JP3038065B2 - Method for producing N-fluoropyridinium salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an N-fluoropyridinium salt. In particular, the present invention
The present invention relates to a production method capable of obtaining a stable N-fluoropyridinium salt by a simple method.

[0002]

2. Description of the Related Art Fluorine, unlike chlorine, bromine and iodine, undergoes a very violent reaction in the reaction with an organic substance, so that carbon-carbon of the organic substance is easily cleaved, which in turn causes ignition or explosion. Is very difficult to control. For this reason, a fluorinating agent capable of introducing fluorine into an organic substance under mild conditions has been demanded. The applicant has previously found that an N-fluoropyridinium salt obtained by reacting a pyridine compound with a Bronsted acid or a Lewis acid is an excellent fluorinating agent that satisfies such a demand (Japanese Patent Publication No. Hei. -33707). Since this compound has high reactivity and selectivity for various organic substances, it is very useful for synthesizing a fluorine compound. Furthermore, in the conventional production method as described above, there is a problem that the reaction yield is low,
Further improvement was required as an industrial method for producing N-fluoropyridinium salt, but the applicant of the present invention has found that the use of a pyridine compound in an amount exceeding an equimolar amount with respect to the Bronsted acid results in an increase in yield. It is also proposed that the rate be significantly improved (Japanese Patent Application No. 3-12583).

[0003]

However, in the above-mentioned conventional manufacturing method, a purification step such as a recrystallization method is required in order to obtain a product having good storage stability. There are problems such as a decrease in
There has been a need for further improvements in the industrial production of fluoropyridinium salts. The present inventors have conducted intensive studies in order to solve this problem, and as a result, surprisingly, first, a less than equimolar amount of a Bronsted acid is added to a pyridine compound, and the resulting mixture is reacted with fluorine. It has been found that a product having very good storage stability can be obtained by further adding a Bronsted acid to the mixture so that the total amount of the Bronsted acid exceeds the equimolar amount with respect to the pyridine compound. It was completed.

[0004]

That is, the present invention provides a compound represented by the following general formula:

Embedded image Is reacted with a Bronsted acid and fluorine represented by the general formula XH

Embedded image In the method for producing an N-fluoropyridinium salt represented by (1) First, a Bronsted acid is added in an amount less than equimolar to a pyridine compound and reacted with fluorine, and (2) the Bronsted acid is added to the reaction solution. In addition, a method for producing an N-fluoropyridinium salt, wherein the amount of all Bronsted acids is more than equimolar to the pyridine compound, wherein R ^{1 to} R ⁵ are hydrogen atoms , Halogen atom, alkyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, nitro group, cyano group, alkylsulfonyl group, arylsulfonyl group, hydroxy group, alkoxy group, aryloxy group, acyloxy Group, acylthio group, amide group, alkanesulfonyloxy group, or arenesulfonyloxy group A group, X ^- is the conjugate base of the Bronsted acid (F where is the conjugate base of the hydrogen halide ^-, Cl ^-, Br ^- and I ^- is excluded.) Is.
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are various combinations,
A cyclic structure may be formed with or without a hetero atom. X ^- is ^{R 1, R 2, R 3} , R 4 and R ⁵ and in various combinations may be bonded not over or through the heteroatom. H is a hydrogen atom. ] Is provided.

Hereinafter, the present invention will be described in more detail. The N-fluoropyridinium salt in the present invention is basically produced by the following reaction.

Embedded image In this case, (1) First, the Brönsted acid is less than equimolar to the pyridine compound, for example, 0.80 to 0.9 in a molar ratio.
9 times, preferably 0.92 to 0.98 times, and reacted with fluorine. (2) A Brönsted acid was further added to the reaction solution, and the amount of all Brönsted acids was equimolar to the pyridine compound. In excess, e.g., from 1.01 to 1.20 by mole.
Mol, preferably 1.02 to 1.05 times. By taking such a method, the storage stability of the produced N-fluoropyridinium salt is greatly improved, and crystals having high purity and high storage stability can be obtained by a simple recovery and purification process.
The Bronsted acid added to the solution after the completion of the reaction is preferably the Bronsted acid used in the first reaction in terms of the process operation, but is not particularly limited thereto, and a different acid may be used.

