JPH06298734A - Production of fluorinated pyridines - Google Patents

Abstract

PURPOSE:To efficiently and safely obtain fluorinated pyridines under industrially advantageous conditions at a high rate of reaction by fluorinating halogenated pyridines with a fluorinating agent in the presence of a tertiary amine. CONSTITUTION:Halogenated pyridines expressed by formula l {X is Cl, Br or I; R is alkyl or fluorinated alkyl; k is 1-5; m is 1-5; n is 0 or 1; k is >=m; [k+m+n] is <=5} are fluorinated with a fluorinating agent (especially an alkali metallic fluoride such as KF) in the presence of a tertiary amine such as triethylamine or tri-n-propylamine to afford fluorinated pyridines expressed by formula II (e.g. 2-fluoropyridine). A fluorinating catalyst such as tetramethylammonium chloride is preferably further used in this reaction. It is important to carry out the fluorinating reaction in the presence of the tertiary amine for the reaction. Thereby, the production of fluorine can be suppressed and this method is a safe one for the working environment. The resultant compounds are useful as an intermediate for medicines, agrichemicals and functional substances such as a liquid crystal.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing fluorinated pyridines, which is useful as an intermediate for medical and agricultural chemicals or an intermediate for functional substances such as liquid crystals.

[0002]

2. Description of the Related Art The following methods are known as conventional methods for producing fluorinated pyridines. (1) Method of diazofluorination of aminopyridines with sodium nitrite in anhydrous hydrofluoric acid (J. Fluorine Chem., 3
8 (3), 435-8,1988). (2) Method for denitrofluorination of halogenated nitropyridines with alkali metal fluoride (DE3,700,779).

(3) A method of reacting halogenated pyridines with an alkali metal fluoride in an aprotic polar solvent such as sulfolane (11th Symposium of Japan Fluorine
Chemistry, Nagoya, October 1986 Abstr., No. 2E-15). (4) A method of fluorinating 2,3-dihalo-5-trifluoromethylpyridine with KF or CsF in the presence of a catalyst (USP 5,073,637).

[0004]

[Problems to be Solved by the Invention]

The method (1) is highly dangerous because it uses anhydrous hydrofluoric acid, and since it is necessary to add solid sodium nitrite at -70 ° C or lower, it is difficult to carry out industrially.

In the method of denitrofluorination of (2), since the decomposition product of the nitrite produced as a by-product has extremely high reactivity, a reaction with a raw material or a product occurs and the yield of the target compound becomes low. Will end up.

The method (3) has a problem that HF is likely to be generated and a by-product derived from the solvent is generated.

Since the method (4) easily produces HF,
There is a problem of reduced yield due to corrosion of the reactor and dimerization of products. In order to improve this, a method of adding potassium carbonate as a deoxidizing agent has been proposed, but in the presence of an inorganic base, the activity of the fluorination catalyst decreases and the yield of the target product decreases.

[0008]

The present invention has been made to solve the above-mentioned problems. That is, the chemical formula (1)
The halogenated pyridines represented by are fluorinated with a fluorinating agent in the presence of a tertiary amine,
It is a method for producing a fluorinated pyridine represented by the chemical formula (2).

[0009]

[Chemical 3]

[0010]

[Chemical 4]

In the formula, X represents a chlorine atom, a bromine atom or an iodine atom. When X is 2 or more, it is the same atom or a combination of different atoms. R represents an alkyl group or a fluorinated alkyl group. k is an integer of 1 to 5, m is an integer of 1 to 5, and n is 0 or 1. Also, k ≧ m, k
+ M + n ≦ 5.

The alkyl group in the chemical formulas (1) and (2) is not particularly limited, but a lower alkyl group is preferable from the viewpoint of easy availability, and particularly preferably a group having 4 or less carbon atoms.

The fluorinated alkyl group in the chemical formulas (1) and (2) is an alkyl group in which at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Also in the case of a fluorinated alkyl group, a lower fluorinated alkyl group is preferable from the viewpoint of easy availability, and a case where the carbon number is 4 or less is particularly preferable. Further, among the fluorinated alkyl groups, a perfluoroalkyl group in which all hydrogen atoms are replaced by fluorine atoms is preferable, and a trifluoromethyl group is particularly preferable.

The alkyl group and fluorinated alkyl group may have either a linear structure or a branched structure.

When the number of X's in the halogenated pyridines of the chemical formula (1) is 2 or more, a combination of the same chlorine atom or bromine atom is preferable since it is easily available.

Examples of the halogenated pyridines represented by the chemical formula (1) are shown below, but the invention is not limited thereto. 2-chloropyridine, 4-chloropyridine, 2-bromopyridine, 3
-Monohalogenated pyridines such as bromopyridine and 2-iodopyridine. 2,5-dichloropyridine, 2,6
-Dichloropyridine, 2,5-dibromopyridine, 2,
6-dibromopyridine, 2,5-diaiodopyridine,
Dihalogenated pyridines such as 2,6-diaiodopyridine.

2,3,6-trichloropyridine, 2,
Trihalogenated pyridines such as 3,5-trichloropyridine, 2,3,6-tribromopyridine and 2,3,5-tribromopyridine. Tetrahalogenated pyridines such as 2,3,5,6-tetrachloropyridine and 2,3,5,6-tetrabromopyridine. Pentahalogenated pyridines such as 2,3,4,5,6-pentachloropyridine and 2,3,4,5,6-pentabromopyridine. 2,3-dichloro-5-trifluoromethylpyridine and the like.

The above halogenated pyridines are commercially available and can be easily obtained.

In the present invention, it is important to carry out the fluorination reaction in the presence of a tertiary amine, whereby the generation of hydrofluoric acid can be suppressed. Therefore, fluorinated pyridines can be produced under conditions more advantageous than conventional methods and in a safer working environment.

When a primary amine or secondary amine having a structure in which a hydrogen atom is bonded to a nitrogen atom is selected instead of the tertiary amine of the present invention, HF may be generated during the reaction. Therefore, in the present invention, it is important to select a tertiary amine having a structure in which a hydrogen atom is not bonded to a nitrogen atom.

The tertiary amine is not particularly limited and may be a known or well known tertiary amine.
For example, triethylamine, tri-n-propylamine,
Tri-i-propylamine, tri-n-butylamine,
Tertiary amines such as tri-i-butylamine, trioctylamine, N-alkylpyrrolidine, N-alkylpiperidine and the like can be mentioned.

Further, the tertiary amine of the present invention may be a diamine. Also in the case of diamine, one having a tertiary amine structure in which hydrogen is not bonded to the nitrogen atom is selected.

Examples of the diamine include known or well-known diamines. Examples thereof include diamines such as tetramethylethylenediamine, tetraethylethylenediamine, tetramethyltrimethylenediamine, tetramethylhexamethylenediamine, and N, N-dialkylpiperazine.

The tertiary amine of the present invention may be a polyamine such as triamine or tetraamine. Also in the case of polyamines, those having a tertiary amine structure in which hydrogen is not bonded to the nitrogen atom can be selected.

The amount of the above amine is 0.001 to 1.0 part by weight, preferably 0.008 to 0.5 part by weight, based on 1 part by weight of the halogenated pyridine compound as a raw material.

The fluorination reaction of the halogenated pyridine represented by the chemical formula (1) of the present invention can be carried out by using an alkali metal fluoride as the fluorinating agent. As the alkali metal fluoride, NaF, KF, or C
Examples thereof include sF, and among these, KF is preferable,
In particular, fine particles of KF spray-dried are preferable.

The amount of the fluorinating agent is preferably 0.5 to 10 equivalents, more preferably 0.6 to 2.5 equivalents, based on the number of X's in the halogenated pyridines.

In the fluorination reaction of the present invention, a fluorination catalyst may be present as a reaction accelerator. As the fluorination catalyst, fluorination catalysts such as quaternary ammonium salt, quaternary phosphonium salt, and pyridinium salt can be used.

Examples of the fluorination catalyst will be given below, but the invention is not limited thereto. Tetramethylammonium chloride,
Quaternary ammonium salts such as tetrabutylammonium chloride. A fourth phosphonium salt such as tetrabutylphosphonium bromide and tetraphenylphosphonium bromide. N
-Neopentyl-4- (N ', N'-dimethylamino)
-Pyridinium chloride, N-neopentyl-4-
Pyridinium salts such as (N ′, N′-dibutylamino) -pyridinium chloride.

These fluorination catalysts may be used alone or in combination.
More than one species can be used. The amount of the fluorination catalyst used was 0.
001 to 1.0 part by weight, preferably 0.01 to 0.5 part by weight.

The fluorination reaction of the present invention can be carried out under any condition without solvent or in the presence of solvent.

When carried out in the presence of a solvent, aprotic polar organic solvents are preferred. Examples of the aprotic polar organic solvent include dimethylacetamide, sulfolane, benzonitrile, N, N'-dimethylimidazolidinone and the like. The amount of solvent is halogenated pyridine 1
0.1 to 10 parts by weight, preferably 0.5
~ 5.0 parts by weight is preferred.

The fluorination reaction of the present invention is usually carried out under heating. The reaction temperature is preferably 100 to 450 ° C, particularly preferably 150 to 250 ° C.

The fluorination reaction of the present invention can be carried out either under normal pressure, under the generation of natural pressure, or under pressure.
When it is carried out under pressure, it is preferable to pressurize with an inert gas such as nitrogen.

The reaction time may be appropriately changed depending on the kinds and amounts of the raw materials and the catalyst, the reaction temperature, etc., but in the usual case, it is preferably about 2 to 50 hours.

Examples of the fluorinated pyridines represented by the chemical formula (2) of the present invention are given, but not limited thereto.

