JP2000239198A - Production of 1-bromo-3-fluorobenzene - Google Patents

Abstract

PROBLEM TO BE SOLVED: To readily and efficiently produce 1-bromo-3-fluorobenzene by brominating a fluorobenzene in the presence of a catalyst, isomerizing the brominated body in the presence of a (halogenated) aluminum, and reacting the obtained product with a specific benzene derivative. SOLUTION: A fluorobenzene is brominated in the presence of a catalyst, and the brominated body is isomerized in the presence of aluminum or a halogenated aluminum of the formula AlX3 (X is a halogen). The isomerized product is reacted with a benzene derivative of the formula (Rn is an electron donor; (n) is 0-5) to provide the objective 1-bromo-3-fluorobenzene. The reaction is carried out without a solvent or in a solvent by using a Lewis acid and/or a metal capable of forming the Lewis acid with bromine as the catalyst. The reaction temperature is preferably (-10)-20 deg.C, more preferably 0-10 deg.C. When the solvent is used, the solvent is preferably an inert solvent such as methylene chloride, chloroform and carbon tetrachloride, and the amount of the bromine used at the bromination is 1-1.2 equivalent based on the fluorobenzene.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 1-bromo-3-fluorobenzene, which is useful as an intermediate for pharmaceuticals, agricultural chemicals and liquid crystals.

[0002]

2. Description of the Related Art 1-Bromo-3-fluorobenzene represented by the following general formula (I) is a useful substance as an intermediate for pharmaceuticals and agricultural chemicals and liquid crystals.

[0003]

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[0004] The previously proposed 1-bromo-3
As a method for producing fluorobenzene, for example, a method of brominating fluorobenzene (US Pat.
095275, JP-A-63-14742, etc.) Method for directly fluorinating bromobenzene with fluorine (J. Am. Chem. Soc., 102, 3511, 1980, etc.) 3-bromo-benzenediazonium tetrafluoroborate (J. Org. Chem., 3, 347, 1938)
Etc.) are known. However, the above method and the above method produce a mixture of three kinds of bromofluorobenzene isomers whose main product is 1-bromo-4-fluorobenzene. Among them, 1-bromo-3 which is slightly generated
-Because fluorobenzene has almost no difference in boiling point from the other two isomers, separation and purification are extremely difficult and the isolation yield is very low. However, it is difficult to obtain 3-bromo-benzenediazonium tetrafluoroborate and to control the decomposition reaction, so that it is not suitable for mass synthesis.
As described above, no satisfactory method has been found for a practical method for synthesizing 1-bromo-3-fluorobenzene.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a simple and efficient method for producing 1-bromo-3-fluorobenzene which has solved the above-mentioned problems.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that fluorobenzene can be brominated and isomerized in the presence of aluminum or aluminum halide, or aluminum halide can be obtained. In the presence, 1-bromo-2-fluorobenzene or 1-bromo-4-fluorobenzene is isomerized, and then a bromine acceptor is added and reacted to obtain 1
-Bromo-3-fluorobenzene was found to be able to be produced efficiently. According to the present invention, 1-bromo-2-fluorobenzene and 1-bromo-3-fluorobenzene having almost no 1-bromo-4-fluorobenzene, which are two types of isomers that are difficult to separate and purify, are used. Can be manufactured. That is, the present invention, in the presence of a catalyst,
After brominating fluorobenzene, the brominated product is converted to aluminum or a general formula (II): AlX ₃ (II) wherein X represents a halogen. Isomerization in the presence of an aluminum halide represented by the general formula (III):

[0007]

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[Wherein, R represents an electron donating group. n is 0
An integer of 5. And a method for producing 1-bromo-3-fluorobenzene (hereinafter, referred to as the first method of the present invention), and a general formula (II): AlX ₃ (II) [ In the formula, X represents a halogen. 1-bromo-2-fluorobenzene (IV) or 1-bromo-4-fluorobenzene (V) or a mixture of isomers thereof in the presence of an aluminum halide represented by the general formula (III): wherein R represents an electron donating group. n
Is an integer of 0 to 5. ]

[0009]

