JP3531039B2 - 1,4-difluorobenzene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] BACKGROUND OF THE INVENTION The present invention relates to a quinolone carboxylic acid
A novel 1,4- useful as an intermediate for the production of synthetic antibacterial agents
It relates to a difluorobenzene derivative. [0002] BACKGROUND OF THE INVENTION 1,4-Difluorobenzene derivatives of the present invention
The conductor is a novel compound not described in the literature. [0003] SUMMARY OF THE INVENTION The present invention relates to 2,4,5
Quinolones produced via trifluorobenzoic acid
1,4- is a useful intermediate of carboxylic synthetic antibacterial agents
A difluorobenzene derivative is provided. [0004] SUMMARY OF THE INVENTION Conventionally, 2,4,5-tri
Fluorobenzoic acid is a synthetic quinolone carboxylic acid antibacterial agent.
It was known to be an important intermediate. The inventor has
To provide this 2,4,5-trifluorobenzoic acid
As a result of repeated research, 1,4-difluoro
New compound not described in the literature by using robenzene
2,5-disubstituted-1,4-difluorobenzene
A conductor is obtained, and the 2,5-disubstituted-1,
2,4,5-
The trifluorobenzoic acid is obtained and the 2,5-disubstituted-
1,4-difluorobenzene derivative is quinolone carboxylic
Recognizing that it can be an important intermediate for acid-based synthetic antibacterial agents,
The present invention has been completed. That is, the present invention provides a compound represented by the general formula [0006] Embedded image (Wherein, X represents a chlorine atom, a bromine atom or a nitrile group)
Y represents a bromine atom or a nitro groupBut Y is bromine source
When X is a chlorine atom, when X is a nitro group, X is
It is a bromine atom or a nitrile group.)
A 4-difluorobenzene derivative is provided. Specific examples of the compounds provided by the present invention
5-bromo-2-chloro-1,4-difluorobe
Benzene (I), 4-bromo-2,5-difluoronitro
Benzene (II), 2,5-difluoro-4-nitroben
Zonitrile (III) and the like can be mentioned. [In addition,
In the following description, the above-mentioned compound (I) of the present invention
Is a compound (I), and the compound of the present invention (II) is a compound
(II), compound (III) of the present invention is referred to as compound (III)
May be described. ] Hereinafter, the present invention will be described in detail. The compound of the present invention, 1,4-difluorobe
The benzene derivative is 1,4-difluorobenzene as a raw material.
Using the method shown in the following flow (Chem. 3).
Can be built. [0009] Embedded image That is, 1,4-difluorobenzene is
Monochlorination by a known method to give 2-chloro-1,4-
After obtaining difluorobenzene, this and bromine, for example,
Compound (I) is reacted by using iron powder as a catalyst to react
Obtainable. At this time, the iron powder is added to the compound (I).
0.01 to 0.1 equivalent, bromine is also 1.0 to 2.0 equivalent
Production by reacting at 30 ° C to 60 ° C using the amount
it can. Here, the bromine atom corresponds to the desired compound (I).
Highly introduced at the substitution position. In addition, the product
When recrystallized with sun or the like, high purity compound (I) can be easily obtained.
Can be Also, 1,4-difluorobenzene is known.
To give 2-bromo-1,4-diphenyl
After obtaining the fluorobenzene, it is passed through, for example, a mixed acid.
2-bromo-1,4-difluorobenzene is converted by a usual method.
Compound (II) can be produced by nitration. So
In this case, nitric acid is 2-bromo-1,4-difluorobenzene
1 to 2 equivalents, and sulfuric acid also use 4 to 8 equivalents.
What is necessary is just to make it react at -40 degreeC. Again, the nitro group is
Highly selective at the target location. In addition, 2-bromo-
Chlorination of 1,4-difluorobenzene by a known method
To give compound (I). Further, for example, the presence of an aprotic polar solvent
In the presence, compound (II) and cuprous cyanide are heated and stirred.