2-fluoropyridine, 3-fluoropyridine, 2-fluoro-5-chloropyridine, 2-fluoro-5-bromopyridine, 2-fluoro-5-iodopyridine, 2,5-difluoropyridine, 2- Fluoro-6-chloropyridine, 2-fluoro-6-bromopyridine, 2-fluoro-6-iodopyridine, 2,6-
Difluoropyridine, 2-fluoro-3,5-dichloropyridine, 2,3-difluoro-5-chloropyridine,
2,3,5-trifluoropyridine, 2,3-difluoro-5-trifluoromethylpyridine, 2-fluoro-3-chloro-5-trifluoromethylpyridine and the like.

[0038]

【Example】

Example 1 In a 500 ml Hastelloy autoclave, 100 g (0.88 mol) of 2-chloropyridine,
60 g (1.0 mol) of spray-dried potassium fluoride,
1 g of tri-n-butylamine, 3 g of tetraphenylphosphonium bromide and 200 g of benzonitrile were charged, and the reaction was carried out at 240 ° C for 10 hours while vigorously stirring. The pressure rose to 3.0 kg / cm ² .

Next, the reaction crude liquid was suction filtered to remove the spray-dried potassium fluoride. When the filtrate was analyzed by gas chromatography, the reaction rate of the raw materials was 92% and the selectivity to 2-fluoropyridine was 88%. The amount of HF in the crude liquid after the reaction was quantified by the titration method.
It was below ppm.

Example 2 In a 500 ml Hastelloy autoclave, 100 g of 2,6-dichloropyridine was added.
(0.67 mol), spray dried potassium fluoride 80
g (1.4 mol), tri-n-butylamine 10 g,
Tetrabutylphosphonium bromide (10 g) and sulfolane (200 g) were charged, and the reaction was carried out at 185 ° C. for 10 hours with vigorous stirring. The pressure rose to 2.0 kg / cm ² .

Next, the reaction crude liquid was suction filtered to remove the spray-dried potassium fluoride. When the filtrate was analyzed by gas chromatography, the reaction rate of the raw material was 100%, and the selectivity was 2-chloro-6-fluoropyridine 35%, 2,6.
-Difluoropyridine 56%. Further, the amount of HF in the crude liquid after the reaction was quantified by the titration method, and was 50 ppm or less.

Example 3 In a 500 ml Hastelloy autoclave, 2,3,5-trichloropyridine 100 was added.
g (0.55 mol), spray dried potassium fluoride 7
0 g (1.21 mol), 3 g of tetraethylethylenediamine, 10 g of tetraphenylphosphonium bromide and 200 g of N, N′-dimethylimidazolidinone were charged, and the reaction was carried out at 200 ° C. for 10 hours with vigorous stirring. The pressure rose to 2.0 kg / cm ² .

Next, the reaction crude liquid was suction filtered to remove the spray-dried potassium fluoride. When the filtrate was analyzed by gas chromatography, the reaction rate of the raw materials was 100%, the selectivity was 15% 3,5-dichloro-2-fluoropyridine,
5-chloro-2,3-difluoropyridine 56%, 2,
It was 3,5-trifluoropyridine 3%. The amount of HF in the crude liquid after the reaction was below the detection limit of the titration method.

[Comparative Example 1] The reaction was carried out under the same conditions as in Example 3 without adding tetraethylethylenediamine.

The filtrate excluding the spray-dried potassium fluoride was analyzed by gas chromatography to find that the reaction rate of the raw materials was 100% and the selectivity was 3,5-dichloro-2-fluoropyridine 13% and 5-chloro-2. , 3-difluoropyridine 59%, 2,3,5-trifluoropyridine 4
%Met. Further, the amount of HF in the crude liquid after the reaction was quantified by the titration method and found to be 962 ppm.

[0046]

Industrial Applicability According to the method of the present invention, fluorinated pyridines can be efficiently produced under industrially advantageous conditions and with a high reaction rate. Since the method of the present invention hardly produces hydrofluoric acid, the method is also excellent in safety.

Claims (4)

[Claims] 1. A fluorinated pyridine represented by the chemical formula (2), which comprises fluorinating a halogenated pyridine represented by the chemical formula (1) with a fluorinating agent in the presence of a tertiary amine. Manufacturing method. [Chemical 1] [Chemical 2] In the formula, X represents a chlorine atom, a bromine atom, or an iodine atom. When X is 2 or more, X is the same atom or a combination of different atoms. R represents an alkyl group or a fluorinated alkyl group. k is an integer of 1 to 5, m is 1 to 5
And n is 0 or 1. Also, k ≧ m, k + m +
n ≦ 5. 2. The method according to claim 1, wherein the tertiary amine is a monoamine or a diamine. 3. The method according to claim 1, wherein the fluorinating agent is an alkali metal fluoride. 4. The method according to claim 1, 2 or 3, wherein the fluorination reaction is carried out in the presence of a fluorination catalyst.