CN116621686B - Preparation method of difluoro acetic acid - Google Patents

Preparation method of difluoro acetic acid Download PDF

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CN116621686B
CN116621686B CN202310896696.XA CN202310896696A CN116621686B CN 116621686 B CN116621686 B CN 116621686B CN 202310896696 A CN202310896696 A CN 202310896696A CN 116621686 B CN116621686 B CN 116621686B
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difluoro
reaction
difluoroacetic acid
molar ratio
chloromethane
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CN116621686A (en
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张潇潇
程贺
程林
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C07C51/44—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
    • Y02E60/10—Energy storage using batteries

Abstract

The application provides a preparation method of difluoro acetic acid, which adopts a brand new synthetic route, takes acetone or dimethyl sulfoxide as a dipolar solvent, takes difluoro chloromethane as a starting material, firstly reacts with pyridine to generate N-difluoro methyl ammonium chloride salt, the N-difluoro methyl ammonium chloride salt is used as a difluoro methyl positive ion intermediate or difluoro carbene source to react with cyanide anions under the catalysis of alkali to generate difluoro acetonitrile, and the difluoro acetonitrile is hydrolyzed, oxidized and acidified to prepare the difluoro acetic acid, the product yield is more than 64%, and the purity is more than 99%; compared with the existing preparation method, the preparation method has the advantages of simple preparation process, mild reaction conditions, short reaction time, better selectivity, low reaction defluorination ratio, high atomic utilization rate, high product yield, low production cost and high feasibility of industrial application, and belongs to the technical field of organic synthesis.

Description

Preparation method of difluoro acetic acid
Technical Field
The application relates to the technical field of organic synthesis, in particular to a preparation method of difluoro acetic acid.
Background
1-methyl-3-difluoromethyl-4-pyrazolecarboxylic acid (difluoro pyrazolecarboxylic acid) is a key intermediate for preparing bactericides such as isopyrazam, bixafen, cyproconazole and the like. The difluoro acetic acid is colorless to pale yellow liquid, is a key precursor for preparing difluoro pyrazole acid, and has wide application in the synthesis of catalysts, medicines, pesticides and new materials, so that the research on the preparation method of the difluoro acetic acid has great significance.
At present, the common preparation methods of difluoroacetic acid in the market mainly comprise three methods, namely, reacting tetrafluoroethylene and inorganic base in an organic solvent under the catalysis of a phase transfer catalyst to generate difluoroacetate, and then acidizing to obtain difluoroacetic acid; reacting tetrafluoroethylene with a potassium hydroxide-methanol system to generate tetrafluoroethane, then reacting with an alumina catalyst to obtain difluoro-acetyl fluoride, and hydrolyzing to obtain difluoro acetic acid; thirdly, tetrafluoroethylene and sodium bisulfate react to generate sodium tetrafluoroethane sulfonate, sodium difluoroacetate is generated by hydrolysis under the action of water, difluoroacetic acid is generated by acidification reaction, or 2,4, 6-trifluoromethyl s-triazine is generated by reaction with ammonia, and difluoroacetic acid is generated by hydrolysis reaction and acidification reaction in alkaline aqueous solution. The three processes all adopt tetrafluoroethylene as a starting material, but the preparation process is complicated, so that the production cost is high, and in addition, the tetrafluoroethylene can only prepare equimolar difluoroacetic acid, so that the atom economy is poor, and in addition, the tetrafluoroethylene is prepared by a difluorochloromethane reaction, so that the process route is prolonged, and the production cost is increased.
Disclosure of Invention
In order to solve the technical problems, the technical scheme adopted by the application is to provide a preparation method of difluoroacetic acid, so as to solve the technical problems of complex preparation process, higher production cost, poorer atom economy and longer preparation time of the existing preparation method of difluoroacetic acid.
