JP3207522B2 - 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 relates to N
The present invention relates to a process for producing a fluoropyridinium salt in high yield.

[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.

[0003]

However, the above-mentioned conventional production methods have problems that the reaction yield is still low and that Bronsted acid which is expensive and difficult to handle must be handled. Further improvement has been required as an industrial production method for N-fluoropyridinium salts. As a result of intensive studies to solve this problem, the present invention has surprisingly found that, instead of using Breasted acid directly, an inexpensive Lewis acid or hydrogen halide is used, and a molar excess of these pyridine compounds is used. Was added to cause a reaction, and it was found that an N-fluoropyridinium salt was produced in a high yield, and the present invention was completed.

[0004]

That is, the present invention provides a compound represented by the following general formula (1):

[0005]

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A pyridine compound represented by the formula (I), a Lewis acid represented by Y, a hydrogen halide represented by HX (where X is F, Cl, Br or I) and fluorine, and Wherein the pyridine compound is present in a molar excess relative to any of the Lewis acid and hydrogen halide,

[0007]

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The present invention provides a method for producing an N-fluoropyridinium salt represented by the formula: [However, in the formula, R ¹
To R ⁵ are a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, an alkylsulfonyl group, an arylsulfonyl group, a hydroxy group, an alkoxy group , An aryloxy group, an acyloxy group, an acylthio group, an amide group, an alkanesulfonyloxy group, or an arenesulfonyloxy group. R ¹ , R ² , R ³ , R ⁴ and R ⁵ may form 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 and in various combinations may be bonded not over or through the heteroatom. H is a hydrogen atom and F is a fluorine atom. ]

Hereinafter, the present invention will be described in more detail. (Pyridine compound) Examples of the pyridine compound for use in the reaction of the present invention include pyridine, (trifluoromethyl) pyridine, bis (trifluoromethyl) pyridine, tris (trifluoromethyl) pyridine, (trichloromethyl) pyridine, Chain, branched or cyclic alkylpyridines such as (pentafluoroethyl) pyridine, (pentafluorooctyl) pyridine, (methoxymethyl) pyridine, ethyl pyridineacetate, pyridylacetonitrile, and pyridylacetone; chloropyridine; bromopyridine; Pyridine, dichloropyridine, trichloropyridine, tetrachloropyridine, pentachloropyridine, difluoropyridine, trifluoropyridine,
Halopyridines such as pentafluoropyridine, chlorofluoropyridine, dichlorofluoropyridine, (trifluoromethyl) chloropyridine, (trifluoromethyl)
Dichloropyridine, (trifluoromethyl) trichloropyridine, (trifluoromethyl) fluoropyridine,
Methylchloropyridine, phenylpyridine, diphenylpyridine, triphenylpyridine, dipyridyl, acetylpyridine, bisacetylpyridine, (methoxycarbonyl) pyridine, (ethoxycarbonyl) pyridine,
(Alkoxycarbonyl) or (aryloxycarbonyl) pyridines such as (butoxycarbonyl) pyridine, bis (ethoxycarbonyl) pyridine, bis (trifluoroethoxycarbonyl) pyridine, tris (methoxycarbonyl) pyridine and (phenoxycarbonyl) pyridine; 3-pyridinecarboxylic anhydride, nitropyridine, cyanopyridine, dicyanopyridine, tricyanopyridine, benzenesulfonylpyridine, methylsulfonylpyridine, chlorocyanopyridine, formylpyridine, (haloformyl) pyridine, nicotinamide, picolinamide, (dimethylamino Carbonyl) pyridine,
Metroxypyridine, dimethoxypyridine, propyloxypyridine, butyloxypyridine, mentoxypyridine, 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.

(Lewis acid) The Lewis acid used in the method of the present invention is not particularly specified, but BF ₃ , P
F ₅ , SbF ₅ , AsF ₅ , BCl _{3 and the} like. Further, these complex compounds, for example, an ether complex, and a solution thereof can also be used as the same compound.

(Hydrogen halide) The hydrogen halide used in the method of the present invention is HF, HCl, HBr, HI and a solution thereof.

