阅读说明：本技术 一种合成3-乙胺基-4-甲基苯酚的方法 (Method for synthesizing 3-ethylamino-4-methylphenol ) 是由 朱亮 于 2021-10-09 设计创作，主要内容包括：本发明提供了一种合成3-乙胺基-4-甲基苯酚的新方法,属于有机合成技术领域。将3-硝基-4-甲基苯酚和路易斯酸催化剂溶于乙醇/四氢呋喃溶剂中,将其加到预热模块,预热到25-30℃,同时把催化剂钯碳填充到反应器中,打开氢气进料阀和氮气进料阀,控制好流速,再将预热好的3-硝基-4-甲基苯酚溶液加至反应模块,进行气液固三相反应,得到目标化合物3-乙胺基-4-甲基苯酚。本发明方法所使用的催化剂可回收利用,节约成本,反应条件温和,反应收率高,纯度高,数控显示操作简单,安全性高。(The invention provides a novel method for synthesizing 3-ethylamino-4-methylphenol, belonging to the technical field of organic synthesis. Dissolving 3-nitro-4-methylphenol and a Lewis acid catalyst in an ethanol/tetrahydrofuran solvent, adding the solution into a preheating module, preheating to 25-30 ℃, simultaneously filling palladium carbon serving as a catalyst into a reactor, opening a hydrogen feeding valve and a nitrogen feeding valve, controlling the flow rate, adding the preheated 3-nitro-4-methylphenol solution into a reaction module, and carrying out gas-liquid-solid three-phase reaction to obtain the target compound 3-ethylamino-4-methylphenol. The catalyst used in the method can be recycled, the cost is saved, the reaction condition is mild, the reaction yield is high, the purity is high, the numerical control display operation is simple, and the safety is high.)

1. A method for synthesizing 3-ethylamino-4-methylphenol adopts an H-Flow full-automatic hydrogenation reactor for reaction; the method is characterized by comprising the following operations: dissolving 3-nitro-4-methylphenol and a Lewis acid catalyst in an organic solvent, and adding the solution to a preheating module; immobilizing a palladium-carbon catalyst into a reactor; adjusting the feeding flow rates of hydrogen and nitrogen, finally adding the preheated 3-nitro-4-methylphenol solution into a reaction module, carrying out gas-liquid-solid three-phase reaction, collecting the effluent reaction liquid, and processing to obtain the 3-ethylamino-4-methylphenol.

2. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the full-automatic hydrogenation reactor H-Flow comprises a preheating module group and a reaction module group, and can be used for liquid feeding and gas feeding; the preheating module group is connected with the reaction module group in series, the plurality of preheating module groups are connected in parallel, and the plurality of reaction module groups are connected in series.

3. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the reaction temperature is 0-60 ℃ and enters the reaction module group.

4. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the organic solvent is selected from ethanol/tetrahydrofuran mixed solvent; the volume ratio of tetrahydrofuran to ethanol is 3: 1.

5. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the Lewis acid catalyst is selected from BPh3 and B (C6F5)3, and the addition amount is 1-5% of the weight of the raw materials.

6. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: 3-nitro-4-methylphenol is dissolved in an organic solvent to form a homogeneous solution.

7. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: 3-nitro-4-methyl phenol is dissolved in an organic solvent to form a 1-1.2mol/L solution.

8. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the particle diameter of the supported catalyst particles was 0.4mm, and the catalyst loading was 4 mL.

9. The method for synthesizing 3-ethylamino-4-methylphenol according to claim 1, wherein: the feeding flow rate of the 3-nitro-4-methylphenol solution is 1 mL/min; the hydrogen feed flow rate was 20 sccm; the nitrogen feed flow rate was 60 sccm.

Technical Field

The invention relates to synthesis of effective ingredients of cosmetics, in particular to a method for synthesizing 3-ethylamino-4-methylphenol, belonging to the technical field of organic synthesis.

Background

3-ethylamino-4-methylphenol, CAS: 120-37-6, light yellow solid. It is used as a cosmetic for caring skin, and is effective in preventing alopecia. The existing process route for synthesizing 3-ethylamino-4-methylphenol is divided into two steps for reaction, and the reaction formula is as follows:

the catalytic hydrogenation synthesis method is a traditional gas-liquid-solid three-phase heterogeneous reaction, high-temperature and high-pressure (15atm) conditions are required for ensuring full contact of three phases, the energy consumption is high, the equipment requirement on a high-pressure reaction kettle is high, huge potential safety hazards exist, palladium and carbon are expensive, the palladium and carbon are difficult to recycle in reaction liquid, the cost is high, and the two-step reaction is complex, time-consuming, labor-consuming and low in efficiency. In addition, the traditional reaction kettle has the disadvantages that the reaction is violent in heat release and generates a large amount of gas during feeding, so that potential safety hazards are very large, and the difficulty of process amplification is increased.

Therefore, it is still necessary to develop a relatively economical and practical method for synthesizing 3-ethylamino-4-methylphenol.

Disclosure of Invention

In order to overcome the defects, the invention adopts a method for synthesizing 3-ethylamino-4-methylphenol by adopting a full-automatic hydrogenation reactor H-Flow. Dissolving 3-nitro-4-methylphenol and a Lewis acid catalyst in an ethanol/tetrahydrofuran mixed solvent, adding the mixture into a preheating module, preheating to 25 ℃, simultaneously filling palladium carbon serving as a catalyst into a reactor, opening a hydrogen feeding valve and a nitrogen feeding valve, controlling the flow rate, adding the preheated 3-nitro-4-methylphenol solution into a reaction module, and carrying out gas-liquid-solid three-phase reaction to obtain the target compound 3-ethylamino-4-methylphenol. The catalyst used in the method can be recycled, the cost is saved, the reaction condition is mild, the reaction yield is high, the purity is high, the numerical control display operation is simple, and the safety is high.

The invention relates to a method for synthesizing 3-ethylamino-4-methylphenol, which adopts an H-Flow full-automatic hydrogenation reactor to carry out reaction; the method comprises the following operations: dissolving 3-nitro-4-methylphenol and a Lewis acid catalyst in an organic solvent, and adding the solution to a preheating module; immobilizing a palladium-carbon catalyst into a reactor; adjusting the feeding flow rates of hydrogen and nitrogen, finally adding the preheated 3-nitro-4-methylphenol solution into a reaction module, carrying out gas-liquid-solid three-phase reaction, collecting the effluent reaction liquid, and processing to obtain the 3-ethylamino-4-methylphenol. The reaction equation is expressed as follows:

further, in the above technical solution, the full-automatic hydrogenation reactor H-Flow includes two parts, namely a preheating module group and a reaction module group, and can perform liquid feeding and gas feeding. The preheating module group is connected with the reaction module group in series, the plurality of preheating module groups are connected in parallel, and the plurality of reaction module groups are connected in series.

Further, in the above technical scheme, the reaction temperature is 0-60 ℃ and enters the reaction module group. More preferably 25 ℃, and the reaction temperature of the materials is the same as the preheating temperature.

Further, in the above technical solution, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetaldehyde, etc. have been tried as the organic solvent; finally, preferably, a mixed solution of ethanol and tetrahydrofuran is used as an organic solvent for the reaction in the step; the volume ratio of tetrahydrofuran to ethanol is 3: 1.

Further, in the technical scheme, the Lewis acid catalyst is selected from BPh3 and B (C6F5)3, and the addition amount is 1-5% of the weight of the raw materials.

Further, in the above technical scheme, the 3-nitro-4-methylphenol is dissolved in an organic solvent to form a uniform solution.

Further, in the technical scheme, the 3-nitro-4-methylphenol is dissolved in an organic solvent to form a 1-1.2mol/L solution.

Further, in the above technical solution, the particle size of the supported catalyst particles is 0.2-2mm, more preferably 0.4 mm; the catalyst loading is 3-7mL, more preferably 4 mL.

Further, in the above technical solution, the feeding flow rate of the 3-nitro-4-methylphenol solution is 0.1-5mL/min, more preferably 1 mL/min; the hydrogen feed flow rate is 5-100sccm, more preferably 20 sccm; the nitrogen feed flow rate is 5-100sccm, more preferably 60 sccm.

Compared with the traditional reaction kettle, the full-automatic hydrogenation reactor H-Flow has the advantages of simple operation, very high heat and mass transfer efficiency, small occupied area, environmental protection and the like, and the contact time of the reaction can be set through the Flow rate; the equipment has the advantages of convenient operation, controllable heat release, greatly shortened production period, high safety, and high yield and purity of the prepared product.

Further, in the above technical scheme, the feeding flow rate in the reaction process is effectively controlled by a feeding valve and a numerical control display; the reaction module group is made of more than one material of special glass, polytetrafluoroethylene and carbon-silicon ceramic stainless steel metal coated with corrosion-resistant layers, and the maximum guaranteed pressure capable of being borne by the reaction module group is 10 MPa; the preheating module is a straight-line structure or a heart-shaped structure module with two inlets and one outlet; the reaction module is a multi-inlet one-outlet or single-inlet single-outlet heart-shaped structure module, wherein the multi-inlet one-outlet reaction module is suitable for mixed reaction after preheating, and the single-inlet single-outlet reaction module is suitable for prolonging the reaction residence time.

Further, in the above technical solution, the post-processing method comprises: collecting the effluent reaction liquid, distilling the mixed solvent of tetrahydrofuran and ethanol, and pulping and purifying by adopting petroleum ether to obtain a brown solid product, namely 3-ethylamino-4-methylphenol, with the purity of 99%.

The invention has the beneficial effects that:

1. different from the traditional high-pressure reaction kettle which needs very high pressure (15atm), the H-Flow of the full-automatic hydrogenation reactor only needs 5atm, and the reaction effect is good.

2. The catalyst palladium-carbon is immobilized in the reactor and can be directly recycled, so that the operation step of recycling is omitted, convenience and rapidness are realized, and the cost is reduced. Reduces waste materials and waste residues, and is more environment-friendly.

3. The device is carried with an on-line ultraviolet-visible and near-infrared detector, and can realize real-time on-line detection and analysis.

4. The phenomenon that the local concentration is too high or the local heat release is violent to cause the too high temperature can be avoided only by slowly dripping at low temperature like a conventional reaction kettle. The full-automatic hydrogenation reactor can accurately control the feeding flow rate of each material, and the research and development efficiency of the process is improved.

5. The full-automatic hydrogenation reactor H-Flow is used, the numerical control operation is simple, the labor cost is reduced, and the occupied space of the equipment is greatly saved.

Detailed Description

The present invention will be further described below by way of specific experiments, but the scope of the present invention is not limited thereto.

Example 1

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 are weighed and dissolved in 1L of mixed solvent of tetrahydrofuran and ethanol 1:1 (volume ratio, the same in the following examples), stirred until the solution is clear, and then injected into a preheating module to be preheated to 10 ℃; the palladium-carbon loading was set to 2mL, the particle size was 0.2mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 0.5 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 3.3%, main impurity (double ethylation) 13.7%, product 82.6%), spin-drying solvent, pulping with 350mL petroleum ether/20 mL methyl tert-butyl ether (the proportion of the following examples is the same) for 1h, suction filtering to obtain white solid, drying to obtain 91g product, yield 60%, HPLC: 95.4 percent.

Example 2

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 2: 1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 25 ℃; the palladium-carbon loading was set to 3mL, the particle size was 0.3mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 30 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 0.75 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 1.1%, main impurity (double ethylation) 8.8%, product 89.9%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction filtering to obtain white solid, drying to obtain 108g product, yield 72%, GC/HPLC: 96.5 percent.

