WO2023070907A1

WO2023070907A1 - Etherification method for halogenated phenol

Info

Publication number: WO2023070907A1
Application number: PCT/CN2021/139662
Authority: WO
Inventors: 陈先朗; 王德花; 李嵘嵘; 韩得满; 武承林; 王梓鉴
Original assignee: 台州学院; 台州市生物医化产业研究院有限公司
Priority date: 2021-10-28
Filing date: 2021-12-20
Publication date: 2023-05-04
Also published as: CN113896618A

Abstract

The present invention relates to the technical field of organic synthesis, and provides an etherification method for a halogenated phenol. According to the preparation method provided in the present invention, a mixture of a halogenated phenol and triethylamine is used as a first material; a mixture of dichloroethane and potassium carbonate is used as a second material; and the first material and the second material are subjected to an etherification reaction in a micro-channel reactor apparatus to obtain an aromatic ether compound. The reaction of the present invention is carried out in the micro-channel reactor, and the specific surface area of the micro-channel reactor is large, such that the materials can be in full contact with one another, the reaction is more complete, and the selectivity of the product is further improved. The data in embodiments of the present invention shows that the conversion rate of the etherification method provided in the present invention is 63.8-93.8%, and the selectivity thereof is 83.1-95.2%.

Description

A kind of etherification method of halogenated phenol

This application claims the priority of the Chinese patent application with the application number 202111265011.9 and the invention title "A Method for Etherification of Halogenated Phenols" submitted to the China Patent Office on October 28, 2021, the entire contents of which are incorporated herein by reference Applying.

technical field

The invention relates to the technical field of organic synthesis, in particular to a method for the etherification of halogenated phenols.

Background technique

The etherification products of halogenated phenols are aromatic ether compounds, which can be used as high-efficiency broad-spectrum antibacterial agents. They have a wide range of killing and inhibiting effects on Gram-negative bacteria, positive bacteria, viruses and yeast, and are widely used in personal Nursing cream, disinfectant hand sanitizer, antibacterial soap, sanitary lotion, shampoo and other daily chemical fields, also used in the finishing of sanitary fabrics and the antiseptic treatment of pulp and polymers. Some can also be used in special drug toothpaste for the prevention of oral diseases. It is used in conjunction with fluoride to have a synergistic and sustained-release effect.

However, in the traditional preparation method, raw materials such as halogenated phenol and ethylene dichloride are added to the autoclave, but the selectivity of etherification of the reaction halogenated phenol in the autoclave is relatively poor, generally 60-70%.

Contents of the invention

In view of this, the object of the present invention is to provide a method for the etherification of halogenated phenols, and the selectivity of the target product of the etherification method provided by the present invention is relatively high.

In order to achieve the above object, the present invention provides the following technical solutions:

In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

The invention provides a method for etherification of halogenated phenols, comprising the following steps: using a mixture of halogenated phenols and triethylamine as the first material; using a mixture of dichloroethane and potassium carbonate as the second material; The first material and the second material are etherified in a microchannel reactor device to obtain an aromatic ether compound; the mass ratio of halogenated phenol and triethylamine in the first material is 1: (0.8-1.2) ;

The mass ratio of ethylene dichloride and potassium carbonate in the second material is (1～10):(0.5～7); The flow rate of the first material in the microchannel reactor is 20～40mL/min.

Preferably, the halogenated phenols include chlorophenols, fluorophenols, bromophenols or iodophenols.

Preferably, the flow rate of the first material in the microchannel reactor is 20-40 mL/min.

Preferably, the flow ratio of the first material and the second material is 1:0.6-4.

Preferably, the temperature of the etherification reaction is 120-220°C.

Preferably, the inlet of the microchannel reactor is also connected with a micromixer, and the first material and the second material enter the microchannel reactor through the micromixer.

Preferably, the gas-liquid interface area per unit volume of the microchannel reactor is 2000-10000m ² /m ³ ;

Preferably, the heat exchange area per unit volume of the microchannel reactor is 2500m ² /m ³ .

The invention provides a method for etherification of halogenated phenols, comprising the following steps: using a mixture of halogenated phenols and triethylamine as the first material; using a mixture of dichloroethane and potassium carbonate as the second material; The first material and the second material are etherified in a microchannel reactor to obtain an aromatic ether compound; the mass ratio of halogenated phenol and triethylamine in the first material is 1: (0.8-1.2); The mass ratio of dichloroethane and potassium carbonate in the second material is (1-10): (0.5-7). In the present invention, by setting the mass ratio range of dichloroethane and potassium carbonate in the second material to the above-mentioned range, the second material can be mixed more uniformly, and the presence of potassium carbonate provides an alkaline environment for the system, which can promote halogenation. The etherification reaction of substituted phenol, thereby improving the selectivity of etherification.