The main raw materials used in the method of the present invention are as follows. (Pyridine compound) General formula (I) used in the present invention
The pyridine compound represented by, for example, pyridine, (trifluoromethyl) pyridine, bis (trifluoromethyl) pyridine, tris (trifluoromethyl) pyridine, (trichloromethyl) pyridine, (pentafluoroethyl) pyridine, (pentafluoro Chain, branched or cyclic alkylpyridines such as octyl) pyridine, (methoxymethyl) pyridine, ethyl pyridineacetate, pyridylacetonitrile and pyridylacetone, chloropyridine, bromopyridine, fluoropyridine, dichloropyridine, difluoropyridine, trichloropyridine Halopyridines such as tetrachloropyridine, pentachloropyridine, difluoropyridine, trifluoropyridine, pentafluoropyridine, chlorofluoropyridine, dichlorofluoropyridine, (Trifluoromethyl) chloropyridine, (trifluoromethyl) dichloropyridine, (trifluoromethyl) trichloropyridine, (trifluoromethyl) fluoropyridine, methylchloropyridine, phenylpyridine, diphenylpyridine, triphenylpyridine, dipyridyl, acetylpyridine, Bisacetylpyridine, (methoxycarbonyl) pyridine, (ethoxycarbonyl) pyridine, (butoxycarbonyl) pyridine, bis (ethoxycarbonyl) pyridine, bis (trifluoroethoxycarbonyl) pyridine, tris (methoxycarbonyl) pyridine, (phenoxycarbonyl) pyridine (Alkoxycarbonyl) or (aryloxycarbonyl) pyridines;
3-pyridinecarboxylic anhydride, nitropyridine, cyanopyridine, dicyanopyridine, tricyanopyridine,
Benzenesulfonylpyridine, methylsulfonylpyridine, chlorocyanopyridine, formylpyridine, (haloformyl) pyridine, nicotinamide, picolinamide, (dimethylaminocarbonyl) pyridine, metroxypyridine, dimethoxypyridine, propyloxypyridine, butyloxypyridine, mentoxy Pyridine, trifluoromethoxypyridine, acetyloxypyridine, trifluoroacetyloxypyridine, phenoxypyridine, acetylthiopyridine, methanesulfonyloxypyridine, benzenesulfonyloxypyridine, acetylaminopyridine, 2,3-tetramethylenepyridine, 3-hydroxypyridine , 1,2,3,4,5,6,7,8-octahydroacridine and the like.

(Bronsted acid) Also, a compound of the general formula XH
Examples of the Bronsted acid represented by methanesulfonic acid, butanesulfonic acid, benzenesulfonic acid,
Toluenesulfonic acid, nitrobenzenesulfonic acid, dinitrobenzenesulfonic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid, perfluorobutanesulfonic acid, perfluorooctanesulfonic acid, trichloromethanesulfonic acid, difluoromethanesulfonic acid, trifluoroethanesulfonic acid, fluoro Sulfonic acid, chlorosulfonic acid, monomethyl sulfuric acid, sulfuric acid, camphorsulfonic acid, bromocamphorsulfonic acid, △ ⁴ −
Cholesten-3-one-6-sulfonic acid, 1-hydroxy-p-methane-2-sulfonic acid, p-styrenesulfonic acid, β-styrenesulfonic acid, poly (p-styrenesulfonic acid), vinylsulfonic acid, poly (Vinyl sulfonic acid), a copolymer with poly (2-acrylamido-2-methyl-1-propanesulfonic acid) and styrene, perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid, poly ( Sulfonic acids such as copolymers with perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid) and tetrafluoroethylene, phosphoric acid, nitric acid,
Perchloric acid, perbronic acid, periodic acid, chloric acid, halogen acids such as bromic acid, acetic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, pentafluoropropionic acid, dichloroacetic acid,
Acrylic acid, polyacrylic acid, poly (perfluoro-3,
Carboxylic acids such as copolymers with 6-dioxa-4-methyl-7-octenoic acid) and tetrafluoroethylene, HB
F ₄ , HPF ₆ , HSbF ₄ , HSbF ₆ , HAsF ₆ and H
BCl ₃ F and the like can be exemplified.

[0008] Hydrogen halides are excluded from the Bronsted acids of the present invention. In N- fluoropyridinium salt of the present invention wherein X ^- is F the conjugate base of the hydrogen halide ^- if, i.e. Pyridine · F ₂ complex is unstable, the serious drawback of causing the explosion at -2 ° C. or higher Have. In the case of Cl ⁻ , Br ⁻ , and I ⁻ , it is difficult to synthesize the corresponding N-fluoropyridinium salt.

(Fluorine) The fluorine used in the present invention is prepared by using an inert gas and having an inert gas volume of 99.9% to 5%.
Preferably, 0% diluted fluorine gas is used. Examples of the inert gas include nitrogen, helium, argon, tetrafluoromethane, and sulfur hexafluoride. In order to carry out the reaction in good yield, the amount of fluorine used is equimolar or more than equimolar to the pyridine compound,
The amount varies depending on the method of introducing fluorine, the reaction temperature, the reaction solvent, the reaction apparatus, and the like. Therefore, the amount of fluorine necessary for the pyridine compound to react with fluorine and disappear can be appropriately selected.

The reaction of the present invention preferably uses a reaction solvent. As the reaction solvent, for example, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, trichlorofluoromethane, trichlorotrifluoroethane, ethyl acetate, diethyl ether, tetrahydrofuran and the like, or a mixture thereof can be selected. The reaction temperature can be selected from the range of -100 ° C to + 40 ° C, but the range of -20 ° C to 0 ° C is preferable for improving the yield.

[0011]

EXAMPLES The present invention will be further described with reference to Examples in which pyridine or 3,5-dichloropyridine is used as a pyridine compound and methanesulfonic acid or trifluoromethanesulfonic acid is used as Bronsted acid. Example 1 Acetonitrile 10 was placed in a 200-ml eggplant-shaped flask.
0 ml, pyridine 8.147 g (0.103 mol), trifluoromethanesulfonic acid 15.007 g (0.100 mol) were added, and after cooling to -20 ° C, 3360 ml of fluorine gas diluted to 20% by volume with nitrogen gas was added. (0.150 mol). Thereafter, 0.75 g (0.005 mol) of trifluoromethanesulfonic acid was added to the above reaction solution, and the reaction solution was concentrated under reduced pressure, crystallized with an excess amount of ethyl acetate, filtered, and filtered. , And dried under reduced pressure to obtain 23.4 g (yield 92.1%) of the product. The N-fluoropyridinium salt crystals thus obtained are placed in a brown glass bottle, stoppered with polyethylene and stored at 40 ° C. for 3 hours.
After leaving it for 0 days, the melting point, purity, and changes in appearance were examined and observed. Table 1 shows the results.

[0012]

[Table 1] Table 1 Melting point purity Appearance Immediately after synthesis 182-184 98.7 White crystals 182-184 98.6 White crystals after 30 days at 40 ° C

Comparative Example 1 The same procedure as in Example 1 was carried out except that the first addition of trifluoromethanesulfonic acid was carried out and the reaction was carried out without adding the second trifluoromethanesulfonic acid to the reaction solution. went. Table 2 shows the results.

[0014]

TABLE 2 mp purity appearance synthesis after 178-180 98.5 white crystals 40 ° C., the change in the 165-170 91.1 yellow after 30 days

Example 2 Acetonitrile 10 was placed in a 200-ml eggplant-shaped flask.
0 ml, pyridine 8.147 g (0.103 mol) and methanesulfonic acid 9.607 g (0.100 mol) were added.
After cooling to 20 ° C., 3360 ml (0.150 mol) of fluorine gas diluted to 20% by volume with nitrogen gas was flowed.
Thereafter, 0.48 g of methanesulfonic acid was added to the above reaction solution.
(0.005 mol), the reaction solution was concentrated under reduced pressure, crystallized with an excess amount of ethyl acetate, filtered, washed with ethyl acetate, and dried under reduced pressure to obtain 18.5 g of the product (yield). 93.2%). The N-fluoropyridinium salt crystals thus obtained were placed in a brown glass bottle, stoppered with polyethylene, and allowed to stand at 40 ° C. for 30 days, and the melting point, purity and changes in appearance were examined and observed. Table 3 shows the results.

