JPS6072850A - Preparation of fluorinated benzonitrile - Google Patents

Abstract

PURPOSE:To obtain the titled compound in high yield, by reacting a nucleus- chlorinated benzonitrile with potassium fluoride in dimethyl sulfoxide with controlling the reaction temperature with the progress of the reaction. CONSTITUTION:A nucleus-chlorinated benzonitrile is reacted with potassium fluoride in a solvent of dimethyl sulfoxide, the temperature is kept at <=165 deg.C until the nucleus halogen substitution ratio reaches at least 35%, and the reaction is then completed at high temperature of >=165 deg.C to give a fluorinated benzonitile. The reaction rate of high-boiling by-product is suppressed by controlling the reaction temperature at two stages in the solvent, and since a large amount of potassium fluoride is present in the reaction system at the early stage of the reaction, the reaction is advanced at low temperature (preferably at 130-165 deg.C), so the final yield can be raised. The fluorine substitution ratio is obtainable by using part of the reaction solution by gas chromatography, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing fluorinated benzonitriles. Specifically, the present invention relates to an industrially advantageous method for producing a benzonitrile compound having a fluorine atom, which is useful as an intermediate for pharmaceuticals, agricultural chemicals, and the like.

Conventionally, fluorinated benzonitriles are produced by reacting nuclear chlorinated benzonitriles (hereinafter simply referred to as chlorobenzonitrile compounds) with a fluorinating agent, particularly potassium fluoride, in an aprotic polar solvent under heating. It is known that it is manufactured by Shiro. In this case, dimethyl sulfoxide is particularly preferable as an aprotic polar solvent because it has high polarity and is advantageous in terms of reaction rate, is liquid at around room temperature and is easy to handle, and is relatively inexpensive. ing. In addition, the reaction temperature is generally the boiling point of dimethyl sulfoxide or a temperature as high as possible near the boiling point, usually 17
It was carried out at 5-190°C.

However, in the conventional method as described above, a by-product of the desired fluorinated benzonitrile is produced, which not only causes a decrease in yield but also complicates the separation operation after the reaction.

In particular, when multiple chlorine atoms bonded to a benzonitrile compound as a raw material are substituted with fluorine in a dimethyl sulfoxide solvent to obtain a benzonitrile compound bonded to multiple fluorines, the yield decreases significantly. . A detailed analysis of the by-products at this time revealed that, for example, a compound pipe with a structure having a benzene ring substituted with one or more methylthio groups, and a by-product with a higher boiling point than the compound, were produced in considerable amounts. I found out that I was doing it. Although such by-products can be suppressed by keeping the reaction temperature low, the reaction rate becomes slow and the reaction efficiency deteriorates. In view of the above problems, the present inventors conducted detailed research on the reaction of replacing chlorine atoms bonded to benzonitrile compounds with fluorine in a dimethyl sulfoxide solvent, and found that by controlling the reaction temperature as the reaction progresses, by-products can be produced. The present inventors have discovered that the production of fluorinated benzonitriles can be effectively suppressed and the desired fluorinated benzonitriles can be obtained efficiently, leading to the completion of the present invention.

That is, the present invention uses dimethyl sulfoxide as a solvent when performing nuclear halogen substitution of radicalized benzonitriles with potassium fluoride, and maintains the temperature below 165 ° C. from the start of the reaction until the fluorine substitution rate reaches at least 35%. This is a method for producing benzoni]zyl fluoride, which is characterized in that the reaction is then carried out at a temperature higher than 165°C.

The fluorine substitution rate as used herein is the proportion (%) of all chlorine atoms to be substituted with fluorine. For convenience, a portion of the reaction solution is extracted and analyzed by gas chromatography, liquid chromatography, etc. to determine the molar ratio of the raw chlorobenzonitrile compound, intermediate fluorine compound, and target fluorinated compound contained therein. If you know, you can roughly estimate the value.

For example, when the raw material is dichlorobenzonitrile, if the molar ratio of dichlorobenzonitrile, monochloromonofluorobenzonitrile, and difluorobenzonitrile in the reaction solution at a certain point is A:B:C, the substitution rate is calculated by the following formula: It will look like this.

Substitution rate (%) - (B+ 20/ 2x (A+B 10)) x 100 According to the present invention, the production of by-products as described above is extremely small, the yield of the target product is high, and the reaction rate is Since the speed is also sufficiently high, it can be carried out industrially advantageously.

31 The chlorbenidryl compound which is the raw material of the present invention is, for example, a compound in which a chlorine atom is bonded to the ortho or para position with respect to a cyan group, such as 2-chlorobenzonitrile or 4-chlorobenzonitrile, or 2. 4-dichlorobenzonitrile, 2,6-dichlorobenzonitrile, 2,4.6-
Some chlorine atoms, such as t-lychlorobenzonitrile, have multiple chlorine atoms bonded to the ortho or para position with respect to the cyano group.

The number of cyan groups is usually one, but may be two. Such compounds include 1,3-dicyano-4-chlorobenzene, 1,2-dicyano=3.4,5,6-titrachlorobenzene, 1,4-dicyano-2,3,5,6-
Examples include chitrachlorobenzene. In addition, compounds in which the hydrogen atom of these compounds is substituted with an alkyl group, etc.
Alternatively, a compound in which the meta position of the cyano group is substituted with a halogen atom may also be used. Among these, particularly favorable results can be obtained when the present invention is applied to 2,4-dichlorobenzonitrile or 2,6-dichlorobenzonitrile.

The dimethyl sulfoxide used in the present invention must be sufficiently dehydrated; if it contains water, the reaction rate will be slow, and the amount of by-products will increase, reducing the yield of the product. .

Dehydration can be done using alumina, calcium hydride, etc.
Methods such as passing through a molecular sieve column and azeotropic dehydration using benzene etc. are used. The above-mentioned dimethyl sulfoxide is generally used in a weight ratio of 2 to 10 times that of the raw material chlorobenzonitrile.

Potassium fluoride is used as the fluorinating agent in the present invention. Generally, potassium fluoride has deliquescent properties, but in the present invention, it is necessary to use it in a sufficiently dry state, otherwise problems similar to those of dimethyl sulfoxide described above will occur. For this purpose, potassium fluoride obtained by a wet synthesis method is crushed and roasted before use, or potassium fluoride obtained by a spray drying method is used. In particular, it has recently been discovered that fine particulate anhydrous potassium fluoride, which is different from conventional wet-synthesized potassium fluoride, can be synthesized by spray drying, and that it can be used to perform substitution reactions of various active chlorine-containing compounds.
It has been reported that the reaction speeds up and the yield greatly improves. In the present invention, preferable results can also be obtained when potassium fluoride obtained by the above-described spray drying method is used.

The amount of potassium fluoride used is 1 equivalent of the theoretically necessary number to fluorine the raw material chlorobenzonitrile compound.
It may be up to 2 times, and is usually used in the range of 1 to 1.5 times.

In particular, when potassium fluoride obtained by spray drying is used, it is used in a smaller amount, usually 1.0 to 1.2 times.

In addition, in order to promote the substitution reaction with potassium fluoride, some catalysts such as cesium fluoride, cesium chloride, tertiary amine, crown ether, polyethylene glycol, etc. may be added to the reaction system, but in this case also. The invention may be implemented in a similar manner.

The present invention is characterized in that the reaction temperature is controlled according to the progress of the reaction. That is, the reaction temperature is maintained at 165°C or less from the start of the reaction until the substitution rate reaches at least 35%, and once the reaction has progressed to the range of the above conditions, the reaction is thereafter completed at a temperature higher than 165°C. It is. In particular, it is important to keep the initial temperature of the reaction lower than 165°C.

The reason why the method of the present invention exhibits remarkable effects is not clear at present, but the inventors of the present invention think as follows. In other words, the compound partially substituted with fluorine and the raw material are much more unstable in the reaction system than the target compound substituted with fluorine, and react with the compound itself or with dimethyl sulfoxide, resulting in a high boiling point. Easily generates by-products. (2) The reaction rate for producing the above-mentioned high-boiling-point by-products decreases below 165°C. ■At the beginning of the reaction, a large amount of potassium fluoride is present in the reaction system, so the reaction temperature is set at 130-165°C.
No matter how low the temperature is, anti-7 still progresses at a considerable speed.

At this time, the upper limit of the fluorine substitution rate is not particularly limited, but if it is too high, the reaction rate will be slow, so it is generally carried out at 80% or less.

If the reaction is carried out at the same temperature from the start to the completion of the reaction without following the invention, the effects of the invention cannot be obtained. For example, if the entire reaction is carried out at a temperature of 165° C. or lower, the yield of the target product will be extremely low even if the reaction is carried out for a long time. Furthermore, when the reaction is carried out at a temperature higher than 165°C, the yield of the target product decreases due to the increase in by-products as described above.

In the present invention, the selection of temperature conditions when controlling the reaction temperature in two stages is determined by the type of raw materials and the
Since the temperature differs depending on the one-t construction, etc., it is sufficient to conduct an experiment in advance and determine the temperature within a range that satisfies the above-mentioned temperature conditions. In this case, the fluorine substitution rate is 35% after the start of the reaction, preferably 35%.
If the reaction temperature to reach 5-80% is higher than 165°C, by-products will increase. Regarding the lower limit, especially limit 8
- However, if the temperature is too low, the reaction will not proceed, so it is generally preferable to carry out the reaction in the range of 130 to 165°C. On the other hand, the reaction temperature after the fluorine substitution rate reached 35% or more was 1
If the temperature is lower than 65°C, the reaction rate is slow and the reaction may not be completed. The upper limit is not particularly limited, but in order to increase the final reaction rate, it is 175 to 19
0°C is preferred.

When determining the reaction temperature at the initial stage and the latter stage of the reaction according to the present invention, each temperature may be kept constant, or either or both may be increased over time. The reaction time is 1 to 20 hours, although it varies depending on the type of tribenzonitrile used as a raw material, reaction temperature, etc.

