JPH0977716A - Production of 4-fluorosalicylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce 4-fluorosalicylic acid useful as an intermediate, etc., for a pharmaceutical or an agrochemical agent from an easily available raw material in a safe and simple manner at high yield and selectivity by reacting 2,4- difluorobenzoic acid with an alkali metal hydroxide in a specific aprotic polar solvent. SOLUTION: A compound of formula III is produced by reacting (B) a compound of formula II (X<1> and X<3> are each H or a halogen; X<2> is H, chlorine or bromine) with (C) an alkali metal hydroxide such as sodium hydroxide in (A) a compound (A2 ) of formula I [A is CH<2> (A1 ) or a group of the formula NR' (R' is a lower alkyl); R and W are each R'; X is H or R' when A is A', and R' when A is A2 ; W and X can bind together to form a lower alkylene or they can bind together with NCA to form a 5-7 membered ring], or a compound of the formula YQZ (Q is SO or SO2 ; Y and Z are each a lower alkyl, or Y and Z can bond together to form a lower alkylene or they can bond together with Q to form a 5-7 membered ring) as a solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for industrially producing 4-fluorosalicylic acids, which are useful as intermediates for medical and agricultural chemicals.

[0002]

2. Description of the Related Art Generally, when a benzoic acid (2,4-difluorobenzoic acid) having a fluorine atom at least at the 2- and 4-positions is reacted with an alkali metal hydroxide in an aqueous solution, the fluorine atom at the 4-position is Is preferentially hydroxylated (for example, JP-A-1-2686).
No. 62).

On the other hand, for example, 4-fluorosalicylic acid has hitherto been obtained by the Balz-Schiemann reaction [Helv. Chim. Acta., Vol. 33, 126] of 4-aminosalicylic acid.
9 (1950); Chem.Abst., Vol.63,16255; Chem.Abst., Vol.6
1,11934; Chem. Abst., Vol. 60, 14426], 4-fluoro-
Oxidation of 2-hydroxytoluene (Chem. Abst., Vol.60,16
38), Kolbe-Schmitt reaction of 3-fluorophenol [J. Org. Chem., Vol. 19, 510 (195
4)], a method of oxidizing 4-fluoro-2-hydroxybenzaldehyde produced by the Reimer-Tiemann reaction of 3-fluorophenol [J.
Chem. Soc., 1632 (1929)] and the like.

However, all of these methods have the drawbacks that they are industrially difficult to carry out, such as the Balz-Siemann reaction, that there are many steps, and that raw material procurement or production is not easy. However, it is disadvantageous and unpractical to apply it as an industrial production method of 4-fluorosalicylic acid or its analogs.

[0005]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a method for producing 4-fluorosalicylic acids, which is simple and industrially safe and in good yield, using readily available raw materials. is there.

[0006]

As a result of intensive studies to solve the problems of the conventional method, the present inventors have surprisingly found that 2,4-difluoro using a specific aprotic polar solvent. When a benzoic acid and an alkali metal hydroxide are reacted, the fluorine atom at the 2-position is selectively hydroxylated.
-Fluorosalicylic acids can be obtained, industrially easily available 2,4-difluorobenzoic acids can be used as a raw material, and the selectivity of the reaction of the 2-position fluorine atom is high, resulting in an advantage in yield. Further, they have found that the reaction used is safe without danger of explosion, and the number of steps is short, and thus the present invention has been completed.

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

[0008]

Embedded image Wherein A is a group —CH ₂ — or a group —NR′— (in the formula,
R 'represents a lower alkyl group. ), R represents a lower alkyl group, W represents a lower alkyl group, X represents a hydrogen atom or a lower alkyl group when A is a group -CH _2- ,
Is a lower alkyl group when is a group -NR'-, W and X combine with each other to form a lower alkylene group, and -N-
It may be a 5- to 7-membered ring together with CA-. ]

A compound represented by the general formula

[0010]

[Chemical 6] (In the formula, Q represents a group —SO— or a group —SO ₂ —;
And Z each independently represent a lower alkyl group, Y and Z are joined to form a lower alkylene group together, group -SO- or a group -SO ₂ - with may be a 4-6 membered ring. )

Using at least one selected from the compounds represented by

[0012]

[Chemical 7] (In the formula, X ¹ and X ³ each independently represent a hydrogen atom or a halogen atom, and X ² represents a hydrogen atom, a chlorine atom, or a bromine atom.)

By reacting 2,4-difluorobenzoic acid represented by the formula with an alkali metal hydroxide, a general formula

[0014]

Embedded image (In the formula, X ¹ , X ² and X ³ have the same meanings as described above.)

The above object has been achieved by providing a method for producing 4-fluorosalicylic acids represented by:

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The method of the present invention uses, as a solvent, at least one selected from the compounds represented by the above general formula [Chemical formula 5] and the compounds represented by the general formula [Chemical formula 6].
After the 2,4-difluorobenzoic acid represented by the general formula [Chemical formula 7] is reacted with an alkali metal hydroxide, a general post-treatment such as acid precipitation is performed to obtain the compound represented by the general formula [Chemical formula 8] The fluorosalicylic acids are taken out, the solvent used characterizing the process according to the invention.

The compound used as a solvent in the method of the present invention is a compound represented by the general formula [Chemical formula 5] or a compound represented by the general formula [Chemical formula 6]. Here, in the general formula [Chem. 5], the lower alkyl group represented by the substituents R, R ′, W, and X each independently has 1 to 4 carbon atoms.
An alkyl group, specifically, for example, a methyl group, an ethyl group,
An n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and the like, and the lower alkylene group formed by the substituents W and X being bonded to each other means a carbon number of 2 to 4
Is an alkylene group, specifically, an ethylene group, a trimethylene group, a tetramethylene group or the like. Further, in the general formula [Chemical Formula 6], the lower alkyl group represented by the substituents Y and Z each independently represents an alkyl group having 1 to 4 carbon atoms, specifically, for example, a methyl group, an ethyl group, n- A lower alkylene group which is a propyl group, an isopropyl group, an n-butyl group, an isobutyl group or the like and which is formed by the substituents Y and Z being bonded to each other is an alkylene group having 3 to 5 carbon atoms, specifically, Examples thereof include a trimethylene group, a tetramethylene group, a pentamethylene group and the like. The above general formula [Chemical formula 5]
Among the compounds represented by the formula or the compounds represented by the general formula [Chemical formula 6], preferable compounds as the solvent in the method of the present invention are:
1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6
-Tetrahydro-2 (1H) -pyrimidinone, dimethyl sulfoxide, N, N-diethylacetamide, 1,
1,3,3-tetramethylurea, tetramethylene sulfone, and dimethyl sulfone. The amount of the solvent used is not limited as long as it can be stirred at the time of reaction, but is usually 0.1 to 6 liters, preferably 0.1 to 1 mol of 2,4-difluorobenzoic acid as a raw material described later. 3 to 3
Used in the l range.

The 2,4-difluorobenzoic acid used as a raw material in the method of the present invention may be any compound represented by the general formula [Chem. 7]. Here, in the formula, the groups represented by X ¹ and X ³ are each independently a halogen atom including a chlorine atom, a bromine atom or a fluorine atom or a hydrogen atom, and the group represented by X ² is a chlorine atom. It may be an atom, a bromine atom or a hydrogen atom. Examples of such 2,4-difluorobenzoic acids include 2,4-difluorobenzoic acid,
Examples include 2,3,4-trifluorobenzoic acid, 2,4,6-trifluorobenzoic acid, 5-chloro-2,4-difluorobenzoic acid and 3,5-dichloro-2,4-difluorobenzoic acid. You can do it. These 2,4-difluorobenzoic acids are obtained by, for example, hydrolyzing 2,4-difluorobenzoic acid fluorides obtained by reacting corresponding readily available 2,4-dichlorobenzoic acid chlorides with potassium fluoride. It can be easily produced in high yield by the method described above.

The alkali metal hydroxides used in the method of the present invention include lithium hydroxide, sodium hydroxide,
Examples thereof include potassium hydroxide and the like, among which sodium hydroxide and lithium hydroxide are preferable, and sodium hydroxide is particularly preferable. The amount of alkali metal hydroxide used is 2,
It may be in the range of 2 to 6 moles, preferably 3 to 5 moles, per mole of 4-difluorobenzoic acid.

The reaction temperature can be arbitrarily selected within the temperature range of the boiling point of the solvent or lower, but is preferably from 80 to 200 ° C, more preferably from 100 to 160 ° C.

The reaction time is usually about 2 to 12 hours.

The pressure during the reaction may be any of normal pressure, increased pressure, and reduced pressure.

The target 4-fluorosalicylic acid can be taken out from the reaction solution after the reaction by a general method, for example, by acidifying the reaction solution after the reaction and then filtering it or after extracting the solvent. It can be taken out by concentrating the extraction solvent. Further, at the end of the reaction, the produced alkali metal salt of the target substance can be filtered out and separated from the solvent, and then removed by acid precipitation. The obtained 4-fluorosalicylic acids are
It can be used as a raw material for the next step without purification. Further, it can be purified by recrystallization with an alcohol-water mixed solvent or the like.

The method of the present invention may be carried out when the amount of water in the reaction system is 15% or less of the solvent used at the time of charging the raw materials, but the yield of the desired product and the reaction rate From the viewpoint, it is preferable that the condition is substantially anhydrous.

Specific examples of the 4-fluorosalicylic acids represented by the general formula [Chemical Formula 8] obtained by the method of the present invention include 4-fluorosalicylic acid, 3,4-difluorosalicylic acid, 4,6-difluorosalicylic acid and 5 Examples thereof include -chloro-4-fluorosalicylic acid and 3,5-dichloro-4-fluorosalicylic acid.

In addition, Example 13 and Example 14, which will be described later,
3,4-difluorosalicylic acid (melting point 1 produced according to the method of the present invention in Examples 15 and 16)
76.8 to 178.2 ° C), 5-chloro-4-fluorosalicylic acid (melting point 200.0 to 201.2 ° C), 3,5
-Dichloro-4-fluorosalicylic acid (melting point 119.4
˜120.9 ° C.) and 4,6-difluorosalicylic acid (melting points 180.8-183.4 ° C.) are novel compounds not described in the literature.

[0027]

The present invention will be described below more specifically with reference to examples and comparative examples.

Example 1 31.6 g (0.2 mol) of 2,4-difluorobenzoic acid was added to a 1-liter four-necked flask equipped with a thermometer, a stirrer and a reflux condenser, and powdery 99% sodium hydroxide 32. 3 g (0.
8 mol) and 1,3-dimethyl-2-imidazolidinone (400 ml) were charged, and they were reacted by stirring at 130 ° C. for 4 hours. After collecting 300 ml of 1,3-dimethyl-2-imidazolidinone under reduced pressure, the remaining reaction solution was added dropwise to 2.5 l of a 3% hydrochloric acid aqueous solution at room temperature. After cooling in an ice bath,
The obtained crystals were filtered, washed with water and dried to obtain 29.7 g of 4-fluorosalicylic acid. Isolation yield 95.1% (2,4
-Based on difluorobenzoic acid), purity 99.2% (high performance liquid chromatographic analysis).

Example 2 The same operation as in Example 1 was carried out except that 400 ml of 1-methyl-2-pyrrolidone was used instead of 400 ml of 1,3-dimethyl-2-imidazolidinone. as a result,
29.4 g of 4-fluorosalicylic acid was obtained. Isolation yield 9
It was 4.2% (based on 2,4-difluorobenzoic acid).

Example 3 400 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone was used in place of 400 ml of 1,3-dimethyl-2-imidazolidinone. The same operation as in Example 1 was performed. As a result, 4-
26.9 g of fluorosalicylic acid was obtained. Isolated yield 86.
It was 2% (based on 2,4-difluorobenzoic acid).

Example 4 The same operation as in Example 1 was carried out except that 400 ml of dimethyl sulfoxide was used instead of 400 ml of 1,3-dimethyl-2-imidazolidinone. As a result, 29.5 g of 4-fluorosalicylic acid was obtained. Isolated yield 94.5
% (Based on 2,4-difluorobenzoic acid).

Example 5 Instead of 32.3 g (0.8 mol) of powdered 99% sodium hydroxide, 33% of granular 95% sodium hydroxide was added.
The same operation as in Example 1 was performed except that 7 g (0.8 mol) was used. As a result, 4-fluorosalicylic acid 2
8.5 g were obtained. The isolated yield was 91.3% (based on 2,4-difluorobenzoic acid).

Example 6 Instead of powdery 99% sodium hydroxide 32.3 g (0.8 mol), a 48% sodium hydroxide aqueous solution 66.
The same operation as in Example 1 was performed except that 7 g (0.8 mol) was used. As a result, 4-fluorosalicylic acid 2
6.5 g was obtained. The isolated yield was 84.9% (based on 2,4-difluorobenzoic acid).