The embodiment of the application provides a preparation method of difluoroacetic acid, which comprises the following steps:
(1) Adding tertiary amine into a dipolar solvent, introducing difluoro chloromethane, heating and stirring to react to generate solid precipitate which is N-difluoro methyl ammonium chloride salt;
(2) Cooling, adding cyanide and alkali metal hydroxide, heating again, and preserving heat to carry out cyanide reaction to generate difluoro acetonitrile; after the cyanidation reaction is finished, cooling again, adding liquid alkali, preserving heat for hydrolysis reaction, then adding hydrogen peroxide, preserving heat for quenching reaction; after the quenching reaction is finished, the reaction material is filtered and rinsed to obtain filtrate, and the filtrate is acidified and rectified at normal pressure to obtain the difluoro acetic acid.
Preferably, in the step (1), the dipolar solvent is any one of acetone, dimethyl sulfoxide, acetonitrile and butanone, and the tertiary amine is any one of pyridine, a pyridine derivative and tri-n-butylamine.
Preferably, in the step (1), the molar ratio of the difluoro chloromethane to the tertiary amine is 1:1.0-1:1.4.
Preferably, in step (1), the reaction temperature is 30℃and the reaction time is 2 hours.
Preferably, in the step (2), the cyanide salt is any one of a sodium cyanide solution and a potassium cyanide solution, and the alkali metal hydroxide is any one of sodium hydroxide and potassium hydroxide.
Preferably, in the step (2), the molar ratio of the difluoro-chloromethane to the cyanide salt is 1:0.8-1:1.2, and the molar ratio of the difluoro-chloromethane to the alkali metal hydroxide is 1:0-1:0.4.
Preferably, in the step (2), the temperature is reduced to below 0 ℃, the cyanidation reaction temperature is 40-60 ℃, and the reaction time is 3-5 h.
Preferably, in the step (2), the temperature is reduced to the room temperature again, the molar ratio of the difluoro chloromethane to the liquid alkali is 1:1.6-1:2.0, the hydrolysis reaction temperature is the room temperature, and the reaction time is 2 hours.
Preferably, in the step (2), the molar ratio of the difluoro chloromethane to the hydrogen peroxide is 1:1.2, the quenching reaction temperature is room temperature, and the reaction time is 2 hours.
Preferably, in the step (2), dilute sulfuric acid is used for acidifying the filtrate, and distillation is carried out at normal pressure to collect fraction at 120-140 ℃ to obtain the difluoroacetic acid.
The beneficial effects of the application are as follows: the application provides a preparation method of difluoro acetic acid, which adopts a brand new synthetic route, takes acetone or dimethyl sulfoxide as a dipolar solvent, takes difluoro chloromethane as a starting material, firstly reacts with pyridine to generate N-difluoro methyl ammonium chloride salt, the N-difluoro methyl ammonium chloride salt is used as a difluoro methyl positive ion intermediate or difluoro carbene source to react with cyanide anions under the catalysis of alkali to generate difluoro acetonitrile, and the difluoro acetonitrile is hydrolyzed, oxidized and acidified to prepare the difluoro acetic acid, the product yield is more than 64%, and the purity is more than 99%; compared with the prior preparation method, the preparation method has the advantages that,
(1) The N-difluoromethyl ammonium chloride salt has the phase transfer catalysis effect, can promote cyanide anions to enter an organic phase more, and performs nucleophilic reaction with a difluoromethyl positive ion intermediate or a difluorocarbene source, thereby being beneficial to improving the main reaction competitiveness and the reaction selectivity;
(2) The dipolar solvent used in the application can inhibit water from participating in competitive side reaction, further improves the reaction selectivity and improves the reaction yield;
(3) According to the application, difluoro chloromethane is used as a starting material to be directly used for preparing difluoro acetic acid, so that the step of preparing tetrafluoroethylene and then preparing difluoro acetic acid by using difluoro chloromethane in the prior art is omitted, the process flow is simplified, the atomic utilization rate is improved, the intermediate salt of the application can be directly used for preparing difluoro acetic acid without further purification, the preparation process is simple, the post-treatment process is simple, the dipole solvent, pyridine and other tertiary amines can be recycled, the production cost is reduced, and the preparation time is shortened;
in conclusion, the preparation method has the advantages of simple preparation process, mild reaction conditions, short reaction time, better selectivity, low reaction defluorination ratio, high atomic utilization rate, high product yield, low production cost and high feasibility of industrial application.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the embodiments or the description of the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance spectrum of the product prepared in example 1 of the present application.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the application is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
Example 1
A process for the preparation of difluoroacetic acid comprising the steps of:
(1) Sequentially adding 50.20g of acetone and 11.13g of pyridine (purity is 99%,0.139 mol) into a high-pressure reaction kettle with a magnetic stirring rod, mixing the kettle, introducing difluoro-chloromethane gas (purity is 100%), recording the weight gain of the reaction kettle to be 10.04g (0.116 mol, the molar ratio of the difluoro-chloromethane to the pyridine is 1:1.2), heating the reaction kettle to 30 ℃, stirring and reacting, wherein after the reaction is finished for 2 hours, solid precipitate which is N-difluoro methyl ammonium chloride salt is generated;
the reaction equation is as follows:
(2) When the reaction kettle is cooled to below 0 ℃, opening the kettle, sequentially adding 18.97g of sodium cyanide solution (purity is 30%, mole ratio of difluoro-chloromethane to sodium cyanide is 1:1.0) and 0.95g of sodium hydroxide solid (purity is 98%, mole ratio of difluoro-chloromethane to sodium hydroxide is 1:0.2) into the kettle, closing the kettle, heating the reaction kettle to 50 ℃, and preserving heat for 4 hours to carry out cyanidation reaction to generate difluoro acetonitrile;
after the cyanation reaction is finished, after the reaction kettle is cooled to room temperature, 26.12g of liquid alkali solution (with the purity of 32 percent, 0.209mol and the molar ratio of difluoromethane to liquid alkali of 1:1.8) is added into the kettle at the rate of 1.0mL/min by using a high-pressure pump, the hydrolysis reaction is carried out by preserving the temperature for 2 hours at room temperature, then 15.80g of hydrogen peroxide solution (with the purity of 30 percent, 0.139mol and the molar ratio of difluoromethane to hydrogen peroxide of 1:1.2) is added into the kettle at the rate of 1.0mL/min by using the high-pressure pump, and the quenching reaction is carried out by preserving the temperature for 2 hours at room temperature;
after the quenching reaction is finished, opening the kettle, filtering and rinsing the reaction material to obtain reddish brown transparent filtrate, acidifying the filtrate by using dilute sulfuric acid, rectifying at normal pressure, and collecting the fraction in the range of 120-140 ℃ to obtain 7.23g of difluoroacetic acid, wherein the gas phase detection purity is 99.20%, and the calculated yield is 64.31%;
the reaction equation is as follows:
example 2
In the process of this embodiment, except for the difference from example 1, in step (1), 9.26g of pyridine (purity: 99%,0.116 mol) was charged into the reaction vessel, 10.02g of difluoromethane chloride gas (purity: 100%,0.116mol, molar ratio of difluoromethane to pyridine: 1:1.0) was introduced, and the other steps were the same, 7.18g of difluoroacetic acid was obtained, the purity of the gas phase was detected to be 99.31%, and the calculated yield was 64.09%.
Example 3
In the process of this embodiment, except for the difference from example 1, in step (1), 13.07g of pyridine (purity: 99%,0.164 mol) was charged into the reaction vessel, 10.10g of difluoromethane chloride gas (purity: 100%,0.117mol, molar ratio of difluoromethane to pyridine: 1:1.4) was introduced, and the other steps were the same, 7.27g of difluoroacetic acid was obtained, the purity of the gas phase was detected to be 99.15%, and the calculated yield was 64.27%.
