JP2003335730A - Method for producing 2,4,5-trifluoro-3-methyl-6- nitrobenzoic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing 2,4,5-trifluoro-3-methyl-6- nitrobenzoic acid from a readily available 2,6-dichlorotoluene in short steps. <P>SOLUTION: The method for producing the 2,4,5-trifluoro-3-methyl-6- nitrobenzoic acid is carried out as follows. A compound represented by formula (1) is nitrated to provide a compound represented by formula (2), which is subsequently fluorinated to afford a compound represented by formula (3). The resultant compound is then reduced to provide a compound represented by formula (4). The Balz-Schiemann reaction is subsequently carried out to afford a compound represented by formula (5), which is then subjected to the Friedel-Crafts reaction with a compound represented by CY<SP>1</SP>Y<SP>2</SP>Y<SP>3</SP>-COX<SP>1</SP>(wherein, Y<SP>1</SP>, Y<SP>2</SP>and Y<SP>3</SP>are each a halogen atom or a hydrogen atom; and X<SP>1</SP>is a chlorine atom or a bromine atom) to afford a compound represented by formula (6). The resultant compound is subsequently nitrated to provide a compound represented by formula (7), which is then subjected to a haloform reaction. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid, which is useful as an intermediate for producing quinolone antibacterial agents and the like.

[0002]

2. Description of the Related Art From 2,6-dichlorotoluene to 2,4
As a method for producing 5-trifluoro-3-methyl-6-nitrobenzoic acid, 2,4,5-trifluoro-3-methylbenzoic acid is obtained from 2,6-dichlorotoluene, and then 2, 4,5-trifluoro-3-methyl-6
-Method of converting to nitrobenzoic acid (JP-A-62-215)
No. 572, EP 0641793) are known.

[0003]

However, the above method is a method which requires 11 steps to obtain a 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid derivative. Further, in the diazotization reaction performed during the process,
It is volatile and requires special consideration in the work environment.
There is a disadvantage that use -C ₄ H ₉ ONO. Therefore, this method was unsuitable as a manufacturing method on an industrial scale.

The present invention uses 2,6-dichlorotoluene in a shorter process and with a reagent which is easy to handle.
An object is to provide a method for producing 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid.

[0005]

The present invention provides a method for producing 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid according to the following production methods 1 to 3.

[Production Method 1] The compound represented by the following formula (1) is nitrated to obtain a compound represented by the following formula (2), and the compound represented by the formula (2) is fluorinated to obtain the following formula. The compound represented by the formula (3), the compound represented by the formula (3) is reduced to a compound represented by the following formula (4), and the compound represented by the formula (4) is subjected to the Baltzmann reaction. Is carried out to obtain a compound represented by the following formula (5), and a compound represented by the formula (5) and a compound represented by CY ¹ Y ² Y ³ —COX ¹ are subjected to Friedel-Crafts reaction to obtain a compound represented by the formula The compound represented by (5) is acylated to a compound represented by the following formula (6), and the compound represented by the formula (6) is nitrated to a compound represented by the following formula (7), A compound represented by the following formula (8), characterized in that the compound represented by the formula (7) is subjected to a haloform reaction. Process for producing 4,5-trifluoro-3-methyl-6-nitrobenzoic acid. However, Y ¹ , Y
² and Y ³ each independently represent a halogen atom or a hydrogen atom, and X ¹ represents a chlorine atom or a bromine atom.

[0007]

[Chemical 5]

[Production Method 2] A compound represented by the following formula (1) is subjected to a trichloromethylation reaction to obtain a compound represented by the following formula (9), and the compound represented by the formula (9) is hydrolyzed. By decomposing it to a compound represented by the following formula (10), the compound represented by the formula (1
In the compound represented by the formula (0), the nitration reaction and the esterification reaction are performed in any order to give the compound represented by the following formula (11), and then the compound represented by the formula (11) is fluorinated. A reaction is performed to obtain a compound represented by the following formula (12),
A compound represented by the following formula (13) is obtained by reducing the compound represented by the formula (12).
Represented by the following formula (8), characterized in that in the compound represented by the formula (13), the Baltzseemann reaction, the nitration reaction, and the hydrolysis reaction are performed in any order. A method for producing 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid. However, R shows the alcohol residue of ester.

[0009]

[Chemical 6]

[Production Method 3] A compound represented by the following formula (1) is subjected to a trichloromethylation reaction to obtain a compound represented by the following formula (9), and the compound represented by the formula (9) is hydrolyzed. By decomposing it to a compound represented by the following formula (10), the compound represented by the formula (1
The compound represented by the formula (11H) is nitrated to give a compound represented by the formula (11H), and the compound represented by the formula (11H) is subjected to a fluorination reaction and represented by the formula (12H). A compound represented by the formula (12H) is reduced to obtain a compound represented by the formula (13H):
In the compound represented by the formula (2), 2,4,5-trifluoro-3-methyl-6-nitro represented by the following formula (8), characterized in that the Baltzseemann reaction and the nitration reaction are performed in any order. Method for producing benzoic acid.

[0011]

[Chemical 7]

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the above production methods 1 to 3 are collectively referred to as the present production method. Moreover, the compound represented by Formula (1) is described as a compound (1). The same applies to compounds represented by other formulas. In this specification, the pressure is described as an absolute pressure.

In the present specification, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The organic group means a group in which a carbon atom is essential. The monovalent group means a group having one bond, and may be a monovalent organic group or a monovalent atom.

Y ¹ , Y ² and Y ³ represent a halogen atom or a hydrogen atom. As a halogen atom, a fluorine atom,
Represents a chlorine atom, a bromine atom, or an iodine atom.

R represents an alcohol residue of the ester,
A monovalent organic group is preferable, and a monovalent organic group having 1 to 30 carbon atoms is particularly preferable. As the monovalent organic group having 1 to 30 carbon atoms,
An alkyl group (for example, methyl group, ethyl group, propyl group, butyl group, isopropyl group, t-butyl group, pentyl group, isopentyl group, hexyl group, etc.), cycloalkyl group (for example, cyclopentyl group, cyclohexyl group, etc.). ), An aryl group or a substituted aryl group (eg, phenyl group, nitrophenyl group, methoxyphenyl group, etc.), an arylalkyl group or a substituted arylalkyl group (eg, benzyl group, methoxybenzyl group,
Dimethoxybenzyl group, nitrobenzyl group, etc. ) Is mentioned.

For the nitration reaction in the present production method, a generally known nitration reaction method can be applied as it is, and it is usually preferable to carry out the reaction with nitric acid or fuming nitric acid under acidic conditions. The dechlorination fluorination reaction in the present production method is performed by using a fluoride metal salt such as KF or HF.
Is preferably carried out by a method of fluorinating with. In the present production method, the reduction reaction for reducing a nitro group to an amino group is preferably carried out by a method such as a catalytic reduction method or a metal chloride / hydrochloric acid method. The nitration reaction, dechlorination fluorination reaction, and reduction reaction can be carried out, for example, by the same method as described in EP287951.

The Baltzseemann reaction used in the present production method is a known reaction and is a reaction for substituting a fluorine atom for an amino group. Specifically, in the presence of an acid such as fluoroboric acid, hexafluorophosphoric acid, or fluoroantimonic acid, a compound having an amino group is reacted with nitrite to form a diazonium salt, and then the diazonium salt is heated. It is a reaction of decomposing and converting an amino group portion into a fluorine atom. The Baltz-Schiemann reaction in this manufacturing method is
It is preferably carried out by the method described in P2879951 or the like.

In the present production method, the reaction of hydrolyzing the esterified carboxyl group to convert it into a carboxyl group can be carried out under known reaction conditions. In the reaction, the ester bond can be hydrolyzed by reacting with water under basic or acidic conditions. The esterification reaction and hydrolysis reaction are described in New Experimental Chemistry Lecture published by Maruzen Co., 14, P921-1062. Can be carried out under the reaction conditions described in the above.

First, the manufacturing method 1 in the present invention will be described. The compound (1) (2,6-dichlorotoluene) is a known compound, and a commercially available product can be obtained at low cost. In the production method 1 of the present invention, the compound (1) is nitrated to obtain the compound (2). When the compound (1) is nitrated,
A compound (2) (2,6-dichloro-3-nitrotoluene) having a nitro group substituted at the 3-position is produced. In the usual case, this reaction for nitrating the 3-position proceeds almost regioselectively, and a nitro group is introduced at the para-position of the chlorine atom.

The compound (2) is then fluorinated to obtain the compound (3). The fluorination reaction can be carried out by a known method known as a dechlorination fluorination reaction method. In the fluorination reaction of the compound (2), the two chlorine atoms are both substituted with the fluorine atom to produce the compound (3) (2,6-difluoro-3-nitrotoluene).

The compound (3) is then reduced to obtain the compound (4). The reduction reaction of compound (3) can be carried out by a known reduction reaction technique for reducing a nitro group to an amino group. In the reduction reaction of compound (3), compound (4) (3
-Amino-2,6-difluorotoluene) is produced.

The compound (4) is then converted into the compound (5) by the Baltz-Sieman reaction. In the Balzsiemann reaction of the compound (4), the amino group of the compound (4) is substituted with a fluorine atom to produce the compound (5).

Then, the compound (5) (2,3,6-trifluorotoluene) and the compound represented by CY ¹ Y ² Y ³ -COX ¹ are subjected to Friedel-Crafts reaction to acylate the compound (5). Compound (6) is obtained. The acylation reaction by the Friedel-Crafts reaction is a reaction of reacting an acid halide compound represented by CY ¹ Y ² Y ³ —COX ¹ in the presence of a Lewis acid such as aluminum chloride to acylate the compound (5). And can be carried out by a known method (for example, the method described in JP-A-2-184650 and the like).

Y¹, Y^Two, And Y^ThreeAre independent
Indicates a halogen atom or hydrogen atom, chlorine atom, odor
Elemental atoms or hydrogen atoms are preferred. X¹Is a chlorine atom
Or a bromine atom, and a chlorine atom is preferable. CY¹Y^Two
Y^Three-COX¹Specific examples of the compound represented by
H_ThreeCOCl, CH_TwoClCOCl, CHCl_TwoCOC
l, CCl_ThreeCOCl, CH_TwoBrCOCl, CHBr
_TwoCOCl, CBr_ThreeCOCl etc. are mentioned. This
In the Riedel-Crafts-acylation reaction, the compound (5)
Compound (6) having an acyl group introduced at the 5-position (5-acyl
-2,3,6-trifluorotoluene) is produced. 5
This reaction, which introduces an acyl group at the position
Almost regioselectively proceeds to the para position of the fluorine atom.
CY¹Y ^TwoY^ThreeA -CO- group can be introduced.

Next, the compound (6) is nitrated to obtain the compound (7). The nitration of compound (6) can be carried out in the same manner as the nitration of compound (1). In the nitration of the compound (6), a nitro group is introduced at the 4-position so that the compound (7) (5-acyl-2,3,6-trifluoro-4
-Nitrotoluene) is produced.

Next, the compound (7) is subjected to a haloform reaction to obtain the compound (8). The haloform reaction is a known method (for example, Chem. Rev. 1934, 15,
275. And the like. ) Can be carried out. For example, when all of Y ¹ , Y ² and Y ³ of the compound (7) are hydrogen atoms, the haloform reaction is carried out by a method of reacting a halogenating reagent such as hypochlorous acid in the presence of a base. Preferably. On the other hand, Y ¹ , Y ² ,
And when at least one of Y ³ is a halogen atom, a halogenating reagent may or may not be used,
A method of reacting in the presence of a base (for example, Japanese Patent Laid-Open No. 2-1
84650 and the like. It is preferable to carry out according to In the haloform reaction, CY ^{1 of} compound (7)
^{Y 2 Y 3 -C (O)} - moiety is a compound which is converted into HOCO- portion (8) so as to generate the (in this ^reaction, HCY ^{1 Y} 2 Y ³⁾ haloform is generated.

When a compound or by-product other than the object is produced in each reaction of the production method 1, a post-treatment for removing them may be carried out after each reaction step. Alternatively, they may be removed in the next step and removed after the appropriate reaction step or in the final product.

Next, the manufacturing method 2 will be described. In production method 2, compound (1) is subjected to a trichloromethylation reaction to obtain compound (9). The compound (1) is a known compound similar to the above, and a commercially available product can be obtained at low cost. The trichloromethylation reaction can be carried out by a known method and is preferably carried out by a method of reacting carbon tetrachloride in the presence of a Lewis acid such as aluminum chloride or aluminum chloride-sodium chloride complex.

In the trichloromethylation reaction of compound (1) (2,6-dichlorotoluene), compound (9) (2,6-dichloro-3-trichloromethyltoluene) having a trichloromethyl group introduced at the 3-position is To generate. The reaction of introducing a trichloromethyl group at the 3-position has low regioselectivity, and therefore, in the usual case, a by-product in which a trichloromethyl group is introduced at the 4-position, which is a regioisomer, is produced. The removal of the by-product may be carried out in the reaction product of the trichloromethylation reaction, or may be carried out in the reaction product of the latter reaction, and in the present invention, in the reaction product of the trichloromethylation reaction. It is preferable to carry out. The removal of this by-product can be easily carried out by distillation.

Next, the compound (9) is hydrolyzed to obtain the compound (10). The hydrolysis reaction can be carried out by a known method, for example, under acidic conditions or basic conditions,
It can be carried out by reacting with water. For these trichloromethylation reaction and hydrolysis reaction, known reaction conditions (for example, the conditions described in JP-A-3-161450) can be applied as they are.

Next, in the production method 2, the compound (1
In 0), the nitration reaction and the esterification reaction are performed in any order to give compound (11). That is, the compound (11) is obtained by a method of subjecting the compound (10) to a nitration reaction and then an esterification reaction, or a method of subjecting the compound (10) to an esterification reaction and then a nitration reaction. These esterification reaction and nitration reaction can be carried out by known methods (for example, Chem. Phar.
m. Bull. , 1982, 30, 3530. The method described in. ).

The esterification reaction is carried out by converting the carboxylic acid into R-OH.
(However, R represents the same group as the group in the compound (11), and examples thereof include the groups described above.) A method of dehydrating and condensing an alcohol compound represented by the formula (I), a carboxylic acid containing thionyl chloride, A method of reacting with a halogenating reagent such as phosphorus oxychloride or oxalyl chloride to form an acid halide, and then reacting with an alcohol compound represented by R-OH (wherein R has the same meaning as described above); An acid is reacted with a metal hydroxide such as lithium hydroxide, cesium hydroxide, sodium hydroxide or potassium hydroxide to give a metal salt of a carboxylic acid.
There may be mentioned a method of reacting with a halogenated compound represented by —X ² (wherein R has the same meaning as described above, X ² represents a halogen atom, and is preferably a chlorine atom).

The nitration reaction can be carried out in the same manner as the nitration reaction of compound (1). This nitration reaction can usually occur regioselectively at the para position of the chlorine atom.

Next, the compound (11) is then fluorinated to obtain the compound (12). The fluorination reaction can be carried out by the method of dechlorination fluorination reaction. Compound (11)
In the fluorination reaction of (2), two chlorine atoms are replaced with fluorine atoms to produce compound (12).

Next, the compound (12) is reduced to obtain the compound (13). The reduction reaction of compound (12) can be carried out by a known reduction reaction method of reducing a nitro group to an amino group. In the reduction reaction of compound (12), compound (1
3) (3-amino-4,6-difluoro-5-methylbenzoic acid ester) is produced.

Next, the compound (13) is subjected to the Baltzmann reaction, nitration reaction, and hydrolysis reaction in any order to obtain the compound (8). The Baltic-Siemann reaction, the nitration reaction, and the hydrolysis reaction may be performed in any order. The Baltzseemann reaction can be carried out by the method described above, and the amino group bonded to the benzene ring is replaced with a fluorine atom. The nitration reaction can be carried out by the method described above, and the nitro group bonded to the benzene ring is reduced to an amino group. The hydrolysis reaction can be carried out by the method described above, and the -COOR group bonded to the benzene ring is converted into a -COOH group.

Next, the manufacturing method 3 will be described. The production method 3 is the same as that of the compound (1
This is a method in which the esterification reaction of 0) and the hydrolysis reaction of the compound (13) are carried out. That is, it is a method of carrying out each reaction step while leaving the carboxyl group of the compound (10) as the carboxyl group.

The trichloromethylation reaction of the compound (1), the hydrolysis reaction of the compound (9) and the nitration reaction of the compound represented by the formula (10) in the production method 3 can be carried out in the same manner as in the production method 2. . Further, the fluorination reaction of compound (11H) and the reduction reaction of compound (12H) can also be carried out in the same manner as the corresponding reaction in Production method 2. In addition, either of the Baltziemann reaction and the nitration reaction in the compound (13H) may be carried out first, and can be carried out in the same manner as these reactions in the compound (13).

In addition, as a method within the scope of the same invention as Production Method 2 or Production Method 3, in each step of producing Compound (11) to Compound (8) in Production Method 2, or in Compound 3 in Production Method 3 In each step of producing 11H) to compound (8), there may be mentioned a method in which the esterification reaction of the carboxyl group is carried out, then the reaction of each step is carried out, and then the esterified carboxyl group is subjected to a hydrolysis reaction. In the production method 3 and the like, the method of producing without esterifying the carboxyl group is a method that can reduce the number of reaction steps, and thus is an efficient production method. However, esterification yields a reaction yield in the fluorination step. Has the advantage of being higher. Further, if the carboxyl group is esterified, purification after the reaction is easy to carry out, whereas if the carboxyl group remains as it is, the recovery rate tends to be low. Therefore, it is preferable to decide whether or not to carry out esterification of the carboxyl group in consideration of the number of steps and the yield.

The compound (8) obtained by the production method of the present invention is a compound useful as an intermediate of a quinolone antibacterial agent. The compound (8) can be converted into a cyclized product represented by the following formula (14), which is useful as an intermediate for the production of quinolone antibacterial agents, by the method described in EP0641793. However, R ¹ represents a monovalent organic group, and an alkyl group, a cycloalkyl group, a halogenated alkyl group, an aryl group,
Alternatively, a halogenated aryl group is preferable.

[0041]

[Chemical 8]

Another method for obtaining the above compound (14)
As the Y of compound (7)¹, Y ^Two, And Y^ThreeIs all
The following compound (16) is reacted with a compound that is a hydrogen atom.
Then, the following compound (15) is obtained, and the compound (15) is
According to the known method described in EP0641793
Thus, a method of converting to compound (14) can be exemplified. here
And R^TwoRepresents an ester residue of alcohol, and R and
A similar example is given. Specific examples of compound (16)
Is CH_Three(CH_Two)_nOCOO (CH_Two)_nCH
_Three(However, n represents an integer of 0 to 15.), PhOC
OOPh (however, Ph represents a phenyl group.
Mr. ), CH_Two= CHCH_TwoOCOOCH_TwoCH = CH
_Two, (CH_Three)_ThreeCOCOOC (CH_Three)_Three, PhCH
_TwoOCOOCH _TwoPh and the like can be mentioned. Compound (7)
The reaction to obtain the compound (15) is carried out under a basic condition.
It is a reaction in which (7) and the compound (16) are condensed. The
The condensation reaction transforms a compound with an active hydrogen atom into an ester.
It is known as a method for guiding, for example, Org. Syn
th. , 1967, 47, 20. According to the reaction conditions described in
Can be implemented.

[0043]

[Chemical 9]

[0044]

EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited to these. [Example 1] Production example of 2,6-dichloro-3-nitrotoluene (production example of compound (2) from compound (1)) 2,6-dichlorotoluene (400 g, 2.48 mo)
Fuming nitric acid (412 mL) was added dropwise to l) at 25 to 30 ° C., and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was added to ice water, extracted with diethyl ether, the diethyl ether layer was washed with 5% NaHCO3 solution, and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was vacuum dried. Two
6-Dichloro-3-nitrotoluene as yellow crystals 4
Obtained 58.3 g (90%). The ¹ H-NMR data was in agreement with the literature value.

[Example 2] Production example of 2,6-difluoro-3-nitrotoluene (Production example of compound (3) from compound (2)) 2,6-dichloro-3-nitrotoluene (3 obtained in Example 1)
KF (spray dried product, 535.5 g, 9.22 mol), 18-crow to 79.8 g, 1.84 mol)
n-6 (3.8 g, 14.2 mmol) and anhydrous dimethyl sulfoxide (1.8 L) were added, and the mixture was stirred at 160 ° C for 6 hours. After the reaction was completed, the reaction solution was added to ice water and extracted with diethyl ether. The diethyl ether layer was washed with water and dried over magnesium sulfate. After drying, the solvent was distilled off, and the residue was distilled under reduced pressure. 185.7 g (58%, boiling point 110-115 ° C / of 2,6-difluoro-3-nitrotoluene)
2.7 kPa) was obtained. ¹ H-NMR data were consistent with literature values.

[Example 3] Method for producing 3-amino-2,6-difluorotoluene (Example of producing compound (4) from compound (3)) 2,6-difluoro-3-nitrotoluene (167) obtained in Example 2 0.1 g, 0.97 mol) to acetic acid (840 m
L), 5% palladium carbon (16.8 g) was added, and
Contact hydrogenation was performed at room temperature under a pressure condition of 46 MPa. When the absorption of hydrogen was completed, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue is added to ice water,
Neutralized to pH 8 with NaHCO ₃ and extracted with dichloromethane. The obtained dichloromethane layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure.
99.5 g of 3-amino-2,6-difluorotoluene
(72%, boiling point 82 to 90 ° C./2.7 kPa) was obtained. ¹
1 H-NMR data were consistent with literature values.

[Example 4] Method for producing 2,3,6-trifluorotoluene (Example of producing compound (5) from compound (4)) 3-amino-2,6-difluorotoluene (95 g) obtained in Example 3 , 0.66 mol) was added with 266 mL of 42% borofluoric acid and 133 mL of water at 5 ° C., and further 10
A solution of NaNO ₂ (47.5 g, 0.69 mol) in water (95 mL) was added dropwise at a temperature of 0 ° C or lower, and the mixture was stirred at 0 ° C for 1 hour.
After completion of the reaction, the precipitated crystals were collected by filtration, and the obtained crystals were washed with ethanol-diethyl ether (1: 2) and diethyl ether in that order, and dried under vacuum at room temperature. 150.9 g (94%, melting point 112-114 ° C.) of 2,4-difluoro-3-methylbenzenediazotetrafluoroborate
Obtained.

The resulting 2,4-difluoro-3-
Methylbenzenediazotetrafluoroborate 150.
5 g (0.62 mol) was placed in a distillation container and heated slowly. Decomposition started at around 180 ° C, and at the same time, distillation of the product started. When the internal temperature reached 220 ° C, the distillation of the product was completed. The obtained distillate was distilled again at atmospheric pressure. 28.2 g of 2,3,6-trifluorotoluene
(31%, boiling point 90-92 ° C) was obtained. ¹ H-NMR data were consistent with literature values.

Example 5 2,3,6-trifluoro-5-
Production Example of Acetyltoluene (Production Example of Compound (6) from Compound (5)) Anhydrous AlCl ₃ (54.7 g, 858 mmol) and Example 4
2,3,6-trifluorotoluene obtained in (50 g, 3
42 mmol) at 70 ° C. with acetyl chloride (3
4.9 g, 445 mmol) was added dropwise over 1 hour, and 1
The mixture was stirred at 05 ° C for 1 hour. After completion of the reaction, the reaction solution was added to 7% hydrochloric acid at 5 ° C or lower, and extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure. 2,3,6-trifluoro-
53.5 g (83%, boiling point 70) of 5-acetyltoluene
˜75 ° C./2.7 kPa) was obtained. The ¹ H-NMR data was in agreement with the literature value.

[Example 6] 2,3,6-trifluoro-4-
Production Example of Nitro-5-acetyltoluene (Compound (6)
Example of the production of compound (7) from 2,3,6-trifluoro-5-acetyltoluene (45 g, 239 mmol) obtained in Example 5 with concentrated sulfuric acid (230
mL) at 0 ° C. and further KNO ₃ (30.0 g, 2
A solution of 87 mmol of concentrated sulfuric acid (80 mL) was added dropwise at 10 ° C or lower, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was added to ice water, extracted with diethyl ether, the organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After drying, the solvent was distilled off, and the obtained residue was purified by column chromatography. 2,3,6-trifluoro-4-
41.3 g (74%) of nitro-5-acetyltoluene
Obtained.

Example 7 2,4,5-trifluoro-3-
Production Example of Methyl-6-nitrobenzoic Acid (Production Example of Compound (8) from Compound (7)) 2,3,6-trifluoro-4-nitro-5 obtained in Example 6
10 to acetyltoluene (30 g, 129 mmol)
% Sodium hypochlorite aqueous solution (480 g) was added, and the mixture was heated under reflux for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature,
Add 0.65 g of sodium sulfite and stir, then add 50
% Sulfuric acid (25 mL) was added and stirred. Then, the mixture was extracted with diethyl ether, the ether layer was dried over magnesium sulfate, and the solvent was distilled off. 2,4,5-trifluoro-3-
Methyl-6-nitrobenzoic acid as yellow crystals 21.0
g (69%) was obtained.

¹ H-NMR (δ ppm, CD ₃ OD):
2.29 (3H, t, J = 2Hz). [Example 8] (2,4,5-trifluoro-3-methyl-6
Production Example of -Nitrobenzoyl) ethyl acetate (Reference example for production of compound (15) from compound (7)) 2,3,6-trifluoro-4-nitro-5 obtained in Example 7
-Acetyltoluene (10 g, 42.9) and diethyl carbonate (15.2 g, 127 mmol) in toluene 50.
Dissolve in mL and add NaH (content 60%, 2.
6 g, 64.3 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour and further heated under reflux for 1 hour. 3.5 after completion of reaction
The mixture was adjusted to pH 1 with% hydrochloric acid and extracted with ethyl acetate. The obtained extract layer was washed successively with saturated NaHCO ₃ , water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Then, the obtained residue was purified by silica gel chromatography to obtain 7.4 g (56%) of ethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl) acetate. ¹ H-NMR data were consistent with literature values.

Example 9 Production Example of 2,6-Dichloro-3-trichloromethyltoluene (Production Example of Compound (1) to Compound (9)) Aluminum tetrachloride (26.7 g,
0.2 mol) was added, 2,6-dichlorotoluene (16.10 g, 0.1 mol) was added dropwise under reflux, and the mixture was reacted for 30 minutes. After the reaction is completed, the reaction solution is cooled to room temperature,
The mixture was poured into 0 mL of ice water and extracted with dichloromethane. The obtained organic layer was washed with water, 5% sodium hydrogen carbonate solution and water in this order, and dried over magnesium sulfate. After drying, dichloromethane and carbon tetrachloride were distilled off under reduced pressure, and the residue was distilled under reduced pressure. 17.5 g (63%) of 2,6-dichloro-3-trichloromethyltoluene was obtained.