Example 7 Same as Example 2 except that 19.2 g (0.8 mol) of lithium hydroxide was used instead of 32.3 g (0.8 mol) of 99% sodium hydroxide in powder form. The operation was performed.
As a result, 23.9 g of 4-fluorosalicylic acid was obtained.
The isolated yield was 76.7% (based on 2,4-difluorobenzoic acid).

Example 8 33.6 g of lithium hydroxide monohydrate instead of 32.3 g (0.8 mol) of 99% sodium hydroxide in powder form
(0.8 mol) was used, and the same operation as in Example 1 was performed except that the reaction temperature was 145 ° C. As a result, 24.2 g of 4-fluorosalicylic acid was obtained. Isolated yield 77.5
% (Based on 2,4-difluorobenzoic acid).

Examples 9 to 12 4-fluorosalicylic acid was produced in the same manner as in Example 1, except that the kind of solvent, reaction temperature and reaction time were changed. The analysis results of the reaction solution after the reaction are shown in [Table 1].
Shown in

[0037]

[Table 1]

Example 13 1.76 of 2,3,4-trifluorobenzoic acid was added to a 100 ml four-dimensional flask equipped with a thermometer, a stirrer and a reflux condenser.
g (0.01 mol), 1.62 g (0.04 mol) of 99% sodium hydroxide in powder form, and 1,3-dimethyl-
Charge 20 ml of 2-imidazolidinone,
Stir for time to react. After the completion of the reaction, 1,3-dimethyl-2-imidazolidinone was partially recovered, and the reaction solution was diluted with 5 parts of water.
After dilution with 00 ml, acid precipitation was performed with a 10% aqueous hydrochloric acid solution.
After cooling in an ice bath, the resulting crystals were filtered, washed with water, dried,
1.66 g of 3,4-difluorosalicylic acid was obtained. The isolation yield was 95.1% (based on 2,3,4-trifluorobenzoic acid).

(Physical properties of 3,4-difluorosalicylic acid) Melting point: 176.8 to 178.2 ° C. (confirmation data) 60 MHz ¹ H-NMR (DMSO-d ₆ + CDC)
l ₃ ) δ value; 6.63 to 7.20 (m, 1H), 7.
47 to 7.90 (m, 1H), 8.33 (brs, 2
H) IR (KBr tablet, cm ^-1 ); 3431, 3211, 3
104, 3079, 3022, 2942, 2864, 2
677, 2546, 2343, 1658, 1573, 1
540, 1512, 1470, 1445, 1384, 1
316, 1277, 1214, 1200, 1149, 1
054, 909, 831, 785, 716, 689, 6
09

Example 14 In a 100 ml four-necked flask equipped with a thermometer, a stirrer and a reflux condenser, 1.93 g (0.01 mol) of 5-chloro-2,4-difluorobenzoic acid and 99% water in powder form were added. 1.62 g (0.04 mol) of sodium oxide, and 1-methyl-
20 ml of 2-pyrrolidone was charged and stirred at 130 ° C. for 3 hours to react. After completion of the reaction, 1,3-dimethyl-2
-Part of the imidazolidinone was recovered and the reaction solution was treated with 500 m of water.
After diluting with l, acid precipitation was performed with a 10% hydrochloric acid aqueous solution. The obtained crystals were filtered, washed with water and dried to obtain 1.67 g of 5-chloro-4-fluorosalicylic acid. Isolated yield 87.6%
(5-chloro-2,4-difluorobenzoic acid standard).

(Physical properties of 5-chloro-4-fluorosalicylic acid) Melting point: 200.0 to 201.2 ° C. (confirmation data) 60 MHz ¹ H-NMR (DMSO-d ₆ + CDCl
₃ ) δ value; 6.79 (d, 1H, J = 10.3H
z), 7.92 (d, 1H, J = 8.8 Hz), 9.4
6 (brs, 2H) IR (KBr tablet, cm ⁻¹ ); 3630-3280, ¹
669, 1616, 1590, 1491, 1475, 1
449, 1377, 1276, 1248, 1212, 1
166, 849, 703, 611

Example 15 3.27 g (0.01 mol) of 3,5-dichloro-2,4-difluorobenzoic acid was added to a 100 ml four-dimensional flask equipped with a thermometer, a stirrer, and a reflux condenser, and 99 in the form of powder. % Sodium hydroxide 1.62 g (0.04 mol) and 1-methyl-2-pyrrolidone 20 ml were charged, and the mixture was stirred at 130 ° C. for 2 hours to cause a reaction. Next, the same post-treatment as in Example 14 was carried out to obtain 1.95 g of 3,5-dichloro-4-fluorosalicylic acid. The isolated yield was 86.7% (based on 3,5-dichloro-2,4-difluorobenzoic acid).

(Physical properties of 3,5-dichloro-4-fluorosalicylic acid) Melting point: 119.4-120.9 ° C. (confirmation data) 60 MHz ¹ H-NMR (DMSO-d ₆ + CDCl
₃ ) δ value; 7.39 (brs, 2H), 7.89
(D, 1H, J = 8.2 Hz) IR (KBr tablet cm ⁻¹ ) 3451, 3428, 167
4, 1641, 1607, 1545, 1474, 145
8, 1432, 1307, 1292, 1241, 105
7, 810, 720, 659

Example 16 1.76 2,4,6-trifluorobenzoic acid was added to a 100 ml four-necked flask equipped with a thermometer, a stirrer and a reflux condenser.
g (0.01 mol), 1.62 g (0.04 mol) of powdery 99% sodium hydroxide, and 20 ml of 1-methyl-2-pyrrolidone, and stirred at 130 ° C. for 3 hours.
It was made to react. Next, the same post-treatment as in Example 14 is performed,
1.47 g of 4,6-difluorosalicylic acid was obtained. The isolated yield was 84.3% (based on 2,4,6-trifluorobenzoic acid).

(Physical properties of 4,6-difluorosalicylic acid) Melting point: 180.8-183.4 ° C. (confirmation data) 60 MHz ¹ H-NMR (DMSO-d ₆ + CDCl
₃ ) δ value; 6.27 to 6.80 (m, 2H), 7.20
(Brs, 2H) IR (KBr tablet, cm ⁻¹ ); 3421, 3274, 3
106, 3005, 2964, 2929, 1667, 1
632, 1598, 1561, 1509, 1465, 1
436, 1365, 1325, 1253, 1178, 1
137, 1065, 854, 830, 787, 612

Comparative Example 3.16 g of 2,4-difluorobenzoic acid was added to a 100 ml four-dimensional flask equipped with a thermometer, a stirrer and a reflux condenser.
(0.02 mol), 48% aqueous sodium hydroxide solution 6.
67 g (0.08 mol) and 40 ml of water were charged, and the mixture was reacted under heating under reflux for 10 hours. Results of analysis of the reaction mixture after completion of the reaction by high performance liquid chromatography (total area%
Values) are shown below. 2,4-difluorobenzoic acid 82.1% 2-fluoro-4-hydroxybenzoic acid 12.6% 4-fluorosalicylic acid 3.2%

[0047]

According to the method of the present invention, selective hydroxylation of the 2-position fluorine atom of 2,4-difluorobenzoic acids proceeds, and 4-fluorosalicylic acids can be easily produced. In the method of the present invention, industrially easily available 2,4-difluorobenzoic acid can be used as a raw material, and the selectivity of the reaction of the 2-position fluorine atom is high, which is advantageous in terms of yield. The reaction itself is safe with no danger of explosion and the number of steps is short, so it is extremely suitable as an industrial production method of 4-fluorosalicylic acids.

Claims (2)

[Claims] 1. A general formula: Wherein A is a group —CH ₂ — or a group —NR′— (in the formula,
R 'represents a lower alkyl group. ), R represents a lower alkyl group, W represents a lower alkyl group, X represents a hydrogen atom or a lower alkyl group when A is a group -CH _2- ,
Is a lower alkyl group when is a group -NR'-, W and X combine with each other to form a lower alkylene group, and -N-
It may be a 5- to 7-membered ring together with CA-. ] And a compound represented by the general formula: (In the formula, Q represents a group —SO— or a group —SO ₂ —;
And Z each independently represent a lower alkyl group, Y and Z are joined to form a lower alkylene group together, group -SO- or a group -SO ₂ - with may be a 4-6 membered ring. ) Using at least one selected from the compounds represented by the formula (In the formula, X ¹ and X ³ each independently represent a hydrogen atom or a halogen atom, and X ² represents a hydrogen atom, a chlorine atom, or a bromine atom.), 2,4-difluorobenzoic acid and an alkali By reacting with a metal hydroxide, the general formula: (In the formula, X ¹ , X ² , and X ³ have the same meanings as described above.) A method for producing 4-fluorosalicylic acids. 2. The method for producing 4-fluorosalicylic acid according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide.