JPH0597794A - Method for producing aromatic fluorine compound and fluorine-containing benzenesulfinic acid derivative to become its raw material - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for agricultural chemicals and medicines in high yield without using a dangerous reagent and an expensive reagent by subjecting a specific aromatic sulfinic acid derivative to elimination reaction of sulfinic acid under a condition from acidity to basicity. CONSTITUTION:An aromatic sulfinic acid derivative of formula I (R is 1-4C alkyl, 1-4C alkoxy or H; X is alkali metal or H; Y is Cl or Br; (1) is 1-2; (m)is 0-3; (n) is 1-4; (1+m+n)=2-5) is subjected to elimination reaction of sulfinic acid under a condition of acidity to basicity to give the objective compound of formula II. In the case of the reaction under an acidic condition, an aqueous solution of sulfuric acid is preferably used as a solvent and under a basic condition, the reaction is preferably carried out in an aprotic solvent such as DMF by using sodium carbonate as a catalyst. 2,4-Difluoro-3-methylbenzenesulfinic acid and its alkali metal salt among the raw material compound of formula I are new compounds.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an aromatic fluorine compound (II) useful as an intermediate for agricultural chemicals and pharmaceuticals (for example, a raw material for an antibacterial agent described in JP-B-63-5390), and the production thereof. The present invention relates to a fluorinated benzenesulfinic acid derivative useful as a raw material.

[0002]

2. Description of the Related Art Conventionally, a method for obtaining an aromatic fluorine compound represented by the general formula (II) by a Baltzseemann reaction of an amino-substituted aromatic compound is known, but this method involves the use of dangerous diazonium salts or corrosive substances. High hydrofluoric acid had to be used.

Further, a method for obtaining pentafluorobenzene by reacting pentafluorobenzenesulfinyllithium with silver nitrate and subjecting it to desulfinic acid reaction [Aust.
J. Chem. , 32 (11), 2381-93 (19
79)] is known. However, the above method
Even if an expensive lithium salt or silver salt was used, the yield was not good, and it was still insufficient as an industrial method.

[0004]

DISCLOSURE OF THE INVENTION The present invention is to provide a method for industrially producing an aromatic fluorine compound and a fluorine-containing benzenesulfinic acid derivative useful as a raw material for producing the same.

[0005]

The present inventor has earnestly conducted research on an industrial method for producing an aromatic fluorine compound, and surprisingly, aromatic sulfinic acid can be easily removed by the method of the present invention. The present invention has been completed by discovering that an aromatic fluorine compound can be efficiently obtained by an acid reaction and a novel fluorine-containing benzenesulfinic acid derivative useful as a raw material for producing the aromatic fluorine compound.

That is, the present invention has the general formula (I)

[0007]

[Chemical 3]

(Wherein R is a C _1-4 alkyl group or C
_1-4 represents an alkoxy group or a hydrogen atom, X represents an alkali metal atom or a hydrogen atom, Y represents a chlorine atom or a bromine atom, l is 1 to 2, m is 0 to 3, and n is 1
An integer of 4 is shown. However, l + m + n is an integer of 2 to 5)

Characterized in that the aromatic sulfinic acid derivative represented by the following is subjected to a desulfinic acid reaction under acidic to basic conditions:

General formula (II)

[0011]

[Chemical 4]

(In the formula, R, Y, l, m and n are synonymous with the above.)

The present invention relates to a method for producing an aromatic fluorine compound represented by and a fluorine-containing benzenesulfinic acid derivative useful as a raw material for the production.

The present invention will be described in detail below.

Aromatic sulfinic acid derivative (I) as a raw material
Is chlorosulfonation of chlorobenzene (III), and the chlorine atom of the obtained aromatic sulfonyl chloride derivative is fluorine-substituted by a known method (for example, application of the method described in JP-A-2-83364). , Can be easily obtained by further reduction. The scheme is shown below.

[0016]

[Chemical 5]

(In the formula, R, X, Y, l, m and n are synonymous with the above.)

Further, the aromatic sulfinic acid derivative is represented by the general formula (I) (wherein R represents a C _1-4 alkyl group or a C _1-4 alkoxy group, or a hydrogen atom, X represents an alkali metal atom, Or a hydrogen atom, Y represents a chlorine atom or a bromine atom, l is 1 to 2, m is 0 to 3, and n is an integer of 1 to 4, provided that l + m + n is an integer of 2 to 5).

Any compound represented by can be used.