Further, in the present invention, by setting the flow rate of the first material to the above range, the full mixing of the first material and the second material can be realized, and then the etherification reaction can be fully carried out, side reactions are less likely to occur, and the selectivity of etherification is further improved. . The etherification reaction of the present invention is carried out in a microchannel reactor, and the specific surface area of the microchannel reactor is large, so that materials can be fully contacted, the reaction is more complete, and the selectivity of products is further improved. The data of the examples of the present invention show that the conversion rate of the etherification method provided by the present invention is 63.8-93.8%, and the selectivity is 83.1-95.2%.

Detailed ways

The invention provides a kind of etherification method of halogenated phenol, comprises the following steps:

A mixture of halogenated phenol and triethylamine is used as the first material;

A mixture of ethylene dichloride and potassium carbonate is used as the second material;

The first material and the second material are subjected to an etherification reaction in a microchannel reactor to obtain an aromatic ether compound.

In the present invention, unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

In the present invention, the halogenated phenol preferably includes fluorophenol, chlorophenol, bromophenol or iodophenol, further preferably includes chlorophenol, bromophenol or iodophenol; the bromophenol preferably includes For bromophenol, the chlorinated phenol preferably includes 2,4-dichlorophenol, and the iodophenol preferably includes 2,4,6-triiodophenol.

In the present invention, the mass ratio of halogenated phenol and triethylamine in the first material is 1:(0.8-1.2), preferably 1:1.

In the present invention, the mass ratio of dichloroethane and potassium carbonate in the second material is (1-10):(0.5-7); preferably (1-3):(5-7).

In the present invention, the flow rate of the first material is preferably 20-40 mL/min, more preferably 20 mL/min.

In the present invention, the flow ratio of the first material and the second material is preferably 1:0.6-4, more preferably 1:0.9-1.5.

In the present invention, the temperature of the etherification reaction is preferably 120-220°C, more preferably 140-200°C.

In the present invention, the inlet of the microchannel reactor is also connected with a micromixer, and the first material and the second material enter the microchannel reactor through the micromixer.

In the present invention, the gas-liquid interface area per unit volume of the microchannel reactor is preferably 2000-10000 m ² /m ³ ; the heat exchange area per unit volume of the microchannel reactor is preferably 2500 m ² /m ³ .

In the present invention, the reaction steps of the first material and the second material in the microchannel reactor equipment preferably include:

Pumping the first material and the second material into a micro mixer for mixing to obtain a mixed material;

The mixed material flows into the microchannel reactor for etherification reaction.

The invention adopts the continuous flow process of microchannel reactor equipment, which can increase the efficiency of mass transfer and heat transfer, and is beneficial to promote the etherification reaction. Compared with the kettle reaction, the reaction time is greatly shortened, and the efficiency of the etherification reaction is obviously improved. At the same time, it avoids the generation of a lot of waste water, which is beneficial to post-treatment and easy to operate.

After the etherification reaction, the present invention preferably also includes post-processing the etherification reaction feed liquid obtained. In the present invention, the post-treatment preferably includes sequentially washing the etherification reaction feed solution with water, extracting and separating to obtain an organic phase; the organic phase is subjected to subsequent precipitation to obtain an etherification product.

In the present invention, the water washing can remove the inorganic alkali; the number of times of the water washing is preferably 3-6 times.

The present invention will be described in detail below in conjunction with specific embodiments.

Example 1

A mixture of 1000g p-bromophenol and 1000g triethylamine was used as the first material, and potassium carbonate and dichloroethane were mixed according to the mass ratio of 1670:5000 to obtain the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, and the obtained organic phase was extracted and separated, and the solvent was removed, and 5 g of the crude product was taken. , diluted 100 times with ethanol, the resulting solution is detected by liquid chromatography, and the standard curve is calculated to obtain 0.31g of p-bromophenol, 4.45g of β-chloro-(bromo)phenetole, and the by-product is 0.24g. The conversion of p-bromophenol The yield was 91.8%, and the selectivity of β-chloro-(bromo)phenetole was 94.9%.

Example 2

A mixture of 1000g 2,4-dichlorophenol and 1000g triethylamine was used as the first material, and potassium carbonate and dichloroethane were mixed according to the mass ratio of 1670:5000 to obtain the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, and the obtained organic phase was extracted and separated, and the solvent was removed, and 5 g of the crude product was taken. , diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 0.26g of 2,4-dichlorophenol, 4.51g of β-chloro-(2,4-dichloro)phenetole, and the by-product The conversion rate of 2,4-dichlorophenol was 93.0%, and the selectivity of β-chloro-(2,4-dichloro)phenetole was 95.1%.

