CN112142567A - Preparation method of 2-fluoro-3-chlorophenol - Google Patents

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

Info

Publication number
CN112142567A
CN112142567A CN202011082097.7A CN202011082097A CN112142567A CN 112142567 A CN112142567 A CN 112142567A CN 202011082097 A CN202011082097 A CN 202011082097A CN 112142567 A CN112142567 A CN 112142567A
Authority
CN
China
Prior art keywords
fluoro
acid
reaction
chloro
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202011082097.7A
Other languages
Chinese (zh)
Other versions
CN112142567B (en
Inventor
邵鸿鸣
张星
余波
胡杰
李宏奎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Original Assignee
ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ZHEJIANG YONGTAI TECHNOLOGY CO LTD filed Critical ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Priority to CN202011082097.7A priority Critical patent/CN112142567B/en
Publication of CN112142567A publication Critical patent/CN112142567A/en
Application granted granted Critical
Publication of CN112142567B publication Critical patent/CN112142567B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a preparation method of 2-fluoro-3-chlorophenol, and relates to the technical field of fine chemical engineering. The invention takes 2, 4-dichloro-3-fluoronitrobenzene as raw material, 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 deammoniates through diazo reduction reaction to prepare 2-fluoro-3-chlorophenylene, and prepares 2-fluoro-3-chlorophenol through one-step cracking, the total yield is 60%, the product purity is more than 98%, and the invention is easy for industrial production.

