JP3261474B2 - Method for producing 2-chloro-4,5-difluorobenzoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Various methods are known for introducing a carboxyl group into an aromatic compound. For example, a method of introducing a methyl group into a benzene ring and then trichloromethylating it with chlorine gas and then hydrolyzing it to convert it to a carboxyl group, a method of oxidizing after acetylation by the Friedel-Crafts reaction, and a method of using phosgene and an aromatic compound also as a solvent A method of reacting an aromatic compound with an acylation catalyst in the presence of an acylation catalyst (see, for example, JP-A-1-226851);
A method of treating a substituted bromobenzene with a metal cyanide to convert a bromo group into a nitrile and then hydrolyzing the nitrile (JP-A-60-72885). But,
These methods have problems in using toxic substances or treating by-products or catalysts.

A method is also conceivable in which an arylmagnesium bromide (Grignard reagent) is obtained from substituted bromobenzene as a raw material, which is reacted with carbon dioxide and then hydrolyzed to obtain an aromatic carboxylic acid. However, in general, in a method of obtaining a carboxylic acid by reacting carbon dioxide with a Grignard reagent, 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 Course 19
Volume, page 409), requiring a great deal of energy for cooling.
Therefore, such a method is considered to be disadvantageous as an industrial production method. Further, when considering the industrial production of individual aromatic carboxylic acids, the availability of starting materials is easy, and the selectivity and yield of each reaction from the starting materials to the target compound can be satisfied. It needs to be on a level. For this reason, safe and efficient methods and reaction routes according to the target compound have been studied.

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

[0005]

That is, the present invention relates to 2-chloro-4,
A process for producing 5-difluorobenzoic acid, which comprises reacting 2-chloro-4,5-difluorobromobenzene with metallic magnesium to produce 2-chloro-4,5-difluorophenylmagnesium bromide. −
Provided is a method characterized by reacting 4,5-difluorophenylmagnesium bromide with carbon dioxide in a solvent and then performing hydrolysis. Further, the present invention relates to 2
A process for producing -chloro-4,5-difluorobenzoic acid, comprising: (i) nitrating o-difluorobenzene to obtain 3,3;
(Ii) reducing the 3,4-difluoronitrobenzene to 3,4-difluoroaniline; (iii) dediazochlorinating the 3,4-difluoroaniline to 3,4-difluorochlorobenzene (Iv) brominating the 3,4-difluorochlorobenzene to 2-chloro-4,5-difluoro-bromobenzene; (v) converting the 2-chloro-4,5-difluoro-bromobenzene to metal magnesium Reacting to produce 2-chloro-4,5-difluorophenylmagnesium bromide, and reacting the 2-chloro-4,5-difluorophenylmagnesium bromide with carbon dioxide in a solvent followed by hydrolysis. 2 characterized by
A method for producing -chloro-4,5-difluorobenzoic acid is provided.

In the present invention, the reaction with carbon dioxide 2
-Chloro-4,5-difluorophenylmagnesium bromide can be produced according to a known method. However, in order to obtain a highly pure product in a high yield, the above (i) to
It is preferable to produce by the route of (v). this house,
The nitration of o-difluorobenzene and the 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.
Difluoronitrobenzene is obtained in high yield. In addition, since there is a large difference in boiling point from by-products, it can be easily purified to a high purity by distillation. In addition, the reduction reaction of (ii)
It is possible to work with a yield of almost 100%.

The dediazochlorination of (iii) can be carried out by a Sandmeyer reaction or a Gutterman reaction. The bromination of (iv) may be performed according to a conventional method. The preparation of the Grignard reagent (v) is generally carried out by a conventional method. That is,
In a sufficiently dried reaction vessel, metallic magnesium was added in a molar ratio of 2-chloro-4,5-difluorobromobenzene.
The solvent is charged 05 times, preferably 1.5 to 2 times, and the solvent is further charged 2 to 10 V / W times that of magnesium, deaerated 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 a W-fold solvent is added to obtain 2-chloro-4,5-difluorophenylmagnesium bromide. Before adding the 2-chloro-4,5-difluorobromobenzene solution, a magnesium activating reagent, for example, 1.5 to 10 V
/ B times ethyl bromide (0.05-0.5 times)
Times the same). According to this series of reactions, an isomer is hardly produced, and a product with extremely high purity can be obtained in a high yield.