Example 3

A mixture of 1000g 2,4,6-triiodophenol and 1000g triethylamine was used as the first material, and potassium carbonate and dichloroethane were mixed according to the mass ratio of 1670:5000 to obtain the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, the obtained organic phase was extracted and separated, the solvent was removed, and the crude product 4.49 g, diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 0.28g of 2,4,6-triiodophenol, β-chloro-(2,4,6-triiodo)phenetole 4.43g, 0.29g of by-products, the conversion rate of 2,4,6-triiodophenol was 93.7%, and the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 93.9%.

Example 4

The mixture of 1000g 2,4,6-triiodophenol and 1000g triethylamine is used as the first material, and potassium carbonate and dichloroethane are mixed according to the mass ratio of 1670:7000 to obtain the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, and the obtained organic phase was extracted and separated, and the solvent was removed, and 5 g of the crude product was taken. , diluted 100 times with ethanol, the obtained solution was detected by liquid chromatography, and the standard curve was calculated to obtain 0.71g of 2,4,6-triiodophenol, 3.69g of β-chloro-(2,4,6-triiodo)phenetole g, 0.60 g of by-products, the conversion rate of 2,4,6-triiodophenol was 84.2%, and the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 86.0%.

Example 5

A mixture of 1000g 2,4,6-triiodophenol and 1000g triethylamine was used as the first material, and potassium carbonate and dichloroethane were mixed according to the mass ratio of 2000:5000 to obtain the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, and the obtained organic phase was extracted and separated, and the solvent was removed, and 5 g of the crude product was taken. , diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 0.97g of 2,4,6-triiodophenol, β-chloro-(2,4,6-triiodo)phenetole 3.11 g, 0.92 g of by-products, the conversion rate of 2,4,6-triiodophenol was 78.6%, and the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 77.2%.

Example 6

Pump the first material and the second material into the micro-mixer for mixing, the flow rate of the first material is 20mL/min, the flow rate of the second material is 20mL/min, then enter the microchannel reactor for etherification reaction , the temperature of the reactor was 160°C at this time, after reacting for 30min, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, the obtained organic phase was extracted and separated, the solvent was removed, and the crude 5g of the product was diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 1.21g of 2,4,6-triiodophenol, β-chloro-(2,4,6-triiodo)benzene Ether 3.45g, by-product 0.34g, the conversion rate of 2,4,6-triiodophenol was 73.5%, the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 91.0%.

Example 7

Pump the first material and the second material into the micro-mixer for mixing. The flow rate of the first material is 20mL/min, and the flow rate of the second material is 20mL/min. They are mixed in the micro-channel mixer, and then enter the micro-channel mixer. In the channel reactor, the temperature of the reactor is 160°C at this time, and after the reaction is stable for 30 minutes, when the reaction reaches a stable state, the reaction feed liquid in the microchannel reactor is extracted and washed with water for 4 times, and the obtained organic phase is extracted and separated. The solvent was removed, and 4.48 g of the crude product was taken, diluted 100 times with ethanol, and the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 0.37 g of 2,4,6-triiodophenol, β-chloro-(2,4, 6-triiodo)phenetole 3.85g, by-product 0.78g, 2,4,6-triiodophenol conversion rate 91.7%, selectivity of β-chloro-(2,4,6-triiodo)phenetole was 83.2%.

Example 8

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 40mL/min, and the flow of the second material is 40mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, the obtained organic phase was extracted and separated, the solvent was removed, and the crude product 4.34 g, diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 1.45g of 2,4,6-triiodophenol, β-chloro-(2,4,6-triiodo)phenetole 2.45g, 0.44g of by-products, the conversion rate of 2,4,6-triiodophenol was 63.8%, and the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 84.8%.

Example 9

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the temperature of the reactor was 160°C, after 30 minutes of reaction, when the reaction reached a steady state, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, and the obtained organic phase was extracted and separated, and the solvent was removed to obtain the crude product 4.39g, diluted 100 times with ethanol, the resulting solution was detected by liquid chromatography, and the standard curve was calculated to obtain 1.20g of 2,4,6-triiodophenol, β-chloro-(2,4,6-triiodo)benzene Diethyl ether was 3.28g, by-product was 0.52g, the conversion rate of 2,4,6-triiodophenol was 73.7%, and the selectivity of β-chloro-(2,4,6-triiodo)phenetole was 86.3%.

Comparative example 1

Put the mixture of 1000g 2,4,6-triiodophenol and 1000g triethylamine as the first material into the autoclave, then mix 1670g potassium carbonate and 5000g dichloroethane into the autoclave, stir to make it fully mixed , and reacted for 20 hours at a temperature of 160°C to obtain 377.36g of β-chloro-(2,4,6-triiodo)phenetole, 223.54g of by-products and 469g of raw materials. After calculation, the conversion rate is 53.1%, and the selectivity is 62.8%.