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, pesticide synthesis, new materials, liquid crystal materials and the like, and has good market demand.
For the synthesis of similar intermediates, for example: chinese patent application 200610098100.8 discloses a process for the preparation of 2- (2,2, 2-trifluoroethoxy) phenol by the following steps: o-nitrochlorobenzene is used as a raw material to carry out etherification reaction with 2,2, 2-trifluoroethanol to obtain an intermediate 2- (2,2, 2-trifluoroethoxy) nitrobenzene, the 2- (2,2, 2-trifluoroethoxy) nitrobenzene is hydrogenated and reduced to obtain 2- (2,2, 2-trifluoroethoxy) aniline, and the 2- (2,2, 2-trifluoroethoxy) aniline is finally diazotized and hydroxyhydrolyzed to prepare the 2- (2,2, 2-trifluoroethoxy) phenol, but the method has low yield and is not beneficial to 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 a 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 2-chloro-6-fluorophenol mixture; (2) after the reaction is finished, adding dilute hydrochloric acid into the reactor, adjusting the pH to 5-6.5, and standing to separate out an organic phase; (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 being operated and produced in large scale in an industrialized mode.
However, no literature report exists on the preparation method of 2-fluoro-3-chlorophenol at present, and in view of the above, the invention provides the preparation method of 2-fluoro-3-chlorophenol, which has the advantages of high yield, good purity and simple operation, and is suitable for industrial production.
Disclosure of Invention
Aiming at the problems 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, firstly etherifies the raw material to prepare 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene, then reduces the 2-alkoxy-3-fluoro-4-chloroaniline or 2-chloro-3-fluoro-4-alkoxyaniline, then deaminizes through diazo reduction reaction to prepare 2-fluoro-3-chlorophenol, and then prepares the 2-fluoro-3-chlorophenol through further cracking, wherein the total yield reaches 60 percent, and the product purity reaches more than 98 percent, is easy for industrialized production.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method of preparing 2-fluoro-3-chlorophenol, comprising the steps of:
(1) etherification: etherifying 2, 4-dichloro-3-fluoronitrobenzene and alcohol to obtain 2-alkoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-alkoxynitrobenzene,
Figure BDA0002719050810000021
(2) 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 2-alkoxy-3-fluoro-4-chloroaniline and 2-chloro-3-fluoro-4-alkoxyaniline,
Figure BDA0002719050810000022
(3) diazo reduction: carrying out diazo reaction on the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline obtained in the step (2) and a diazo reagent, then carrying out reduction reaction on the obtained diazo reaction product and a reducing agent to generate 2-fluoro-3-chlorophenyl ether,
Figure BDA0002719050810000023
(4) cracking: the 2-fluoro-3-chlorophenyl ether obtained in the step (3) is subjected to a cracking reaction to prepare 2-fluoro-3-chlorophenol,
Figure BDA0002719050810000024
wherein R represents an alkyl group including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and the like. Preferably, in 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 perform etherification, wherein the alcohol solvent includes but is not limited to methanol, ethanol, isopropanol, propanol, butanol and the like, and methanol is further preferred. Preferably, the base comprises one or more of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide and potassium hydroxide, and further preferably sodium methoxide; the concentration of the alcoholic solution of the alkali is 15-25%, and the concentration is more preferably 20%; the temperature of the etherification reaction is 0-100 ℃, and the more preferable temperature is 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 from the viewpoint of environmental friendliness, hydrogenation reduction is more preferable.
Preferably, in step (2), the solvent is an alcohol solvent including, but not limited to, methanol, ethanol, isopropanol, propanol, butanol, and the like, and more preferably methanol.
Preferably, in the step (2), a catalyst is required to be added when the reduction reaction is hydrogenation reduction, and the mass usage amount of the catalyst is 1% -10% of that of the 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene, and is further preferably 1% -2%; the catalyst includes but is not limited to Pd/C, Pt/C, Raney nickel, further preferred from the economic point of view is Raney nickel.
Preferably, in the step (2), the temperature of the reduction reaction is 20 to 100 ℃, and more preferably 40 to 50 ℃.
Preferably, the step (3) is specifically: 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, dropwise adding a diazo reagent to carry out diazo reaction to obtain a clarified diazo solution, dropwise adding the diazo solution into a solution containing a diazonium salt reducing agent and a catalyst to carry out reduction reaction to generate the 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 the preferable sulfuric acid is 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 diazo reagent is one or more of sodium nitrite, nitrous acid, potassium nitrite and nitroso sulfuric acid; sodium nitrite is further preferable from the viewpoint of safety and economy.
Preferably, the diazotization reaction temperature is-20-20 ℃, and more preferably-5-5 ℃.
Preferably, the molar ratio of the 2-alkoxy-3-fluoro-4-chloroaniline or the 2-chloro-3-fluoro-4-alkoxyaniline to the diazotizing agent to the acid is 1:1 to 1.2:1 to 10, and more preferably 1:1 to 1.05:2 to 5.
Preferably, the method further comprises a step of eliminating the oxidability after the diazotization reaction and before the reduction reaction, specifically, a reducing agent is added into the obtained clear diazotized solution to eliminate the oxidability, 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 reducer includes, but is not limited to, sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol, isopropanol, HMPA, thiophenol, sodium stannous salt, and the like, and further preferably sodium hypophosphite.