Specifically, 4-fluorobenzenesulfinic acid, 2,4-difluorobenzenesulfinic acid,
Sodium 2,4-difluorobenzenesulfinate,
2,4-difluoro-3-methylbenzenesulfinic acid, potassium 2,4-difluoro-3-methylbenzenesulfinate, 2,4-difluoro-5-methylbenzenesulfinic acid, 2,4-difluoro-5-methylbenzene Sodium sulfinate, 4,5-difluoro-2
-Methylbenzenesulfinic acid, 4,5-difluoro-
Sodium 2-methylbenzenesulfinate, 2,6-
Difluoro-4-methylbenzenesulfinic acid, 2,6
-Sodium difluoro-4-methylbenzenesulfinate, 2,4,6-trifluoro-3-methylbenzenesulfinic acid, sodium 2,4,6-trifluoro-3-methylbenzenesulfinate, 2,4-difluoro- 5-methoxybenzenesulfinic acid, sodium 2,4-difluoro-5-methoxybenzenesulfinate,
4,5-difluoro-2-methoxybenzenesulfinic acid, 3-chloro-4-fluorobenzenesulfinic acid,
3-chloro-2,4-difluorobenzenesulfinic acid, sodium 3-chloro-2,4-difluorobenzenesulfinate, 3-chloro-2,6-difluorobenzenesulfinic acid, 2,3-dimethoxy-4-fluorobenzene Sulfinic acid, 2,6-dimethoxy-4-fluorobenzenesulfinic acid, 2,4-difluoro-3-
Butylbenzenesulfinic acid, 2,4-difluoro-5
-Isopropylbenzenesulfinic acid, 4,5-difluoro-2-ethylbenzenesulfinic acid, 2,6-difluoro-4-tertiarybutylbenzenesulfinic acid,
2,4,5-Trifluoro-3-ethylbenzenesulfinic acid, 2,4-difluoro-5-isobutyloxybenzenesulfinic acid, 4,5-difluoro-2-propyloxybenzenesulfinic acid, 3-bromo-4-fluoro -Benzenesulfinic acid, 2,6-difluoro-3
-Bromobenzenesulfinic acid, 4-fluoro-2,3
-Diethoxybenzenesulfinic acid, 2-fluoro-
3,4,5,6-tetrachlorobenzenesulfinic acid,
2-Bromo-3-fluoro-4,5-dichlorobenzenesulfinic acid, 1,2,3,4-tetrafluorobenzenesulfinic acid and the like can be exemplified.

As described above, the general formula (I) (wherein
R is a C _1-4 alkyl group or a C _1-4 alkoxy group,
Or a hydrogen atom, X is an alkali metal atom or a hydrogen atom, Y is a chlorine atom or a bromine atom,
1 is an integer of 1 to 2, m is an integer of 0 to 3, and n is an integer of 1 to 4. However, any compound represented by 1 + m + n is an integer of 2 to 5) can be used as the raw material of the present invention, and is not limited to this example.

The desulfinic acid reaction proceeds under a wide range of conditions from acidic to basic. The reaction temperature can be generally from room temperature to the boiling point of the solvent, and about 150 to 200 ° C. is suitable for efficient reaction. As a solvent used in the reaction, an aqueous sulfuric acid solution having an appropriate concentration is used under acidic conditions, and dimethylimidazolidinone (DMI), dimethylacetamide (DMAC), dimethylformamide (DM) under basic conditions.
It is preferable to use an aprotic polar solvent such as F) or dimethyl sulfoxide (DMSO). A base is used as a catalyst under basic conditions, and preferred examples of the base include sodium carbonate, potassium carbonate, potassium fluoride and the like. The base can be used in a wide range from the catalytic amount to the equivalent or more, but is preferably about 0.05 to 1 equivalent. The desulfinic acid reaction proceeds only in a fluorine-containing benzenesulfinic acid derivative as a raw material or in a reaction system in which a solvent is added thereto, but it is preferable to carry out the reaction under acidic or basic conditions. .. Further, this reaction may be carried out under an inert gas atmosphere.

[0023]

INDUSTRIAL APPLICABILITY According to the present invention, an aromatic fluorine compound (II) can be easily obtained by subjecting an aromatic sulfinic acid derivative (I) to a desulfinic acid reaction under acidic to basic conditions. Therefore, aromatic fluorine compound (II) can be obtained in good yield without using hydrofluoric acid, which is highly corrosive as in the past, dangerous diazonium salt intermediates, or expensive lithium salts and silver salts. It is a method of high industrial value.

[0024]

EXAMPLES The present invention will be described in more detail with reference to the following examples.