From examples 1 to 3, it is understood that the mass and calculated yield of the product difluoroacetic acid are significantly increased as the molar ratio of difluoromethane to pyridine is increased from 1:1.0 to 1:1.2, but the mass of the product difluoroacetic acid is not changed when the molar ratio of difluoromethane to pyridine is increased from 1:1.2 to 1:1.4, the calculated yield is slightly decreased, and the reaction thoroughness of the difluoromethane is ensured considering that tertiary amine such as pyridine can be recovered, and therefore, the molar ratio of difluoromethane to pyridine is preferably 1:1.2.
Example 4
The difference between the method and example 1 is that in the step (1), 10.03g of difluoromethane chloride gas (purity: 100%,0.116 mol) was introduced into the reactor, in the step (2), 15.16g of sodium cyanide solution (purity: 30%,0.093mol, molar ratio of difluoromethane chloride to sodium cyanide: 1:0.8) was added into the reactor, and the other steps were the same, whereby 7.04g of difluoroacetic acid was obtained, the purity of which was detected in the gas phase: 99.24%, and the calculated yield was 62.75%.
Example 5
The difference between the method and example 1 is that in the step (1), 10.07g of difluoro-chloromethane gas (purity: 100%,0.116 mol) was introduced into the reactor, in the step (2), 22.83g of sodium cyanide solution (purity: 30%,0.140mol, molar ratio of difluoro-chloromethane to sodium cyanide: 1:1.2) was added into the reactor, and the other steps were the same, to obtain 7.34g of difluoro-acetic acid, the gas phase detection purity thereof was 99.43%, and the calculated yield was 65.23%.
From examples 1, 4-5, it is understood that as the molar ratio of difluoromethane to sodium cyanide increases from 1:0.8 to 1:1.0, the mass and calculated yield of the product difluoroacetic acid increase significantly, and as the molar ratio of difluoromethane to sodium cyanide increases from 1:1.0 to 1:1.2, the mass and calculated yield of the product difluoroacetic acid increase still, but the increase in the magnitude is not significant, and therefore, from an economic standpoint, the molar ratio of difluoromethane to sodium cyanide is preferably 1:1.0.
Example 6
The difference between the method and example 1 is that in the step (1), 10.04g of difluoro-chloromethane gas (purity: 100%,0.116 mol) was introduced into the reactor, in the step (2), 0.00g of sodium hydroxide solid (molar ratio of difluoro-chloromethane to sodium hydroxide: 1:0) was added into the reactor, and the other steps were the same, to obtain 6.25g of difluoro-acetic acid, the gas phase detection purity thereof was 99.17%, and the calculated yield was 55.62%.
Example 7
The difference between the method and example 1 is that in the step (1), 10.08g of difluoro-chloromethane gas (purity: 100%,0.117 mol) was introduced into the reactor, in the step (2), 1.90g of sodium hydroxide solid (purity: 98%,0.047mol, molar ratio of difluoro-chloromethane to sodium hydroxide: 1:0.4) was obtained, and the other steps were the same, to obtain 6.80g of difluoro-acetic acid, the gas phase detection purity thereof was 99.02%, and the calculated yield was 60.15%.
From examples 1, 6-7, it is seen that as the molar ratio of difluoromethane to sodium hydroxide increases from 1:0 to 1:0.2, the quality and calculated yield of the product difluoroacetic acid increases significantly, but as the molar ratio of difluoromethane to sodium hydroxide increases from 1:0.2 to 1:0.4, the quality and calculated yield of the product difluoroacetic acid decreases significantly, and therefore, the molar ratio of difluoromethane to sodium hydroxide is preferably 1:0.2.
Example 8
The difference between the method and example 1 is that 10.01g of difluoro chloromethane gas (purity 100%,0.116 mol) was introduced into the reactor in step (1), the reactor was heated to 40℃in step (2) to carry out the cyanation reaction, and 7.12g of difluoro acetic acid was obtained in the same manner as in other steps, the gas phase detection purity was 99.26%, and the calculated yield was 63.56%.
