol solution is any one of toluene, 1, 2-dichloroethane, xylene and ethyl acetate.
In one embodiment, the reaction time of the aromatic aldehyde, the secondary amine and the lewis acid is 0.5 to 2 hours.
In one embodiment, the 2, 6-disubstituted phenol solution is added for continuous reaction for 3-5 hours.
As described above, the invention provides a preparation method for synthesizing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof, the method is a one-pot water-splitting reaction using lewis acid (including zinc chloride, zinc iodide, aluminum chloride, ferric chloride, ferrous chloride, boron trifluoride and the like) as a catalyst, and has great advantages over the traditional mannich reaction, and compared with the traditional mannich reaction, the method provided by the invention can increase the reaction molar yield from 40-60% to more than 70% under the condition of the same phenolic substrate. The method shortens the traditional Mannich two-step reaction into one-step reaction, greatly shortens the reaction time, improves the production efficiency, takes about 6-10 hours, avoids high-boiling-point impurities generated by long-time reaction due to the shortened reaction time, and avoids the protection of introducing inert gas.
Due to the shortened reaction time, the volatilization of the secondary amine is relatively reduced, and the improvement is realized in both economic and environmental aspects. The deamidation reaction of the Mannich base in the method is carried out by pyrolysis reaction. The reaction speed is accelerated due to the catalytic action of the Lewis acid, the reaction activation temperature threshold is reduced, and the decomposition temperature of the Mannich base is obviously reduced, so that the Mannich base is decomposed and the generation of high-boiling-point impurities is avoided.
Under the premise that Lewis acid is used as a catalyst, the reaction temperature can be greatly reduced, the Mannich base can be decomposed at high temperature, the problems of prolonged reaction time and the like caused by reducing the reaction temperature are also solved, and the organic solvent, the secondary amine and the benzaldehyde used in the method can be recovered. In addition, as Lewis acid is used as a catalyst, compared with other traditional processes without adding a catalyst or adding an organic acid and an inorganic acid catalyst, the consumption of raw materials and energy is effectively reduced, the original two-step operation is shortened into one-step operation, the manual consumption is reduced, the conversion rate of the 2, 6-di-tert-butylphenol and derivatives thereof is improved, and the occurrence of side reactions is reduced. Various solvents and acid aqueous solutions used in the reaction process and the post-treatment can be recycled, gas is not discharged in the reaction, a drying agent or solid substances are not used, and the preparation method does not generate three wastes and is green and environment-friendly.
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FIG. 1 shows the reaction equation for the preparation of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one according to the present invention.
FIG. 2 is a graph showing the result of nuclear magnetic hydrogen spectroscopy detection of sample 1 of the present invention.
Detailed Description
Referring to fig. 1-2, embodiments of the present invention are described below with specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Note that "%" and "part(s)" shown herein mean "% by mass" and "part(s) by mass", respectively, unless otherwise specified.
Hereinafter, the present invention will be more specifically explained by referring to examples, which should not be construed as limiting. Appropriate modifications may be made within the scope consistent with the gist of the present invention, and all of them fall within the technical scope of the present invention.
In one embodiment, a method for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one, comprising the steps of: adding 106 g (1mol) of benzaldehyde, 85 g (1mol) of piperidine, 6.67 g (0.05mol) of aluminum trichloride and 1200mL of toluene into a water distributor, heating and refluxing for 0.5-2 hours, then dropwise adding 800mL of 2, 6-di-tert-butylphenol toluene solution (the concentration is 1.25mol/L), and continuing to carry out water diversion and refluxing for 3-8 hours. Cooling to room temperature, washing the reaction solution with 1000mL of 3N diluted hydrochloric acid, 1000mL of water and 500mL of saturated saline solution once respectively, introducing the secondary amine into the diluted hydrochloric acid after the reaction solution is washed, and subsequently recovering the secondary amine through extraction. And (2) concentrating the toluene layer by reduced pressure distillation, recovering and utilizing the distilled benzaldehyde and toluene, filtering a crude product after concentration to recover a solvent toluene, recrystallizing the crude product by using a mixed solvent of ethyl acetate and n-hexane to obtain 221.3 g of a yellow crystal product, wherein the molar yield is 75.17 percent to obtain a sample 1, and carrying out HPLC (high performance liquid chromatography) detection and 1H-NMR (nuclear magnetic hydrogen spectrometry) detection on the sample 1, wherein the detection results are shown as follows.
