JPS63203636A - Fluorination of halogenated aromatic compound - Google Patents

Abstract

PURPOSE:To obtain the titled fluorinated compound in high yield, by substituting halogen of a halogenated aromatic compound having one or more halogen atoms other than F with fluorine using an alkali metal fluoride in the presence of a specific pyridinium compound. CONSTITUTION:A halogenated aromatic compound having at least one halogen atom other than F, e.g. 1,2,3-trichlorobenzene is made to react with an alkali metal fluoride such as KF at 100-200 deg.C under normal pressure or autogenous pressure for 2-50hr in the presence of a pyridinium compound of formula (R<1> is tert-amino; R<2> is >=3C alkyl) having high heat-resistance and enabling fluorination reaction at >=200 deg.C without decomposition, e.g. N-neopentyl-4-(N',N''- dimethylamino)-pyridinium chloride. The halogen atom of the halogenated aromatic compound is substituted with F by the reaction to obtain the objective compound useful for the production of a fluorinated aromatic compound useful as an intermediate for pharmaceuticals, agricultural chemicals, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a method for fluorinating a fluorinated aromatic compound to obtain a fluorinated aromatic compound useful as an intermediate for medicines, agricultural chemicals, etc. It is.

[Prior Art 1] A fluorination reaction in which a halogenated aromatic compound is reacted with an alkali metal fluoride to exchange a halogen atom such as a chlorine or bromine atom with a fluorine atom has been known for a long time. These reactions are generally carried out in an aprotic polar solvent such as dimethyl sulfoxide or sulfolane. There are also examples in which quaternary ammonium salts and phosphonium salt compounds are added to increase the reaction rate.

[Problem to be solved by the invention 1] A halogenated aromatic compound having an electron-withdrawing group such as a nitro group, a cyano group, or a trifluoromethyl group on the benzene ring has an ortho-position with respect to the electron-withdrawing group, or It is well known that since the halogen atom at the rose position is activated, it reacts with KF in an aprotic polar solvent and fluorine substitution of the halogen atom occurs. However, in the absence of an electron-withdrawing group, fluorine substitution is said to be difficult. It is also known that when attempting to fluorine such a halogen atom with low activity, the reaction rate is improved by fluorine substitution with KF in the presence of a quaternary ammonium salt or phosphonium salt. However, ammonium salts decompose at temperatures above 150°C and cannot be used for fluorination reactions at temperatures higher than this. Phosphonium salts can be used up to 200°C, but their additive effect is lower than that of ammonium salts. It has disadvantages, such as the fact that it is difficult to substitute fluorine for halogen atoms, which are small and have low activity.

[Means for Solving the Problems] The present invention has been made to solve the problems of the prior art, such as low reaction rate and inability to react at high temperatures. In a method for fluorinating a halogenated aromatic compound in which the halogen atom of the halogenated aromatic compound having at least one halogen atom is replaced with fluorine using an alkali metal fluoride, the fluorination reaction is carried out by the following general formula ( The present invention relates to a method for fluorinating a halogenated aromatic compound, which is carried out in the presence of a pyridinium compound represented by I).

(In the formula, R1 represents a tertiary amino group, and R2 represents an alkyl group having 3 or more carbon atoms.) The halogenated aromatic compound as a starting material contains at least one halogen atom other than fluorine, such as chlorine or bromine, in the aromatic nucleus. It is a compound with

Particularly preferred are derivatives having at least one chlorine atom and/or bromine atom.
Examples of electron-withdrawing groups which may have fluorine atoms include nitro groups, cyano groups, carboxyl groups, trifluoromethyl groups, etc. The feature of the present invention is that compounds without these electron-withdrawing groups Even if it is present, it can be easily fluorinated. Specific examples of such halogenated aromatic compounds include chlorobenzenes such as 1,2,3-trichlorobenzene, and chlorobenzonitrile such as metachlorobenzonitrile.

3.4-dichlorobenzotrifluoride, 2,3,4
．． Examples include chlorobenzonylilulides such as 5-tetraqualobenzotrifluoride, nitrobenzenes such as 3,4-dichloronitrobenzene, and 2,3,4-trichloronitrobenzene.

According to the present invention, halogen atoms other than fluorine atoms in a halogenated aromatic compound are substituted with fluorine atoms. When there are two or more halogen atoms other than fluorine atoms, only one of them can be replaced with the fluorine layer F, or all two or more halogen atoms can be replaced with fluorine atoms. The degree of fluorine substitution can be adjusted by adjusting the reaction temperature, reaction time, and other fluorination conditions.

The pyridinium compound used in the present invention has the following general formula (I
) can be expressed as

In the formula, R1 represents a tertiary amine 7 group, R2 represents an alkyl group having 3 or more carbon atoms, and R1 preferably represents (provided that) 73. )74 each represents an alkyl group, or R3 and R4 may form a ring.

When R3 and R11 each represent alkyl) &, it is suitably a fullylene group having 1 to 12 carbon atoms, especially
1 to 6 alkyl groups are preferred, in which case R3, R4
It is particularly preferred that R3 are the same alkyl group.
When forming a ring with R4 and
A fullkylene group having carbon a4 to a6 forming a 7-membered heterocycle is preferable, and a pentamethylene group forming a piperidine ring is particularly preferable.Furthermore, the alkylene group forming this heterocycle includes a substituent such as an alkyl group. and R2 has 4 to 12 carbon atoms. Particularly preferred are 5-8 branched or straight-chain alkyl groups.

The pyridinium compound added in the present invention is Tetr
ahedron Letters, 25.3383 (
For example, it can be obtained by the following reaction.

Kon? H3 CHiS03CI2G-CH3 The fluorination reaction is carried out in the presence of a pyridinium compound represented by the general formula CI) without a solvent or in an aprotic polar solvent by allowing an alkali metal fluoride to act on a halogenated aromatic compound. Can be done. As the solvent, dimethylsulfoxide, sulfolane, tomethyl-2-pyrrolidone, dimethylformamide, dimethylsulfone, acetonitrile, hexamethylphosphortriamide, benzonitrile, etc. can be used. As the alkali metal fluoride, potassium fluoride is preferred because it is easy to handle and is commercially available, especially spray-dried fine particulate potassium fluoride. An error range is 0.5 to 10 times, preferably 1.1 to 2 times, the mole of the halogen atom to be substituted with fluorine. The amount of the pyridinium compound represented by the general formula (I) used is preferably 0.001 to 1.0 parts by weight, preferably 0.01 to 0.1 parts by weight, based on the halogenated aromatic compound as the raw material. be.

The reaction temperature of the present invention is suitably in the range of 100 to 300°C, preferably 130 to 250°C. The reaction time may be carried out under pressure with an inert gas such as 2 to 50 hours, although it varies depending on the degree of the reactor and the raw materials.

In general, halogen exchange reactions are preferably carried out under anhydrous conditions as much as possible in order to increase the reaction rate and to avoid side reactions. Potassium fluoride, solvents, etc. used in the zero-water reaction are all highly hygroscopic, so the reaction The reaction product obtained according to the method of the present invention is preferably thoroughly dehydrated beforehand, and the target substance fluorine can be easily obtained in extremely high yield through ordinary separation operations such as filtration, solvent distillation, extraction, and distillation. aromatic compounds can be obtained.

Examples of the present invention will be described in more detail below.

[Example] Example 1 In a 2001 autoclave, 50 g (Q, 275 mol) of 1.2.3-trichlorobenzene, 50 g (0,882 mol) of spray-dried potassium fluoride, and N-neopentyl-4-(N', N 2.5 g of '-dimethylamino)-pyridinium chloride was charged with 100 g of sulfolane as a solvent and reacted at 210°C for 30 hours with vigorous stirring. Gas chromatography analysis of the reaction solution revealed that the reaction rate of the raw materials was 30%. The selectivity to l,3-dichloro-2-fluorobenzene was 91%.

Comparative Example 1 Toneopentyl-4-(N',N'-dimethylamino)-pyridinium chloride was charged into a reactor under the same conditions as in Example 1, except that 4-(N',N'-dimethylamino)-pyridinium chloride was not added, and the mixture was reacted at 250°C for 30 hours with vigorous stirring. When the reaction solution was analyzed by gas chromatography, the reaction rate of the raw materials was 1% or less.

Example 2 In a 2001 glass reactor equipped with a reflux condenser, 20 g (0,145 mal) of metachlorobenzonitrile,
Spray dried KF 1B, 9g (0,291mol)
, sulfolane 50g, toneopentyl-4-(N'
, N'-dimethylamino)-pyridinium chloride 1g
Prepared.

Gas chromatography analysis of the 0 reaction solution reacted at 230° C. for 10 hours revealed that the reaction rate of the raw materials was 35% and the selectivity to metafluorobenzonitrile was 89%.

Example 3 In a 2001 autoclave, 50 g (0,2329 mol) of 3,4-dichlorobenzotrifluoride, 27 g (0,488 mol) of spray-dried KF, 100 g of sulfolane, toneopentyl-4-(N',N'-dimethylamino)-pyridinium chloride Gas chromatography analysis of the reaction solution, which was prepared by charging 2 g and reacting at 180°C for 15 hours with vigorous stirring, revealed that the selectivity to 3,4-difluorobenzotri7-olide was 22%, and the remainder was 3-dichloro-4. -fluorobenzotrifluoride.

Example 4 2001 200 g of 2,3,4,5-tetrachlorobenzotrifluoride (0,070 mal
), spray dried K F 24.5g (0,422s+
ol), sulfolane 50g, neopentyl-4-(
When 2 g of N', N'-dimethylamino)-pyridinium chloride was charged and reacted at 180°C for 9 hours with vigorous stirring, the reaction solution was analyzed by gas chromatography, and the reaction rate of the raw materials was 100%, 2,3L4,5 - Selectivity to tetrachlorobenzotrifluoride 14%, 5-chloro-2
The selectivity to ,3,4-trifluorobenzotrifluoride was 43%, and the selectivity to 3,5-dichloro-2,4-difluorobenzotrifluoride was 11%.

Example 5 In a 2001 glass reactor equipped with a reflux condenser
, 50 g of 4-dichloronitrobenzene, spray dried K
F20g, N-(2-ethyl-hexylamino)
265 g of -4-(N', N'-dimethyl)-pyridinium chloride and sulfolane IQO were charged and reacted at 190°C for 15 hours with vigorous stirring. Gas chromatography analysis of the reaction solution revealed that the reaction of the raw materials was 4< tt
10 (1%, the selectivity to 3,4-difluoronitrobenzene was 23%, and the selectivity to 3-chloro-4-fluoronitrobenzene was 52%.

Example 6 In a 2001 glass reactor equipped with a reflux condenser
．． 3.4-) 50 g of dichloronitrobenzene, spray dried KF2O,, N-neopentyl-4-(N',
N'-dibutylamino)-pyridinium chloride 2.5
g, and 100 g of sulfolane were added thereto and reacted at 150°C for 12 hours with vigorous stirring. When the reaction solution was analyzed by gas chromatography, the reaction rate of the raw material was t* too%, 2
, 3.4-) Selectivity to refluoronitrobenzene 1s
%, the selectivity to 3-chloro-2,4-difluoronitrobenzene was 46%.

Comparative Example 2 It was charged into a reactor under the same conditions as in Example 3, except that toneopentyl (N', N'-dimethylamino)-pyridinium chloride was replaced with tetrabutylphosphonium chloride, and heated at 185°C for 15 minutes with vigorous stirring. Gas chromatography analysis of the reaction solution reacted for 1 hour revealed that the selectivity to 3,4-difluorobenzotrifluoride was 2%, and the rest was 3-difluorobenzotrifluoride.
It was chlorofluorobenzotrifluoride.

Comparative Example 3 N-(2-ethyl-hexylamino)-4-(N',
N'dimethyl)pyridinium chloride was replaced with tetramethylphosphonium chloride, the same conditions as in Example 5 were used to charge the reactor, and the temperature was heated to 150°C while stirring vigorously.
When the reaction solution reacted for 10 hours was analyzed by gas chromatography, the main product was 3-chloro-4-fluoronitrobenzene, and the selectivity to 3,4-difluoronitrobenzene was 1% or less. Furthermore, the reaction temperature was increased to 190℃
Although the reaction was continued, the E reaction did not proceed any further.

[Effect of the Invention 1] The pyridinium compound of the present invention has high heat resistance, so it is possible to perform a fluorination reaction at 200° C. or higher without decomposing, and the fluorination reaction can be carried out with a correspondingly higher yield. Furthermore, it has extremely high fluorination activity compared to conventional quaternary ammonium salts, phosphonium salts, etc., and can obtain fluorinated products in high yield.

Claims (1)

[Scope of Claims] In a method for fluorinating a halogenated aromatic compound, the halogen atom of the halogenated aromatic compound having at least one halogen atom other than a fluorine atom is substituted with fluorine using an alkali metal fluoride, A method for fluorinating a halogenated aromatic compound, characterized in that the fluorination reaction is carried out in the presence of a pyridinium compound represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼------(I) (In the formula, R^1 represents a tertiary amino group, and R^2 represents an alkyl group with 3 or more carbon atoms.)