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A method for producing 1-bromo-3-fluorobenzene characterized by reacting with a benzene derivative represented by the formula (hereinafter referred to as the second method of the present invention). The selectivity of the product is almost the same regardless of which method is used.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The bromination reaction of fluorobenzene in the first method of the present invention is performed without a solvent or in a solvent using a Lewis acid and / or a metal that forms a Lewis acid with bromine as a catalyst. Among them, a particularly preferred catalyst is aluminum or an aluminum halide represented by the general formula (II).
The reaction temperature is -10 to 20C, preferably 0 to 10C.
As the solvent used in this reaction, starting materials, catalysts,
Preferred are inert solvents which do not react with the product, such as, but not limited to, halogens such as methylene chloride, chloroform, carbon tetrachloride and the like. The amount of bromine used is preferably 1 to 1.2 equivalents to fluorobenzene. Bromine can of course be used as a reaction solvent, as well as a reaction solvent. As the bromine, a liquid may be dropped or a vaporized one may be blown. The amount of Lewis acid and / or metal forming a Lewis acid with bromine is suitably 0.01 to 1 equivalent to fluorobenzene, but is preferably 0.01 to 0.1 equivalent industrially. Although an increase in the amount used is preferable because it promotes the reaction, excessive use is disadvantageous in terms of an increase in by-products and cost. As the Lewis acid, for example, aluminum halides such as aluminum bromide and aluminum chloride, iron halides such as iron bromide and iron chloride, antimony fluoride, titanium chloride, boron fluoride, tin chloride, zinc chloride and the like are preferable. Among them, aluminum halide and iron halide are particularly preferred. As a metal forming a Lewis acid with bromine, for example, aluminum, iron, tin, titanium, zinc and the like are preferable, and aluminum and iron are particularly preferable.

The isomerization reaction of bromofluorobenzene in the first and second methods of the present invention is carried out without a solvent or in a solvent using aluminum halide as a catalyst. The reaction temperature is from 10 to 150 ° C, preferably from 10 to 80 ° C. Although a higher reaction temperature is advantageous in terms of the reaction rate, it is disadvantageous in increasing by-products. The reaction time is 3 to 24 hours,
Preferably, it is 3 to 5 hours. Equilibrium composition of isomers,
Ortho body: Meta body: Para body is 5-6%: 60-65%: 30-
Times reaching 34% are particularly preferred. If the reaction time is extremely long, the disproportionation of 1-bromo-3-fluorobenzene proceeds, which is not preferable. The amount of the aluminum halide to be used is suitably 0.01 to 1 equivalent relative to fluorobenzene, but is preferably 0.01 to 0.1 equivalent industrially. Preferred examples of the aluminum halide include aluminum bromide and aluminum chloride. The aluminum halide may be prepared in the same system by adding aluminum and halogen. As the solvent used in this reaction, methylene chloride,
Suitable examples include halogens such as chloroform and carbon tetrachloride, but are not limited thereto. The amount of the benzene derivative used for the reduction reaction in the present invention is suitably 1 to 5 equivalents to fluorobenzene or bromofluorobenzene, but industrially 1.
Four to two equivalents are preferred. The reaction temperature is 10 to 100 ° C, preferably 10 to 50 ° C. The reaction time is 12 to 24 hours, preferably 15 to 20 hours. A reaction that takes a long time is not preferable because the reduction of 1-bromo-3-fluorobenzene proceeds. As the bromine acceptor used in the above reaction, benzenes having an electron donating group are preferable, and for example, ethylbenzene, toluene, xylene, phenol, 1,2-dimethoxybenzene and the like are preferable, but not limited thereto. It is not something to be done.

In the present invention, aluminum bromide is easily prepared in a reaction system by using aluminum or aluminum halide as a catalyst and bromine as a brominating agent, and the bromination, isomerization, reduction or isomerization, reduction Such a series of reactions can be performed sequentially or in the same reactor. 1-Bromo-3-fluorobenzene obtained by the reaction can be easily isolated to a high purity by ordinary post-treatment and distillation. Fluorobenzene and unreacted benzene derivative by-produced by the reaction are recovered by distillation and can be reused.

[0014]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Example 1 576 g of fluorobenzene and 16 g of aluminum powder were placed in a 2 L four-necked flask equipped with a condenser, a dropping funnel and an exhaust port, and the system was cooled to 10 ° C. Dropped in time. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. The equilibrium composition at this time was 5.3%: 63.5%: 31.2% for ortho-form: meta-form: para-form. Subsequently, 773 g of toluene was added and reacted at room temperature for 15 hours. After completion of the reaction, water was added to decompose the remaining aluminum bromide, and then the organic layer was separated. The obtained crude product is distilled under normal pressure to recover fluorobenzene and toluene, and then distilled under reduced pressure to obtain 495 g of 1-bromo-3-fluorobenzene having a GC purity of 99% or more.
was gotten. For this, GC and GC-M
S confirmed that it was 1-bromo-3-fluorobenzene. This example shows that the recovered fluorobenzene was obtained in 68% yield (based on fluorobenzene) since it can be reused in the bromination step.