1H-NMR measurement results: (600MHz, CDCl3) δ, ppm: 7.54(d, J ═ 2.2Hz,1H), 7.48-7.43 (m,4H), 7.41-7.37 (m,1H),7.19(s,1H),7.03(d, J ═ 2.3Hz,1H),1.35(s,9H),1.32(s, 9H).
As can be seen from Table 1, sample 1 has a peak of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one at a retention time of 11.065min, the content can reach more than 98%, 7 equivalent hydrogens are shown by FIG. 2 and nuclear magnetic hydrogen spectrum detection results, and sample 1 conforms to the structural formula characteristics of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one.
Table 1 HPLC assay results: (detection wavelength 246nm)
In one embodiment, a method for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one, comprising the steps of: adding 106 g (1mol) of benzaldehyde, 85 g (1mol) of piperidine, 6.82 g (0.05mol) of zinc chloride and 1200mL of toluene into a water separator, heating and refluxing for 0.5-2 hours, then dropwise adding 800mL of 2, 6-di-tert-butylphenol toluene solution (the concentration is 1.25mol/L), and continuing to carry out water separation and refluxing for 3-8 hours. Cooling to room temperature, washing the reaction solution with 1000mL of 3N diluted hydrochloric acid, 1000mL of water and 500mL of saturated saline solution once respectively, introducing the secondary amine into the diluted hydrochloric acid after the reaction solution is washed, and subsequently recovering the secondary amine through extraction. Concentrating a toluene layer by reduced pressure distillation, recycling distilled benzaldehyde and toluene, filtering a crude product after concentration to recycle a solvent toluene, recrystallizing the crude product by using a mixed solvent of ethyl acetate and n-hexane to obtain 227.86 g of a yellow crystal product, wherein the molar yield is 77.39% to obtain a sample 2, carrying out HPLC (high performance liquid chromatography) detection and 1H-NMR (nuclear magnetic hydrogen spectrometry) detection on the sample 2 to obtain a detection result similar to that of the sample 1, and the sample 2 conforms to the structural formula characteristic of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one.
In one embodiment, a method for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one, comprising the steps of: adding 106 g (1mol) of benzaldehyde, 85 g (1mol) of piperidine, 8.11 g (0.05mol) of ferric trichloride and 1200mL of toluene into a water distributor, heating and refluxing for 0.5-2 hours, then dropwise adding 800mL of 2, 6-di-tert-butylphenol toluene solution (the concentration is 1.25mol/L), and continuing to carry out water diversion and refluxing for 3-8 hours. Cooling to room temperature, washing the reaction solution with 1000mL of 3N diluted hydrochloric acid, 1000mL of water and 500mL of saturated saline solution once respectively, introducing the secondary amine into the diluted hydrochloric acid after the reaction solution is washed, and subsequently recovering the secondary amine through extraction. Concentrating a toluene layer by reduced pressure distillation, recycling distilled benzaldehyde and toluene, filtering a crude product after concentration to recycle a solvent toluene, recrystallizing the crude product by using a mixed solvent of ethyl acetate and n-hexane to obtain 219.38 g of a yellow crystal product, obtaining a sample 3 by the molar yield of 74.51%, and carrying out HPLC detection and 1H-NMR nuclear magnetic hydrogen spectrum detection on the sample 3 to obtain a detection result similar to that of the sample 1, wherein the sample 3 conforms to the structural formula characteristic of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one.
In one embodiment, a method for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one, comprising the steps of: adding 106 g (1mol) of benzaldehyde, 85 g (1mol) of piperidine, 6.34 g (0.05mol) of ferrous chloride and 1200mL of toluene into a water separator, heating and refluxing for 0.5-2 hours, then dropwise adding 800mL of 2, 6-di-tert-butylphenol toluene solution (the concentration is 1.25mol/L), and continuing to carry out water separation and refluxing for 3-8 hours. Cooling to room temperature, washing the reaction solution with 1000mL of 3N diluted hydrochloric acid, 1000mL of water and 500mL of saturated saline solution once respectively, introducing the secondary amine into the diluted hydrochloric acid after the reaction solution is washed, and subsequently recovering the secondary amine through extraction. Concentrating a toluene layer by reduced pressure distillation, recycling distilled benzaldehyde and toluene, filtering a crude product after concentration to recycle a solvent toluene, recrystallizing the crude product by using a mixed solvent of ethyl acetate and n-hexane to obtain 223.24 g of a yellow crystal product, obtaining a sample 4 by the molar yield of 75.82%, and carrying out HPLC (high performance liquid chromatography) detection and 1H-NMR (nuclear magnetic hydrogen spectrometry) detection on the sample 4 to obtain a detection result similar to that of the sample 1, wherein the sample 4 accords with the structural formula characteristic of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one.