Example 1 In a 10 ml round-bottomed flask, 5 g of dimethylimidazolidinone (DMI), 0.89 g (0.005 mol) of 2,4-difluorobenzenesulfinic acid and 0.53 g (0.005 mol) of sodium carbonate were added. Was charged, stirred with a magnetic stirrer and heated to an oil bath temperature of 200 ° C. and reacted for 1 hour. After cooling to room temperature, it was extracted with 30 ml of xylene, filtered, and xylene was added to make about 50 ml. About 0.5 g of toluene was accurately added as an internal standard substance, and 1 μl thereof was taken and analyzed by GC. From the calibration curve prepared in advance, the yield of 1,3-difluorobenzene was 77.9%.

GC / MS: m / z = 114 (M ⁺ )

EXAMPLE 2 Dimethyl imidazolidinone (D
MI) 5 g, 2,4-difluorobenzenesulfinic acid 0.89 g (0.005 mol), potassium fluoride [Morita Chemical Co., Ltd., Spray Dry-KF] 0.29 g (0.
(005 mol) was charged, and the mixture was stirred with a magnetic stirrer to raise the oil bath temperature to 200 ° C. and reacted for 1 hour. After cooling to room temperature, it was extracted with 30 ml of xylene, filtered, and xylene was added to make about 50 ml. About 0.5 g of toluene as an internal standard was accurately added, and 1 μl was analyzed by GC.
From the calibration curve prepared in advance, the yield of 1,3-difluorobenzene was 77.0%.

Example 3 In a 10 ml round-bottomed flask, 5 g of 80% sulfuric acid and 1 g of sodium 2,4-difluorobenzenesulfinate (0.0
(05 mol) was charged, and the mixture was stirred with a magnetic stirrer to raise the temperature of the oil bath to 200 ° C. and reacted for 1 hour. After cooling to room temperature, extraction was performed with 30 ml of xylene, and xylene was further added to make about 50 ml. About 0.5 g of toluene as an internal standard was accurately added, and 1 μl was analyzed by GC. From the calibration curve prepared in advance, the yield of 1,3-difluorobenzene was 41.8%.

Example 4 In a 10 ml eggplant-shaped flask, 3 g of dimethylimidazolidinone (DMI) containing 10% of water, 1 g (0.005 mol) of sodium 2,4-difluorobenzenesulfinate, and 0.53 g of sodium carbonate ( (0.005 mol) was charged, and the mixture was stirred with a magnetic stirrer to raise the oil bath temperature to 200 ° C. and reacted for 5 hours. After cooling to room temperature, it was extracted with 30 ml of xylene, filtered, and xylene was added to make about 50 ml. About 0.5 g of the internal standard toluene
Exactly 1 μl was analyzed by GC. Yield of 1,3-difluorobenzene from the calibration curve prepared in advance 13
%Met.

Example 5 A 10 ml tester was charged with 0.17 g (0.001 mol) of 2,4-difluorobenzenesulfinic acid and reacted at an oil bath temperature of 200 ° C. for 1 hour. After cooling to room temperature, 10 ml of chlorobenzene and 0.1 g of toluene as an internal standard were accurately added and 1 μl GC analysis was carried out. From the calibration curve prepared in advance, the yield of 1,3-difluorobenzene was 30%.

Example 6 In a 500 ml four-necked flask, 150 ml of dimethylimidazolidinone (DMI), 9.6 g (0.05 mol) of 2,4-difluoro-3-methylbenzenesulfinic acid and 5.3 g of sodium carbonate ( (0.05 mol) was charged, the mixture was stirred and the temperature of the oil bath was raised to 200 ° C., and the reaction was performed for 1.5 hours. After cooling to room temperature, extraction with ether, filtration,
It was washed with water to remove DMI. After the ether layer was dried, the ether was distilled off and distilled to obtain 4.3 g of 2,6-difluorotoluene (yield 79%).

Boiling point: 112 ° C./740 mmHg NMR (CCl ₄ ): δ 2.18 (3H, s, CH ₃ ).
6.63-7.10 (3H, m, aromatic ring): GC / MS: m / z = 128 (M ⁺ ), 127 (M ⁺
-1)

The 2,4-difluorobenzenesulfinic acid and sodium 2,4-difluorobenzenesulfinate used as raw materials were synthesized by the following method.

