JP3225361B2 - Method for producing aromatic fluorine compound and fluorine-containing benzenesulfinic acid derivative as raw material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process 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 its production. The present invention relates to a fluorine-containing benzenesulfinic acid derivative useful as a raw material.

[0002]

2. Description of the Related Art Conventionally, a method of obtaining an aromatic fluorine compound of the general formula (II) by a Bartz-Siemann reaction of an amino-substituted aromatic compound is known. High hydrofluoric acid had to be used.

Also, a method of reacting pentafluorobenzenesulfinyllithium with silver nitrate and obtaining pentafluorobenzene by a desulfinic acid reaction [Aust.
J. Chem. , 32 (11), 2381-93 (19
79)] is known. However, the above method
Even when expensive lithium salts and silver salts are used, the yield is not good, and it has not been sufficient as an industrial method.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a process 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 inventors of the present invention have conducted intensive studies on an industrial method for producing an aromatic fluorine compound. Unexpectedly, aromatic sulfinic acid can be easily removed by the method of the present invention. The inventors have found 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 same has completed the present invention.

That is, the present invention provides a compound represented by the general formula (I)

[0007]

Embedded image

(Wherein R is a C _1-4 alkyl group or C
_1-4 alkoxy or hydrogen,, X represents a sodium atom or a potassium atom, Y represents a chlorine atom or a bromine atom, l is 1 to 2, m is 0 to 3, n is 1 to
Indicates an integer of 4. (Where l + m + n is an integer of 2 to 5)

Wherein the aromatic sulfinic acid derivative represented by the formula is subjected to desulfinic acid reaction under acidic to basic conditions.

Formula (II)

[0011]

Embedded image

(Wherein R, Y, l, m and n are as defined above)

And a fluorine-containing benzenesulfinic acid derivative useful as a raw material for producing the aromatic fluorine compound.

Hereinafter, the present invention will be described in detail.

Aromatic sulfinic acid derivative (I) as raw material
Can be obtained by chlorosulfonating chlorobenzenes (III) and subjecting the obtained aromatic sulfonyl chloride derivative to fluorine substitution 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]

Embedded image

(Wherein, R, X, Y, 1, m, and n are the same as described 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, and X represents a sodium atom or a potassium atom. Wherein Y represents a chlorine atom or a bromine atom, l is an integer of 1 to 2, m is an integer of 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 the formula (1) may be used.

Specifically, sodium 2,4-difluorobenzenesulfinate, potassium 2,4-difluoro-3-methylbenzenesulfinate, sodium 2,4-difluoro-5-methylbenzenesulfinate, 4,4
Sodium 5-difluoro-2-methylbenzenesulfinate, sodium 2,6-difluoro-4-methylbenzenesulfinate, 2,4,6-trifluoro-3-
Examples thereof include sodium methylbenzenesulfinate, sodium 2,4-difluoro-5-methoxybenzenesulfinate, sodium 3-chloro-2,4-difluorobenzenesulfinate and the like.

As described above, the general formula (I) (wherein
R represents an alkyl group or an alkoxy group C _1-4 of C _1-4 or a hydrogen atom,, X represents a sodium atom or a potassium <br/> atom, Y represents a chlorine atom or a bromine atom, l Represents an integer of 1-2, m represents an integer of 0-3, and n represents an integer of 1-4. However,
l + m + n is an integer of 2 to 5), and can be used as a raw material of the present invention, and the present invention is not limited thereto.

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 appropriate for performing the reaction efficiently. As a solvent used in the reaction, an aqueous solution of sulfuric acid having an appropriate concentration is used under acidic conditions, and dimethylimidazolidinone (DMI), dimethylacetamide (DMAC), dimethylformamide (DMM) is used under basic conditions.
It is preferable to use an aprotic polar solvent such as F) and dimethyl sulfoxide (DMSO). Under basic conditions, a base is used as a catalyst, and examples of suitable bases include sodium carbonate, potassium carbonate, and potassium fluoride. The base can be used in a wide range from a catalytic amount to an equivalent or more, preferably about 0.05 to 1 equivalent. The desulfinic acid reaction proceeds in a reaction system in which only a fluorinated benzenesulfinic acid derivative as a raw material or a solvent is added thereto, but the reaction is preferably performed under acidic or basic conditions. . This reaction may be performed in an inert gas atmosphere.

[0023]

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, the aromatic fluorine compound (II) can be obtained in good yield without using hydrofluoric acid having a high corrosive property, an intermediate of a dangerous diazonium salt, or an expensive lithium salt or silver salt as in the prior art. It is an industrially valuable method.

[0024]

The present invention will be described more specifically with reference to the following examples.

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

GC / MS: m / z = 114 (M ⁺ )

Example 2 A 10 ml eggplant-shaped flask was charged with dimethylimidazolidinone (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), stirred with a magnetic stirrer, heated to an oil bath temperature of 200 ° C., and reacted for 1 hour. After cooling to room temperature, the mixture was extracted with 30 ml of xylene. After filtration, xylene was added to make about 50 ml. About 0.5 g of the internal standard toluene was accurately added, and 1 μl was analyzed by GC.
From the previously prepared calibration curve, the yield of 1,3-difluorobenzene was 77.0%.

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

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

Example 5 0.17 g (0.001 mol) of 2,4-difluorobenzenesulfinic acid was charged into a 10 ml tester, 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 the internal standard toluene were accurately added, and 1 μl of the mixture was analyzed by GC. From the calibration curve prepared in advance, the yield of 1,3-difluorobenzene was 30%.

Example 6 150 ml of dimethylimidazolidinone (DMI), 9.6 g (0.05 mol) of 2,4-difluoro-3-methylbenzenesulfinic acid, 5.3 g of sodium carbonate (500 ml) were placed in a 500 ml four-necked flask. (0.05 mol), stirred, heated to an oil bath temperature of 200 ° C., and reacted for 1.5 hours. After cooling to room temperature, extracted with ether, filtered,
It was washed with water to remove DMI. After drying the ether layer, the ether was rectified and distilled off 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 Dimethylformamide (D) was placed in a 200 ml four-necked flask.
MF) (17 g, 0.23 mol) was added, and sulfuryl chloride (28 g, 0.21 mol) was added dropwise at 5 to 20 ° C. over 30 minutes. After the reaction as it was for 2 hours, 27 g (0.20 mol) of 60% fuming sulfuric acid was added dropwise at 17 to 20 ° C. over 30 minutes. Then 21 g of 1,3-dichlorobenzene
(0.14 mol) was added dropwise. The temperature was raised to 100 ° C. and reacted for 2.5 hours. After cooling to room temperature, the mixture was poured into 250 g of ice with stirring. The precipitated crystals were collected by filtration, dissolved in 250 ml of ether, and washed with 100 ml of water. The ether layer was dried and concentrated to obtain 29.3 g of a crude product (crude yield: 85.2%). This 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. The 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 of sulfolane were placed.
g, potassium fluoride (Morita Chemical Co., Ltd., Spray Dry-KF) 15.1 g (0.26 mol) and 2.72 g (0.065 mol) of tetraphenylphosphonium bromide 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,
After dissolving the contents in 120 ml of toluene and filtering solids, the mixture was concentrated and subjected to simple distillation to thereby give fraction--1 of 8.74.
g (purity, 94.4%) and 17.03 g (purity, 6.9%) of fraction-2 were obtained. The net yield is 74.0.
%Met. By rectification, 29.5%
4-Difluorobenzenesulfonyl fluoride was obtained.
The boiling point was 58-59 ° C / 4 mmHg.

Synthesis of sodium 2,4-difluorobenzenesulfinate In a 500 ml four-necked flask, 100 ml of acetone, 2,2
9.78 4-Difluorobenzenesulfonyl fluoride
g (0.05 mol) was stirred and stirred, and a solution of 12.48 g (0.1 mol) of sodium sulfite and 8.32 g (0.13 mol) of sodium hydrogen carbonate dissolved in 270 ml of water was added dropwise. . Next, the temperature was raised to 50 ° C., and the reaction was performed for 2 hours. After cooling to room temperature, the contents were
After extracting an organic substance with 70 ml, the aqueous layer was freeze-dried to obtain 23.30 g of a solid substance. Methanol 17
After dissolving the organic substance in 0 ml and filtering off the inorganic substance, about 4
It was concentrated to 0 ml. The organic matter was further dissolved in 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 were placed in a 100 ml four-necked flask.
(0.05 mol), stirred and cooled to 0 ° C.
Here, 5.21 g (0.05 mol) of concentrated hydrochloric acid was added dropwise over 5 minutes. After stirring for 1 hour, methylene chloride 20
The mixture was extracted twice with 0 ml, and the 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 1.75-8.05 (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 16.1 g of 2,6-dichlorotoluene 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 the end point was obtained. The reaction solution was slowly dropped into ice to decompose excess chlorosulfuric acid. The precipitated crystals were separated by filtration and dried. The product is distilled and has a boiling point of 140 DEG C./1 to 2 mmHg (mp.
5 ° C.) to obtain 22.2 g of 2,4-dichloro-3-methyl-benzenesulfonyl chloride. The yield was 86%.

Synthesis of 2,4-difluoro-3-methyl-benzenesulfonyl fluoride In a four-necked flask, 50 ml of sulfolane, potassium fluoride [Spray Dry-KF, manufactured by Morita Chemical Co., Ltd.] 23.2
g, 4.2 g of tetraphenylphosphonium bromide and 50 ml of toluene, and 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 content was extracted with ether, washed with water, separated and dried, the ether was concentrated, and further distilled to obtain 2,4-difluoro-3-methyl-benzenesulfonyl fluoride having a boiling point of 110 ° C / 10 mmHg. 6 g were 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 hydrogen carbonate (48.0) were added.
A solution of 5 g in 1573 ml of water was added dropwise.
Next, the temperature was raised to 50 ° C., and the reaction was performed for 2 hours. After cooling to room temperature, the contents were extracted with 1 l of methylene chloride, and the organic layer was extracted. The aqueous layer was concentrated by a rotary evaporator to obtain 160.2 g of a solid. The organic matter was dissolved in 1 liter of methanol, the inorganic matter was filtered off, and then concentrated to about 200 ml.
Further, the organic matter was dissolved in 1 l of ether, the insoluble matter was filtered off, and the ether layer was concentrated and dried to give 2,4-
59.5 g of sodium difluoro-3-methyl-benzenesulfinate were 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) In a 500 ml four-necked flask, 260 ml of water,
Sodium 2,4-difluorobenzenesulfinate 4
2.8 g was charged, stirred and cooled to 0 ° C. To this, 20.9 g of concentrated hydrochloric acid was added dropwise 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 mp of 78-80 ° C.
4-difluoro-3-methyl-benzenesulfinic acid 3
2.36 g were obtained. The yield was 84%.

IR (KBr) (cm ^-1 ): 1620, 159
0, 1480, 1430, 1270, 1100, 108
0,1050,940,820 NMR (CDCl ₃ ): δ 10.41 (s, 1H, —SO ₂
H), 7.61 (t, J = 7.32 Hz, 1H, aromatic ring), 7.01 (t, J = 8.76 Hz, 1H, aromatic ring), 2.23 (s, 3H, CH ₃ )

The 2,4-difluoro-3-methylbenzenesulfinic acid and salts thereof obtained in Examples -7 and -8 are novel compounds not described in any literature.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI C07C43 / 225 C07C43 / 225A (56) References JP-A-59-95284 (JP, A) Fluorine Chem. (1975), 6 (5), 437-448 Aust. J. Chem. (1979), 32 (11), 2382-2393 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 313/00 C07B 35/00 C07C 17/00 C07C 25/00 C07C 41/00 C07C 43 / 00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (I) (Wherein, R represents an alkyl group or an alkoxy group C _1-4 of C _1-4 or a hydrogen atom,, X represents a sodium atom or <br/> potassium atom, Y is a chlorine atom or a bromine atom Wherein 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. General formula (II), characterized by performing a desulfinic acid reaction under basic conditions. (Wherein, R, Y, 1, m, and n have the same meanings as described above). 2. A sodium or potassium salt of 2,4-difluoro-3-methylbenzenesulfinic acid. 3. The method according to claim 1, wherein the desulfinic acid reaction is carried out in an aprotic polar solvent under basic conditions.
The method for producing an aromatic fluorine compound according to the above.