(Fluorine) The fluorine used in the present invention is prepared by using an inert gas and having a capacity 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.

In the present invention, when reacting a pyridine compound, a Lewis acid and hydrogen halide in the presence of fluorine, the pyridine compound is present in an excess molar amount with respect to either the Lewis acid or hydrogen halide. It is necessary. In the aforementioned Japanese Patent Publication No. 2-23707, column 10, lines 10 to 13, "In order to carry out the reaction in good yield, the amount of the Bronsted acid compound used must be based on the substrate (applicant's note: pyridine compound). Although they are equimolar or more than equimolar, equimolar is preferred in consideration of economics. "
It is described. However, in this prior art, no consideration is given to using pyridine in excess. In addition, there is no suggestion of reacting pyridine with a Lewis acid and hydrogen halide as in the present invention, and that there is no excess of pyridine at that time.

In the present invention, the pyridine compound is present in an excess amount based on the Lewis acid and the hydrogen halide. The Lewis acid and the hydrogen halide are desirably equimolar, but are not particularly limited. If both are not equimolar, it is necessary that the pyridine is still in excess relative to the higher amount. The extent of the excess is not particularly limited, but is preferably 0.001 to 0.2 times in consideration of economy and yield, and is preferably 0.02 times.
More preferably, it is doubled to 0.08 times.

(Reaction solvent) It is preferable to use a reaction solvent in the reaction of the present invention. As a 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.

[0016]

The present invention will be further described with reference to the following examples. Example 1 7.91 g (100 mmol) of pyridine was added to acetonitrile 10
The mixture was cooled to 0 ° C. while stirring and 1.89 g (94.5 mmol) of hydrofluoric anhydride was vaporized, and boron trifluoride gas was added at 20 ml / min using a mass flow meter at a total volume of 2128 ml.
(0 ° C., 95 mmol in terms of 1 atm) was added. Then -2
After cooling to 0 ° C, a mixed gas of fluorine and nitrogen (1: 4)
It was introduced at a flow rate of 0 ml / min. The number of moles of the introduced fluorine gas was 200 mmol. After completion of the reaction, the solvent is distilled off,
Crystallized from ethyl acetate, 17.03 g of N-fluoropyridinium tetrafluoroborate (yield: 92.1%)
I got Its physical properties were as follows. Melting point: 195-197 ° C (recrystallized from CH ₃ CN) ¹⁹ F-NMR (ppm, CFCl ₃ internal standard in CD ₃ CN) -48.7 (1F, NF) 150 (4F, BF ₄ )

COMPARATIVE EXAMPLE 1 7.90 g (100 mmol) of pyridine was added to acetonitrile 10
The mixture was cooled to 0 ° C. while stirring, and 2.02 g (101 mmol) of hydrofluoric anhydride was added thereto with steam, and boron trifluoride gas was added at a flow rate of 226 g / min using a mass flow meter at a flow rate of 20 ml / min.
5 mL (0 ° C., 1 atm conversion, 101 mmol) was added. Thereafter, the mixture was cooled to −20 ° C. and mixed gas of fluorine and nitrogen (1:
4) was introduced at a flow rate of 50 ml / min. The number of moles of the introduced fluorine gas was 200 mmol. After completion of the reaction, the solvent was distilled off, and the product obtained by crystallization with ethyl acetate was 1.52 g of pyridinium tetrafluoroborate. The target product of the present invention, N-fluoropyridinium tetrafluoroborate, was obtained from ¹⁹ F-NMR. I could not confirm.