Example 3

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 2: 1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 40 ℃; the palladium-carbon loading was set to 4mL, the particle size was 0.4mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 0.75 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 4.9%, main impurity (double ethylation) 10.3%, product 84.5%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction filtering to obtain white solid, drying to obtain 110g product, yield 73%, HPLC: 94.1 percent.

Example 4

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 2: 1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 60 ℃; the palladium-carbon loading was set to 5mL, the particle size was 0.5mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 0.8 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 3.2%, main impurity (bis-ethylation) 19.4%, product 77.3%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction filtering to obtain white solid, drying to obtain 75g product, yield 50%, HPLC: 92.1 percent.

Example 5

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 25 ℃; the palladium-carbon loading was set to 4, the particle size was 0.4mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the preheated reaction module at the feeding flow rate of 1 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 1.7%, main impurity (bis-ethylation) 4.8%, product 93.4%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction filtering to obtain white solid, drying to obtain 125g product, yield 83%, HPLC: 97.1 percent.

Example 6

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 25 ℃; the palladium-carbon loading was set to 4, the particle size was 0.4mm, the pressure was set to 3atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 1 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 6.6%, main impurity (bis-ethylation) 7.9%, product 85.3%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction-filtering to obtain white solid, drying to obtain 113g product, yield 75%, HPLC: 94.4 percent.

Example 7

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 70 ℃; the palladium-carbon loading was set to 5mL, the particle size was 0.5mm, the pressure was set to 8atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the preheated reaction module at the feeding flow rate of 2 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 0.9%, main impurity (double ethylation) 15.2%, product 83.8%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction filtering to obtain white solid, drying to obtain 109g product, yield 72%, HPLC: 96.3 percent.

Example 8

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring and dissolving the mixed solvent, then injecting the mixed solvent into a preheating module, and preheating to 25 ℃; the palladium-carbon loading was set to 4mL, the particle size was 0.4mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 20 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the reaction module preheated in advance at the feeding flow rate of 1 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 0.6%, main impurity (bis-ethylation) 1.1%, product 98.2%), spin-drying solvent, pulping with petroleum ether/methyl tert-butyl ether mixed solvent for 1h, suction-filtering to obtain white solid, drying to obtain 145g product, yield 95%, HPLC: 99.2 percent.

Example 9

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 25 ℃; the palladium-carbon loading was set to 4mL, the particle size was 0.4mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 30 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the preheated reaction module at the feeding flow rate of 1 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 0.3%, main impurity (bis-ethylation) 2.5%, product 97.1%), spin-drying solvent, pulping with petroleum ether for 1h, suction filtering to obtain white solid, drying to obtain 139g product, yield 92%, HPLC: 98.3 percent.

Example 10

153g of 3-nitro-4-methylphenol and 2.55g B (C6F5)3 were weighed out and dissolved in 1L of tetrahydrofuran and ethanol 3:1, stirring the mixed solvent until the mixed solvent is clear, and then injecting the mixed solvent into a preheating module to preheat the mixed solvent to 25 ℃; the palladium-carbon loading was set to 5mL, the particle size was 1mm, the pressure was set to 5atm, and then the feed flow rate of H2 was controlled to 30 sccm; the feeding flow rate of N2 is 60sccm, and finally the preheated 3-nitro-4-methylphenol solution is pumped into the preheated reaction module at the feeding flow rate of 1 mL/min. Collecting effluent reaction liquid (sampling HPLC analysis, raw material 1.6%, main impurity (bis-ethylation) 4.7%, product 93.5%), spin-drying solvent, pulping with petroleum ether for 1h, suction filtering to obtain white solid, drying to obtain 124g product, yield 82%, HPLC: 97.0 percent.

By contrast, example 8 is the best case, and the other cases have relatively low yields due to insufficient reaction of the starting materials and formation of more disubstituted impurities. The invention develops a synthetic method of 3-ethylamino-4-methylphenol, and utilizes an H-FLOW automatic hydrogenation reaction device to enable the synthetic process to be more efficient. The method has the advantages of low cost, simple operation, mild reaction conditions, high yield, high purity and the like.

The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.