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 is further 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, and more preferably 1:1-2: 0.2-0.3.
Preferably, the step (4) is specifically: and (3) carrying out a cracking reaction on the 2-fluoro-3-chlorophenyl ether obtained in the step (3) in an acid solution to prepare the 2-fluoro-3-chlorophenol, wherein the acid solution is an aqueous solution of 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 further preferably the hydrobromic acid.
Preferably, in the step (4), the mass concentration of the acid solution is 20 to 60%, and 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 the step (4), the reaction temperature for the cracking is 50-150 ℃, and more preferably 100-110 ℃.
The invention has the beneficial effects that:
the new 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
The present invention will be further explained with reference to specific examples in order to make the technical means, the technical features, the technical objectives and the effects of the present invention easier to understand, but the following examples are only preferred embodiments of the present invention, and not all embodiments of the present invention. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.
In the following examples, unless otherwise specified, all the procedures and equipment used were conventional procedures and equipment used was conventional equipment. In the following examples, the percentages relating to concentrations are given by mass, unless otherwise specified.
In the following examples, 2, 4-dichloro-3-fluoronitrobenzene was purchased from Shanghai saging Co;
Pd/C catalyst was purchased from Xian Kelly corporation;
raney nickel catalyst was purchased from sienna keli.
Example 1
(1) Taking a 2L four-mouth bottle, sequentially adding 500mL of methanol and 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the methanol is dissolved, then heating to 40-50 ℃, dropwise adding 283.5g of 20% sodium methoxide methanol solution, keeping the temperature for reaction for 2 hours after the dropwise adding is finished, sampling, controlling the concentration, and performing HPLC: the reaction is finished when the 2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 1 percent, and the 2-methoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-methoxynitrobenzene are more than or equal to 95 percent. Cooling to 20-30 deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove the salt.
(2) Putting the mother liquor obtained in the step (1) into a 2L high-pressure kettle, adding 4.2g of Raney nickel catalyst, and closing the high-pressure kettle. Replacing nitrogen for three times, replacing hydrogen for three times, heating to 40-50 ℃, controlling the pressure to be 10-15bar, and carrying out hydrogenation reaction for 4 hours until hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30 ℃, emptying, replacing with nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquid to dryness to obtain 158g 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.
(3) And (3) putting 158g of the mixture of the 2-methoxy-3-fluoro-4-chloroaniline and the 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 ℃, precipitating a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after dropwise adding, dissolving the solid clear, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the test of starch potassium iodide test paper does not turn blue, and obtaining the diazonium solution.
And adding 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid into another 3L four-mouth bottle, heating to 30-40 ℃, and dripping heavy nitrogen liquid, wherein nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 5h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 112.4g of 2-fluoro-3-chloroanisole, and performing HPLC: more than or equal to 98 percent.
(4) Adding 112.4g of 2-fluoro-3-chloro anisole obtained in the step (3) and 600g of 50% hydrobromic acid into a 2L four-port bottle, heating to 100-plus 110 ℃, carrying out reflux and heat preservation reaction for 7h, sampling, controlling, and carrying out HPLC: stopping the reaction when the 2-fluoro-3-chloroanisole is less than or equal to 5 percent and the 2-fluoro-3-chlorophenol is more than or equal to 95 percent. Cooling to 20-30 ℃, adding 300g of dichloromethane 3 for extraction for three times, performing back extraction on an oil layer by using 200g of 20% liquid alkali, cooling a water layer to 0-10 ℃, slowly dropwise adding hydrochloric acid to adjust the pH value to be 1-2, separating out a large amount of white crystals, filtering, washing with a small amount of water, and performing vacuum drying at 20-30 ℃ for 24 hours to obtain 87.9g of 2-fluoro-3-chlorophenol, and performing HPLC: not less than 98 percent and total yield of 60 percent.
Example 2
Taking a 2L four-mouth bottle, sequentially adding 500mL of ethanol and 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the ethanol is dissolved, then heating to 40-50 ℃, dropwise adding 357g of 20% sodium ethoxide ethanol solution, keeping the temperature for reaction for 4 hours after the dropwise addition, sampling, controlling the concentration, and performing HPLC: the reaction is finished when the 2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 2 percent, and the 2-methoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-methoxynitrobenzene are more than or equal to 94 percent. Cooling to 20-30 deg.C, adding hydrochloric acid ethanol solution dropwise, adjusting pH to about 7, and filtering to remove the salt.
The subsequent reaction steps were the same as in example 1, and 83.5g of 2-fluoro-3-chlorophenol was prepared, HPLC: not less than 98 percent and the total yield is 57 percent.
Example 3
Taking a 2L four-mouth bottle, sequentially adding 500mL of methanol and 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the methanol is dissolved, then heating to 60-70 ℃, dropwise adding 283.5g of 20% sodium methoxide methanol solution, keeping the temperature for reaction for 1h after the dropwise adding is finished, sampling, controlling the concentration, and performing HPLC: the reaction is finished when the 2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 0.5 percent, and the 2-methoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-methoxynitrobenzene are more than or equal to 90 percent. Cooling to 20-30 deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove the salt.
