CN112142567B - Preparation method of 2-fluoro-3-chlorophenol - Google Patents

Preparation method of 2-fluoro-3-chlorophenol Download PDF

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CN112142567B
CN112142567B CN202011082097.7A CN202011082097A CN112142567B CN 112142567 B CN112142567 B CN 112142567B CN 202011082097 A CN202011082097 A CN 202011082097A CN 112142567 B CN112142567 B CN 112142567B
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acid
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diazonium
chloro
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CN112142567A (en
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邵鸿鸣
张星
余波
胡杰
李宏奎
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ZHEJIANG YONGTAI TECHNOLOGY CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • 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

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Abstract

The invention discloses a preparation method of 2-fluoro-3-chlorophenol, and relates to the technical field of fine chemical engineering. The invention uses 2, 4-dichloro-3-fluoronitrobenzene as raw material, firstly etherifies to prepare 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene, then reduces to 2-alkoxy-3-fluoro-4-chloroaniline or 2-chloro-3-fluoro-4-alkoxyaniline, then deaminates through diazonium reduction reaction to prepare 2-fluoro-3-chlorophenyl ether, and then prepares 2-fluoro-3-chlorophenol through one-step pyrolysis, the total yield is 60%, the product purity is more than 98%, and the industrial production is easy.

Description

Preparation method of 2-fluoro-3-chlorophenol
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a preparation method of 2-fluoro-3-chlorophenol.
Background
The 2-fluoro-3-chlorophenol is a novel fine chemical intermediate, can be applied to the fields of medicine and pesticide synthesis, new materials, liquid crystal materials and the like, and has good market demands.
Regarding the synthesis of similar intermediates, for example: chinese patent application 200610098100.8 discloses a process for preparing 2- (2, 2-trifluoroethoxy) phenol according to the following steps: using o-nitrochlorobenzene as a raw material to carry out etherification reaction with 2, 2-trifluoroethanol to obtain an intermediate 2- (2, 2-trifluoroethoxy) nitrobenzene, carrying out hydrogenation reduction on the 2- (2, 2-trifluoroethoxy) nitrobenzene to obtain 2- (2, 2- (2, 2-trifluoroethoxy) aniline and 2- (2, 2-trifluoroethoxy) aniline are finally subjected to diazotization and hydroxylation reaction to prepare 2- (2, 2-trifluoroethoxy) phenol, but the method has low yield and is unfavorable for production.
For another example, chinese patent application 201310382592.3 discloses a method for preparing 2-chloro-6-fluorophenol, comprising the steps of: (1) Adding o-fluorophenol into a reactor, slowly dropwise adding sodium hypochlorite aqueous solution into the reactor, wherein the molar ratio of sodium hypochlorite to o-fluorophenol is (1.0-2.0) to 1, heating the reactor to 0-77 ℃, and carrying out heat preservation reaction to generate a mixture of 2-chloro-6-fluorophenol; (2) After the reaction is finished, dilute hydrochloric acid is added into the reactor, the pH is regulated to be 5 to 6.5, and the mixture is stood to separate out an organic phase; (3) And (3) purifying and drying the organic phase separated in the step (2) to obtain the 2-chloro-6-fluorophenol. The preparation method is simple to operate, low in cost and capable of realizing industrialized mass operation and production.
However, the current preparation method of 2-fluoro-3-chlorophenol has not been reported in literature, and in view of the fact, the invention provides a preparation method of 2-fluoro-3-chlorophenol, which has high yield, good purity and simple operation, and is suitable for industrial production.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a novel method for preparing 2-fluoro-3-chlorophenol, which takes 2, 4-dichloro-3-fluoronitrobenzene as a raw material, prepares 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene by etherification, reduces the 2-alkoxy-3-fluoro-4-chloroaniline or 2-chloro-3-fluoro-4-alkoxyaniline into 2-alkoxy-3-chloroaniline, then deaminates the 2-fluoro-3-chlorophenol by diazonium reduction reaction, prepares 2-fluoro-3-chlorophenol by one-step pyrolysis, and has the total yield of 60 percent, the product purity of more than 98 percent, and is easy for industrial production.