In one embodiment, a method for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one, comprising the steps of: adding 106 g (1mol) of benzaldehyde, 85 g (1mol) of piperidine, 7.10 g (0.05mol) of boron trifluoride diethyl etherate and 1200mL of toluene into a water separator, heating and refluxing for 0.5-2 hours, then dropwise adding 800mL of 2, 6-di-tert-butylphenol toluene solution (the concentration is 1.25mol/L), and continuing to carry out water separation and refluxing for 3-8 hours. Cooling to room temperature, washing the reaction solution with 1000mL of 3N diluted hydrochloric acid, 1000mL of water and 500mL of saturated saline solution once respectively, introducing the secondary amine into the diluted hydrochloric acid after the reaction solution is washed, and subsequently recovering the secondary amine through extraction. Concentrating a toluene layer by reduced pressure distillation, recycling distilled benzaldehyde and toluene, filtering a crude product after concentration to recycle a solvent toluene, recrystallizing the crude product by using a mixed solvent of ethyl acetate and n-hexane to obtain 217.26 g of a yellow crystal product, obtaining 73.79% of a molar yield to obtain a sample 5, carrying out HPLC (high performance liquid chromatography) detection and 1H-NMR (nuclear magnetic hydrogen spectrometry) detection on the sample 5 to obtain a detection result similar to that of the sample 1, wherein the sample 5 conforms to the structural formula characteristic of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one.
The structural formula of the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one obtained by the samples 1-5 is shown as follows:
in conclusion, the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one with high purity is prepared by the method. Therefore, the invention effectively overcomes various defects in the prior art and has high industrial utilization value. The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A preparation method of 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof is characterized by comprising the following steps:
reacting aromatic aldehyde, secondary amine and Lewis acid in a solvent, adding a 2, 6-disubstituted phenol solution, and continuously reacting to obtain a reaction solution;
washing the reaction liquid to separate an organic layer to obtain the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof, wherein the structural formula of the 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one and derivatives thereof is as follows:
wherein R is1Is any one of methyl, ethyl, isopropyl and tert-butyl, R2Is any one of phenyl, 4-chlorophenyl, 4-bromophenyl, 3-chlorophenyl, 3-bromophenyl, 2-chlorophenyl, 2-bromophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 1-naphthyl and 2-naphthyl.
2. The method of claim 1, wherein: the aromatic aldehyde is any one of benzaldehyde, p-bromobenzaldehyde, p-chlorobenzaldehyde, m-bromobenzaldehyde, m-chlorobenzaldehyde, p-methoxybenzaldehyde, m-methoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, p-methylbenzaldehyde, p-cyanobenzaldehyde, p-nitrobenzaldehyde and 1-naphthaldehyde.
3. The method of claim 1, wherein: the secondary amine is any one of piperidine, tetrahydropyrrole, morpholine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine and di-n-butylamine.
4. The method of claim 1, wherein: the Lewis acid is one or more of zinc chloride, aluminum chloride, ferric trichloride, ferrous chloride and boron trifluoride diethyl etherate.
5. The method of claim 1, wherein: the molar yield of the method is 70-80%.
6. The method of claim 1, wherein: the reaction is a heating reflux water diversion reaction.
7. The method of claim 1, wherein: the total reaction time of the method is 6-10 hours.
8. The method of claim 1, wherein: the reaction time of the aromatic aldehyde, the secondary amine and the Lewis acid is 0.5-2 hours.
9. The method of claim 1, wherein: the reaction temperature is 90-100 ℃.
10. The method of claim 1, wherein: the molar ratio of the Lewis acid to the 2, 6-disubstituted phenol is 0.01-0.05.
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| CN115536506A (en) * | 2021-06-30 | 2022-12-30 | 常州锐博生物科技有限公司 | Preparation method of 4-phenylmethylene-2,6-di-tert-butyl-2,5-cyclohexadiene-1-one and derivative thereof |
| CN115536506B (en) * | 2021-06-30 | 2023-10-20 | 常州锐博生物科技有限公司 | Process for preparing 4-phenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadien-1-one and derivatives thereof |
| CN113979846A (en) * | 2021-11-23 | 2022-01-28 | 山东大学 | Method for synthesizing 2, 6-disubstituted-4-aryl methylene-2, 5-cyclohexadiene-1-one by one-step method |
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