The subsequent reaction steps were the same as in example 1, and 78.3g of 2-fluoro-3-chlorophenol was prepared, HPLC: not less than 98 percent and the total yield is 53.4 percent.
Example 4
Taking a 2L four-mouth bottle, sequentially adding 500mL of methanol and 210g of 2, 4-dichloro-3-fluoronitrobenzene, stirring until the methanol is dissolved, then heating to 40-50 ℃, dropwise adding 312g of 20% sodium methoxide methanol solution, keeping the temperature for reaction for 2 hours after the dropwise adding is finished, sampling, controlling the concentration, and performing HPLC: the reaction is finished when the 2, 4-dichloro-3-fluoronitrobenzene is less than or equal to 0.5 percent, and the 2-methoxy-3-fluoro-4-chloronitrobenzene and the 2-chloro-3-fluoro-4-methoxynitrobenzene are more than or equal to 92 percent. Cooling to 20-30 deg.C, adding hydrochloric acid methanol solution dropwise, adjusting pH to about 7, and filtering to remove the salt.
The subsequent reaction steps were the same as in example 1, whereby 73.6g of 2-fluoro-3-chlorophenol was prepared, HPLC: not less than 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. Replacing nitrogen for three times, replacing hydrogen for three times, heating to 40-50 ℃, controlling the pressure to be 10-15bar, and carrying out hydrogenation reaction for 4 hours until hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30 ℃, emptying, replacing with nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquid to dryness to obtain 159g 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.
Compared with the catalyst in the embodiment 1, after the dosage of the catalyst is increased, the obtained mixture of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is increased from 158g to 159g, the yield is not obviously improved, and the catalyst with lower dosage in the embodiment 1 is preferred from the aspect 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 a 5% Pd/C catalyst was added, and the autoclave was closed. Replacing nitrogen for three times, replacing hydrogen for three times, heating to 40-50 ℃, controlling the pressure to be 10-15bar, and carrying out hydrogenation reaction for 4 hours until hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30 ℃, emptying, replacing with nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquid to dryness to obtain 158g 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.
It can be seen that, compared with example 1, the reaction effect is the same after using the Pd/C catalyst with higher cost, so from the economic point of view, Raney nickel is selected as the catalyst.
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. Replacing nitrogen for three times, replacing hydrogen for three times, heating to 60-70 ℃, controlling the pressure to be 10-15bar, and carrying out hydrogenation reaction for 2 hours until hydrogen is not absorbed any more. Stopping hydrogenation, cooling to 20-30 ℃, emptying, replacing with nitrogen for three times, and discharging. Filtering the hydrogenation reaction liquid, recovering Raney nickel, concentrating the mother liquid 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: not less than 90 percent.
As compared with example 1, the reaction time was shortened by increasing the hydrogenation temperature, but the impurities increased and the purity was slightly lowered.
Example 8
The etherification step (1)) and the reduction step (2)) were the same as in example 1.
And (3) putting 158g of the mixture of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2) and 1500g of 20% hydrochloric acid into a 2L four-mouth bottle, heating to completely dissolve, slowly cooling to-5-5 ℃, precipitating a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after dropwise adding, dissolving the solid clear, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the test of starch potassium iodide test paper does not turn blue, and obtaining the diazonium solution.
And adding 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 30% hydrochloric acid into another 3L four-mouth bottle, heating to 30-40 ℃, and beginning to drip heavy nitrogen liquid, wherein nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 5h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 125g of 2-fluoro-3-chloroanisole, and performing HPLC: not less than 85 percent.
It can be seen that, after hydrochloric acid is used, more chlorinated byproducts are generated, so that the purity is reduced to a certain degree.
Example 9
The etherification step (1)) and the reduction step (2)) were the same as in example 1. And (3) putting 158g of the mixture of the 2-methoxy-3-fluoro-4-chloroaniline and the 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 5-10 ℃, precipitating a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after dropwise adding, dissolving the solid clear, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the test of starch potassium iodide test paper does not turn blue, and obtaining the diazonium solution.
And adding 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid into another 3L four-mouth bottle, heating to 30-40 ℃, and dripping heavy nitrogen liquid, wherein nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 5h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 107.4g of 2-fluoro-3-chloro-anisole, and performing HPLC: more than or equal to 98 percent.
The results show that an increase in the diazotization 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. And (3) putting 158g of the mixture of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline obtained in the step (2) and 2000g of 20% sulfuric acid into a 3L four-mouth bottle, heating to completely dissolve, slowly cooling to-5-5 ℃, precipitating a large amount of white solid, then slowly dropwise adding 155g of 50% sodium nitrite solution, after dropwise adding, dissolving the solid, adding a small amount of sulfamic acid to remove excessive sodium nitrite, and obtaining the diazonium solution until the test of starch potassium iodide test paper does not turn blue.