According to the present invention, the target product can be obtained with a high yield of 82% or more.

As described above, the present invention is characterized by specifying the reaction temperature. Therefore, conditions other than the reaction temperature, such as the material and structure of the reaction vessel, or the reaction method, are not particularly limited, but it is preferable to stir vigorously during the reaction.

Further, in order to separate the desired product and increase its purity, after the reaction, filtration, centrifugation, etc. are performed as necessary, and then operations such as steam distillation, atmospheric distillation or vacuum distillation, extraction, etc. are performed. Typically, the solvent is separated and reused. Suppression of the production of high-boiling point by-products is very advantageous in terms of separation operations.

EXAMPLES Hereinafter, examples will be shown to explain the present invention in detail, but the present invention is not limited to the following examples.

Example 1 For the purpose of obtaining 2.6-difluorobenzonitrile, 2.
40 g of 6-cyclobenzonitrile, 31 g of anhydrous potassium fluoride obtained by spray drying, and 141 g of dimethyl sulfoxide were placed in a flask and heated to 145 g with stirring.
The reaction was carried out by heating at 155°C for 1 hour, then at 185°C for 1 hour and 30 minutes. 2,6-dichlorobenzonitrile contained in the reaction solution after performing the reaction at 155°C.

2-chloro-6-fluorobenzonitrile, 2.6-
Cyfluorobenzoni 1-lyl has a molar ratio of 9=41:50
Met. This corresponds to a fluorine substitution rate of 70.5%.

After the reaction is complete, water is added and steam distillation is performed to dry the distilled oil, followed by vacuum distillation to reduce the boiling point to 98-102°C (
2.6=difluorobenzonitrile 2 at 30 mmHg)
9.4 (1 (yield 91%).

0.8 g of 2-chloro-6-fluorobenzonitrile with a boiling point of 103-105°C (11aonHO) was obtained.

In addition to these, a white to yellow by-product with a higher boiling point was obtained as a solid. As a result of analysis, it was found that 2-di-11-lo-6-(methylthio)benzonitrile, 2-fluoro-6-(methylthio)benzonitrile, etc. were contained. Note that the raw material 2,6-dichlorobenzonitrile did not remain.

12- Comparative Example 1 The reaction and separation operations were carried out in exactly the same manner as in Example 1, except that the reaction temperature was 185° C. and the reaction time was 2 hours and 20 minutes. This allows 2,6-cyfluorobenzonitrile 2
4.6 (1 (76% yield)) and 0.7 (1) of 2-chloro-6-fluorobenzonitrile were obtained.

It was found that much more high-boiling point by-products were produced than in Example 1. There was no remaining raw material 2,6-dichlorobenzonitrile.

Note that when the reaction time was shorter than 2 hours and 20 minutes, the fluorine reaction became insufficient and the amount of 2-chloro-6-fluorobenzonitrile remaining increased.

Comparative Example 2 The reaction and separation operations were carried out in exactly the same manner as in Example 1, except that the reaction was carried out by heating at 145° C. for 45 minutes and then at 185° C. for 2 hours and 10 minutes. The fluorine substitution rate after the reaction at 145°C was 13%. This results in 2
．． 6-Cyclolbenzonitrile 25.5a (yield 79
%) and 2-chloro-6-fluorobenzonitrile 1.8
I got g. There was no remaining raw material 2,6-dichlorobenzonitrile. As in Comparative Example 1, a large amount of high boiling point by-products were obtained. If the reaction time is shorter than 2 hours and 10 minutes, the fluorination reaction becomes insufficient and 2-chloro-6
-The amount of fluorobenzonitrile remaining increased.

Example 2 40q of 2-chlorobenzonitrile, 20(l) of anhydrous potassium fluoride obtained by a spray drying method, and 140g of dimedyl sulfoxide were placed in a flask and heated at 160°C under stirring.
The reaction was carried out by heating at 180 to 190° C. for 1 hour and 30 minutes. The fluorine substitution rate after the reaction at 155°C was 68%. After the reaction was completed, the same operation as in Example 1 was performed to obtain 2-fluorobenzonitrile 2
9.9 (1 was obtained (yield 85%).

15- Comparative Example 3 The reaction was carried out in exactly the same manner as in Example 1 except that the reaction temperature was 155° C. and the reaction time was 7 hours. A portion of the reaction solution was sampled, and the molar ratio of 2,6-dichlorobenzonitrile, 2-chloro-6-fluorobenzonitrile, and 2,6-difluoropendinitrile contained therein was determined to be 2:27: It was 71.

patent applicant Tokuyama Soda Co., Ltd. 16-

Claims (1)

[Claims] 1) When performing nuclear halogen substitution on nuclear benzonitrile chlorides with potassium fluoride, dimethyl sulfoxide is used as a solvent, and the temperature is maintained at 165°C or lower until the substitution rate reaches at least 35%, and then at a temperature higher than 165°C. 1 of the fluorinated benzonitriles that are characterized by their ability to complete the reaction! ! Construction method.