Reference Example 1 Synthesis of 2,4-dichlorobenzenesulfonyl chloride In a 200 ml four-necked flask, dimethylformamide (D
17 g (0.23 mol) of MF) was charged, and 28 g (0.21 mol) of sulfuryl chloride was added dropwise at 5 to 20 ° C. over 30 minutes. After reacting for 2 hours as it was, 27 g (0.20 mol) of 60% fuming sulfuric acid was added dropwise at 17 to 20 ° C over 30 minutes. Then 1,3-dichlorobenzene 21g
(0.14 mol) was added dropwise. The temperature was raised to 100 ° C. and the reaction was performed for 2.5 hours. After cooling to room temperature, the mixture was poured into 250 g of ice with stirring. The precipitated crystals were separated by filtration, dissolved in 250 ml of ether, and washed with 100 ml of water. The ether layer was dried and then concentrated to obtain 29.3 g of a crude product (crude yield 85.2%). This product was recrystallized from 20 ml of hexane and a small amount of toluene and dried to obtain 2,4-dichlorobenzenesulfonyl chloride having a purity of 99% or more. Yield is 62.0%
And the melting point was 55.5-58 ° C.

Synthesis of 2,4-difluorobenzenesulfonyl fluoride In a four-necked flask, 20 ml of toluene and 48.8 sulfolane were used.
g, potassium fluoride [manufactured by Morita Chemical Co., Ltd., Spray Dry-KF] 15.1 g (0.26 mol), tetraphenylphosphonium bromide 2.72 g (0.065 mol) were charged, stirred and heated, After azeotropic dehydration, toluene was distilled off. Under a nitrogen atmosphere, 15.96 g (0.065 mol) of 2,4-dichlorobenzenesulfonyl chloride was charged and reacted at 180 ° C for 5 hours. After cooling to room temperature,
The content was dissolved in 120 ml of toluene, the solid matter was filtered, then concentrated and subjected to simple distillation to obtain Fraction-1 of 8.74.
g (purity, 94.4%) and Fraction-2 were obtained 17.03 g (purity, 6.9%), respectively. The net conversion yield is 74.0.
%Met. By rectification, the purity of 99.5% 2,
4-Difluorobenzenesulfonyl fluoride was obtained.
The boiling point was 58 to 59 ° C./4 mmHg.

Synthesis of sodium 2,4-difluorobenzenesulfinate In a 500 ml four-necked flask, 100 ml of acetone, 2,
4-difluorobenzenesulfonyl fluoride 9.78
g (0,05 mol) was charged and stirred, and a solution prepared by dissolving 12.48 g (0.1 mol) of sodium sulfite and 8.32 g (0.13 mol) of sodium hydrogen carbonate in 270 ml of water was added dropwise. .. Then, the temperature was raised to 50 ° C. and the reaction was performed for 2 hours. After cooling to room temperature, the contents are methylene chloride 1
After extracting the organic matter with 70 ml, the aqueous layer was freeze-dried to obtain 23.30 g of a solid matter. Methanol 17
Dissolve organic matter in 0 ml and filter out inorganic matter, then
Concentrated to 0 ml. Further, the organic matter was dissolved with 170 ml of ether, the insoluble matter was filtered off, and the ether layer was concentrated and dried to obtain 6.00 g of sodium 2,4-difluorobenzenesulfinate. The yield was 74.0%.

IR (KBr) (cm ^-1 ): 3600, 320
0, 1600, 1480, 1410, 1270, 113
0,1050

Synthesis of 2,4-difluorobenzenesulfinic acid 65 ml of water and 10.00 g of sodium 2,4-difluorobenzenesulfinate in a 100 ml four-necked flask.
(0.05 mol) was charged, stirred and cooled to 0 ° C.
5.21 g (0.05 mol) of concentrated hydrochloric acid was added dropwise thereto over 5 minutes. After stirring for 1 hour, methylene chloride 20
This was extracted twice with 0 ml, and this methylene chloride layer was washed with 150 ml of saturated saline. The methylene chloride layer was dried and concentrated, and the obtained solid was vacuum dried for 8 hours to obtain 3.75 g of 2,4-difluorobenzenesulfinic acid having a melting point of 60 to 62 ° C. The yield was 42.1%.

IR (KBr) (cm ^-1 ): 3100,275
0, 2400, 1600, 1470, 1270, 114
0, 1080, 1060 NMR (CDCl ₃ ): δ 1.75 to 8.05 (m, 3H,
Aromatic ring), 10.79 (s, 1H, -SO 2 H)

Reference Example 2 Synthesis of 2,4-dichloro-3-methyl-benzenesulfonyl chloride In a 200 ml four-necked flask, 46.6 g of chlorosulfuric acid was charged, and 2,6-dichlorotoluene 16.1 was added with a dropping funnel.
g was added dropwise. At this time, the liquid temperature rose to 40 ° C. The disappearance of the raw materials was confirmed by gas chromatography and set as the end point. The reaction solution was slowly dropped into ice to decompose excess chlorosulfuric acid. The precipitated crystals were filtered out and dried. The product is distilled to a boiling point of 140 ° C / 1-2 mmHg (melting point 54-5
22.2 g of 2,4-dichloro-3-methyl-benzenesulfonyl chloride (5 ° C) was obtained. The yield was 86%.

Synthesis of 2,4-difluoro-3-methyl-benzenesulfonyl fluoride In a four-necked flask, 50 ml of sulfolane, potassium fluoride [Morita Chemical Co., Ltd., Spray Dry-KF] 23.2
g, tetraphenylphosphonium bromide 4.2 g, and toluene 50 ml were charged, and the mixture was stirred and heated in a nitrogen stream,
After azeotropic dehydration, toluene was distilled off. 26 g of 2,4-dichloro-3-methyl-benzenesulfonyl chloride was charged and reacted at 180 ° C. for 4 hours. After cooling to room temperature, the contents were extracted with ether, washed with water, separated and dried, ether was concentrated, and further distilled to give 2,4-difluoro-3-methyl-benzenesulfonyl fluoride having a boiling point of 110 ° C / 10 mmHg. 6 g was obtained. The yield was 74%.

Example 7 (Synthesis of sodium 2,4-difluoro-3-methylbenzenesulfinate) In a 2 l four-necked flask, 2,4
-Difluoro-3-methyl-benzenesulfonyl fluoride (60 g) and acetone (572 g) were charged and stirred, and sodium sulfite (72.1 g) and sodium hydrogencarbonate (48.0) were stirred.
A solution prepared by dissolving 5 g in 1573 ml of water was added dropwise.
Then, the temperature was raised to 50 ° C. and the reaction was performed for 2 hours. After cooling to room temperature, the organic matter was extracted from the contents with 1 l of methylene chloride, and the aqueous layer was concentrated with a rotary evaporator to obtain 160.2 g of a solid matter. The organic matter was dissolved in 1 liter of methanol and the inorganic matter was filtered off, and then concentrated to about 200 ml.
Further, the organic matter is dissolved with 1 l of ether, the insoluble matter is filtered off, and the ether layer is concentrated and dried to give 2,4-
59.5 g of sodium difluoro-3-methyl-benzenesulfinate was obtained. The yield was 97%.

IR (KBr) (cm ^-1 ): 1620, 158
0,1475,1420,1260,1210,113
0, 1080, 1020, 980, 940

Example 8 (Synthesis of 2,4-difluoro-3-methyl-benzenesulfinic acid) 260 ml of water was added to a 500 ml four-necked flask.
Sodium 2,4-difluorobenzenesulfinate 4
2.8 g was charged, stirred and cooled to 0 ° C. 20.9 g of concentrated hydrochloric acid was added dropwise thereto over 5 minutes. After stirring for 1 hour, the mixture was extracted twice with 800 ml of methylene chloride, and the methylene chloride layer was washed with 600 ml of saturated saline. The methylene chloride layer was dried and concentrated to give a melting point of 78-80 ° C.
4-difluoro-3-methyl-benzenesulfinic acid 3
2.36 g was obtained. The yield was 84%.

IR (KBr) (cm ^-1 ): 1620, 159
0, 1480, 1430, 1270, 1100, 108
_{0,1050,940,820 NMR (CDCl 3): δ10.41} (s, 1H, -SO 2
H), 7.61 (t, J = 7.32Hz, 1H, aromatic), 7.01 (t, J = 8.76Hz, 1H, aromatic), 2.23 (s, 3H, CH 3)

The 2,4-difluoro-3-methylbenzenesulfinic acid and its salts obtained in Examples 1 and 2 are novel compounds not described in the literature.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 43/225 A 8619-4H

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R represents a C _1-4 alkyl group or a C _1-4 alkoxy group, or a hydrogen atom, X represents an alkali metal atom or a hydrogen atom, and Y represents a chlorine atom or a bromine atom, 1 is 1 to 2, m is 0 to 3, and n is an integer of 1 to 4, provided that 1 + m + n is an integer of 2 to 5). The compound of the general formula (II) is characterized in that it undergoes a desulfinic acid reaction under conditions. (In the formula, R, Y, l, m and n are synonymous with the above), and a method for producing an aromatic fluorine compound. 2. 2,4-Difluoro-3-methylbenzenesulfinic acid and its alkali metal salt