JPS5822135B2 - Method for fluorinating salicylaldehyde - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for the fluorination of salicylaldehyde, in particular,
The present invention relates to a process for producing fluorosalicylaldehyde, in particular 3-fluorosalicylaldehyde and 5-fluorosalicylaldehyde, by direct fluorination of salicylaldehyde with fluorine gas, optionally in an inert medium under the reaction conditions.

Conventionally, as a method for introducing fluorine into aromatic compounds (including heterocyclic compounds), the aromatic compound is nitrated, the nitro group is converted into an amine group, and then nitrous acid is added in borofluoric acid or hydrofluoric acid. After diazotization with soda, the obtained diazonium salt is thermally decomposed using the so-called Dieman method. Furthermore, chlorinated aromatic compounds having electron-withdrawing groups such as nitro groups are treated with an aprotic polar solvent such as dimethylformamide. Among them, the so-called halogen exchange method, which involves fluorination with an alkali metal fluoride, is known.

However, these methods use many expensive raw materials, require a large number of reaction steps, and have a low overall yield of the target product, and the former method in particular requires the handling of unstable diazonium salts. There are also drawbacks such as these, and it is difficult to say that it is a desirable method as an industrial method.

In recent years, direct liquid phase fluorination of aromatic compounds using fluorine gas has been proposed as a low-order fluorination method for aromatic compounds [for example, V. Gracarascas (V, Gra
Kauskas), The Journal of Organic Chemistry (J, Org, Chem, )
See Vol. 35, p. 723, 1970].

Methods for the fluorination of aromatic compounds using special fluorinating agents such as xenon difluoride have also been reported [The Journal of Organic Chemistry (J, O.
rg, Chem, ) Vol. 40, p. 807, 1975 and Chemical Communications (Chem + Co.
mmun, ) 1968, p. 8□06].

However, these methods have drawbacks such as difficulty in reaction control, handling risks, and low yields, except when specific compounds are used as raw materials (for example, see Japanese Patent Publication No. 54-3875). However, it has not been used industrially yet.

By the way, fluorosalicylaldehydes, such as 3
-For the production of fluoroaldehyde, 2-
A method in which fluorine is introduced from amino-4-chloroanisole by the Zieman method and then several steps are carried out [see US Pat. No. 2,576,064], in which an alkali salt of orthofluorophenol is carboxylated using a Kolbe-Schmidt reaction. Thereafter, a method of ring formation with sodium amalgam [see US Pat. No. 2,493,654], a method of synthesis from orthofluorophenol by Reimer-Tiemann reaction [Journal of the American Chemical Society (J-Am, Chem, Soc, ) No. 6
Vol. 8, p. 2502, 1946], air oxidation of 3-fluorosalicyl alcohol [see Japanese Patent Publication No. 54-9187], and aldehyde conversion of orthofluorophenol [see Japanese Patent Publication No. 54-9188]. It has been reported that.

However, all of these methods are industrially unsatisfactory, such as the contamination of isomers, the need for high-pressure equipment, the treatment of mercury, the large number of steps, the use of expensive starting materials, and low production yields. It's a method.

As a result of intensive research into a method for direct fluorination of organic compounds using fluorine gas, the present inventors have discovered that monofluorination of salicylaldehyde, in particular, the selection of 3- and 5-fluorosalicylaldehydes from salicylaldehyde in a one-step reaction. The present inventors have found a method that can be produced in a practical manner and is industrially satisfactory, and have completed the present invention.

According to the method of the present invention, monofluorination of salicylaldehyde can be carried out with high yield, and there is no need for nitration or ring element, which is a preliminary step to fluorine introduction, which was a drawback of the conventional method.

Furthermore, the method of the present invention does not require the use of expensive raw materials such as fluorosalicyl alcohol and fluorophenol, nor does it require the use of high-pressure equipment or mercury, and can be carried out in one step from the raw material salicylaldehyde. .

The method of the present invention preferably involves dissolving a raw material compound in a medium that is substantially inert under reaction conditions, and dissolving a fluorine gas in a temperature range above the freezing point and below the boiling point of the medium, with vigorous stirring or while circulating. The solution is brought into contact with the medium solution as it is or diluted with an inert gas.

The raw material compound used in the present invention is a substituted or unsubstituted salicylaldehyde, and examples of the substituent include halogen, an alkyl group, and an aryl group.

The raw material compound is subjected to the fluorination reaction as it is or, if necessary, diluted with a substantially inert medium under the reaction conditions.

As the inert medium, inorganic acids such as acetonitrile, halogenated hydrocarbons, diglyme, ether, hydrogen fluoride, hydrofluoric acid, and sulfuric acid are used, among others, halogenated hydrocarbons, acetonitrile, hydrogen fluoride, Hydrofluoric acid is preferred. Since this reaction is an exothermic reaction, it is desirable to remove heat in the reaction system by stirring or circulating the reaction solution in order to make the reaction proceed smoothly.

Fluorine gas is blown into the reaction medium neat, preferably diluted with an inert gas such as nitrogen, argon, etc., or introduced onto the surface of the reaction medium.

The reaction temperature is generally above the freezing point and below the boiling point of the inert medium.

As the reaction method, either a batch method or a continuous circulation method using a countercurrent contact method can be adopted.

In the reaction of the present invention, in order to increase the yield of the desired fluorinated product, the conversion rate of the raw material compound is maintained within a certain range (for example, 50 to 60%), and after the fluorinated product is separated and recovered, A method is adopted in which the remainder is subjected to the reaction again.

This makes it possible to significantly reduce the production of polymeric by-products that cause a decrease in yield.

In addition, in this reaction, side reactions can be suppressed using a dehydrofluorination agent, if necessary.

Examples of the dehydrofluorination agent include molecular sieves and sodium fluoride.

According to the method of the present invention, a monofluorinated product in which fluorine is introduced mainly at the ortho or para position relative to the hydroxyl group of the starting compound can be obtained, but depending on the reaction temperature, reaction time, or necessity. By selecting the type of medium used, the ratio of fluorine introduced into the ortho or para position can be changed.

Although the main purpose of the present invention is monofluorination, it is of course possible to carry out further fluorination depending on the reaction conditions.

As described above, the present invention provides a method for directly introducing fluorine into substituted or unsubstituted salicylaldehyde using fluorine gas, and if necessary, the inert medium, reaction temperature, and reaction time may be changed under the reaction conditions. This method makes it possible to selectively introduce fluorine into specific positions, and is a very advantageous method from an industrial perspective as it allows fluorine to be introduced into the raw material compound in one step compared to conventional methods. be.

Next, examples will be shown to specifically explain the method of the present invention.

Example 1 5.0 g (0,041 mol) of salicylaldehyde, 45 g of acetonitrile,
2 g of sodium fluoride is charged, and 0.062 mol of fluorine diluted with nitrogen is introduced over 4 hours while cooling to 2-4°C.

The reaction was completed at a conversion rate of salicylaldehyde of 93.8%, and the solvent acetonitrile was distilled off to obtain 1.70 g of a crude product.

The gas chromatography results showed 3-fluorosalicylaldehyde (0.979gC yield: 18.2%), 5-fluorosalicylaldehyde (0.42gC yield: 7.9%), unreacted raw material 0.31J', and a small amount of difluorosalicyl. It was an aldehyde.

3-Fluorosalicylaldehyde Boiling point 85-88°C/10 mvtHg Melting point 65-66°C Mass spectrometry m/e; 140 (M+), 122 (M
+-F), 111 (M-CHO), 94 (M+-CH
0+10H).

Elemental analysis, calculated value; C, 60,00%; H, 3,57%
; F, 13.57%, actual value; C, 59,23%; H,
3,27%; F, 12.89%.

5-Fluorosalicylaldehyde Melting point 81-83°C Example 2 5.0 g (0,041 mol) of salicylaldehyde was dissolved in 57.59 mol of anhydrous hydrofluoric acid, and 0.062 mol of fluorine was diluted with nitrogen. Introduce for 60 minutes at 4°C.

Hydrofluoric acid was distilled off to obtain 6.0 g of a crude product.

The results of gas chromatography analysis were 1.91 g (33.3%) of 3-fluorosalicylaldehyde, 0.41 g (7.1%) of 5-fluorosalicylaldehyde, and a small amount of unreacted raw materials and difluorosalicylaldehyde. .

Example 3 5.1 (0,041 mol) of salicylaldehyde was added to 1.1
．． Dissolved in 45 g of 2-trichloro-1,2,2-1-lifluoroethane (hereinafter referred to as Freon 113),
62 mol of fluorine are introduced diluted with nitrogen over a period of 90 minutes at 0-5°C.

Freon 113 was distilled off to obtain crude product 1.96.9.

The results of gas chromatography analysis showed that 3-fluorosalicylaldehyde 1.36g (25.6%), 5-fluorosalicylaldehyde 0.20p (3°8%), unreacted raw material 0.40g and a small amount of difluorosalicylaldehyde. there were.

Example 4 When the same procedure as in Example 1 was repeated except that sodium fluoride was not used, almost the same results as in Example 1 were obtained.

This shows that the addition of sodium fluoride does not substantially affect the reaction.

Claims (1)

[Scope of Claims] 1. A fluorination method characterized by fluorinating salicylaldehyde with fluorine gas and introducing fluorine into the salicylaldehyde. 2. The fluorination method according to claim 1, which is carried out in an inert medium under the reaction conditions. 3. The fluorination method according to claim 2, wherein the inert medium is a halogenated hydrocarbon, acetonitrile or an inorganic acid. 4. The fluorination method according to claim 2 or 3, wherein the reaction temperature is above the freezing point and below the boiling point of the inert medium. 5. The fluorination method according to claim 1, which uses fluorine gas diluted with an inert gas. 6. The fluorination method according to claim 1, wherein the products are 3-fluorosalicylaldehyde and 5-fluorosalicylaldehyde.