Example 9
The difference between the method and example 1 is that in the step (1), 10.05g of difluoromethane chloride gas (purity: 100%,0.116 mol) was introduced into the reactor, and in the step (2), the reactor was heated to 60℃to carry out the cyanation reaction, and the other steps were the same, whereby 7.25g of difluoroacetic acid was obtained, the gas phase detection purity thereof was 99.33%, and the calculated yield was 64.52%.
As is clear from examples 1, 8 to 9, as the reaction temperature of the cyanation reaction increases from 40℃to 50℃the mass and calculated yield of the product difluoroacetic acid increase significantly, and as the reaction temperature increases from 50℃to 60℃the mass and calculated yield of the product difluoroacetic acid increase still, but the increase in the magnitude is not significant, and therefore, from an economic point of view, the reaction temperature of the cyanation reaction is preferably 50 ℃.
Example 10
The difference between the method and example 1 is that 10.02g of difluoromethane chloride gas (purity: 100%,0.116 mol) was introduced into the reactor in the step (1), the time for the cyanation reaction was 3 hours in the step (2), and the other steps were the same, whereby 7.16g of difluoroacetic acid was obtained, the purity of the product was detected in the gas phase: 99.19%, and the calculated yield was 63.79%.
Example 11
The difference between the method and example 1 is that in the step (1), 10.12g of difluoromethane chloride gas (purity: 100%,0.117 mol) was introduced into the reactor, and in the step (2), the time of the cyanation reaction was 5 hours, and the other steps were the same, whereby 7.29g of difluoroacetic acid was obtained, the purity of the gas phase detection was 99.37%, and the calculated yield was 64.45%.
As is clear from examples 1, 10-11, the mass and calculated yield of the product difluoroacetic acid increased significantly as the reaction time of the cyanation reaction increased from 3 hours to 4 hours, but the mass of the product difluoroacetic acid did not change as the reaction time increased from 4 hours to 5 hours, and the calculated yield increased slightly, so that the reaction time of the cyanation reaction was preferably 4 hours from an economical point of view.
Example 12
The difference between the method and example 1 is that in the step (1), 10.08g of difluoro monochloromethane gas (purity 100%,0.117 mol) was introduced into the reactor, in the step (2), 23.31g of aqueous alkali solution (purity 32%,0.186mol, molar ratio of difluoro monochloromethane to aqueous alkali 1:1.6) was added into the reactor, and the other steps were the same, to obtain 7.09g of difluoro acetic acid, the gas phase detection purity thereof was 99.21%, and the calculated yield was 62.87%.
Example 13
The difference between the method and example 1 is that in the step (1), 10.04g of difluoro chloromethane gas (purity 100%,0.116 mol) was introduced into the reactor, in the step (2), 29.03g of aqueous alkali solution (purity 32%,0.232mol, molar ratio of difluoro chloromethane to aqueous alkali 1:2.0) was added into the reactor, and the other steps were the same, to obtain 7.25g of difluoro acetic acid, the gas phase detection purity thereof was 99.44%, and the calculated yield was 64.62%.
From examples 1, 12-13, it is seen that as the molar ratio of difluoromethane to liquid base increases from 1:1.6 to 1:1.8, the quality and calculated yield of the product difluoroacetic acid increases significantly, but as the molar ratio of difluoromethane to liquid base increases from 1:1.8 to 1:2.0, the magnitude of the increase in quality and calculated yield of the product difluoroacetic acid does not significantly remain substantially similar, and therefore, the molar ratio of difluoromethane to liquid base is preferably 1:1.8.
Please refer to table 1, which is a summary of experimental data and experimental results of examples 1-13.
TABLE 1 summary of experimental data and experimental results for examples 1-13
As can be seen from Table 1, when acetone is used as a dipolar solvent and difluoromethane is used as a starting material, the molar ratio of difluoromethane to pyridine in the preparation reaction of N-difluoromethyl ammonium chloride salt is 1:1.2, the reaction temperature is 30 ℃, the reaction time is 2h, the molar ratio of difluoromethane to sodium cyanide to sodium hydroxide in the cyanation reaction is 1:1.0:0.2, the reaction temperature is 50 ℃, the reaction time is 4h, the molar ratio of difluoromethane to liquid alkali in the hydrolysis reaction is 1:1.8, the reaction temperature is room temperature, the reaction time is 2h, the molar ratio of difluoromethane to hydrogen peroxide in the quenching reaction is 1:1.2, the reaction temperature is room temperature, and the reaction time is 2h, the calculated yield of the product difluoroacetic acid reaches 64.31%.
Example 14
In the present embodiment, except for the difference from example 1, in the step (1), 50.15g of dimethyl sulfoxide was added as a dipolar solvent to the reaction vessel, and 10.03g of difluoromethane chloride gas (purity 100%,0.116 mol) was introduced, and the other steps were the same, 7.21g of difluoroacetic acid was obtained, the purity of the gas phase detection was 99.41%, and the calculated yield was 64.39%.
Example 15
The difference between the method and example 1 is that in the step (1), 50.10g of acetonitrile was added as a dipolar solvent to a reaction vessel, 10.02g of difluoromethane chloride gas (purity 100%,0.116 mol) was introduced, and the other steps were the same, to obtain 7.01g of difluoroacetic acid, the purity of which was 99.34% by gas phase detection, and the calculated yield was 62.56%.
Example 16
The difference between the method and example 1 is that in the step (1), 50.30g of methyl ethyl ketone was added as a dipolar solvent to a reaction vessel, 10.06g of difluoro chloromethane gas (purity 100%,0.116 mol) was introduced, and the other steps were the same, to obtain 6.70g of difluoro acetic acid, the gas phase detection purity thereof was 99.09%, and the calculated yield thereof was 59.42%.
As is clear from examples 1 and 14 to 16, the quality and calculated yield of the product difluoroacetic acid change with the change of the type of the dipolar solvent, and when acetone and dimethyl sulfoxide are selected as the dipolar solvents, the calculated yield of the product difluoroacetic acid is highest, acetonitrile is inferior, and therefore, the dipolar solvent is preferably acetone or dimethyl sulfoxide.
Example 17
In the process of this embodiment, except for the difference from example 1, in step (1), 26.16g of tri-n-butylamine (purity: 99%,0.140 mol) was charged into the reaction vessel, 10.07g of difluoromethane chloride gas (purity: 100%,0.116mol, molar ratio of difluoromethane chloride to tri-n-butylamine: 1:1.2) was introduced, and the other steps were the same, to obtain 7.05g of difluoroacetic acid having a gas phase detection purity of 99.22% and a calculated yield of 62.53%.
Example 18
The difference between the method and example 1 is that in the step (1), 13.30g of 4-methylpyridine (purity: 98%,0.140 mol) was charged into the reaction vessel, 10.11g of difluoromethane chloride gas (purity: 100%,0.117mol, molar ratio of difluoromethane to 4-methylpyridine: 1:1.2) was introduced, and the other steps were the same, to obtain 7.14g of difluoroacetic acid, the purity of which was detected in the gas phase: 99.32%, and the calculated yield: 63.19%.
As is clear from examples 1 and 17 to 18, the quality and calculated yield of the product difluoroacetic acid change with the change of the type of tertiary amine, and when pyridine is selected to participate in the reaction, the calculated yield of the product difluoroacetic acid is highest, 4-methylpyridine, and tri-n-butylamine is worst, so that the tertiary amine is preferably pyridine.
Please refer to table 2, which is a summary of experimental data and experimental results of examples 1, 14-18.
TABLE 2 summary of experimental data and experimental results for examples 1, 14-18
As shown in Table 2, acetone or dimethyl sulfoxide is used as a dipolar solvent, difluoromethane is used as a starting material, difluoromethane is reacted with pyridine to generate N-difluoromethyl ammonium chloride salt, then the N-difluoromethane chloride salt is reacted with cyanide anions under the catalysis of alkali to generate difluoroacetonitrile, and the difluoroacetonitrile is hydrolyzed, oxidized and acidified to prepare difluoroacetic acid with high yield, wherein the product yield is up to more than 64%.
As can be seen from tables 1-2, preferred conditions for the preparation of difluoroacetic acid are: acetone or dimethyl sulfoxide is used as a dipolar solvent, difluoromethane chloride is used as a starting material, the molar ratio of the difluoromethane chloride to pyridine in the preparation reaction of N-difluoromethyl ammonium chloride salt is 1:1.2, the reaction temperature is 30 ℃, the reaction time is 2h, the molar ratio of the difluoromethane chloride to sodium cyanide and sodium hydroxide in the cyanidation reaction is 1:1.0:0.2, the reaction temperature is 50 ℃, the reaction time is 4h, the molar ratio of the difluoromethane chloride to liquid alkali in the hydrolysis reaction is 1:1.8, the reaction temperature is room temperature, the reaction time is 2h, the molar ratio of the difluoromethane chloride to hydrogen peroxide in the quenching reaction is 1:1.2, the reaction temperature is room temperature, and the reaction time is 2h.
The product prepared in example 1 is detected, and the nuclear magnetic hydrogen spectrum is shown in figure 1. As can be seen from fig. 1, the product prepared in example 1 includes two types of hydrogen, namely, a peak at chemical shift δ5.23 and a peak at chemical shift δ10.37, the ratio of the peak areas is 1:1, that is, the number ratio of the two types of hydrogen is 1:1, wherein the triplet peak at chemical shift δ5.23 is generated by spin-coupling with a fluorocarbon atom, the ratio of the peak areas is 1:2:1, and the peak at chemical shift δ10.37 represents a carboxyl hydrogen atom, so that it can be presumed from the chemical shift and the number of the hydrogen, and the structure of the product prepared in example 1 is identical to that of difluoroacetic acid, thereby knowing that the product prepared in example 1 is difluoroacetic acid.
The application provides a preparation method of difluoro acetic acid, which adopts a brand new synthetic route, takes acetone or dimethyl sulfoxide as a dipolar solvent, takes difluoro chloromethane as a starting material, firstly reacts with pyridine to generate N-difluoro methyl ammonium chloride salt, the N-difluoro methyl ammonium chloride salt is used as a difluoro methyl positive ion intermediate or difluoro carbene source to react with cyanide anions under the catalysis of alkali to generate difluoro acetonitrile, and the difluoro acetonitrile is hydrolyzed, oxidized and acidified to prepare the difluoro acetic acid, the product yield is more than 64%, and the purity is more than 99%; compared with the prior preparation method, the preparation method has the advantages that,
(1) The N-difluoromethyl ammonium chloride salt has the phase transfer catalysis effect, can promote cyanide anions to enter an organic phase more, and performs nucleophilic reaction with a difluoromethyl positive ion intermediate or a difluorocarbene source, thereby being beneficial to improving the main reaction competitiveness and the reaction selectivity;
(2) The dipolar solvent used in the application can inhibit water from participating in competitive side reaction, further improves the reaction selectivity and improves the reaction yield;
(3) According to the application, difluoro chloromethane is used as a starting material to be directly used for preparing difluoro acetic acid, so that the step of preparing tetrafluoroethylene and then preparing difluoro acetic acid by using difluoro chloromethane in the prior art is omitted, the process flow is simplified, the atomic utilization rate is improved, the intermediate salt of the application can be directly used for preparing difluoro acetic acid without further purification, the preparation process is simple, the post-treatment process is simple, the dipole solvent, pyridine and other tertiary amines can be recycled, the production cost is reduced, and the preparation time is shortened;
in conclusion, the preparation method has the advantages of simple preparation process, mild reaction conditions, short reaction time, better selectivity, low reaction defluorination ratio, high atomic utilization rate, high product yield, low production cost and high feasibility of industrial application, and can be widely applied to the technical field of organic synthesis.
It should be noted that:
(1) The raw materials and the devices used in the application are conventional commercial products unless specified otherwise, and the methods used in the application are conventional methods unless specified otherwise.
(2) In the application, cyanide is used for providing cyanide anions, so that N-difluoromethyl ammonium chloride salt reacts with the cyanide anions to generate difluoroacetonitrile, thus sodium cyanide and potassium cyanide can be used as cyanide anion sources, and the cyanide anion sources can be other cyanide salts except sodium cyanide and potassium cyanide; the alkali metal hydroxide is used to provide base catalysis conditions for the reaction of the N-difluoromethyl ammonium chloride salt and cyanide anions, so that sodium hydroxide and potassium hydroxide can be used as the alkali metal hydroxide, and the alkali metal hydroxide can be other alkali metal hydroxides besides sodium hydroxide and potassium hydroxide, and even can be alkaline earth metal hydroxide.
The above embodiments are only for illustrating the technical solution of the present application, and not for limiting the same; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present application, and are intended to be included in the scope of the present application.

Claims (7)

1. A process for the preparation of difluoroacetic acid comprising the steps of:
(1) Adding tertiary amine into a dipolar solvent, introducing difluoro chloromethane, heating to 30 ℃ and stirring for reaction to generate solid precipitate which is N-difluoro methyl ammonium chloride salt;
(2) Cooling, adding cyanide and alkali metal hydroxide, heating to 40-60 ℃ again, and preserving heat for cyaniding reaction to generate difluoroacetonitrile; after the cyanidation reaction is finished, cooling again, adding liquid alkali, preserving heat for hydrolysis reaction, then adding hydrogen peroxide, preserving heat for quenching reaction; after the quenching reaction is finished, filtering and rinsing the reaction materials to obtain filtrate, and acidifying and rectifying the filtrate at normal pressure to obtain difluoro acetic acid;
in the step (1), the dipolar solvent is any one of acetone, dimethyl sulfoxide, acetonitrile and butanone, the tertiary amine is any one of pyridine, 4-methylpyridine and tri-n-butylamine, and the molar ratio of difluoro chloromethane to the tertiary amine is 1:1.0-1:1.4;
in the step (2), the molar ratio of the difluoro-chloromethane to the cyanide salt is 1:0.8-1:1.2, and the molar ratio of the difluoro-chloromethane to the alkali metal hydroxide is 1:0-1:0.4.
2. The process for producing difluoroacetic acid as claimed in claim 1, wherein in the step (1), the reaction time is 2 hours.
3. The method for producing difluoroacetic acid as claimed in claim 1, wherein in the step (2), the cyanide salt is any one of a sodium cyanide solution and a potassium cyanide solution, and the alkali metal hydroxide is any one of sodium hydroxide and potassium hydroxide.
4. The process for producing difluoroacetic acid as claimed in claim 1, wherein in the step (2), the temperature is lowered to 0℃or lower and the reaction time is 3 to 5 hours.
5. The method for producing difluoroacetic acid as claimed in claim 1, wherein in the step (2), the temperature is lowered again to room temperature, the molar ratio of difluoromethane chloride to the liquid base is 1:1.6-1:2.0, the hydrolysis reaction temperature is room temperature, and the reaction time is 2 hours.
6. The process for producing difluoroacetic acid as claimed in claim 1, wherein in the step (2), the molar ratio of difluoromethane chloride to hydrogen peroxide is 1:1.2, the quenching reaction temperature is room temperature, and the reaction time is 2 hours.
7. The method for producing difluoroacetic acid as claimed in claim 1, wherein in the step (2), the filtrate is acidified with dilute sulfuric acid, and the fraction is collected at 120 to 140 ℃ by normal pressure distillation to obtain difluoroacetic acid.
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