React to replace the bromine atom of compound (II) with cyano
Thus, compound (III) can be produced. Used here
As the aprotic polar solvent, an aprotic polar solvent is usually used.
Solvents, such as tetramethylene sulfo
(Sulfolane), dimethyl sulfoxide, tetramethyl
Sulfur-containing aprotic polar solvents such as lensulfoxide,
Or N, N-dimethylacetamide, N, N-dimethyl
Tylformamide, 1-methyl-2-pyrrolidinone,
Contains nitrogen such as 1,3-dimethyl-2-imidazolidinone
Use aprotic polar solvent such as aprotic polar solvent
The amount used is 50 ml / compound (II).
Mol to 1000 ml / mol, preferably 100 ml / mol to
It may be 500 ml / mol. Also, cuprous cyanide is
It is used in an amount of 1.0 to 2.0 equivalents relative to compound (II). In addition,
Instead of the cuprous cyanide, cuprous halide 0.1.
05 to 0.5 equivalents and potassium cyanide or cyanide
It may be used in combination with 1.0 equivalent or more of sodium chloride
It is possible. The reaction temperature is 40 ° C to 250 ° C, preferably
Is preferably carried out at 80 ° C to 100 ° C, and the reaction pressure is usually
Is performed at normal pressure. In the production of the compound of the present invention, the
As a raw material in the no-chlorination or mono-bromination process
To produce using 1,4-difluorobenzene
Compounds have no positional isomers and are easily purified by distillation
The desired product can be obtained. Compounds of the present invention [compound (I), compound (I
I) and compound (III)] are shown in the following flow chart (Chem. 4).
Therefore, if necessary, cyanation and / or fluorination,
Distillation can be easily performed to obtain high-purity 2,4,5
-To trifluorobenzonitrile,
Isomers are hydrolyzed in the usual way to give positional isomers
High purity 2,4,5-trifluoroammonium with almost no contamination
Can lead to benzoic acid. In addition, 2,4,5-triflu
Orobenzoic acid is a quinolone carboxylic acid synthetic antibacterial agent
Are known to be important compounds. [0015] Embedded image [0016] [0017] The 1,4-difur provided by the present invention
Orobenzene derivatives are novel compounds that have not been described in the literature.
The compound of the present invention can be easily prepared as shown in the flow chart (Chem. 4).
Which can be converted to 4,5-trifluorobenzoic acid
Therefore, in the production of quinolone carboxylic acid synthetic antibacterial agent
It is an important intermediate. Further, the compound of the present invention can be used in a flow (formula 3).
As shown, in particular, 1,4-difluorobenzene was used as a raw material.
Position obtained by monochlorination or monobromination used
2-halogeno-1,4-difluorobenes without stereoisomers
Substantially regioisomers are obtained using zen derivatives as direct raw materials.
It can be manufactured by a method that is not suitable for
Excellent product can be obtained.
Has the following advantages: [0019] The present invention will be described in more detail with reference to the following examples.
Will be described. Reference Example 1 2-bromo-1,4-diflu
Synthesis of Orobenzene 1,4-difluorobenzene in a 200 ml four-necked flask
142.6 g (1.25 mol) and iron powder 1.75 g (0.
025 molar equivalents) and stirring at 40-50 ° C.
179.8 g (1.125 mol) of bromine were added dropwise over 50 minutes.
I gave it. After completion of the dropwise addition, the mixture was stirred for 20 minutes at 45 ° C.
After that, the mixture was bubbled with nitrogen. Next, add sulfurous acid to the reaction solution.
An aqueous sodium hydrogen solution was added, and insolubles were removed by filtration.
After that, the liquid is separated and washed sequentially with water, aqueous sodium bicarbonate, and water
And dried over anhydrous sodium sulfate. Product obtained
Is distilled using a Goodlow rectification column (made of SUS)
2-butane as a colorless transparent liquid with a fraction of 86 ° C / 90 mmHg
95.2 g of lomo-1,4-difluorobenzene was obtained.
The yield was 39.5% (1,4-difluorobenzene).
Standard). Example 1 4-bromo-2,5-diflu
Synthesis of Oronitrobenzene [Compound (II)] 82.6 g of 95% concentrated sulfuric acid in a 500 ml four-necked flask
(0.8 mol) and 70% nitric acid under cooling in an ice bath
19.8 g (0.22 mol) at 10 ° C or less for 25 minutes
And dropped. Next, 2-bromo-1,4-difluoro
38.6 g (0.2 mol) of benzene was added to 1,2-dichloro
A solution dissolved in 100 ml of ethane is kept at 10 ° C or lower for 1 hour 4
It was added dropwise over 0 minutes. After dropping, 30 minutes at 4-5 ° C
After stirring and aging, the mixture is further stirred at room temperature for 2 hours.
went. After aging, pour the reaction mixture into ice and extract with ether.
I left. After washing the obtained ether layer with water,
Make alkaline with sodium, wash twice, and
After washing with a saline solution, the extract was dried over anhydrous sodium sulfate.
The obtained ether layer was concentrated under reduced pressure, and the concentrated residue was n-hexane.
By adding 100 g of sun, 4-bromo-2,5-
30.8 g of difluoronitrobenzene was obtained. The yield is
64.8%. (Confirmation data) Appearance: pale yellowish white needle-like crystal Melting point: 56.7-58.1 ° C¹ H-NMR (CDCl_Three): Δ 7.17 to 8.36 (m,
2H) IR (KBr): 3400, 1590, 1525, 147
0, 1380, 1333, 1270, 1180, 98
0,885,780 cm^-1 Example 2 2,5-difluoro-4-ni
Synthesis of Trobenzonitrile [Compound (III)] In a 100 ml four-necked flask, add 4-bromo-2,5-diflu
Oronitrobenzene 16.7 g (0.07 mol), 99
%-Cuprous cyanide (7.6 g, 0.084 mol)
35 ml of methylacetamide was charged, and 3.5
Aged for hours. Next, dimethylacetamide is removed under reduced pressure.
Collected, toluene and water were added to the residue. Filtering insolubles
The mixture was removed by filtration using an agent, and the toluene layer was separated and washed with water.
Performed twice and dried over anhydrous sodium sulfate. Decompress the solvent
After concentration, add 33 g of isopropyl ether and wash under stirring.
Was cleaned. Finally, it is filtered off, dried and 2,5-difluoro-
8.4 g of 4-nitrobenzonitrile was obtained. The yield is 6
It was 5.1%. (Confirmation data) Appearance: brown crystal Melting point: 100.4-102.1 ° C¹ H-NMR (CDCl_Three): Δ 7.45 to 8.22 (m,
2H) IR (KBr): 3050, 2220, 1590, 153
0, 1485, 1400, 1340, 1290, 120
0,900,845,795,750 cm^-1 Reference Example 2 2,4,5-Trifluorobe
Synthesis of nzonitrile 20 ml of sulfolane and toluene in a 100 ml four-necked flask
After charging 20 ml and performing azeotropic dehydration for 1 hour, toluene
Was recovered. Next, 2,5-difluoro-4-nitrobe
3.68 g (0.02 mol) of zononitrile, sprayed
Rye = 4.07 g (0.07 mol) of potassium fluoride,
4.06 g (0.02 mol) of tallic acid dichloride and te
Traphenylphosphonium bromide 0.08 g (0.
0002 mol). Subsequently, the temperature was raised to 150 ° C
The mixture was stirred for 2 hours and aged. After aging, cool the reaction solution
Then, ether and water were added. After ether extraction, wash 3 times
I went twice. Finally, by distillation, 2,4,5-trifluoro
2.17 g of lobenzonitrile was obtained. The yield is 69.1%
Met. (Confirmation data) Appearance: colorless transparent liquid Boiling point: 82-83 ° C / 20mmHg¹ H-NMR (CDCl _Three): Δ 6.87 to 7.80 (m,
2H) IR (NaCl plate): 3050, 2220, 1616, 15
10,1430,1350,1215,1155,88
0,840 cm^-1 Reference Example 3 2-Chloro-1,4-difur
Synthesis of Orobenzene A 300 ml four-port filter equipped with a stirrer, Dimroth and thermometer
228 g of 1,4-difluorobenzene (2 m
), 2.28 g (1% by weight) of iron (III) chloride
At 40 ° C. Approximately 1 mole of chlorine at 5:00
I blew it over time. The reaction is gas chromatography
Following the reaction, a reaction mixture having the following composition was obtained. [0028]     1,4-difluorobenzene 37.2%     2-chloro-1,4-difluorobenzene 54.7%     6.6% of 2,5-dichloro-1,4-difluorobenzene The reaction solution was purged with nitrogen, rectified,
140.1 g of 1,4-difluorobenzene was obtained.
(Boiling point: 131 ° C.). The yield was 47%. Also,
70.8 g of raw material 1,4-difluorobenzene was recovered.
Was. Example 3 5-Bromo-2-chloro-
Synthesis of 1,4-difluorobenzene [compound (I)] 500 ml four-port filter equipped with stirrer, Dimroth and thermometer
In Lasco, 2-chloro-1,4-difluorobenzene 1
30 g (0.88 mol), iron powder 2.42 g (0.04
) And heated to 50 ° C. 169 g of bromine there
(1.06 mol) was added dropwise over 5 hours.
Followed by chromatograph, the raw material 2-chloro-1,4
-The mixture was stirred and aged until difluorobenzene disappeared.
After cooling to room temperature, aqueous sodium bisulfite solution and ether
And insolubles were removed by filtration. Separate ether layer
Liquid, washed with water and dried over anhydrous sodium sulfate.
Was concentrated. The obtained concentrate is further n-hex
The sun was reconstituted twice and 5-bromo-2-chloro-1,4
-84 g of difluorobenzene were obtained. The yield is 42%
Was. (Confirmation data) Appearance: White needle crystal Melting point: 47.6-48.8 ° C¹ H-NMR (CDCl_Three): Δ 6.8 to 7.7 (m, 2
H) IR (KBr): 1500, 1390, 1270, 119
0,785 cm^-1M⁺= 228 Reference Example 4 4-Chloro-2,5-difur
Synthesis of Orobenzonitrile 200 ml four-port filter equipped with stirrer, Dimroth and thermometer
5-Bromo-2-chloro-1,4-difluoro on Lasco
47.0 g (0.21 mol) of benzene, N, N-dimethyl
Charge 100ml of luacetamide and add cyanide first
22.1 g (0.25 mol) of copper was added, and the temperature was raised to 140 ° C.
did. Aged at the same temperature for 4 hours. After completion of the reaction, to room temperature
After cooling, water was added and extracted with ether. Ether layer
Wash sequentially with water and saturated saline, and dry with anhydrous sodium sulfate.
And dried. After concentrating the ether layer, n-hexane
After recrystallization, 4-chloro-2,5-difluorobenzo
19 g (0.11 mol) of nitrile were obtained. 53% yield
Met. Reference Example 5 2,4,5-Trifluorobe
Synthesis of nzonitrile 100 ml four-port filter equipped with stirrer, Dimroth and thermometer
Lasco, 4-chloro-2,5-difluorobenzonit
8.7 g (0.05 mol) of ril, 25 ml of sulfolane,
Play dry = potassium fluoride 6.38g (0.11m
And heated to 180 ° C. 8 hours stirring at the same temperature
The mixture was analyzed by gas chromatography after stirring.
58% of 4,5-trifluorobenzonitrile is formed
Was.

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Claims (1)

(57) [Claims] [Claim 1] The general formula: (Wherein, X represents a chlorine atom, a bromine atom or a nitrile group, Y indicates a bromine atom or a nitro group but, Y is bromine Hara
When X is a chlorine atom, when X is a nitro group, X is
It is a bromine atom or a nitrile group. )
4-difluorobenzene derivatives.