And adding 96.8g of sodium hypophosphite, 31.7g of cuprous oxide and 500g of 50% sulfuric acid into another 5L four-mouth bottle, heating to 30-40 ℃, and dripping heavy nitrogen liquid, wherein nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 5h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 111.9g of 2-fluoro-3-chloroanisole, and performing HPLC: more than or equal to 98 percent.
The use of an excessive amount of sodium nitrite and sulfuric acid does not improve the yield as compared with example 1, 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 the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline and 1500g of 20% sulfuric acid, heating to completely dissolve, slowly cooling to-5-5 ℃, precipitating a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after the dropwise adding, dissolving the solid clearly, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite, and keeping the test of starch potassium iodide paper from turning 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 ℃, heavy nitrogen liquid is dripped, and nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 12h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 102.7g of 2-fluoro-3-chloroanisole, and performing HPLC: not less than 90 percent.
It can be seen that when the diazonium salt reducer is ethanol and the catalyst is copper acetate, the effect is inferior to that of sodium hypophosphite and cuprous oxide.
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 the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline and 1500g of 20% sulfuric acid, heating to completely dissolve, slowly cooling to-5-5 ℃, precipitating a large amount of white solid, then slowly dropwise adding 144.9g of 50% sodium nitrite solution, after the dropwise adding, dissolving the solid clearly, adding a small amount of sulfamic acid to eliminate excessive sodium nitrite until the test of starch potassium iodide paper does not turn blue, and obtaining the diazonium solution.
And adding 120g of sodium hypophosphite, 15g of cuprous oxide and 500g of 50% sulfuric acid into another 3L four-mouth bottle, heating to 30-40 ℃, and beginning to drip heavy nitrogen liquid, wherein nitrogen is discharged in the dripping process. After dripping, the reaction is kept for 5h, sampling is controlled, and HPLC: the diazosalt of the 2-methoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-methoxyaniline is less than or equal to 1 percent, and the reaction is finished. Heating water vapor distillation, separating fractions, washing an oil layer twice by using 100g x 2 of 20% sodium hydroxide solution, standing and separating to obtain 110g of 2-fluoro-3-chloroanisole, 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)) are the same as in example 1. Taking a 2L four-mouth bottle, adding 112.4g of the obtained 2-fluoro-3-chloroanisole and 1000g of 30% hydrochloric acid, heating to 100-plus-110 ℃, carrying out reflux insulation reaction for 20 hours, sampling, controlling, and carrying out HPLC: stopping the reaction when the 2-fluoro-3-chloroanisole is less than or equal to 10 percent and the 2-fluoro-3-chlorophenol is more than or equal to 90 percent. Cooling to 20-30 ℃, adding 300g of dichloromethane 3 for extraction for three times, performing back extraction on an oil layer by using 200g of 20% liquid alkali, cooling a water layer to 0-10 ℃, slowly dropwise adding hydrochloric acid to adjust the pH value to be 1-2, separating out a large amount of white crystals, filtering, washing with a small amount of water, and performing vacuum drying at 20-30 ℃ for 24 hours to obtain 77.4g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent.
Hydrobromic acid is preferred because hydrochloric acid is selected for cleavage, resulting in longer reaction times and lower yields.
Example 14
The etherification step (1)), the reduction step (2)), and the diazonium reduction step (3)) are the same as in example 1. Taking a 2L four-mouth bottle, adding 112.4g of the obtained 2-fluoro-3-chloroanisole and 600g of 50% sulfuric acid, heating to 110-plus-120 ℃, carrying out reflux insulation reaction for 20 hours, sampling, controlling, and carrying out HPLC: stopping the reaction when the 2-fluoro-3-chloroanisole is less than or equal to 15 percent and the 2-fluoro-3-chlorophenol is more than or equal to 85 percent. Cooling to 20-30 ℃, adding 300g of dichloromethane 3 for extraction for three times, performing back extraction on an oil layer by using 200g of 20% liquid alkali, cooling a water layer to 0-10 ℃, slowly dropwise adding hydrochloric acid to adjust the pH value to be 1-2, separating out a large amount of white crystals, filtering, washing with a small amount of water, and performing vacuum drying at 20-30 ℃ for 24 hours to obtain 69.9g of 2-fluoro-3-chlorophenol, and performing HPLC: more than or equal to 98 percent.
Hydrobromic acid is preferred because the use of sulfuric acid for cleavage results in longer reaction times and lower yields.
Example 15
The etherification step (1)), the reduction step (2)), and the diazonium reduction step (3)) are the same as in example 1.
Taking a 2L four-mouth bottle, adding 112.4g of the obtained 2-fluoro-3-chloro anisole and 600g of 50% hydrobromic acid, heating to 80-90 ℃, carrying out heat preservation reaction for 17h, sampling, controlling in a central way, and carrying out HPLC: stopping the reaction when the 2-fluoro-3-chloroanisole is less than or equal to 5 percent and the 2-fluoro-3-chlorophenol is more than or equal to 95 percent. Cooling to 20-30 ℃, adding 300g of dichloromethane 3 for extraction for three times, performing back extraction on an oil layer by using 200g of 20% liquid alkali, cooling a water layer to 0-10 ℃, slowly dropwise adding hydrochloric acid to adjust the pH value to be 1-2, separating out a large amount of white crystals, filtering, washing with a small amount of water, and performing vacuum drying at 20-30 ℃ for 24 hours 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 cracking reaction temperature is reduced, but the reaction time is prolonged.
The present invention is not limited to the above-described preferred embodiments, but rather, the present invention is to be construed broadly and cover all modifications, equivalents, and improvements falling within the spirit and scope of the present invention.

Claims (10)

1. A preparation method of 2-fluoro-3-chlorophenol is characterized by comprising the following steps:
(1) etherification: etherifying 2, 4-dichloro-3-fluoronitrobenzene and alcohol to obtain 2-alkoxy-3-fluoro-4-chloronitrobenzene and 2-chloro-3-fluoro-4-alkoxynitrobenzene,
Figure FDA0002719050800000011
(2) reduction: reducing the 2-alkoxy-3-fluoro-4-chloronitrobenzene and the 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,
Figure FDA0002719050800000012
(3) diazo reduction: carrying out diazo reaction on the 2-alkoxy-3-fluoro-4-chloroaniline and the 2-chloro-3-fluoro-4-alkoxyaniline obtained in the step (2) and a diazo reagent, then carrying out reduction reaction on the obtained diazo reaction product and a reducing agent to generate 2-fluoro-3-chlorophenyl ether,
Figure FDA0002719050800000013
(4) cracking: the 2-fluoro-3-chlorophenyl ether obtained in the step (3) is subjected to a cracking reaction to prepare 2-fluoro-3-chlorophenol,
wherein R represents an alkyl group.
2. The preparation 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 production method according to claim 2, wherein in the step (1), the solvent is methanol; the temperature of the etherification reaction is 40-50 ℃; the base is sodium methoxide; the molar ratio of the 2, 4-dichloro-3-fluoronitrobenzene to the alkali is 1: 1-1.1.
4. The preparation method according to claim 1, wherein in the step (2), the reduction is iron powder reduction or hydrogenation reduction, the hydrogenation reduction requires adding a catalyst, and the mass amount of the catalyst is 1-10% of the mass amount of the 2-alkoxy-3-fluoro-4-chloronitrobenzene and/or the 2-chloro-3-fluoro-4-alkoxynitrobenzene; the catalyst is Pd/C, Pt/C or Raney nickel; the temperature of the reduction reaction is 20-100 ℃.
5. The preparation method according to claim 4, wherein in the step (2), the mass amount of the catalyst is 1-2% of the mass amount of the 2-alkoxy-3-fluoro-4-chloronitrobenzene or 2-chloro-3-fluoro-4-alkoxynitrobenzene; the catalyst is Raney nickel; the temperature of the reduction reaction is 40-50 ℃.
6. The preparation method according to claim 1, wherein the step (3) is specifically: 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, dropwise adding a diazo reagent to carry out diazo reaction to obtain a clarified diazo solution, dropwise adding the diazo solution into a solution containing a diazonium salt reducing agent and a catalyst to carry out reduction reaction to generate the 2-fluoro-3-chlorophenyl ether; the molar ratio of the 2-alkoxy-3-fluoro-4-chloroaniline or the 2-chloro-3-fluoro-4-alkoxyaniline to the diazo reagent to the acid is 1:1-1.2: 1-10; the temperature of the diazotization reaction is-20-20 ℃; the acid comprises one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid and hydrobromic acid.
7. The preparation 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 reducer comprises sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol, isopropanol, HMPA, thiophenol or sodium stannous salt; 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.
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 to the diazonium reagent to the 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 reducer is sodium hypophosphite, and the catalyst is cuprous oxide.
9. The preparation method according to claim 1, wherein the step (4) is specifically: carrying out a cracking reaction on the 2-fluoro-3-chlorophenyl ether obtained in the step (3) in an acid solution to prepare 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 method as claimed in claim 9, wherein in the step (4), the acid is hydrobromic acid, and the reaction temperature for the cracking is 100-110 ℃.
CN202011082097.7A 2020-10-12 2020-10-12 Preparation method of 2-fluoro-3-chlorophenol Active CN112142567B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011082097.7A CN112142567B (en) 2020-10-12 2020-10-12 Preparation method of 2-fluoro-3-chlorophenol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011082097.7A CN112142567B (en) 2020-10-12 2020-10-12 Preparation method of 2-fluoro-3-chlorophenol

Publications (2)

Publication Number Publication Date
CN112142567A true CN112142567A (en) 2020-12-29
CN112142567B CN112142567B (en) 2023-11-14

Family

ID=73951415

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011082097.7A Active CN112142567B (en) 2020-10-12 2020-10-12 Preparation method of 2-fluoro-3-chlorophenol

Country Status (1)

Country Link
CN (1) CN112142567B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024023012A1 (en) 2022-07-28 2024-02-01 Bayer Aktiengesellschaft Process for preparation of 2-chloro-3-fluoro-4-alkoxy-anilines and 2-fluoro-3-chlorophenol

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05286882A (en) * 1992-04-03 1993-11-02 Seimi Chem Co Ltd Production of 2,3-difluorophenols
CN1789224A (en) * 2005-12-20 2006-06-21 阜新金鸿泰化工有限公司 Preparation method of 2.3-difluoro-5-bromophenol
CN101037380A (en) * 2007-04-29 2007-09-19 上海康鹏化学有限公司 Preparation method of 2,3-Difluoro-5-Bromophenol
CN102584546A (en) * 2011-09-26 2012-07-18 盘锦兴福化工有限公司 Synthesis method of 2,3-difluorobenzene ester
CN110498730A (en) * 2019-08-13 2019-11-26 浙江林江化工股份有限公司 A kind of synthetic method of 1,2,4- trifluoro-benzene