In order to achieve the above object, the present invention has the following technical scheme:
a process for preparing 2-fluoro-3-chlorophenol comprising the steps of:
(1) Etherification: etherification reaction is carried out on 2, 4-dichloro-3-fluoronitrobenzene and alcohol to obtain 2-alkoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-alkoxynitrobenzene,
(2) And (3) reduction: the 2-alkoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-alkoxynitrobenzene obtained in the step (1) are subjected to reduction reaction in a solvent to prepare the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline,
(3) Diazo reduction: carrying out diazonium reaction on the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline obtained in the step (2) and a diazonium reagent, then carrying out reduction reaction on the diazonium reaction product and a reducing agent to generate 2-fluoro-3-chlorophenyl ether,
(4) Cracking: the 2-fluoro-3-chlorophenol obtained in the step (3) is subjected to a cracking reaction to obtain the 2-fluoro-3-chlorophenol,
wherein R represents an alkyl group including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and the like. Preferably, in the step (1), the 2, 4-dichloro-3-fluoronitrobenzene is dissolved in an alcohol solvent, and an alcohol solution of a base is dropwise added to perform an etherification reaction, wherein the alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, propanol, butanol, etc., and further preferably methanol. Preferably, the base comprises one or more of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide and potassium hydroxide, and more preferably sodium methoxide; the alcohol solution concentration of the alkali is 15-25%, more preferably 20%; the temperature of the etherification reaction is 0-100 ℃, and more preferably 40-50 ℃; the molar ratio of the 2, 4-dichloro-3-fluoronitrobenzene to the base is 1:1-1.5, and more preferably 1:1-1.1.
Preferably, in the step (2), the reduction is iron powder reduction or hydrogenation reduction, and more preferably hydrogenation reduction from the viewpoint of environmental friendliness.
Preferably, in step (2), the solvent is an alcoholic solvent, including but not limited to methanol, ethanol, isopropanol, propanol, butanol, etc., and more preferably methanol.
Preferably, in the step (2), a catalyst is required to be added during hydrogenation reduction, and the mass amount of the catalyst is 1-10% of the mass of the 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene, and more preferably 1-2%; the catalyst includes, but is not limited to Pd/C, pt/C, raney nickel, and Raney nickel is further preferred from an economical point of view.
Preferably, in step (2), the temperature of the reduction reaction is 20 to 100 ℃, more preferably 40 to 50 ℃.
Preferably, the step (3) specifically comprises: dissolving the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline obtained in the step (2) in an acid solution, dripping a diazonium reagent for diazonium reaction to obtain a clear diazonium solution, dripping the diazonium solution into a solution containing a diazonium salt reducing agent and a catalyst, and carrying out reduction reaction to generate 2-fluoro-3-chlorophenyl ether, wherein the acid in the acid solution comprises one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid and hydrobromic acid, and further preferably sulfuric acid; the acid solution is specifically an aqueous solution of the above acid, and the mass concentration is 10 to 30%, and more preferably 20%.
Preferably, the diazonium reagent is one or more of sodium nitrite, nitrous acid, potassium nitrite and nitrososulfuric acid; sodium nitrite is further preferred from the viewpoint of safety and economy.
Preferably, the temperature of the diazonium reaction is from-20 to 20 ℃, more preferably from-5 to 5 ℃.
Preferably, the molar ratio of the 2-alkoxy-3-fluoro-4-chloroaniline or 2-chloro-3-fluoro-4-alkoxyaniline, the diazonium reagent and the acid is 1:1-1.2:1-10, and more preferably 1:1-1.05:2-5.
Preferably, the method further comprises the step of eliminating the oxidizing property after the diazo reaction and before the reduction reaction, specifically adding a reducing agent to the obtained clear diazo liquid to eliminate the oxidizing property, wherein the reducing agent is a common reducing agent, such as sulfamic acid, sodium sulfite, sodium bisulfite, sodium thiosulfate, sodium dithionite and the like.
Preferably, the diazonium salt reducing agent includes, but is not limited to, sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol, isopropanol, HMPA, thiophenol, sodium stannous, and the like, with sodium hypophosphite being further preferred.
Preferably, the catalyst is selected from one or more of copper sulfate, cuprous oxide, copper nitrate, potassium trifluoroacetate, sodium trifluoroacetate, trifluoroacetic acid, copper acetate, copper carbonate, sodium acetate and potassium acetate, and more preferably cuprous oxide.
Preferably, the molar ratio of the diazonium reagent, the diazonium salt reducing agent and the catalyst is 1:1-5:0.1-1, more preferably 1:1-2:0.2-0.3.
Preferably, the step (4) specifically comprises: the 2-fluoro-3-chlorophenol obtained in the step (3) is subjected to a cleavage reaction in an acid solution to obtain 2-fluoro-3-chlorophenol, wherein the acid solution is an aqueous solution of an acid, and the acid comprises, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic anhydride, sulfuric acid, pyridine hydrobromide, pyridine hydroiodide and pyridine hydrochloride, and hydrobromic acid is further preferred.
Preferably, in step (4), the mass concentration of the acid solution is 20 to 60%, more preferably 30 to 50%.
Preferably, in the step (4), the molar ratio of the 2-fluoro-3-chlorophenyl ether to the acid is 1:1-20.
Preferably, in step (4), the reaction temperature of the cleavage is 50-150 ℃, more preferably 100-110 ℃.
The beneficial effects of the invention are as follows:
the novel method for preparing the 2-fluoro-3-chlorophenol is provided, the yield is high, and the total yield can reach 60%; the purity is good and reaches more than 98 percent; is easy for industrialized production.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention.
In the following examples, unless otherwise specified, the methods of operation used were conventional, and the equipment used was conventional. In the examples described below, the percentages relating to the concentrations are mass fractions, if specified.
In the examples below, 2, 4-dichloro-3-fluoronitrobenzene was purchased from Shanghai Jiding Corp;
Pd/C catalyst was purchased from Sean Kaili company;
raney nickel catalysts were purchased from the company Seamikai.
Example 1
(1) Taking a 2L four-port bottle, sequentially adding 500mL of methanol, 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the solution is dissolved, then heating to 40-50 ℃, dropwise adding 283.5g of 20% sodium methoxide methanol solution, carrying out heat preservation reaction for 2h after dropwise adding, sampling, controlling the temperature, and carrying out HPLC:2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 1 percent, 2-methoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-methoxynitrobenzene are less than or equal to 95 percent, and the reaction is finished. Cooling to 20-30deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove generated salt.
(2) The mother liquor obtained in the step (1) was charged into a 2L autoclave, 4.2g of Raney nickel catalyst was added, and the autoclave was closed. Nitrogen is replaced for three times, hydrogen is replaced for three times, the temperature is raised to 40-50 ℃, the pressure is controlled to be 10-15bar, and hydrogenation reaction is carried out for 4 hours until the hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30deg.C, evacuating, replacing nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquor to dryness to obtain a mixture 158g of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline, and performing HPLC: more than or equal to 95 percent.
(3) Adding 158g of the mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2) and 1500g of 20% sulfuric acid into a 2L four-mouth bottle, heating to completely dissolve, slowly cooling to-5-5 ℃ to separate out a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, dissolving the solid after dropwise adding, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until a starch potassium iodide test paper is tested to be not changed into blue, and obtaining a diazonium solution.
Another 3L four-mouth bottle is taken, 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid are added, the temperature is raised to 30-40 ℃, the nitrogen liquid is added dropwise, and nitrogen is discharged in the dropwise adding process. After the dripping, the reaction is carried out for 5 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 112.4g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 98 percent.
(4) Adding 112.4g of 2-fluoro-3-anisole obtained in the step (3) and 600g of 50% hydrobromic acid into a 2L four-necked flask, heating to 100-110 ℃ for reflux heat preservation reaction for 7h, sampling, controlling in a middle way, and performing HPLC: 2-fluoro-3-chloroanisole is less than or equal to 5 percent, 2-fluoro-3-chlorophenol is more than or equal to 95 percent, and the reaction is stopped. Cooling to 20-30deg.C, adding 300g of dichloromethane 3, extracting for three times, back extracting the oil layer with 200g of 20% liquid alkali, cooling the water layer to 0-10deg.C, slowly dripping hydrochloric acid to adjust pH=1-2, precipitating a large amount of white crystals, filtering, washing with a small amount of water, vacuum drying at 20-30deg.C for 24h to obtain 87.9g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent and the total yield is 60 percent.
Example 2
Taking a 2L four-mouth bottle, sequentially adding 500mL of ethanol, 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the solution is dissolved, then heating to 40-50 ℃, dropwise adding 357g of 20% sodium ethoxide ethanol solution, carrying out heat preservation reaction for 4 hours after the dropwise adding, sampling, controlling the concentration, and carrying out HPLC:2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 2 percent, 2-methoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-methoxynitrobenzene are less than or equal to 94 percent, and the reaction is finished. Cooling to 20-30deg.C, dripping ethanol hydrochloride solution, adjusting pH to about 7, and filtering to remove salt.
Subsequent reaction steps the same as in example 1, 83.5g of 2-fluoro-3-chlorophenol can be prepared, HPLC: more than or equal to 98 percent and the total yield is 57 percent.
Example 3
Taking a 2L four-port bottle, sequentially adding 500mL of methanol, 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the solution is dissolved, then heating to 60-70 ℃, dropwise adding 283.5g of 20% sodium methoxide methanol solution, carrying out heat preservation reaction for 1h after dropwise adding, sampling, controlling in a middle way, and carrying out HPLC: the 2, 4-dichloro-3-fluoronitrobenzene is not less than 0.5 percent, the 2-methoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-methoxynitrobenzene are not less than 90 percent, and the reaction is finished. Cooling to 20-30deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove generated salt.
Subsequent reaction procedure as in example 1, 78.3g of 2-fluoro-3-chlorophenol can be prepared, HPLC: more than or equal to 98 percent and the total yield is 53.4 percent.
Example 4
Taking a 2L four-port bottle, sequentially adding 500mL of methanol, 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the solution is dissolved, then heating to 40-50 ℃, dropwise adding 312g of 20% sodium methoxide methanol solution, carrying out heat preservation reaction for 2h after the dropwise addition, sampling, controlling the concentration, and carrying out HPLC:2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 0.5 percent, 2-methoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-methoxynitrobenzene are less than or equal to 92 percent, and the reaction is finished. Cooling to 20-30deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove generated salt.
Subsequent reaction procedure as in example 1, 73.6g of 2-fluoro-3-chlorophenol can be prepared, HPLC: more than or equal to 98 percent and the total yield is 50.2 percent.
Example 5
The etherification step (1)) was the same as in example 1.
The mother liquor obtained after etherification was charged into a 2L autoclave, 8g of Raney nickel catalyst was added, and the autoclave was closed. Nitrogen is replaced for three times, hydrogen is replaced for three times, the temperature is raised to 40-50 ℃, the pressure is controlled to be 10-15bar, and hydrogenation reaction is carried out for 4 hours until the hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30deg.C, evacuating, replacing nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquor to dryness to obtain 15g of a mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline, and performing HPLC: more than or equal to 95 percent.
As compared with example 1, after increasing the catalyst amount, the resulting mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline was increased from 158g to 159g, and the yield was not significantly increased, and the lower amount of catalyst in example 1 was preferred from the viewpoint of cost.
Example 6
The etherification step (1)) was the same as in example 1. The mother liquor obtained after etherification was charged into a 2L autoclave, 4.2g of 5% Pd/C catalyst was added thereto, and the autoclave was closed. Nitrogen is replaced for three times, hydrogen is replaced for three times, the temperature is raised to 40-50 ℃, the pressure is controlled to be 10-15bar, and hydrogenation reaction is carried out for 4 hours until the hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30deg.C, evacuating, replacing nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquor to dryness to obtain a mixture 158g of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline, and performing HPLC: more than or equal to 95 percent.
It can be seen that the reaction effect is the same after the Pd/C catalyst with higher cost is used as compared with the catalyst in example 1, so that Raney nickel is selected as the catalyst from the economical point of view.
Example 7
The etherification step (1)) was the same as in example 1.
The mother liquor obtained after etherification was charged into a 2L autoclave, 4.2g of Raney nickel catalyst was added, and the autoclave was closed. Nitrogen is replaced for three times, hydrogen is replaced for three times, the temperature is raised to 60-70 ℃, the pressure is controlled to be 10-15bar, hydrogenation reaction is carried out for 2 hours, and the hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30deg.C, evacuating, replacing nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquor to dryness to obtain 157g of a mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline, and performing HPLC: more than or equal to 90 percent.
Compared with example 1, the reaction time is shortened after the hydrogenation reaction temperature is increased, but the impurity is increased and the purity is slightly reduced.
Example 8
The etherification step (1)) and the reduction step (2)) were the same as in example 1.
Taking a 2L four-mouth bottle, adding 158g of the mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2), 1500g of 20% hydrochloric acid, heating to completely dissolve, slowly cooling to-5-5 ℃ to separate out a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after the dropwise adding, dissolving the solid, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the starch potassium iodide test paper is not changed into blue, and obtaining the diazonium solution.
Another 3L four-mouth bottle is taken, 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 30% hydrochloric acid are added, the temperature is raised to 30-40 ℃, the nitrogen liquid is added dropwise, and nitrogen is discharged in the dropwise adding process. After the dripping, the reaction is carried out for 5 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 125g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 85 percent.
It can be seen that more chlorinated byproducts are generated after hydrochloric acid is used, so that the purity is reduced to a certain extent.
Example 9
The etherification step (1)) and the reduction step (2)) were the same as in example 1. Taking a 2L four-mouth bottle, adding 158g of the mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2), 1500g of 20% sulfuric acid, heating to completely dissolve, slowly cooling to 5-10 ℃ to separate out a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after the dropwise adding, dissolving the solid, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the starch potassium iodide test paper is not changed into blue, and obtaining a diazonium solution.
Another 3L four-mouth bottle is taken, 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid are added, the temperature is raised to 30-40 ℃, the nitrogen liquid is added dropwise, and nitrogen is discharged in the dropwise adding process. After the dripping, the reaction is carried out for 5 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 107.4g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 98 percent.
The results show that the increase in diazonium reaction temperature reduces the yield to some extent.
Example 10
The etherification step (1)) and the reduction step (2)) were the same as in example 1. Taking a 3L four-mouth bottle, adding 158g of the mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2), 2000g of 20% sulfuric acid, heating to completely dissolve, slowly cooling to-5-5 ℃ to separate out a large amount of white solid, then slowly dropwise adding 155g of 50% sodium nitrite solution, dissolving the solid after dropwise adding, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until a starch potassium iodide test paper is not changed into blue, and obtaining a diazonium solution.
Another 5L four-mouth bottle is taken, 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid are added, the temperature is raised to 30-40 ℃, the nitrogen liquid is added dropwise, and nitrogen is discharged in the dropwise adding process. After the dripping, the reaction is carried out for 5 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 111.9g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 98 percent.
As compared with example 1, the use of excessive sodium nitrite and sulfuric acid does not increase the yield, and is not preferable in view of cost.
Example 11
The etherification step (1)) and the reduction step (2)) were the same as in example 1.
Taking a 2L four-mouth bottle, adding 158g of the obtained mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline and 1500g of 20% sulfuric acid, heating to completely dissolve, slowly cooling to-5-5 ℃ to separate out a large amount of white solid, then slowly dripping 144.9g of 50% sodium nitrite solution, after dripping, dissolving the solid, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite, and testing by using starch potassium iodide test paper until the test does not change blue.
Another 3L four-mouth bottle is taken, 100g of ethanol, 31.7g of copper acetate and 500g of 50% sulfuric acid are added, the temperature is raised to 30-40 ℃, the nitrogen liquid is added dropwise, and nitrogen is discharged during the dropwise adding process. After the dripping, the reaction is carried out for 12 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 102.7g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 90 percent.
It can be seen that the effect is less than that of sodium hypophosphite and cuprous oxide when ethanol is used as the diazonium salt reducing agent and copper acetate is used as the catalyst.
Example 12
The etherification step (1)) and the reduction step (2)) were the same as in example 1. Taking a 2L four-mouth bottle, adding 158g of the obtained mixture of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline and 1500g of 20% sulfuric acid, heating to the total solution, slowly cooling to-5-5 ℃ to separate out a large amount of white solid, then slowly dripping 144.9g of 50% sodium nitrite solution, after dripping, dissolving the solid, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until a starch potassium iodide test paper is tested to be not changed into blue, and obtaining a diazonium solution.
Another 3L four-mouth bottle is taken, 120g of sodium hypophosphite, 15g of cuprous oxide and 500g of 50% sulfuric acid are added, the temperature is raised to 30-40 ℃, the nitrogen adding liquid begins to drop, and nitrogen is discharged in the dropping process. After the dripping, the reaction is carried out for 5 hours under the heat preservation, the sampling is controlled, and the HPLC is carried out: the diazonium salt of 2-methoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1%, and the reaction is finished. Heating up water vapor for distillation, separating the fractions, washing an oil layer twice by 100g of 20% sodium hydroxide solution, standing and separating to obtain 110g of 2-fluoro-3-anisole, and performing HPLC: more than or equal to 98 percent.
Example 13
The etherification step (1)), the reduction step (2)) and the diazonium reduction step (3)) were the same as in example 1. Taking a 2L four-port bottle, adding 112.4g of the obtained 2-fluoro-3-anisole and 1000g of 30% hydrochloric acid, heating to 100-110 ℃ for reflux and heat preservation reaction for 20h, sampling, controlling in a central manner, and performing HPLC: the 2-fluoro-3-chloroanisole is less than or equal to 10 percent, the 2-fluoro-3-chlorophenol is more than or equal to 90 percent, and the reaction is stopped. Cooling to 20-30deg.C, adding 300g of dichloromethane 3, extracting for three times, back extracting the oil layer with 200g of 20% liquid alkali, cooling the water layer to 0-10deg.C, slowly dripping hydrochloric acid to adjust pH=1-2, precipitating a large amount of white crystals, filtering, washing with a small amount of water, vacuum drying at 20-30deg.C for 24h to obtain 77.4g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent.
Hydrochloric acid is used for cleavage, which leads to an increase in reaction time and a decrease in yield, and hydrobromic acid is therefore preferred.
Example 14
The etherification step (1)), the reduction step (2)) and the diazonium reduction step (3)) were the same as in example 1. Taking a 2L four-necked flask, adding 112.4g of the obtained 2-fluoro-3-anisole and 600g of 50% sulfuric acid, heating to 110-120 ℃ for reflux and heat preservation reaction for 20h, sampling, controlling in a central manner, and performing HPLC: the 2-fluoro-3-chloroanisole is less than or equal to 15 percent, the 2-fluoro-3-chlorophenol is more than or equal to 85 percent, and the reaction is stopped. Cooling to 20-30deg.C, adding 300g of dichloromethane 3, extracting for three times, back extracting the oil layer with 200g of 20% liquid alkali, cooling the water layer to 0-10deg.C, slowly dripping hydrochloric acid to adjust pH=1-2, precipitating a large amount of white crystals, filtering, washing with a small amount of water, vacuum drying at 20-30deg.C for 24h to obtain 69.9g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent.
Sulfuric acid is used for cleavage, which leads to an increase in reaction time and a decrease in yield, and hydrobromic acid is therefore preferred.
Example 15
The etherification step (1)), the reduction step (2)) and the diazonium reduction step (3)) were the same as in example 1.
Taking a 2L four-necked flask, adding 112.4g of the obtained 2-fluoro-3-anisole and 600g of 50% hydrobromic acid, heating to 80-90 ℃ for heat preservation reaction for 17h, sampling, controlling in a central manner, and performing HPLC: 2-fluoro-3-chloroanisole is less than or equal to 5 percent, 2-fluoro-3-chlorophenol is more than or equal to 95 percent, and the reaction is stopped. Cooling to 20-30deg.C, adding 300g of dichloromethane 3, extracting for three times, back extracting the oil layer with 200g of 20% liquid alkali, cooling the water layer to 0-10deg.C, slowly dripping hydrochloric acid to adjust pH=1-2, precipitating a large amount of white crystals, filtering, washing with a small amount of water, vacuum drying at 20-30deg.C for 24h to obtain 86.5g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent.
The results show that the reaction effect is consistent after the cleavage reaction temperature is reduced, but the reaction time is prolonged.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. The preparation method of the 2-fluoro-3-chlorophenol is characterized by comprising the following steps of:
(1) Etherification: etherification reaction is carried out on 2, 4-dichloro-3-fluoronitrobenzene and alcohol to obtain 2-alkoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-alkoxynitrobenzene,
(2) And (3) reduction: reducing the 2-alkoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-alkoxynitrobenzene obtained in the step (1) to prepare 2-alkoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-alkoxyaniline; the reduction is hydrogenation reduction, a catalyst is added in the hydrogenation reduction, the mass dosage of the catalyst is 1-10% of the mass of the 2-alkoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-alkoxynitrobenzene, and the catalyst is Raney nickel;
(3) Diazo reduction: dissolving the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline obtained in the step (2) in an acid solution, dripping a diazonium reagent for diazonium reaction to obtain a clear diazonium solution, dripping the diazonium solution into a solution containing a diazonium salt reducing agent and a catalyst for reduction reaction, and preserving the temperature for 5 hours to generate 2-fluoro-3-chlorophenyl ether; the diazonium reaction needs to be carried out in an acid solution, the acid being sulfuric acid,
(4) Cracking: the 2-fluoro-3-chlorophenol obtained in the step (3) is subjected to a cracking reaction to obtain the 2-fluoro-3-chlorophenol,
wherein R represents an alkyl group.
2. The method according to claim 1, wherein in the step (1), the 2, 4-dichloro-3-fluoronitrobenzene is dissolved in an alcohol solvent, and an alcohol solution of a base is added dropwise to carry out etherification reaction; the temperature of the etherification reaction is 0-100 ℃; the alkali comprises one or more of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide and potassium hydroxide; the molar ratio of the 2, 4-dichloro-3-fluoronitrobenzene to the alkali is 1:1-1.5.
3. The method according to claim 2, wherein in the step (1), the solvent is methanol; the temperature of the etherification reaction is 40-50 ℃; the alkali is sodium methoxide; the molar ratio of the 2, 4-dichloro-3-fluoronitrobenzene to the alkali is 1:1-1.1.
4. The method according to claim 1, wherein in the step (2), the temperature of the reduction reaction is 20 to 100 ℃.
5. The method according to claim 4, wherein in the step (2), the catalyst is used in an amount of 1 to 2% by mass of the 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene; the temperature of the reduction reaction is 40-50 ℃.
6. The preparation method according to claim 1, wherein the step (3) is specifically: the molar ratio of the 2-alkoxy-3-fluoro-4-chloroaniline or 2-chloro-3-fluoro-4-alkoxyaniline to the diazonium reagent to the acid is 1:1-1.2:1-10; the temperature of the diazo reaction is-20-20 ℃; the acid is sulfuric acid.
7. The method according to claim 6, wherein in the step (3), the diazonium reagent is one or more of sodium nitrite, nitrous acid, potassium nitrite, and nitrososulfuric acid, and the diazonium salt reducing agent comprises sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol, isopropanol, HMPA, thiophenol, or sodium stannate; the catalyst is one or more selected from copper sulfate, cuprous oxide, copper nitrate, potassium trifluoroacetate, sodium trifluoroacetate, trifluoroacetic acid, copper acetate, copper carbonate, sodium acetate and potassium acetate.
8. The preparation method according to claim 6 or 7, wherein in the step (3), the molar ratio of the 2-alkoxy-3-fluoro-4-chloroaniline or the 2-chloro-3-fluoro-4-alkoxyaniline, a diazonium reagent and an acid is 1:1-1.05:2-5, the temperature of the diazonium reaction is-5-5 ℃, the diazonium reagent is sodium nitrite, the diazonium salt reducing agent is sodium hypophosphite, and the catalyst is cuprous oxide.
9. The preparation method according to claim 1, wherein the step (4) is specifically: the 2-fluoro-3-chlorophenol obtained in the step (3) is subjected to a cracking reaction in an acid solution to obtain the 2-fluoro-3-chlorophenol; the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic anhydride, sulfuric acid, pyridine hydrobromide, pyridine hydroiodide or pyridine hydrochloride; the reaction temperature of the cracking is 50-150 ℃.
10. The process of claim 9, wherein in step (4) the acid is hydrobromic acid and the cleavage reaction temperature is 100-110 ℃.
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