Example 2 3.96 g (50.1 mmol) of pyridine was added to acetonitrile 5
In 0 ml, under ice-cooling, 2.08 g of hydrofluoric acid (containing 46% hydrofluoric acid) (47.8 mmol of hydrofluoric acid), and then 6.67 g of boron trifluoride / diethyl ether complex were added.
(47.0 mmol) was added. Thereafter, the mixture was cooled to −20 ° C. and mixed with 50% of a mixed gas of fluorine and nitrogen (1: 4) while stirring.
It was introduced at a flow rate of ml / min. The number of moles of the introduced fluorine gas was 100 mmol. After completion of the reaction, the solvent was distilled off, and the residue was crystallized from ethyl acetate to obtain 8.51 g (yield: 91.8%) of N-fluoropyridinium tetrafluoroborate. Its physical properties were as follows. Melting point: 195-197 ° C (recrystallized from CH ₃ CN) ¹⁹ F-NMR (ppm, CFCl ₃ internal standard in CD ₃ CN) -48.7 (1F, NF) 150 (4F, BF ₄ )

Comparative Example 2 3.94 g (49.8 mmol) of pyridine was added to acetonitrile 5
0 ml, and under ice-cooling, 2.22 g of hydrofluoric acid (containing 46% hydrofluoric acid) (51.1 mmol of hydrofluoric acid), followed by 7.24 g of boron trifluoride / diethyl ether complex
(51.0 mmol) was added. Thereafter, the mixture was cooled to −20 ° C. and mixed with 50% of a mixed gas of fluorine and nitrogen (1: 4) while stirring.
It was introduced at a flow rate of ml / min. The number of moles of the introduced fluorine gas was 100 mmol. After completion of the reaction, the solvent was distilled off, which was crystallized in ethyl acetate pyridinium tetrafluoroborate 7.26 g (yield: 87.3%), and ¹⁹
N-fluoropyridinium tetrafluoroborate could not be confirmed by F-NMR.

Example 3 3.784 g (25.23 mmol) of 3,5-dichloropyridine
And 1.074 g of hydrofluoric acid (containing 46% hydrofluoric acid)
(4.70 mmol) in 25 ml of acetonitrile, followed by boron trifluoride / diethyl ether complex 3.
332 g (23.48 mmol) were added. Thereafter, the mixture was cooled to -20 ° C and a mixed gas of fluorine and nitrogen (1: 4) was introduced at a flow rate of 50 ml / min with stirring. The number of moles of the introduced fluorine gas was 50 mmol. After the reaction, the solvent was distilled off, crystallized from ethyl acetate, and 4.64 g of N-fluoro-3,5-dichloropyridinium tetrafluoroborate (yield: 7)
6.2%). Its physical properties were as follows. Melting point: 195-197 ° C ¹⁹ F-NMR (ppm, CFCl ₃ internal standard in CD ₃ CN) -52.6 (1F, NF) 150 (4F, BF ₄ )

[0021]

According to the present invention, as described above, an N-fluoropyridinium salt can be produced in high yield by using an inexpensive Lewis acid without using a Breasted acid which is inconvenient to handle. be able to. In addition, since the by-produced HF is a low-boiling compound (boiling point 19.5 ° C.) called hydrogen fluoride, there is no need for filtration or recrystallization. Therefore, the conventional production process can be greatly shortened, and is an epoch-making production method as an industrial production method of N-fluoropyridinium salt.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-63-10764 (JP, A) JP-A-2-231474 (JP, A) JP-A-4-253969 (JP, A) (58) Investigation Field (Int. Cl. ⁷ , DB name) C07D 213/89

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) With a Lewis acid represented by Y, a hydrogen halide represented by HX (where X is F, Cl, Br or I), and fluorine. Wherein the pyridine compound is present in a molar excess relative to any of the Lewis acid and the hydrogen halide; A method for producing an N-fluoropyridinium salt represented by the formula:
[Wherein, R ^{1 to} R ⁵ represent a hydrogen atom, a 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 , An amide group, an alkanesulfonyloxy group, or an arenesulfonyloxy group. R ¹ , R ² , R ³ , R ⁴ and R ⁵
May form a cyclic structure with or without a hetero atom in various combinations. X ^- represents R ¹ , R ² , R ³ , R ⁴
And R ⁵ in various combinations with or without a hetero atom. H is a hydrogen atom and F is a fluorine atom. ] 2. The method for producing an N-fluoropyridinium salt according to claim 1, wherein the pyridine compound is present in a 0.001-0.2-fold molar excess with respect to both the Lewis acid and hydrogen halide.