Comparative example 2

Put the mixture of 1000g p-bromophenol and 1000g triethylamine as the first material into the autoclave, then mix 1670g potassium carbonate and 5000g dichloroethane into the autoclave, stir to make it fully mixed, at a temperature of 160°C 386.86g of β-chloro-(bromo)phenetole, 181.22g of by-products and 498g of raw materials were obtained. After calculation, the conversion rate is 50.2%, and the selectivity is 68.1%.

Comparative example 3

The mixture of 1000g 2,4-dichlorophenol and 1000g triethylamine is put into the autoclave as the first material, then 1670g of potassium carbonate and 5000g of dichloroethane are mixed and added into the autoclave, stirred to make it fully mixed, At a temperature of 160°C, reacted for 20 hours to obtain 476.32 g of β-chloro-(2,4-dichloro)phenetole, 299.45 g of by-products and 438 g of raw materials. After calculation, the conversion rate is 56.2%, and the selectivity is 61.4%.

Comparative example 4

A mixture of 1000g of p-bromophenol and 1000g of triethylamine was used as the first material, and potassium carbonate and dichloroethane were mixed according to the mass ratio of 1670:8000 to obtain a mixed solution as the second material.

The first material and the second material are mixed in the micro-mixer by pumping, the flow of the first material is 20mL/min, and the flow of the second material is 20mL/min, and then the etherification reaction is carried out in the microchannel reactor. When the reactor temperature was 160°C, after 30 minutes of reaction, the reaction feed liquid in the microchannel reactor was extracted and washed with water for 4 times, the obtained organic phase was extracted and separated, and the solvent was removed, and 4.78 g of the crude product was diluted with ethanol for 100 times, the resulting solution is detected by liquid chromatography, and the calibration curve is calculated to obtain 1.89g of p-bromophenol, 2.27g of β-chloro-(bromo)phenetole, and the by-product is 0.84g, and the transformation rate of p-bromophenol is 54.8%. The selectivity of β-chloro-(bromo)phenetole was 73.0%.

Comparative example 5

The only difference from Embodiment 1 is that the flow rate of the first material is 10 mL/min, and the flow rate of the second material is 10 mL/min. After reacting for 30min, extract the reaction feed liquid in the microchannel reactor and wash with water 4 times, extract and separate the obtained organic phase, remove the solvent, get 4.69g of the crude product, dilute 100 times with ethanol, and the obtained solution passes liquid chromatography Carry out detection, standard curve calculation, obtain p-bromophenol 2.22g, β-chloro-(bromo) phenetole 1.95g, by-product is 0.83g, the conversion rate of p-bromophenol is 48.0%, β-chloro-(bromo) benzene The selectivity to diethyl ether was 70.1%.

By comparing Examples 1-8 and Comparative Examples 1-5, it is shown that the technical solution provided by the present invention has higher conversion rate and selectivity compared with the comparative examples in which the reaction kettle is used to etherify halogenated phenols.

The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, these improvements and Retouching should also be regarded as the protection scope of the present invention.

Claims

A method for the etherification of halogenated phenols, comprising the following steps:

A mixture of halogenated phenol and triethylamine is used as the first material;

A mixture of ethylene dichloride and potassium carbonate is used as the second material;

The first material and the second material are subjected to an etherification reaction in a microchannel reactor to obtain an aromatic ether compound;

The mass ratio of halogenated phenol and triethylamine in the first material is 1: (0.8～1.2)

The mass ratio of dichloroethane and potassium carbonate in the second material is (1-10): (0.5-7).
The etherification method according to claim 1, wherein the halogenated phenol comprises chlorophenol, fluorophenol, bromophenol or iodophenol.
The etherification method according to claim 1, characterized in that the flow rate of the first material in the microchannel reactor is 20-40 mL/min.
The etherification method according to claim 1 or 3, characterized in that the flow ratio of the first material and the second material is 1:0.6-4.
The etherification method according to claim 1, characterized in that the temperature of the etherification reaction is 120-220°C.
The etherification method according to claim 1, wherein the inlet of the microchannel reactor is also connected with a micromixer, and the first material and the second material enter the microchannel reactor through the micromixer middle.
The etherification method according to claim 1, characterized in that the gas-liquid interface area per unit volume of the microchannel reactor is 2000-10000m 2 /m 3 .
The etherification method according to claim 1, characterized in that the heat exchange area per unit volume of the microchannel reactor is 2500m 2 /m 3 .
The etherification method according to claim 1, characterized in that, after the etherification reaction, further comprising post-processing the obtained etherification reaction feed liquid to obtain an etherification product.
The etherification method according to claim 9, wherein the post-treatment comprises sequentially washing, extracting and separating the etherification reaction liquid to obtain an organic phase; the obtained organic phase is subjected to precipitation to obtain an etherification product .