CN109134204B - Synthesis method of intermediate 2-bromo-4-fluoro-5-chlorophenol - Google Patents
Synthesis method of intermediate 2-bromo-4-fluoro-5-chlorophenol Download PDFInfo
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- CN109134204B CN109134204B CN201811368899.7A CN201811368899A CN109134204B CN 109134204 B CN109134204 B CN 109134204B CN 201811368899 A CN201811368899 A CN 201811368899A CN 109134204 B CN109134204 B CN 109134204B
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention provides a synthesis method of an intermediate 2-bromo-4-fluoro-5-chlorophenol, which comprises the steps of firstly adding a solvent into 3-chloro-4-fluorophenol, stirring, cooling to-10-0 ℃, then adding bromine, and then carrying out heat preservation reaction at-5-0 ℃ for 3-10 hours to obtain a reaction solution; adding NaHSO into the obtained reaction liquid3Quenching the aqueous solution, layering, and taking an organic layer I; adding a NaCl aqueous solution into the obtained organic layer I, layering, and taking an organic layer II; concentrating the obtained organic layer II under reduced pressure until the organic layer II is dried, adding petroleum ether serving as a solvent into the obtained product, stirring until the petroleum ether is completely dissolved, performing low-temperature crystallization at the temperature of-2 ℃, and filtering to obtain a filter cake; and finally, drying the obtained filter cake to obtain the 2-bromo-4-fluoro-5-chlorophenol. The reaction solvent is chloroform, dichloromethane or carbon tetrachloride, and compared with the prior art which adopts toluene as the reaction solvent, the method has the advantages of mild reaction conditions, low cost, high yield, high purity and the like.
Description
Technical Field
The invention relates to a method for synthesizing an organic matter, in particular to a method for synthesizing and refining a high-purity intermediate 2-bromo-4-fluoro-5-chlorophenol.
Background
2-bromo-4-fluoro-5-chlorophenol is used as an intermediate for OLED materials, liquid crystal display materials, medicines, and agricultural products. The preparation process of the 2-bromo-4-fluoro-5-chlorophenol is accompanied by the generation of a large amount of by-products of the 2-bromo-3-chloro-4-fluorophenol, and the commercial price is expensive due to low purity.
An invention patent having a conventional publication number of CN105358523B "polymerizable compound, polymerizable composition, liquid crystal composite, optically anisotropic body, liquid crystal display element, and use thereof" proposes a method for producing 2-bromo-4-fluoro-5-chlorophenol (paragraph 321):
3-chloro-4-fluorophenol and bromine are used as raw materials, tert-butylamine is used as an acid-binding agent, and the reaction is carried out in a toluene solution at the temperature of minus 70 ℃ to obtain a main product 2-bromo-4-fluoro-5-chlorophenol and 2-bromo-3-chloro-4-fluorophenol accompanied with a large amount of byproducts. Because the structures of the 2-bromo-4-fluoro-5-chlorophenol and the 2-bromo-3-chloro-4-fluorophenol are similar, the purification yield of the product by a chromatographic column is only 57 percent.
In view of the above, further improvements to the prior art are needed.
Disclosure of Invention
The invention aims to provide a synthesis method of a high-purity intermediate 2-bromo-4-fluoro-5 chlorophenol with high purity and high yield.
In order to solve the technical problem, the invention provides a synthesis method of an intermediate 2-bromo-4-fluoro-5-chlorophenol, which comprises the following steps:
1) and synthesis:
adding a solvent into 3-chloro-4-fluorophenol, stirring (the stirring time is 10-20 minutes), cooling to-10-0 ℃, adding bromine (the temperature of the system is ensured not to exceed 0 ℃ in the adding process), and then carrying out heat preservation reaction at-5-0 ℃ for 3-10 hours to obtain a reaction solution;
the 3-chloro-4-fluorophenol: the molar ratio of bromine to bromine is 1: 1-1.4;
note: GC (gas chromatography) can be adopted for control, when the conversion rate of the 2-bromo-4-fluoro-5-chlorophenol is higher than 87% and the byproduct is less than 10%, the reaction is finished, and a reaction solution (red solution) is obtained;
the dropwise addition of bromine was completed within 2 h.