Example 10 Production Example of 2,4-dichloro-3-methylbenzoic acid (Production Example of Compound (10) from Compound (9)) 2,6-Dichloro obtained in Example 9 in 47 g of 95% sulfuric acid. -3-
Trichloromethyltoluene 17.5 g (63 mmol)
Was added dropwise at 40 to 45 ° C., and the mixture was stirred as it was for 2 hours. After the reaction was completed, it was poured into 300 mL of ice water, and the precipitated crystals were collected by filtration. The obtained crystals were washed with a small amount of cold water and then vacuum dried. 2,4-dichloro-3-methylbenzoic acid was added to 11.6
g (90%) was obtained.

[Example 11] Production example of ethyl 2,4-dichloro-3-methyl-5-nitrobenzoate (compound (10))
Example of production of compound (11) from 2,4,2-dichloro-3-methylbenzoic acid 1 obtained in Example 10
0.6 g (52 mmol) was added to 16 g of concentrated sulfuric acid, and 2.9 g of fuming nitric acid was further added dropwise at 40 ° C or lower. Then 4
Stir at 0 ° C. for 3 hours, pour the reaction into 150 mL of ice water,
The precipitated crystals were collected by filtration, and the obtained crystals were washed with a small amount of cold water and dried in vacuum. 2,4-dichloro-3-methyl-5
10.5 g (81%) of nitrobenzoic acid was obtained.

Next, 2,4-dichloro-3-methyl-5
-Nitrobenzoic acid 10.0g (40mmol) was dissolved in ethanol 100mL, concentrated sulfuric acid 800mg was added, and the reaction liquid was heated and refluxed for 12 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed successively with 5% sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. Then, the ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. 2,4-
8.7 g (78%) of ethyl dichloro-3-methyl-5-nitrobenzoate was obtained.

Example 12 Production Example of Ethyl 2,4-difluoro-3-methyl-5-nitrobenzoate (Compound (1
Production Example of Compound (12) from 1)) To a solution of ethyl 2,4-dichloro-3-methyl-5-nitrobenzoate (8.3 g, 30 mmol) obtained in Example 11 in sulfolane 45 mL, KF (spray dried product, 7.1
g, 120 mmol) was added, and the mixture was heated with stirring at 120 ° C. for 3 hours. After completion of the reaction, pour the reaction solution into 150 mL of ice water,
After adding ethyl acetate and stirring sufficiently, it was filtered through Celite. Then, the organic layer of the filtrate was separated, washed successively with water and 5% sodium hydrogen carbonate and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography. 4.2 g of ethyl 2,4-difluoro-3-methyl-5-nitrobenzoate
(57%) obtained.

Example 13 Production Example of Ethyl 5-amino-2,4-difluoro-3-methylbenzoate (Compound (1
Production Example of Compound (13) from 2)) Ethanol 2,4-difluoro-3-methyl-5-nitrobenzoate (4.2 g, 17 mmol) obtained in Example 12 was added to a solution of Raney nickel (Kawaken Fine Chemicals) in 40 mL of ethanol. NDT-65, 50% water content, 820 mg)
Was added, and catalytic reduction was performed at room temperature for 6 hours under a hydrogen pressure condition of 0.5 MPa. After completion of the reaction, the reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography. 3.6 g (98%) of ethyl 5-amino-2,4-difluoro-3-methylbenzoate
Obtained.

Example 14 2,4,5-Trifluoro-3
-Production Example of Ethyl Methyl Benzoate (Baltzsiemann Reaction Example of Compound (13)) The ethyl 5-amino-2,4-difluoro-3-methylbenzoate (3.6 g, 17 mmol) obtained in Example 13 was used as 42
% Borofluoric acid (24 mL), and sodium nitrite (1.7 g, 25 mmol) in water (3 m) at -3 to 0 ° C.
L) solution was added dropwise over 30 minutes, and the mixture was further stirred at 0 to 5 ° C for 3 hours. After the reaction was completed, the precipitated crystals were filtered, washed with a small amount of ethanol, and dried in vacuum for 1 day. 4.3 g (81%) of 2,4-difluoro-3-methyl-5-ethoxycarbonylbenzenediazotetrafluoroborate
Obtained.

The resulting 2,4-difluoro-3-
Methyl-5-ethoxycarbonylbenzene diazotetrafluoroborate 4.3 g (14 mmol) and sea sand (5
(0-80 mesh) was placed in a distillation flask and slowly heated with a gas burner. When the generation of gas subsided, heating was stopped, and after cooling, the flask and the receiver were washed with methylene chloride, the obtained methylene chloride layer was washed with water, and then dried with magnesium sulfate. After drying, the solvent was distilled off, and the residue was separated and purified by silica gel chromatography. 2,4,5
2.1 g of ethyl trifluoro-3-methylbenzoate
(70%) was obtained.

Example 15 2,4,5-Trifluoro-3
Production Example of Ethyl -methyl-6-nitrobenzoate Ethyl 2,4,5-trifluoro-3-methylbenzoate (2.1 g, 14 mmol) obtained in Example 14 was added to sulfuric acid (4.
2 g) To the solution, 790 mg of fuming nitric acid was added dropwise at 20 to 25 ° C, and the mixture was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction solution was poured into 40 mL of ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with 5% sodium hydrogen carbonate and saturated saline and dried over magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography. Two
1.4 g (54%) of ethyl 4,5-trifluoro-3-methyl-6-nitrobenzoate was obtained.

Example 16 2,4,5-Trifluoro-3
-Methyl-6-nitrobenzoic acid (Production Example of compound (8)) 2,4,5-trifluoro-3-methyl-obtained in Example 15
Ethyl 6-nitrobenzoate (1.4 g, 5.32 mmo
1) was dissolved in 20 mL of ethanol, 1 mol / L NaOH solution (8 mL, 8.0 mmol) was added at 5 ° C., and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH 1 with concentrated hydrochloric acid, ethanol was distilled off under reduced pressure, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. 1.1 g (91%) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid was obtained as yellow crystals.
¹ H-NMR data was consistent with that of Example 7.

[0063]

EFFECTS OF THE INVENTION According to the production method of the present invention, 2,4-dichlorotoluene is inexpensive and easily available to give 2,4
5-Trifluoro-3-methyl-6-nitrobenzoic acid can be prepared. The present manufacturing method is an industrially useful manufacturing method that is free from problems in the working environment and can be carried out at a lower manufacturing cost than conventional methods.

Claims (4)

[Claims] 1. A compound represented by the following formula (1) is nitrated to obtain a compound represented by the following formula (2), and the compound represented by the formula (2) is fluorinated to obtain the following formula (3). A compound represented by the following formula (4) is prepared by reducing the compound represented by the formula (3).
The compound represented by the formula (4) is subjected to a Baltzmann reaction to obtain the compound represented by the following formula (5), and the compound represented by the formula (5) and CY ¹ Y ² Y ³
A compound represented by formula (5) is acylated by a Friedel-Crafts reaction with a compound represented by —COX ¹ to give a compound represented by formula (6) below, which is represented by formula (6) 2,4 represented by the following formula (8), characterized in that the compound represented by the following formula (7) is nitrated to a compound represented by the following formula (7), and the compound represented by the formula (7) is subjected to a haloform reaction. ，
A method for producing 5-trifluoro-3-methyl-6-nitrobenzoic acid. However, Y ¹ , Y ² , and Y ³ each independently represent a halogen atom or a hydrogen atom, and X ¹ represents a chlorine atom or a bromine atom. [Chemical 1] 2. A compound represented by the following formula (5) and CY ¹ Y ²
A compound represented by the formula (5) is acylated by a Friedel-Crafts reaction with a compound represented by Y ³ —COX ¹ to give a compound represented by the following formula (6):
The compound represented by the formula (7) is nitrated to a compound represented by the formula (7), and the compound represented by the formula (7) is haloformated. , 4,
A method for producing 5-trifluoro-3-methyl-6-nitrobenzoic acid. However, Y ¹ , Y ² , and Y ³ each independently represent a halogen atom or a hydrogen atom. [Chemical 2] 3. A compound represented by the following formula (1) is subjected to a trichloromethylation reaction to obtain a compound represented by the following formula (9), and the compound represented by the formula (9) is hydrolyzed. A compound represented by the following formula (10), wherein the compound represented by the formula (10) is subjected to a nitration reaction and an esterification reaction in any order to obtain a compound represented by the following formula (11): A compound represented by the formula (11) is subjected to a fluorination reaction to obtain a compound represented by the following formula (12), and the compound represented by the formula (12) is reduced to obtain a compound represented by the following formula (13). A compound represented by the formula (13), wherein the Baltzmann reaction, the nitration reaction, and the hydrolysis reaction are carried out in any order. Process for producing 4,5-trifluoro-3-methyl-6-nitrobenzoic acid. However, R shows the alcohol residue of ester. [Chemical 3] 4. A compound represented by the following formula (1) is subjected to a trichloromethylation reaction to obtain a compound represented by the following formula (9), and the compound represented by the formula (9) is hydrolyzed. A compound represented by the following formula (10), nitrating the compound represented by the formula (10) into a compound represented by the following formula (11H), and then a compound represented by the formula (11H) Is subjected to a fluorination reaction to obtain a compound represented by the following formula (12H), and the compound represented by the formula (12H) is reduced to give the compound represented by the following formula (13
H), the compound represented by the formula (13H), wherein the Balts-Sieman reaction and the nitration reaction are carried out in any order. Process for producing 4,5-trifluoro-3-methyl-6-nitrobenzoic acid. [Chemical 4]