JPH06100492A - Production of 2-chloro-4,5-difluorobenzoic acid - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate, etc., for medicines from a readily available raw material in high yield under mild conditions by reacting a Grignard reagent obtained by reacting chlorodifluorobromobenzene with metallic Mg with CO2 and then hydrolyzing the reactional product. CONSTITUTION:2-Chloro-4,5-difluorobromobenzene is made to react with metallic Mg, usually in a solvent such as THF to afford 2-chloro-4,5- difluorophenylmagnesium bromide. CO2 is introduced into the reactional solution, preferably at 5-30 deg.C and then the reactional product is hydrolyzed to provide the objective compound. Furthermore, 2-chloro-4,5-difluorobromobenzene which is a raw material is preferably obtained by successively subjecting 0- difluorobenzene to nitration and reduction to afford 3,4-difluoroaniline, subjecting this compound to de-diazotization and chlorination to give 3,4- difluorochlorobenzene and further brominating this compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing 2-chloro-4,5-difluorobenzoic acid, which is useful as a pharmaceutical intermediate or liquid crystal intermediate.

[0002]

2. Description of the Related Art Various methods are known as methods for introducing a carboxyl group into an aromatic compound. For example, a method of introducing a methyl group into the benzene ring, trichloromethylating it with chlorine gas and then hydrolyzing it to convert it to a carboxyl group, a method of acetylating by Friedel-Crafts reaction and then oxidizing, phosgene and aroma that also serve as a solvent. A method of reacting a group compound with an acylation catalyst (see, for example, JP-A-1-226851),
Examples thereof include a method in which a substituted bromobenzene is treated with a metal cyanide to convert a bromo group into a nitrile and then this is hydrolyzed (JP-A-60-72885). But,
These methods suffer from the use of toxic substances or the treatment of by-products or catalysts.

It is also conceivable to obtain arylmagnesium bromide (Grignard reagent) using substituted bromobenzene as a raw material, react this with carbon dioxide and then hydrolyze it to obtain an aromatic carboxylic acid. However, generally, in the method of obtaining a carboxylic acid by reacting a Grignard reagent with carbon dioxide, temperature control is important. That is, it is necessary to carry out the reaction at a low temperature of less than 0 ° C, preferably -20 ° C or less (Experimental Chemistry Lecture 19
Volume 409, etc.) requires a large amount of energy for cooling.
Therefore, such a method is considered to be disadvantageous as an industrial manufacturing method. Further, when considering the industrial production of individual aromatic carboxylic acids, the starting materials are easily available, and the selectivity and yield of the reaction at each stage from the starting materials to the target compound can be satisfied. It needs to be standard. Therefore, safe and efficient methods and reaction pathways have been investigated depending on the target compound.

The present inventors conducted various studies on the industrial production method of 2-chloro-4,5-difluorobenzoic acid, which is useful as a pharmaceutical intermediate and a liquid crystal intermediate. As a result, regarding 2-chloro-4,5-difluorophenylmagnesium bromide (Grignard reagent), its reaction with carbon dioxide can be carried out at 0 to 50 ° C. without lowering the yield or increasing by-products. I have obtained an unexpected finding that it is possible. Further, in this method, the fact that the target compound can be obtained from a starting material which is relatively easy to obtain via a high yield of reaction was found, and the present invention was completed.

[0005]

That is, the present invention relates to 2-chloro-4,
A method for producing 5-difluorobenzoic acid, which comprises reacting 2-chloro-4,5-difluorobromobenzene with magnesium metal to produce 2-chloro-4,5-difluorophenylmagnesium bromide, which is produced by the above-mentioned 2-chloro- −
There is provided a method characterized in that 4,5-difluorophenyl magnesium bromide and carbon dioxide are reacted in a solvent and then hydrolyzed. In addition, the present invention is 2
A process for producing -chloro-4,5-difluorobenzoic acid, comprising the step of nitrating (i) o-difluorobenzene,
4-difluoronitrobenzene; (ii) the 3,4-difluoronitrobenzene is reduced to 3,4-difluoroaniline; (iii) the 3,4-difluoroaniline is dediazochlorinated to 3,4-difluorochlorobenzene And (iv) brominated the 3,4-difluorochlorobenzene to 2-chloro-4,5-difluoro-bromobenzene; (v) the 2-chloro-4,5-difluoro-bromobenzene with metallic magnesium. Producing 2-chloro-4,5-difluorophenyl magnesium bromide by reacting, reacting the 2-chloro-4,5-difluorophenyl magnesium bromide with carbon dioxide in a solvent, and then performing hydrolysis. Characterized by 2
-Providing a method for producing chloro-4,5-difluorobenzoic acid.

2 to react with carbon dioxide in the present invention
-Chloro-4,5-difluorophenylmagnesium bromide can be produced according to a known method, but in order to obtain a highly pure product in a high yield, the above (i)
It is preferable to manufacture by the route of (v). this house,
The nitration of o-difluorobenzene and reduction of the nitro group in (i) to (ii) can be carried out according to a conventional method.
In the nitration reaction of (i), nitration at the ortho position with respect to fluorine is extremely unlikely to occur, so that the target 3,4-
Difluoronitrobenzene is obtained in high yield. Further, since the boiling point difference with the by-product is large, it can be easily purified to high purity by distillation. In addition, the reduction reaction of (ii)
It is possible to perform with a yield of almost 100%.

The dediazochlorination of (iii) can be carried out by Sandmeyer reaction or Gatterman reaction. Bromination of (iv) may be performed according to a conventional method. The preparation of the Grignard reagent of (v) is generally performed by a conventional method. That is,
1. Metallic magnesium was added to a sufficiently dried reaction vessel in a molar ratio of 2-chloro-4,5-difluorobromobenzene.
It is charged at a rate of 05 times, preferably 1.5 to 2 times, and further charged at a solvent of 2 to 10 V / W times that of magnesium, degassed by a vacuum pump and replaced with dry nitrogen. 0 ° C to reflux temperature,
Preferably, the upper limit is 20 to 50 ° C. and 1.5 to 10 V /
2-Chloro-4,5-difluorobromobenzene dissolved in W-fold solvent is added to give 2-chloro-4,5-difluorophenylmagnesium bromide. In addition, before adding the 2-chloro-4,5-difluorobromobenzene solution, a magnesium activating reagent, for example, 1.5 to 10 V
Ethyl bromide (0.05-0.5)
Double mole) may be added. According to this series of reactions, an extremely high-purity product can be obtained in a high yield with almost no production of isomers.

The reaction of 2-chloro-4,5-difluorophenylmagnesium bromide with carbon dioxide is carried out by dissolving the former in a solvent and introducing carbon dioxide into this solution. The solvent used here is generally a solvent that can be used in the Grignard reaction. Examples of such solvents include tetrahydrofuran and the like. The introduction of carbon dioxide is carried out by blowing in an equimolar amount or more, preferably 1.5 to 10 times the molar amount of 2-chloro-4,5-difluoro-bromobenzene and ethyl bromide according to a conventional method.
The introduction temperature of carbon dioxide is preferably 5 ° C to 30 ° C. If the introduction temperature is lower than 0 ° C., cooling cost will be disadvantageous. If the introduction temperature exceeds 60 ° C, a by-product is generated or the yield is lowered. Hydrolysis and isolation of the product may be performed according to a conventional method.

The manufacturing method of the present invention will be specifically described below based on Examples. 3,4-Difluoronitrobenzene production process A flask equipped with a stirrer, a condenser, a dropping funnel and a thermometer was charged with 913 g (8 mol) of o-difluorobenzene and 2282 g of concentrated sulfuric acid, and stirred well while cooling in an ice bath. To this, 738 g of 70% nitric acid was gradually added from a dropping funnel, and the internal temperature was kept at 10 ° C. in an ice bath. After completion of dropping, the internal temperature is kept as it is and the mixture is stirred for 1 hour. Then, the reaction solution is poured into ice water. The organic layer is separated and washed successively with 300 ml of water, 500 ml of 5% aqueous sodium carbonate solution and 300 ml of water. Each aqueous layer is extracted with chloroform and then distilled together with the organic layer to obtain 1,240 g of 3,4-difluoronitrobenzene (boiling point: 76-80 ° C / 11 mmHg).

Process for producing 3,4-difluoroaniline
(1) In an autoclave equipped with a stirrer, 223 g (1.4 mol) of 3,4-difluoronitrobenzene and 15 parts of ethyl acetate were added.
0 ml and 10% -Pd / C 8.2 g were charged and the system was replaced with nitrogen. After that, hydrogen is introduced at 10 to 50 ° C., and when the absorption of hydrogen is stopped, the system is replaced with nitrogen again. Next, the reaction product is taken out, 10% -Pd / C is separated by filtration, and the organic layer is separated from the filtrate. This is distilled to obtain 172 g of 3,4-difluoroaniline (boiling point: 77 ° C / 7 mmHg).

Process for producing 3,4-difluoroaniline
(2) A flask equipped with a stirrer, a cooler, a dropping funnel, and a thermometer is charged with 3 liters of water, 23 g of 35% hydrochloric acid, and 1002 g of iron powder. While stirring at room temperature, 956 g of 3,4-difluoronitrobenzene was gradually added from a dropping funnel, and the mixture was gently refluxed. Then 27 g of sodium hydroxide are added. Next, steam distillation is carried out to separate the organic layer from the distillate, and the aqueous layer is extracted with dichloromethane and distilled together with the organic layer to give 732 g of 3,4-difluoroaniline.
(Boiling point: 77 ° C / 7 mmHg) is obtained.

Production of 3,4-difluorochlorobenzene
Step (1) A flask equipped with a stirrer, a cooler, a dropping funnel, and a thermometer was charged with 19 g of copper powder, 413 g of water, and 1044 g of 35% hydrochloric acid, and 516 g (4 mol of 4 mol of 4,4-difluoroaniline was stirred from the dropping funnel at room temperature. ) Is gradually added. After the dropping is completed, 413 g of water is added and heated until the internal temperature reaches 80 ° C. Next, an aqueous sodium nitrite solution (312 g of sodium nitrite + 640 g of water) is added over 7.5 hours. This dropping of sodium nitrite advances the diazotization reaction to generate nitrogen gas. After completion of dropping, the mixture is refluxed and stirred for 1 hour. Next, steam distillation is performed, the organic layer is separated from the distillate, and 250 ml of water and 150% of 10% sodium carbonate aqueous solution are added.
After washing with ml, each aqueous layer is extracted with dichloromethane.
This was combined with the above organic layer, dried over anhydrous magnesium sulfate and then distilled to obtain 491 g of 3,4-difluorochlorobenzene (boiling point: 127 to 128 ° C.).

Production of 3,4-difluorochlorobenzene
Step (2) A flask equipped with a stirrer, a condenser, a dropping funnel, and a thermometer is charged with 720 g of water and 1000 g of 35% hydrochloric acid, and 334 g of 3,4-difluoroaniline is gradually added with stirring at room temperature. After the dropping is completed, the internal temperature is kept at 0 ° C. In another flask, 1349 g of 90% CuCl, 100% of 35% hydrochloric acid
Charge 0 g, keep at 0 ° C. and stir. An aqueous solution of the diazonium salt prepared above is gradually added to this. After the addition is completed, the mixture is agitated and aged. Next, steam distillation is carried out to separate the organic layer from the distillate, and the organic layer is washed successively with 250 ml of water, 200 ml of a 5% sodium carbonate aqueous solution, and 250 ml of water. Each aqueous layer was extracted with dichloromethane, combined with the above organic layer, dried over anhydrous magnesium sulfate, and then distilled.
332 g of 4-difluorochlorobenzene (boiling point: 127-
128 ℃).

2-chloro-4,5-difluorobrombe
In a flask equipped with a stirrer, a condenser, a dropping funnel, and a thermometer, 1040 g (7 parts) of 3,4-difluorochlorobenzene was added.
mol) and 21 g of iron powder are charged and stirred at an internal temperature of 30 to 35 ° C. Bromine 1176 g (7.3 mo from the dropping funnel)
l) is added over 6 hours. After the addition is complete, increase the internal temperature to 40
Keep at around ℃ and stir for 3 hours. Next, the reaction solution was mixed with an aqueous solution of sodium thiosulfate (88 g of sodium thiosulfate + 1.2 g of water).
kg). Iron powder is filtered off from the treatment liquid, and the organic layer is separated. It is washed twice with 200 ml of water and 200 ml of 10% aqueous sodium carbonate solution. Each aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate together with the above organic layer, and then distilled to give 1370 g of 2-chloro-4,5-difluorobromobenzene (boiling point: 84-86 ° C /
26mmHg).

[0015]

Example 1 39 g of magnesium (1.6 mol) was charged into a flask equipped with a stirrer, a condenser, a dropping funnel, and a thermometer, and the system was replaced with nitrogen. Next, 150 ml of tetrahydrofuran (hereinafter referred to as "THF") is added from the dropping funnel and stirred. To this is added a solution of ethyl bromide in THF (44 g of ethyl bromide + 160 ml of THF) over 45 minutes. After the addition was completed, a THF solution (2-chloro-4,5-difluorobromobenzene 227 g + THF 400 ml) as a raw material was added to the solution while maintaining the internal temperature at 20 to 40 ° C. with a water bath.
Add dropwise over 0 minutes. After completion of the dropping, maintain the internal temperature at around -20 ° C with dry ice-acetone to remove carbon dioxide 6
Introduce for 0 minutes. Next, THF is distilled off under reduced pressure, and the obtained residue is dissolved in 300 ml of chloroform. Water 40
0 ml was added, and 175 g of 35% hydrochloric acid was added dropwise to dissolve excess magnesium, and the organic layer and the aqueous layer were separated. The organic layer is separated, the aqueous layer is extracted twice with 150 ml of chloroform, and the organic layer is combined with the organic layer and dried over 30 g of anhydrous magnesium sulfate. After filtering off the desiccant, chloroform was distilled off under reduced pressure, and the resulting residue was washed with hexane and dried to obtain 154 g of white powder (melting point: 104-105 ° C).
It was confirmed by ¹ H-NMR and IR that the product was 2-chloro-4,5-difluorobenzoic acid (yield 80%).

[0016]

[Example 2] 39 g (1.6 mol) of magnesium was charged into a flask equipped with a stirrer, a cooler, a dropping funnel, and a thermometer, and the inside of the system was replaced with nitrogen. Then TH from the dropping funnel
Add 150 ml of F and stir. Ethyl bromide in THF
The solution (44 g of ethyl bromide + 160 ml of THF) is added over 45 minutes. After the addition was completed, the internal temperature was adjusted to 20-
While maintaining the temperature at 40 ° C, the raw material THF solution (2-chloro-
4,5-Difluorobromobenzene 227g + THF4
00 ml) is added dropwise over 150 minutes. After the completion of dropping, the internal temperature is kept at around 5 to 35 ° C. and carbon dioxide is introduced for 60 minutes. Next, THF is distilled off under reduced pressure, and the obtained residue is dissolved in 300 ml of chloroform. To this, 400 ml of water was added, and 175 g of 35% hydrochloric acid was added dropwise to dissolve excess magnesium, and the organic layer and the aqueous layer were separated.
Separate the organic layer and 150 ml of chloroform for the aqueous layer.
It is extracted twice with and combined with the organic layer, anhydrous magnesium sulfate 3
Dry at 0 g. After filtering off the desiccant, chloroform was distilled off under reduced pressure, and the resulting residue was washed with hexane and dried to give 2-
154 g of chloro-4,5-difluorobenzoic acid (melting point:
104-105 ° C). Yield 80%.

[0017]

[Table 1] Example Reaction solvent CO ₂ introduction temperature Yield Example 1 THF -20 ° C 80% 〃 2 〃 0-25 ° C 80%

[0018]

According to the present invention, high-purity 2-chloro-
It is possible to obtain 4,5-difluorobenzoic acid in a high yield by a simple and safe method. In particular, the method of the invention is
Since it can be performed at room temperature, the energy cost can be kept low, which is economical.

Claims (3)

[Claims] 1. A method for producing 2-chloro-4,5-difluorobenzoic acid, which comprises reacting 2-chloro-4,5-difluoro-bromobenzene with metallic magnesium to produce 2-chloro-4,5-difluorobenzoic acid.
A method characterized in that chloro-4,5-difluorophenylmagnesium bromide is produced, carbon dioxide is introduced into the solution to cause a reaction, and then hydrolysis is carried out. 2. The method according to claim 1, wherein the reaction of the magnesium bromide with carbon dioxide is carried out at 0 to 50 ° C.
Preferably, the method is performed at 5 to 35 ° C. 3. A method for producing 2-chloro-4,5-difluorobenzoic acid, which comprises (i) nitrating o-difluorobenzene into 3,4-difluoronitrobenzene;
i) reducing the 3,4-difluoronitrobenzene to give 3,
4-difluoroaniline; (iii) dediazochlorination of the 3,4-difluoroaniline to 3,4-difluorochlorobenzene; (iv) bromination of the 3,4-difluorochlorobenzene to 2-chloro-4, 5-difluoro-bromobenzene, and (v) the 2-chloro-4,5-
2-chloro-4,5-difluorophenylmagnesium bromide was prepared by reacting difluoro-bromobenzene with magnesium metal, the 2-chloro-
A method for producing 2-chloro-4,5-difluorobenzoic acid, which comprises reacting 4,5-difluorophenylmagnesium bromide with carbon dioxide in a solvent and then performing hydrolysis.