Example 2 In a 2 L four-necked flask equipped with a condenser, a dropping funnel and an exhaust port, 576 g of fluorobenzene and 10 parts of iron chloride were placed.
g, cool the system to 10 ° C, and add 1.0 equivalent of bromine.
959 g were added dropwise over 4 hours. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. At this time, the composition was 0.9%: 0.4%: 98.7% of ortho-form: meta-form: para-form. Subsequently, 80 g of aluminum chloride was added and reacted at 80 ° C. for 4 hours. After cooling the system to 40 ° C, add 954 g of xylene and
The reaction was performed for 20 hours. Thereafter, by performing the same treatment as in Example 1, 1-bromo-3- with a GC purity of 99% or more.
500 g of fluorobenzene were obtained. About this thing, it confirmed that it was 1-bromo-3-fluorobenzene by GC and GC-MS. In this example, 70
% Yield (based on fluorobenzene).

Example 3 1-bromo-4-fluorobenzene was placed in a 2 L four-necked flask equipped with a condenser, a dropping funnel and an exhaust port.
875 g and 67 g of aluminum chloride were added and reacted at 80 ° C. for 3 hours. After cooling the system to 30 ° C, toluene 644
g was added and reacted for 15 hours. Thereafter, water was added to decompose the remaining aluminum chloride, and then the organic layer was separated. The resulting crude product is distilled under normal pressure to recover fluorobenzene and toluene, and then distilled under reduced pressure to obtain 1-bromo-3 having a GC purity of 99% or more.
458 g of fluorobenzene were obtained. About this thing, it confirmed that it was 1-bromo-3-fluorobenzene by GC and GC-MS. In this embodiment,
This indicates that the compound was obtained in a yield of 52% (1-bromo-
4-fluorobenzene standard).

Example 4 1-bromo-2-fluorobenzene was placed in a 2 L four-necked flask equipped with a condenser, a dropping funnel and an exhaust port.
875 g and 67 g of aluminum chloride were added and reacted at 80 ° C. for 5 hours. After cooling the system to 30 ° C., 742 g of ethylbenzene was added, and the reaction was carried out for 20 hours. Thereafter, the same treatment as in Example 3 was performed to obtain 420 g of 1-bromo-3-fluorobenzene having a GC purity of 99% or more.
This was analyzed by GC and GC-MS to give 1-
It was confirmed that it was bromo-3-fluorobenzene. This example shows that the yield was 48% (based on 1-bromo-2-fluorobenzene).

Comparative Example 1 200 ml with condenser, dropping funnel and exhaust port
In a four-necked flask, put 48 g of fluorobenzene and 0.2 g of aluminum powder, cool the system to 10 ° C, and add bromine.
80 g was added dropwise in 0.5 hours. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours.

After completion of the reaction, water was added to decompose the remaining aluminum bromide, and then the organic layer was separated. Fluorobenzene was recovered by distilling the crude product under normal pressure.
The composition of the obtained product is as follows: ortho form: meta form: para form
4.0%: 0.6%: 81.5%.

Comparative Example 2 200 ml with condenser, dropping funnel and exhaust port
In a four-neck flask, 40 g of fluorobenzene and 0.2 of iron powder
After cooling the system to 10 ° C, 25 g of bromine was added to 0.5 g
Dropped in time. After completion of the dropwise addition, the temperature was raised to 40 ° C., and the mixture was stirred for 2 hours. After completion of the reaction, water was added to decompose the remaining iron bromide, and then the organic layer was separated. Fluorobenzene was recovered by distilling the crude product under normal pressure. The composition of the product obtained is as follows: ortho-form: meta-form: para-form: 1.0%: 0.5%:
98.5%.

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Claims (2)

[Claims] (1) After brominating fluorobenzene in the presence of a catalyst, the brominated product is converted to aluminum or a general formula (II): AlX ₃ (II) wherein X represents a halogen. Isomerization in the presence of an aluminum halide represented by the general formula (III): [Wherein, R represents an electron donating group. n is an integer of 0-5. ]
A method for producing 1-bromo-3-fluorobenzene, characterized by reacting with a benzene derivative represented by the formula: 2. A general formula (II): AlX ₃ (II) wherein X represents a halogen. 1-bromo-2-fluorobenzene (IV) or 1-bromo-4-fluorobenzene (V) or a mixture of isomers thereof in the presence of an aluminum halide represented by the general formula (III): wherein R represents an electron donating group. n
Is an integer of 0 to 5. ] A method for producing 1-bromo-3-fluorobenzene, characterized by reacting with a benzene derivative represented by the formula: