JPS6236336A - Production of benzotrifluoride derivative - Google Patents

Abstract

PURPOSE:To produce a benzotrifluoride derivative useful as an intermediate for medicines and agricultural chemicals in high purity and yield, by directly fluorinating benzotrifluoride with fluorine gas. CONSTITUTION:A benzotrifluoride expressed by formula I (X is at least one selected from F, Br and Cl; m is an integer 0-3), e.g. 4-chlorobenzotrifluoride, is reacted with fluorine gas, preferably in a lower alkylcarboxylic acid to afford the aimed benzotrifluoride derivative expressed by formula II (n is an integer 1 or 2), e.g. 3-fluoro-4-chlorobenzotrifluoride. This method is particularly effective when it is desirable to introduced fluorine into the m-position to the -CH3 group of the benzotrifluoride.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing pensitrifluoride derivatives useful as pharmaceutical and agricultural intermediates.

[Prior Art] Conventionally, the method for introducing fluorine into an aromatic compound is to nitrate the aromatic compound, then reduce the nitro group to convert it into an amino group, and then oxidize it in borofluoric acid or hydrofluoric acid. A method in which chlorine-containing aromatic compounds having electron-withdrawing groups such as nitro groups are reacted with sodium nitrate to diazotize and then thermally decomposed (such as potassium fluoride) in an aprotic polar solvent such as sulfolane. A method of fluorination with an alkali metal fluoride (halogen exchange method) is known.

[Problems to be solved by the invention] Conventional methods require a large number of reaction steps, and especially in the former method, unstable diazonium salts must be handled, and the total yield of the target product is However, as a low-order fluorination method for aromatic compounds, a liquid phase direct fluorination method using fluorine gas as a fluorination agent has been proposed. There is [
For example, V., Grakauskas, J., Org., Che.
*35732 (1970) However, this liquid phase direct fluorination method is difficult to obtain when specific compounds are used as raw materials, except for pyrimidine compounds such as those shown in JP-A-54-7!3288.54-90184. It has not been used industrially due to low yield and difficulty in controlling the reaction.

[Means for Solving the Problems] The present inventors have carried out extensive research on methods for introducing fluorine into aromatic compounds, and have found that direct fluorination using fluorine gas is easy for pensitrifluorides. The pensitrifluoride in the present invention has a general formula in which X is at least one selected from F, Br, and CI, and 1m is an integer of O to 3. By directly fluorinating pencitrifluoride with fluorine gas, a mono- or difluorinated pencitrifluoride derivative represented by the integer of general formulas 1 to 2 can be obtained.

The fluorination reaction of the present invention may be carried out without a solvent, but it is preferably carried out in a solvent that is inert to the starting materials and reaction products. Preferred solvents include chlorinated carbon tetrachloride, methylene chloride, etc. Hydrocarbons, trichlorofluoromethane.

1.1.2-) Chlorinated fluorinated hydrocarbons such as refluoroethane, glymes such as diglyme and triglyme, lower alkyl carboxylic acids such as formic acid, acetic acid, and trifluoroacetic acid, perfluorobutyltetrahydrofuran,
Examples include perfluoro compounds such as perfluorotributylamine, and a mixed solvent of two or more of these can also be used. 0, lower alkyl carboxylic acids are preferable. In these solvents, benztrinoluolide as a starting material is dissolved, and in a temperature range above the melting point and below the boiling point of the mixture, The dilution rate is as follows:
5 to 1 (10 times the amount, preferably 10 to 50 times the amount is appropriate) per volume part of the fluorine gas. -The fluorination reaction of the present invention is an exothermic reaction, so in order to perform the reaction smoothly, It is desirable to heat the reaction solution sufficiently by circulating or stirring the reaction solution.In order to increase the yield of the pensitrifluoride derivative of the fluorinated product, it is desirable to heat the starting material. After suppressing the reaction rate of the trifluoride to about 20 to 50% and separating and recovering the desired fluorinated product, it is preferable to carry out fluorination of the unreacted raw material again. Undesirable side reactions such as polymerization reactions can be suppressed.

The fluorination reaction of the present invention is a reaction in which fluorine is likely to be selectively introduced into the meta position with respect to the trifluoroalkyl group of the starting material.For example, the following reactions are likely to occur selectively and selectively.

Of course, if both halogen atoms are already present at the meta position relative to the -CF3 group of the starting material, fluorination at the ortho or para position will proceed. The reaction temperature at which not only fluorination but also difluorination can be carried out varies depending on the starting materials, the solvent used, etc., but is usually -40 to 50°C, preferably -20 to 2
A temperature of 0°C is adopted. If the temperature is lower than this, the reaction rate will drop rapidly, and if the temperature is higher than this, side reactions such as decomposition reactions will easily occur, which is not preferable.

The reaction pressure may be reduced pressure, normal pressure, or increased pressure, but it is usually preferable to carry out the reaction at normal pressure.The amount of fluorine gas introduced is 0.2 of the theoretical amount of nuclear fu/reaction required for hydrogenation. ~5
The appropriate amount is 0.3 to 2 times, preferably 0.3 to 2 times, and it is not preferable to introduce more than this because it increases side reactions.
The desired fluorinated product can be obtained with high purity and good yield through conventional separation operations such as solvent distillation, extraction, and distillation.

[Function] In the present invention, the reason why the meta-position of the -CF3 group of the starting material pencitrifluoride is likely to be selectively fluorinated is that electrons are withdrawn by the -CF3 group, the meta-position is activated, and the electrophilic group This is thought to be due to the fact that it is more susceptible to attack by (for example, F''), and furthermore, it is stabilized by the presence of the -Ch group, making it difficult for decomposition reactions to occur.

[Example] Example 1 Dissolved in 200 g of 4-chlorobencitrifluoride acid, and dissolved in 5
It was charged into a US-318L% reactor and maintained at -15°C while being cooled from the outside.

Fluorine gas (F27mQ/sin, N7 140mQ/5in) diluted to about 5 Mao1z with nitrogen gas.
While stirring vigorously, fluorine gas is supplied to the raw material at a molar ratio of IG"2/CF3G CI=1%
/l/ratio) 6. After the reaction, the solvent was distilled, and 19 g of the reaction product was recovered.

As a result of analyzing this by gas chromatography and NMR using parafluorophenol as a standard substance, it was found that the reaction rate of the raw material tochlorbenzotrifluoride was 52% and the selectivity of 3-fluoro-4-chlorobenzotrifluoride was 85%.

Example 2 2,4-dichloropenecitrial olide as raw material Example 1
As a result of carrying out the reaction under the same conditions, the raw material reaction rate was 45
%, and the monofluorinated reaction product 3-fluoro-2,
4-dichlorobenzotrifluoride chlorobenzotrifluoride was obtained.

[Effects of the invention] Conventional methods for introducing fluorine into aromatic compounds required multiple steps, required the use of borofluoric acid, which is harmful to the human body, and were not industrially advantageous. According to the method of the present invention, fluorine can be introduced into pensitrifluorides in one step, which is extremely advantageous industrially. In addition, the method of the present invention is particularly effective when it is desired to introduce fluorine into the meta position of the 10F3 group of pencitrifluorides.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula,
X is at least one selected from F, Br or Cl, m
▲There are mathematical formulas, chemical formulas, tables, etc.▼[In the formula, Xm is the same as above, n is an integer from 1 to 2]. ] A method for producing a benzotrifluoride derivative, which is characterized by obtaining a benzotrifluoride derivative represented by the following.