[0016]

TABLE 3 mp purity appearance synthesis after 140-143 99.2 white crystals 40 ° C., 30 days after 139 to 142 98.9 White crystals

Comparative Example 2 The first operation was carried out by adding methanesulfonic acid in the same manner as in Example 2, and the other operations were carried out in the same manner without adding the second operation of methanesulfonic acid to the reaction solution. . Table 4 shows the results.

[0018]

[Table 4 mp purity appearance synthesis after 140-142 98.5 white crystals 40 ° C., the change in the 128-134 93.1 yellow after 30 days

EXAMPLE 3 Acetonitrile 10 was placed in a 200 ml eggplant-shaped flask.
0 ml, 15.39 g of 3,5-dichloropyridine (0.104
Mol), 15.007 g of trifluoromethanesulfonic acid
(0.100 mol), cooled to −20 ° C., and 3360 ml of fluorine gas diluted to 20% by volume with nitrogen gas
(0.150 mol). Thereafter, 0.90 g (0.006 mol) of trifluoromethanesulfonic acid was added to the above reaction solution, and the reaction solution was concentrated under reduced pressure, crystallized with an excess amount of diethyl ether, filtered, and filtered. , And dried under reduced pressure to obtain 29.4 g of the product (yield: 8).
9.5%). The N-fluoropyridinium salt crystals thus obtained were placed in a brown glass bottle, stoppered with polyethylene and allowed to stand at 30 ° C. for 30 days, and the melting point, purity, and changes in appearance were examined and observed. Table 5 shows the results.

[0020]

Table 5 mp purity appearance synthesis after 112-116 98.7 white crystals 30 ° C., 30 days after 110-114 98.6 white crystals

COMPARATIVE EXAMPLE 3 The same procedure as in Example 3 was carried out except that trifluoromethanesulfonic acid was added for the first reaction and the reaction was carried out without adding trifluoromethanesulfonic acid for the second time. went. Table 6 shows the results.

[0022]

Table 6 Immediately after melting purity appearance synthetic 111-114 98.5 white crystals 30 ° C., the change in 80-95 83,2 yellow after 30 days

[0023]

Since the production method of the present invention is constituted as described above, an N-fluoropyridinium salt having excellent storage stability can be produced by a simple method. Therefore, the filtration and recrystallization operations can be performed with relatively simple operations, so that the conventional production process can be greatly shortened and the N-fluoropyridinium salt can be easily stored.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) C07D 213/89

Claims (2)

(57) [Claims] 1. A compound of the general formula A pyridine compound represented by the general formula XH is reacted with a Brönsted acid represented by the general formula XH and fluorine to obtain a compound represented by the general formula: In the method for producing an N-fluoropyridinium salt represented by: (1) First, a Brönsted acid is added in less than an equimolar amount to a pyridine compound and reacted with fluorine, and (2) a Brönsted acid is added to the reaction solution. In addition, a method for producing an N-fluoropyridinium salt, wherein the amount of all Bronsted acids is more than equimolar to the pyridine compound: wherein R ^{1 to} R ⁵ are hydrogen atoms , Halogen atom, alkyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, nitro group, cyano group, alkylsulfonyl group, arylsulfonyl group, hydroxy group, alkoxy group, aryloxy group, acyloxy Group, acylthio group, amide group, alkanesulfonyloxy group, or arenesulfonyloxy group A sheet group, X ^- is the conjugate base of the Bronsted acid (provided that the conjugate base of the hydrogen halide F ^-, C
l ^-, Br ^- and I ^- are excluded. ). R ¹ , R ² , R
³ , R ⁴ and R ⁵ may take a cyclic structure in various combinations with or without a hetero atom. X ^- is R
¹ , R ² , R ³ , R ⁴ and R ⁵ may be bonded in various combinations with or without a hetero atom. H
Is a hydrogen atom. ]. 2. The amount of the Brönsted acid used in (1) is 0.80 to 0.99 times in molar ratio with respect to the pyridine compound, and the total amount of the Brönsted acid in (2) is used in the pyridine compound. The molar ratio is 1.01 to 1.2 times the molar ratio.
The method for producing an N-fluoropyridinium salt according to the above item.