The reaction between 2-chloro-4,5-difluorophenylmagnesium bromide and carbon dioxide is carried out by dissolving the former in a solvent and introducing carbon dioxide into the solution. The solvent used here is a solvent generally usable in the Grignard reaction. Examples of such solvents include tetrahydrofuran and the like. The introduction of carbon dioxide is carried out by blowing at least equimolar amounts of 2-chloro-4,5-difluoro-bromobenzene and ethyl bromide, preferably 1.5 to 10 times, according to a conventional method.
The temperature for introducing carbon dioxide is preferably 5 to 30C. If the introduction temperature is lower than 0 ° C., cooling costs are disadvantageously increased. When the introduction temperature exceeds 60 ° C., a by-product is generated or the yield is reduced. Hydrolysis and isolation of the product may be performed according to a conventional method.

Hereinafter, the manufacturing method of the present invention will be specifically described based on examples. Production process of 3,4-difluoronitrobenzene 913 g (8 mol) of o-difluorobenzene and 2282 g of concentrated sulfuric acid are charged into a flask equipped with a stirrer, a cooler, a dropping funnel, and a thermometer, and stirred well while cooling in an ice bath. To this, 738 g of 70% nitric acid is gradually added from a dropping funnel, and the internal temperature is kept at 10 ° C. in an ice bath. After completion of the dropwise addition, the mixture is stirred for 1 hour while maintaining the internal temperature. Thereafter, the reaction solution is poured into ice water. The organic layer is separated and washed successively with 300 ml of water, 500 ml of a 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 1240 g of 3,4-difluoronitrobenzene (boiling point: 76 to 80 ° C / 11 mmHg).

[0010]Production process of 3,4-difluoroaniline
(1) In an autoclave with a stirrer, add 3,4-difluoronit
223 g (1.4 mol) of robenzene, ethyl acetate 15
0 ml and 8.2 g of 10% -Pd / C were charged.
Replace with Thereafter, hydrogen is introduced at 10 to 50 ° C.
When the absorption of nitrogen stops, the inside of the system is replaced with nitrogen again. Next
The reaction product was taken out and 10% -Pd / C was filtered off.
The organic layer is separated from the liquid. This is distilled to give 3,4-di
172 g of fluoroaniline (boiling point: 77 ° C./7 mmHg) was obtained.
You.

[0011]Production process of 3,4-difluoroaniline
(2) Flask with stirrer, cooler, dropping funnel, thermometer
3 liters of water, 23% of 35% hydrochloric acid, 1002g of iron powder
Prepare. 3,4-diflu from the dropping funnel with stirring at room temperature
Add 956 g of Oronitrobenzene gradually and slowly
Bring to reflux. Then add 27g of sodium hydroxide
You. Next, an organic layer is separated from the distillate by performing steam distillation.
The aqueous layer was extracted with dichloromethane and combined with the organic layer.
Distilled together, 732 g of 3,4-difluoroaniline
(Boiling point: 77 ° C./7 mmHg).

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

Production of 3,4-difluorochlorobenzene
Step (2) In a flask equipped with a stirrer, a condenser, a dropping funnel and a thermometer, 720 g of water and 1000 g of 35% hydrochloric acid are charged, and 334 g of 3,4-difluoroaniline is gradually added while stirring at room temperature. After completion of the dropwise addition, the internal temperature is maintained at 0 ° C. In a separate flask, 1349 g of 90% CuCl, 100% of 35% hydrochloric acid
Charge 0 g, stir at 0 ° C. An aqueous solution of the diazonium salt prepared earlier is gradually added. After completion of the addition, the mixture is sufficiently stirred and aged. Next, the organic layer is separated from the distillate by performing steam distillation, and sequentially washed with 250 ml of water, 200 ml of a 5% aqueous solution of sodium carbonate, and 250 ml of water. Each aqueous layer was extracted with dichloromethane, combined with the previous organic layer, dried over anhydrous magnesium sulfate, and then distilled.
332 g of 4-difluorochlorobenzene (boiling point: 127 to
128 ° C).

2-Chloro-4,5-difluorobrombe
In a flask equipped with a stirrer, a cooler, a dropping funnel and a thermometer, 1040 g of 3,4-difluorochlorobenzene (7
mol) and 21 g of iron powder and stirred at an internal temperature of 30 to 35 ° C. 1176 g of bromine (7.3 mo from the dropping funnel)
l) is added over 6 hours. After the addition is completed, raise the internal temperature to 40
Stir for about 3 hours while maintaining the temperature at around ° C. Next, the reaction solution was treated with an aqueous solution of sodium thiosulfate (88 g of sodium thiosulfate + 1.2 of water).
kg). The iron powder is separated from the treatment liquid by filtration, and the organic layer is further separated. This is washed twice with 200 ml of water and 200 ml of a 10% aqueous sodium carbonate solution. Each aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate together with the organic layer, and distilled, and 1370 g of 2-chloro-4,5-difluorobromobenzene (boiling point: 84 to 86 ° C /
26mmHg).

[0015]

Example 1 A flask equipped with a stirrer, a condenser, a dropping funnel and a thermometer was charged with 39 g (1.6 mol) of magnesium, and the system was purged 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 completion of the addition, the THF solution (227 g of 2-chloro-4,5-difluorobromobenzene + 400 ml of THF) was added to 15 parts of the THF solution while maintaining the internal temperature at 20 to 40 ° C. with a water bath.
Add dropwise over 0 minutes. After completion of the dropwise addition, the internal temperature was maintained at about −20 ° C. with dry ice-acetone to remove carbon dioxide for 6 hours.
Introduce 0 minutes. Next, THF was distilled off under reduced pressure, and the obtained residue was 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 separate an organic layer and an aqueous layer. The organic layer is separated, and the aqueous layer is extracted twice with 150 ml of chloroform, and dried with 30 g of anhydrous magnesium sulfate together with the organic layer. After the desiccant is filtered off, chloroform is distilled off under reduced pressure, and the obtained residue is washed with hexane and dried to obtain 154 g of a white powder (melting point: 104 to 105 ° C).
^The product was confirmed to be 2-chloro-4,5-difluorobenzoic acid by ¹ H-NMR and IR (80% yield).

[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 system was purged with nitrogen. Next, 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, the internal temperature is adjusted to 20 to
While maintaining the temperature at 40 ° C, a THF solution of the raw material (2-chloro-
227 g of 4,5-difluorobromobenzene + THF4
00 ml) is added dropwise over 150 minutes. After completion of the dropping, carbon dioxide is introduced for 60 minutes while maintaining the internal temperature at about 5 to 35 ° C. Next, THF is distilled off under reduced pressure, and the obtained residue is dissolved in 300 ml of chloroform. 400 ml of water was added thereto, and 175 g of 35% hydrochloric acid was added dropwise to dissolve excess magnesium and separate an organic layer and an aqueous layer.
The organic layer was separated, and the aqueous layer was chloroform 150 ml.
Extract twice and combine 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 simple and safe manner in high yield. In particular, the method of the present invention
Since it can be performed at room temperature, energy costs can be kept low and it is economical.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 51/15 C07C 63/68

Claims (3)

(57) [Claims] 1. A process for producing 2-chloro-4,5-difluorobenzoic acid, comprising reacting 2-chloro-4,5-difluoro-bromobenzene with magnesium metal to produce 2-chloro-4,5-difluorobenzoic acid.
A method comprising producing chloro-4,5-difluorophenylmagnesium bromide, introducing carbon dioxide into the solution to cause a reaction, and then performing hydrolysis. 2. The method according to claim 1, wherein the reaction between the magnesium bromide and carbon dioxide is carried out at 0 to 50 ° C.
Preferably, the method is carried out at 5-35 ° C. 3. A process for producing 2-chloro-4,5-difluorobenzoic acid, comprising: (i) nitrating o-difluorobenzene to 3,4-difluoronitrobenzene;
i) reducing the 3,4-difluoronitrobenzene to 3,
(Iii) dediazochlorination of the 3,4-difluoroaniline to 3,4-difluorochlorobenzene; (iv) bromination of the 3,4-difluorochlorobenzene to 2-chloro-4, (V) the 2-chloro-4,5-
By reacting difluoro-bromobenzene with metallic magnesium, 2-chloro-4,5-difluorophenylmagnesium bromide is produced and 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, followed by hydrolysis.