A preparation method of 2-fluoro-6-chlorophenol

Abstract

The present invention discloses a preparation method of 2-fluoro-6-chlorophenol. In an organic solvent, at a certain temperature, 2,6-dichloronitrobenzene is used as a raw material, and the product 2-fluoro-6-chlorophenol is obtained through three-step reactions of fluorination, reduction, and diazotization hydrolysis. The method of the present invention has multiple raw material sources and obvious cost advantages. The preparation method is safer, more convenient, has a high total yield and less three wastes, which is beneficial to industrialization.

Description

Technical Field

[0001] The present invention relates to a method for preparing 2-fluoro-6-chlorophenol, and specifically to a method for obtaining the product 2-fluoro-6-chlorophenol through three-step reactions of fluorination, reduction, and diazotization hydrolysis using 2,6-dichloronitrobenzene as a raw material. Background Art

[0002] 2-Fluoro-6-chlorophenol is an important intermediate for the herbicides fluroxypyr-meptyl and fluroxypyr manufactured by Dow AgroSciences, and is also an important pharmaceutical intermediate. The synthetic methods reported in the literature mainly include the following three: 1. CN1301949C and CN103435452A use chlorination of 2-fluorophenol. The process involves poor control of chlorination selectivity and high raw material price of 2-fluorophenol, resulting in high production costs; 2. CN104844399B uses palladium-catalyzed C-H bond fluorination synthesis method. Although a directing group is introduced to improve selectivity in the process, the palladium catalyst is expensive and it is not easy to remove the protecting group, resulting in high costs; 3. CN103787846A uses 2,3-dichloronitrobenzene as a raw material, through methoxy substitution, nitro reduction, and diazotization fluorination. The diazotization fluorination in the process has a relatively high safety risk and a high probability of explosion. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for preparing 2-fluoro-6-chlorophenol in view of the deficiencies in the prior art. The method is to obtain the product 2-fluoro-6-chlorophenol through three-step reactions of fluorination, reduction, and diazotization hydrolysis using 2,6-dichloronitrobenzene as a raw material in an organic solvent at a certain temperature. The method of the present invention has multiple raw material sources and obvious cost advantages. The preparation method is safer, more convenient, has a high total yield and less three wastes, and is conducive to industrialization.

[0004] To achieve the above object, the present invention adopts the following technical solutions:

[0005] A method for preparing a 4-cyclopropyl-substituted benzoic acid analogue, comprising the following steps:

[0006] (1) In an organic solvent, at a certain temperature, add 2,6-dichloronitrobenzene, potassium fluoride, and catalyst A for a fluorination reaction to obtain a product 2-fluoro-6-chloro-nitrobenzene intermediate;

[0007] (2) In a high-pressure hydrogenation reactor, in an organic solvent, at a certain temperature, add the 2-fluoro-6-chloro-nitrobenzene intermediate and catalyst B for a hydrogenation reaction to obtain a product 2-fluoro-6-chloroaniline intermediate;

[0008] (3) In a reaction kettle, at a certain temperature, add 2-fluoro-6-chloroaniline, 30% concentrated sulfuric acid, and a nitrosating reagent C for a denitrification hydrolysis reaction to obtain a product 2-fluoro-6-chlorophenol;

[0009] The reaction formula is:

[0010] .

[0011] In the above technical solution, the preparation method is specifically as follows:

[0012] (1) Under nitrogen protection, add organic solvent, 2,6-dichloronitrobenzene, potassium fluoride, and catalyst A to the reaction vessel in sequence. After stirring evenly, raise the temperature to the set temperature; keep the temperature at this level until the gas chromatography normalized content of 2,6-dichloronitrobenzene in the total material is <1%; after solvent desorption and solvent recovery, perform vacuum distillation to obtain the intermediate 2-fluoro-6-chloro-nitrobenzene;

[0013] (2) In a high-pressure hydrogenation autoclave, add organic solvent, 2-fluoro-6-chloro-nitrobenzene, and catalyst B in sequence. After stirring evenly, raise the temperature and pressure to the set values; keep the temperature at this level until the gas chromatography normalized content of 2-fluoro-6-chloro-nitrobenzene in the total material is <1%; after solvent desorption, perform vacuum distillation to obtain the product 2-fluoro-6-chloroaniline intermediate;

[0014] (3) Under nitrogen protection, add 30% concentrated sulfuric acid, 2-fluoro-6-chloroaniline intermediate, and nitrosation reagent C to the reaction vessel in sequence. After stirring evenly, raise the temperature to the set temperature; keep the temperature at this level until the gas chromatography normalized content of 2-fluoro-6-chloroaniline in the total material is <1%; after the reaction is completed, add a solvent for extraction, and after solvent desorption, perform vacuum distillation to obtain 2-fluoro-6-chlorophenol.

[0015] In the above technical solution, in step (1), the molar ratio of 2,6-dichloronitrobenzene to potassium fluoride is 1:1 - 5, the molar ratio of the dosage of the organic solvent to 2,6-dichloronitrobenzene is 1 - 10:1, and the molar ratio of 2,6-dichloronitrobenzene to catalyst A is 1 - 20:1; in step (2), the molar ratio of the 2-fluoro-6-chloro-nitrobenzene intermediate to catalyst B is 1 - 50:1, and the molar ratio of the dosage of the organic solvent to the 2-fluoro-6-chloro-nitrobenzene intermediate is 1 - 10:1; in step (3), the molar ratio of the 2-fluoro-6-chloroaniline intermediate to sulfuric acid is 1:1 - 5, the molar ratio of the 2-fluoro-6-chloroaniline intermediate to the nitrosation reagent is 1:1 - 5, and the molar ratio of the dosage of the organic extraction solvent to the 2-fluoro-6-chloroaniline intermediate is 1 - 10:1.

[0016] In the above technical solution, the reaction temperature in steps (2) and (3) is 20 - 80 °C; the reaction temperature in step (1) is 100 - 220 °C.

[0017] In the above technical solution, the organic solvent described in steps (1), (2), and (3) is any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents, alcohol solvents, and strongly polar solvents containing heteroatoms.

[0018] In the above technical solution, the catalyst A described in step (1) is any one of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, imidazole-based ionic liquids, or a mixture of two of them.

[0019] The catalyst B described in step (2) is any one of palladium-carbon, Raney nickel, ruthenium-carbon, rhodium-carbon, platinum-carbon, or a mixture of two of them.

[0020] The nitrosation reagent C described in step (3) is any one of sodium nitrite, nitrosylsulfuric acid, alkyl nitrites, or a mixture of two of them.

[0021] Preferably, the halogenated hydrocarbon solvents are dichloromethane, dichloroethane, etc.; the aromatic solvents are toluene, xylene, etc.; the ether solvents are tetrahydrofuran, etc.; the ester solvents are methyl acetate, ethyl acetate, etc.; the alcohol solvents are methanol, ethanol, ethylene glycol, etc.; and the strongly polar solvents containing heteroatoms are DMF, DMA, DMSO, NMP, sulfolane, DMI, etc.

[0022] In the above technical solution, in steps (2) and (3), the reaction temperature is preferably 20 - 50 °C; in step (1), the reaction temperature is preferably 150 - 180 °C.

[0023] The method of the present invention has multiple raw material sources and obvious cost advantages. The preparation method is safer, more convenient, has a high total yield and less three wastes, which is conducive to industrialization. Specific Embodiments

[0024] The following describes in detail the specific embodiments of the technical solution of the present invention, but the present invention is not limited to the following description:

[0025] Example 1: 2-Fluoro-6-chlorophenol

[0026]

[0027] Small-scale preparation of the target product:

[0028] (1) Charge 19.1 g (0.10 mol) of 2,6-dichloronitrobenzene, 100 mL of DMF, 8.7 g (0.15 mol) of potassium fluoride, and 1 g of solid tetraphenylphosphonium bromide into a 500 mL reaction kettle, heat to 150 °C and stir for reaction for 12 h, recover DMF under reduced pressure (directly applied to the next batch of reactions), with a recovery rate of 90%, and obtain 14 g of 2-fluoro-6-chloronitrobenzene intermediate with a purity of >98% by vacuum distillation, with a yield of 80%;

[0029] (2) In a 500 mL hydrogenation reactor, 17.5 g (0.10 mol) of 2-fluoro-6-chloronitrobenzene intermediate, 50 mL of ethanol, and 1 g of Raney nickel were charged. The pressure was set at 0.5 MPa, and the mixture was heated to 60 °C and stirred for 8 h. After cooling and filtering to recover the catalyst, ethanol was recovered under reduced pressure (directly applied to the next batch of reactions), with a recovery rate of 92%. By vacuum distillation, 13.4 g of 2-fluoro-6-chloroaniline intermediate with a purity of >99% was obtained, and the yield was 92.5%.

[0030] (3) In a 500 mL reactor, 14.5 g (0.10 mol) of 2-fluoro-6-chloroaniline intermediate and 150 mL of 30% sulfuric acid were charged. After stirring evenly, 41.4 g of a 20% sodium nitrite (0.12 mol) aqueous solution was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 °C for 3 h, then heated to 50 °C and kept warm for 1 h to complete the reaction. 50 mL of dichloromethane was added for extraction, liquid separation, and the dichloromethane was recovered by desolvation (directly applied to the next batch of reactions), with a recovery rate of 93%. By vacuum distillation, 11.7 g of the target product 2-fluoro-6-chlorophenol with a purity of >99% was obtained, and the yield was 80%.

[0031] Example 2: 2-Fluoro-6-chlorophenol

[0032]

[0033] Process for pilot-scale preparation of the target product:

[0034] (1) In a 500 L reactor, 19.1 kg (100 mol) of 2,6-dichloronitrobenzene, 200 L of DMF, 8.7 kg (0.15 mol) of potassium fluoride, and 1 g of solid catalyst tetraphenylphosphonium bromide were charged. The mixture was heated to 150 °C and stirred for 12 h. DMF was recovered under reduced pressure (directly applied to the next batch of reactions), with a recovery rate of 95%. By vacuum distillation, 14.35 kg of 2-fluoro-6-chloronitrobenzene intermediate with a purity of >98% was obtained, and the yield was 82%.

[0035] (2) In a 500 L hydrogenation reactor, 17.5 kg (100 mol) of 2-fluoro-6-chloronitrobenzene intermediate, 150 L of ethanol, and 100 g of Raney nickel were charged. The pressure was set at 0.5 MPa, and the mixture was heated to 60 °C and stirred for 8 h. After cooling and filtering to recover the catalyst, ethanol was recovered under reduced pressure (directly applied to the next batch of reactions), with a recovery rate of 95%. By vacuum distillation, 13 kg of 2-fluoro-6-chloroaniline intermediate with a purity of >99% was obtained, and the yield was 89.7%.

[0036] (3) In a 500L reactor, 14.5 kg (100 mol) of the intermediate 2-fluoro-6-chloroaniline and 150 L of 30% sulfuric acid were charged. After stirring evenly, an aqueous solution of 20% sodium nitrite (120 mol), 41.4 kg, was added dropwise at 0 °C. After the addition, the mixture was stirred and reacted at 0 °C for 3 h, then heated to 50 °C and kept warm for 1 h to complete the reaction. 50 L of dichloromethane was added for extraction, liquid separation, and solvent stripping to recover dichloromethane (directly applied to the next batch of reactions), with a recovery rate of 90%. Vacuum distillation yielded 12.4 kg of the target product 2-fluoro-6-chlorophenol with a purity of >99%, and the yield was 85%.

[0037] Example 3: 2-Fluoro-6-chloronitrobenzene

[0038]

[0039] Small-scale preparation of the target product, comparison of different solvents and catalyst A:

[0040] (1) In a 500 mL reactor, 19.1 g (0.10 mol) of 2,6-dichloronitrobenzene, 100 mL of solvent, 8.7 g (0.15 mol) of potassium fluoride, and 1 g of solid catalyst were charged. The mixture was heated to 150 °C and stirred for 12 h. DMF was recovered under reduced pressure (directly applied to the next batch of reactions), and vacuum distillation yielded 2-fluoro-6-chloronitrobenzene with a purity of >98%.

[0041] Serial number Solvent Catalyst Yield 1 DMSO Tetraphenylphosphonium bromide 62% 2 DMF Tetraphenylphosphonium bromide 80% 3 DMI Tetraphenylphosphonium bromide 80% 4 Sulfolane Tetraphenylphosphonium bromide 50% 5 DMF 18-Crown-6 38% 6 DMF N-Butylimidazole hydrochloride 5% 7 DMF Tetrabutylammonium chloride 65%

[0042] Example 4: 2-Fluoro-6-chloroaniline

[0043] Small-scale preparation of the target product, comparison of different solvents and catalyst B:

[0044] (1) In a 500 mL hydrogenation reactor, 17.5 g (0.10 mol) of the intermediate 2-fluoro-6-chloronitrobenzene, 50 mL of solvent, and 1 g of catalyst B were charged. The pressure was set at 0.5 MPa, and the mixture was heated to 60 °C and stirred for 8 h. After cooling and filtering to recover the catalyst, ethanol was recovered under reduced pressure (directly applied to the next batch of reactions), and vacuum distillation yielded the intermediate 2-fluoro-6-chloroaniline with a purity of >99%.

[0045] Serial number Solvent Catalyst Yield 1 Ethanol Raney nickel 92.5% 2 Methanol Raney nickel 90% 3 Toluene Raney nickel 15% 4 THF Raney nickel 60% 5 Ethanol 5% Palladium on carbon 65% 6 Ethanol 2% Ruthenium on carbon 58% 7 Ethanol 1% Platinum on carbon 96%

[0046] The above examples are only used to illustrate the technical concept and features of the present invention, and should not be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A preparation method of 2-fluoro-6-chlorophenol, characterized in that, It includes the following steps: (1) In an organic solvent, at a certain temperature, 2,6-dichloronitrobenzene, potassium fluoride, and catalyst A are added for a fluorination reaction to obtain the product 2-fluoro-6-chloro-nitrobenzene intermediate; wherein, the catalyst A is any one or a mixture of two of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, and imidazole-based ionic liquids; (2) In a high-pressure hydrogenation autoclave, in an organic solvent, at a certain temperature, the 2-fluoro-6-chloro-nitrobenzene intermediate and catalyst B are added for a hydrogenation reaction to obtain the product 2-fluoro-6-chloroaniline intermediate; wherein, the catalyst B is any one or a mixture of two of palladium-carbon, Raney nickel, ruthenium-carbon, and platinum-carbon; (3) In a reaction kettle, at a certain temperature, 2-fluoro-6-chloroaniline, 30% concentrated sulfuric acid, and nitrosation reagent C are added for a denitrification hydrolysis reaction to obtain the product 2-fluoro-6-chlorophenol; wherein, the nitrosation reagent C is any one or a mixture of two of sodium nitrite, nitrosylsulfuric acid, and alkyl nitrite; The reaction formula is: 。 2. The method according to claim 1, wherein It includes the following steps: (1) Under nitrogen protection, an organic solvent, 2,6-dichloronitrobenzene, potassium fluoride, and catalyst A are successively added to a reaction vessel, stirred evenly, and then heated to a set temperature; keep warm at this temperature until the gas chromatography normalization content of 2,6-dichloronitrobenzene in the total material < 1%; after solvent stripping and solvent recovery, vacuum distillation is carried out to obtain the intermediate 2-fluoro-6-chloro-nitrobenzene; (2) In a high-pressure hydrogenation autoclave, an organic solvent, 2-fluoro-6-chloro-nitrobenzene, and catalyst B are successively added, stirred evenly, and then heated to a set temperature and set pressure; keep warm at this temperature until the gas chromatography normalization content of 2-fluoro-6-chloro-nitrobenzene in the total material < 1%; after solvent stripping, vacuum distillation is carried out to obtain the product 2-fluoro-6-chloroaniline intermediate; (3) Under nitrogen protection, 30% concentrated sulfuric acid, 2-fluoro-6-chloroaniline intermediate, and nitrosation reagent C are successively added to a reaction vessel, stirred evenly, and then heated to a set temperature; keep warm at this temperature until the gas chromatography normalization content of 2-fluoro-6-chloroaniline in the total material < 1%; after the reaction is completed, solvent extraction is carried out, and after solvent stripping, vacuum distillation is carried out to obtain 2-fluoro-6-chlorophenol.

3. The method according to claim 2, wherein In step (1), the molar ratio of 2,6-dichloronitrobenzene to potassium fluoride is 1:1 - 5, the molar ratio of the dosage of the organic solvent to 2,6-dichloronitrobenzene is 1 - 10:1, and the molar ratio of 2,6-dichloronitrobenzene to catalyst A is 1 - 20:1; in step (2), the molar ratio of the 2-fluoro-6-chloro-nitrobenzene intermediate to catalyst B is 1 - 50:1, and the molar ratio of the dosage of the organic solvent to the 2-fluoro-6-chloro-nitrobenzene intermediate is 1 - 10:1; in step (3), the molar ratio of the 2-fluoro-6-chloroaniline intermediate to sulfuric acid is 1:1 - 5, the molar ratio of the 2-fluoro-6-chloroaniline intermediate to the nitrosation reagent is 1:1 - 5, and the molar ratio of the dosage of the solvent to the 2-fluoro-6-chloroaniline intermediate is 1 - 10:

1.

4. The method according to claim 2, wherein The set temperature described in steps (2) and (3) is 20 - 80°C; the set temperature described in step (1) is 100 - 220°C.

5. The method according to claim 2, characterized in that The organic solvent described in steps (1), (2), and (3) is any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents, alcohol solvents, and strongly polar solvents containing heteroatoms.

Images