2) And refining:
adding NaHSO into the reaction liquid obtained in the step 1)3Quenching the aqueous solution (until the red color of the reaction solution disappears), and layering to obtain an organic layer I (positioned at the lower layer);
adding a NaCl aqueous solution into the obtained organic layer I, and layering to obtain an organic layer II (positioned at the lower layer);
concentrating the obtained organic layer II to dryness under reduced pressure (60 ℃ and-0.05 MPa), adding petroleum ether into the obtained product, stirring until the petroleum ether is completely dissolved, performing low-temperature crystallization at the temperature of-2 ℃, and filtering to obtain a filter cake;
and drying the obtained filter cake to obtain the 2-bromo-4-fluoro-5-chlorophenol.
As an improvement of the synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol in the invention:
in the step 1), 1-1.2L of solvent is used for every 1mol of 3-chloro-4-fluorophenol.
As a further improvement of the synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol in the invention:
the solvent is chloroform, dichloromethane or carbon tetrachloride.
As a further improvement of the synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol in the invention:
in the step 2), 0.4-1.0L of saturated NaHSO is used for every 1mol of 3-chloro-4-fluorophenol3The aqueous solution thereby achieves quenching.
As a further improvement of the synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol in the invention:
in the step 2), 0.8-1.3L of saturated NaCl aqueous solution is used for every 1mol of 3-chloro-4-fluorophenol to realize layering.
As a further improvement of the synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol in the invention:
in the step 2), 0.4-1.0L of petroleum ether is used for every 1mol of 3-chloro-4-fluorophenol.
The method takes 3-chloro-4-fluorophenol and bromine as raw materials, prepares the single 2-bromo-4-fluoro-5-chlorophenol with high purity and high yield by changing a reaction solvent and reducing the reaction temperature without using an acid-binding agent, and has the following synthetic route:
compared with the prior art, the invention has the technical advantages that:
the method adopts chloroform as a reaction solvent, has mild reaction conditions, few byproducts and high yield (the yield is more than or equal to 65 percent), and can obtain the high-purity (the purity is more than or equal to 98 percent) 2-bromo-4-fluoro-5-chlorophenol after refining.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1, synthesis of intermediate 2-bromo-4-fluoro-5-chlorophenol, comprising the sequential steps of:
1. synthesizing:
adding 943g of 3-chloro-4-fluorophenol (6.45mol) and 7L of chloroform into a 20L reaction bottle, stirring (the stirring time is 20 minutes), cooling to-10-0 ℃, dropwise adding 1500g of bromine (7.75mol, dropwise adding within 2 hours), and controlling the temperature of the solution in the reaction bottle to be not more than 0 ℃ by using a water bath in the dropwise adding process; after the dropwise addition is finished, the reaction is carried out for 3 hours at the temperature of 0 ℃; and (3) adopting GC (gas chromatography) for control, wherein the conversion rate of the 2-bromo-4-fluoro-5-chlorophenol is higher than 87%, and the by-product is less than 10%, namely, the reaction is finished, and obtaining a reaction solution (red solution).
2. Refining:
to the reaction solution (red solution) in the reaction flask was added 3L of saturated NaHSO3Quenching with aqueous solution until red color disappears, separating layers, collecting organic layer I (organic layer I is at the lower layer), adding 6L saturated NaCl aqueous solution into organic layer I, separating layers, and collecting organic layer II (organic layer II is at the lower layer).
Concentrating the obtained organic layer II under reduced pressure at 60 ℃ and-0.05 MPa until the organic layer II is dried, adding 3L of petroleum ether into the obtained product, stirring until the petroleum ether is completely dissolved, carrying out low-temperature crystallization at 0 ℃, filtering to obtain 1300g of filter cake, drying the filter cake at 50 ℃ (drying to constant weight) to obtain 1082-bromo-4-fluoro-5-chlorophenol, wherein the yield is 75%, and the purity of the obtained 2-bromo-4-fluoro-5-chlorophenol is 98.6% through GC detection.
In example 2, the chloroform in example 1 was changed to carbon tetrachloride, and the amount thereof was the same as in example 1 except for the change.
947g of 2-bromo-4-fluoro-5-chlorophenol was obtained in 66% yield with 98.6% purity by GC.
In example 3, the chloroform in example 1 was changed to methylene chloride, and the amount thereof was changed, and the rest was the same as in example 1.
This example gave 971g of 2-bromo-4-fluoro-5-chlorophenol in a yield of 67% and a purity of 98.1% by GC.
Comparative example 1 the chloroform in example 1 was changed to toluene and the amount used was the same as in example 1.
The comparative example obtained 37g of 2-bromo-4-fluoro-5-chlorophenol, with a yield of 2.6% and a purity of 15% by GC.
Note: when the reaction solvent is toluene, the reaction cannot be carried out under the reaction conditions of example 1, and thus the yield and purity of 2-bromo-4-fluoro-5-chlorophenol are extremely low.
Comparative example 2, the reaction solvent in step 1 of example 1 was changed from chloroform to a mixed solution of chloroform and t-butylamine in an amount of 839g (11.5mol), and the mixture was sufficiently stirred for 2 minutes to obtain a mixed solution. The rest of the same is the same as in example 1.
768g of 2-bromo-4-fluoro-5-chlorophenol was obtained in 53% yield, 89.2% purity by GC.
In conclusion, the reaction solvent is chloroform, dichloromethane or carbon tetrachloride, compared with the prior art that toluene is adopted as the reaction solvent, the reaction condition of the method is mild (the reaction temperature is reduced from-70 ℃ to-10 ℃), the by-product is less, the yield is high (the yield is more than or equal to 65%), the cost is reduced (tert-butylamine which is used as an acid binding agent is not used), and the high-purity (the purity is more than or equal to 98%) 2-bromo-4-fluoro-5-chlorophenol can be obtained after refining.
Comparative example 3, the chloroform in example 1 was changed to carbon disulfide, and the amount was the same as in example 1.
594g of 2-bromo-4-fluoro-5-chlorophenol was obtained with a yield of 41% and a purity of 73.1% by GC.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested directly from the disclosure of the present invention by a person skilled in the art are to be considered within the scope of the present invention.
Claims (1)
1. The synthesis method of the intermediate 2-bromo-4-fluoro-5-chlorophenol is characterized by comprising the following steps:
1) and synthesis:
adding 6.45mol of 3-chloro-4-fluorophenol and 7L of chloroform into a 20L reaction bottle, stirring for 20 minutes, cooling to-10-0 ℃, dropwise adding 7.75mol of bromine, completing dropwise adding within 2 hours, and controlling the temperature of the solution in the reaction bottle to be not more than 0 ℃ by using a water bath in the dropwise adding process; after the dropwise addition is finished, the reaction is carried out for 3 hours at the temperature of 0 ℃; GC is adopted for control, the conversion rate of the 2-bromo-4-fluoro-5-chlorophenol is higher than 87%, the byproduct is less than 10%, and the reaction solution is obtained after the reaction is finished;
2) and refining:
3L of saturated NaHSO was added to the reaction solution in the reaction flask3Quenching the aqueous solution until red disappears, layering, taking an organic layer I, adding 6L of saturated NaCl aqueous solution into the organic layer I, layering, and taking an organic layer II;
concentrating the obtained organic layer II under reduced pressure at 60 ℃ and-0.05 MPa until the organic layer II is dried, adding 3L of petroleum ether into the obtained product, stirring until the petroleum ether is completely dissolved, carrying out low-temperature crystallization at 0 ℃, filtering to obtain 1300g of filter cake, drying the filter cake at 50 ℃ until the weight is constant to obtain 2-bromo-4-fluoro-5-chlorophenol, and detecting the purity of the obtained 2-bromo-4-fluoro-5-chlorophenol by GC to be 98.6%.
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