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05286882A (en) * 1992-04-03 1993-11-02 Seimi Chem Co Ltd Production of 2,3-difluorophenols
CN1789224A (en) * 2005-12-20 2006-06-21 阜新金鸿泰化工有限公司 Preparation method of 2.3-difluoro-5-bromophenol
CN101037380A (en) * 2007-04-29 2007-09-19 上海康鹏化学有限公司 Preparation method of 2,3-Difluoro-5-Bromophenol
CN102584546A (en) * 2011-09-26 2012-07-18 盘锦兴福化工有限公司 Synthesis method of 2,3-difluorobenzene ester
CN110498730A (en) * 2019-08-13 2019-11-26 浙江林江化工股份有限公司 A kind of synthetic method of 1,2,4- trifluoro-benzene

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024023012A1 (en) 2022-07-28 2024-02-01 Bayer Aktiengesellschaft Process for preparation of 2-chloro-3-fluoro-4-alkoxy-anilines and 2-fluoro-3-chlorophenol

Also Published As

Publication number Publication date
CN112142567B (en) 2023-11-14

Similar Documents

Publication Publication Date Title
CN112142567A (en) Preparation method of 2-fluoro-3-chlorophenol
CN106117067B (en) A kind of method that diazotising prepares 3,5 difluoro, 4 chloronitrobenzene
CN106242990B (en) Preparation method of 2-amino-4-acetamino anisole
CN110698352B (en) Synthetic method of 3-bromo-5-aminocatechol dimethyl ether
CN103242190B (en) Synthetic method of propyzamide
AU2021107114A4 (en) Method for preparing epalrestat
CN111116319B (en) Synthesis and refining method of 1, 6-dihydroxynaphthalene
CN108546232B (en) Preparation method of mono-substituted or di-substituted benzoate compound
CN102173993B (en) Method for synthesizing 4,6-diamino resorcinol dihydrochloride (DAR)
CN101168520A (en) Method for producing 1,1'-phenylsulfonyl-4,4'-diallyl (2) ether
CN107089903B (en) Preparation method of o-isopropoxyphenol
CN108129536A (en) A kind of preparation method of Dexamethasone Intermediate
CN106748671B (en) Method for synthesizing 2-alkoxy-4-methylphenol from 2-bromo-4-methylphenol
CN110790650A (en) Synthesis method of trans-4 '- (4-alkyl phenyl) (1, 1' -dicyclohexyl) -4-ketone
CN111072745A (en) Preparation method of 6-methylene-7-ketocholic acid
CN103772151A (en) Preparation method of 2-methyl-3-phenyl benzyl alcohol
CN111848438B (en) Process for preparing 4, 6-diphenyl azo resorcinol and 4, 6-diamino resorcinol
CN103819418A (en) Method for synthesizing carfentrazone-ethyl and carfentrazone-ethyl intermediate
CN109180423B (en) Synthetic method of 2, 3-dibromo naphthalene
CN106957235A (en) A kind of preparation method of TAM
CN107915570B (en) Preparation method of 4-bromo-1-methyl-2- (trifluoromethyl) benzene
CN101863836A (en) Method for preparing 5,5-diphenyl-2-thiohydantoin
CN103787846B (en) The preparation method of the chloro-6-fluoroanisole of a kind of 2-and intermediate thereof
CN117924177A (en) Preparation method of pazopanib intermediate 2, 3-dimethyl-6-amino-2H-indazole and analogues thereof
CN116217522A (en) Chiral purification method of key intermediate of GLP-1 receptor agonist

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant