JPH09255657A - Production of n-fluoropyridiniumtetrafluoroborate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a fluorine atom introducing agent by reacting a pyridine compound with boron trifluoride and a fluorine gas in the presence of both water and hydrogen fluoride. SOLUTION: A pyridine compound of formula I (R<1> to R<4> are each H, a halogen, an alkyl, an aryl, an acyl, an alkoxycarbonyl, an aryloxycarbonyl, nitro, cyano, hydroxy, amino, etc.) is reacted with boron trifluoride and a fluorine gas in an organic solvent (e.g. acetonitrile) in the presence water and hydrogen fluoride at -100 to 40 deg.C for 3-5 hours to give an N- fluorohyridiniumtetrafluoroborate of formula II. The amount of water is 1-150mol% based on the compound of formula I, that of hydrogen fluoride is 1-150mol% and that of boron trifluoride is 1-1.2 equivalent. The presence of water is essentially required for this reaction but the objective substance is undesirably hydrolyzed by the excessive existence of water.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing N-fluoropyridinium tetrafluoroborate, which is useful as a fluorine atom introduction reagent.

[0002]

2. Description of the Related Art The following general formula (2)

[0003]

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(Wherein R ^{1 to} R ⁵ are the same or different and each is 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, N-fluoropyridinium tetra represented by 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. Fluoroborate is known to be useful as a reagent for introducing a fluorine atom (Japanese Patent Publication No. 2-33707).

As a method for producing the N-fluoropyridinium tetrafluoroborate, a Brønsted acid for removing water and introducing fluorine after adding about 40% of an aqueous solution of fluoroboric acid (HBF ₄ ) to a pyridine compound is used. Method: A salt exchange method of introducing fluorine after adding an alkali metal salt of fluoroboric acid; B introducing fluorine after adding boron trifluoride (BF ₃ ) as a gas or ether adduct
The F ₃ method and the like are known (Japanese Patent Publication No. 2-33707). However, the Bronsted acid method and the salt exchange method require a step of removing water and alkali fluoride formed as a by-product, respectively. Also, the BF ₃ method is
Although there are no by-products, the yield is poor, and expensive ether adducts are used, which are both unsuitable for mass production.

Further, a pyridine-boron trifluoride complex is used as a starting material, and this is reacted with fluorine gas in the presence of water to give the following formula (3):

[0007]

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A method for producing N-fluoropyridinium pyridine heptafluorodiborate represented by the following formula has been proposed (Japanese Patent Laid-Open No. 4-501424). However, the above method also has a low yield.

[0009]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for producing N-fluoropyridinium tetrafluoroborate (2) which is simple and suitable for mass production in high yield.

[0010]

Under the circumstances, as a result of intensive studies by the present inventors, the pyridine compound represented by the following formula (1) is coexistent with water and hydrogen fluoride in an organic solvent. Under the circumstances, it was found that N-fluoropyridinium tetrafluoroborate (2) can be obtained in high yield by reacting with boron trifluoride and fluorine gas, and completed the present invention.

That is, the present invention provides the following general formula (1):

[0012]

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(Wherein R ^{1 to} R ⁵ are the same or different and each is 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, A pyridine compound represented by 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 is used as an organic solvent. General formula (2) characterized by reacting with boron trifluoride and fluorine gas in the presence of water and hydrogen fluoride in a medium

[0014]

[Chemical 6]

A method for producing N-fluoropyridinium tetrafluoroborate represented by the formula (wherein R ^{1 to} R ⁵ are the same as above) is provided.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION In the pyridine compound which is a raw material of the present invention, examples of the halogen atom represented by R ^{1 to} R ^{5 in} the general formula (1) include chlorine, bromine, fluorine and iodine atoms. As the alkyl group, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, s
Examples thereof include ec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and decyl groups.
Examples of the aryl group include phenyl and naphthyl groups. Examples of the acyl group include formyl, acetyl, propionyl and benzoyl groups.

Examples of the alkoxycarbonyl group include a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl group and the like. Is mentioned.

Examples of the aryloxycarbonyl group include phenoxycarbonyl, α-naphthyloxycarbonyl and β-naphthyloxycarbonyl groups.

As the alkyl of the alkylsulfonyl group, the same alkyl groups as mentioned above can be mentioned. Examples of the aryl of the arylsulfonyl group include the same as the above aryl group.

Examples of the alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butanesulfonyloxy groups.

Examples of the arenesulfonyloxy group include a benzenesulfonyloxy group and a naphthalenesulfonyloxy group.

Specific examples of the pyridine compound represented by the above general formula (1) include, for example, pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, tetramethylpyridine, pentanemethylpyridine, ethylpyridine, diethylpyridine and butylpyridine. , Dibutylpyridine, tributylpyridine, pentylpyridine, hexylpyridine, decylpyridine, (trifluoromethyl)
Pyridine, bis (trifluoromethyl) pyridine, tris (trifluoromethyl) pyridine, (trichloromethyl) pyridine, (pentafluoroethyl) pyridine,
(Pentafluorooctyl) pyridine, (methoxymethyl) pyridine, chain-like, branched or cyclic alkyl pyridine such as ethyl pyridyl acetate, pyridyl acetonitrile, pyridyl acetone, chloropyridine, bromopyridine,
Fluoropyridine, dichloropyridine, difluoropyridine, trichloropyridine, tetrachloropyridine, pentachloropyridine, difluoropyridine, halopyridine such as trifluoropyridine, pentafluoropyridine, chlorofluoropyridine, dichlorofluoropyridine, (trifluoromethyl) chloropyridine, (Trifluoromethyl) dichloropyridine, (trifluoromethyl) trichloropyridine, (trifluoromethyl) fluoropyridine, methylchloropyridine, phenylpyridine, diphenylpyridine, triphenylpyridine, dipyridyl, acetylpyridine, bisacetylpyridine, benzoylpyridine, (Methoxycarbonyl) pyridine,
(Ethoxycarbonyl) pyridine, (butoxycarbonyl) pyridine, bis (ethoxycarbonyl) pyridine,
(Alkoxycarbonyl) or (aryloxycarbonyl) pyridine such as bis (trifluoroethoxycarbonyl) pyridine, tris (methoxycarbonyl) pyridine, (phenoxycarbonyl) pyridine, 2,3-pyridinecarboxylic acid anhydride, nitropyridine, cyanopyridine , Dicyanopyridine, tricyanopyridine, benzenesulfonylpyridine, methylsulfonylpyridine, chlorocyanopyridine, formylpyridine, (haloformyl) pyridine, nicotinamide, picolinamide, (dimethylaminocarbonyl) pyridine, methoxypyridine, dimethoxypyridine, propyloxypyridine , Butyloxypyridine, Menthoxypyridine, Trifluoromethoxypyridine, Acetyloxypyridine, Trifluoroacetyloxy Lysine, phenoxy pyridine,
Acetylthiopyridine, methanesulfonyloxypyridine, benzenesulfonyloxypyridine, acetylaminopyridine, 2,3-tetramethylenepyridine, 3-hydroxypyridine, 1,2,3,4,5,6,7,8-
Examples include octahydroacridine and the like. Among these, pyridine or a pyridine compound such as dichloropyridine having an electron-withdrawing group bonded to the pyridine ring is preferable.

In the production method of the present invention, the compound (1)
When a pyridine compound represented by is reacted with boron trifluoride and fluorine gas in the presence of water and hydrogen fluoride in an organic solvent, the order of addition to these reactors is not particularly limited, but for example, pyridine A method in which water and hydrogen fluoride are added to the organic solvent solution, and then boron trifluoride and fluorine gas are sequentially blown in can be mentioned.

Examples of the organic solvent used in the production method of the present invention include acetonitrile, methylene chloride, chloroform, carbon tetrachloride, trichlorofluoromethane, trichlorotrifluoroethane, ethyl acetate, diethyl ether and tetrahydrofuran. These can be used alone or as a mixture. The amount of the organic solvent used is not particularly limited, but for example, in the case of 2,6-dichloropyridine, it is 1 per gram.
It is preferably 0 to 20 ml.

In the production method of the present invention, it is preferable to allow water and hydrogen fluoride to coexist in an organic solvent prior to the introduction of fluorine gas. The amount of water used is not particularly limited, but may be based on the pyridine compound. , 1 to 150 mol%
It is preferable that

Further, the use of hydrogen fluoride is preferable since the fluorination to the N-position is efficiently carried out when a pyridine compound having an electrophilic substituent such as a halogen atom is used as a raw material. The amount of the hydrogen fluoride used is not particularly limited, but is 1 to the pyridine compound.
The amount is preferably 150 mol%, preferably 10 to 100 mol%.

In the production method of the present invention, it is preferable to introduce water and hydrogen fluoride in an organic solvent and then introduce boron trifluoride gas and fluorine gas. The amount of the boron trifluoride used is not particularly limited, and is preferably equivalent amount or more with respect to the pyridine compound, and particularly 1 to
1.2 equivalents are preferred.

Fluorine gas may be introduced as it is, but if the inert gas is used and the volume of the inert gas is 99.9%.
Using ˜50% diluted fluorine gas is preferred because it controls the violent reaction. Examples of the inert gas include nitrogen, helium, argon, tetrafluoromethane, sulfur hexafluoride and the like. The amount of the fluorine gas used is preferably equimolar or equimolar or more with respect to the pyridine compound, but the pyridine compound reacts with fluorine because it varies depending on the method of introducing fluorine, the reaction temperature, the reaction solvent, the reaction apparatus and the like. It is preferable to appropriately select the amount of fluorine required to disappear.

In the production method of the present invention, the reaction is preferably carried out at a temperature of −100 ° C. to 40 ° C., particularly preferably −90 ° C. to room temperature for 3 to 5 hours in order to improve the yield.

The desired product obtained by the above method may be separated by a conventional method. For example, after distilling off the organic solvent, the product is crystallized with a crystallization solvent such as ethyl acetate, chloroform, methylene chloride, diethyl ether or THF. After precipitation, the crystals can be collected by filtration and dried to separate the desired product. The target substance may be identified by melting point, ¹⁹ F and ¹ H nuclear magnetic resonance, infrared absorption spectrum, mass spectrometry, and elemental analysis.

[0031]

According to the production method of the present invention, N-fluoropyridinium tetrafluoroborate useful as a fluorine atom-introducing agent can be easily obtained in a high yield,
Suitable for mass production.

[0032]

EXAMPLES Next, the present invention will be described more specifically by way of examples, but these are merely examples and do not limit the present invention.

Example 1 3.21-kg (21.7 mol) of 2,6-dichloropyridine
Was dissolved in 42 liters of acetonitrile in a Teflon-coated metal container, and 378 g (21 mol) of water and 420 g (21 mol) of hydrogen fluoride were added. Then, the solution is cooled to −15 ° C., and boron trifluoride (BF ₃ ) gas 5 is added.
17 liters (23.1 mol) were passed into the solution. Then, while mixing nitrogen and fluorine, each 25 minutes
The solution was passed through at a flow rate of 1 liter and 5 liters. The total amount of fluorine conducted is 1176 liters (52.5 mol).
Met. After the reaction was completed, acetonitrile was distilled off under reduced pressure,
White-yellow crystals were obtained. Ethyl acetate (18 liters) was added to the obtained white-yellow crystals, and the mixture was washed with stirring at 0 ° C. for 4 hours. Then, the crystals were collected by filtration with a Nutsche and dried under vacuum for 12 hours to give white crystals N-fluoro-2,6- 4186 g (yield 76%) of dichloropyridinium tetrafluoroborate was obtained. The physical property values are shown below.

Melting point: 203 to 205 ° C. Mass (m / e); 167 ¹⁹ F-NMR (CFCl ₃ internal standard in CD ₃ CN) δppm; -32.4 (bs, 1F, N-
F), 151.2 (s, 4F, BF),

Example 2 3.21-kg (21.7 mol) of 2,6-dichloropyridine
Was carried out in the same manner as in Example 1 except that 1.714 kg (21.7 mol) of pyridine was used instead of pyridine, and 3089 g of white crystalline N-fluoropyridinium tetrafluoroborate was obtained.
(Yield 77%) was obtained. The physical property values are shown below.

Melting point: 196 to 198 ° C. Mass (m / e); 104 ¹⁹ F-NMR (CFCl ₃ internal standard in CD ₃ CN) δ ppm; −48.75 (bs, 1F,
NF), 149.6 (s, 4F, BF ₄ )

Comparative Example 1 3.21-kg (21.7 mol) of 2,6-dichloropyridine
42% fluoroboric acid (HBF ₄ ) solution 4.39 kg
(21 mol) was added and reacted at 50 ° C. for 30 minutes, and then water was removed using a rotary evaporator. The obtained crystals were dissolved in 42 liters of acetonitrile and transferred to a Teflon-coated metal container, and the solution was cooled to -15 ° C.
And cooled. Then, while mixing nitrogen and fluorine, the solution was introduced into the solution at a flow rate of 25 liters per minute and 5 liters per minute. The total amount of conducted fluorine is 1176 liters (5
2.5 mol). After completion of the reaction, acetonitrile was distilled off under reduced pressure to obtain white-yellow crystals. Ethyl acetate (18 liters) was added to the obtained white-yellow crystals, and the mixture was washed with stirring at 0 ° C. for 4 hours. Then, the crystals were collected by filtration with a Nutsche and dried under vacuum for 12 hours to give white crystals N-fluoro-2,6- 3745 g of dichloropyridinium tetrafluoroborate (yield 6
8%). The physical property values were the same as those obtained in Example 1.

Fluoroboric acid (HBF) used in Comparative Example 1
₄ ) The aqueous solution is unstable at high concentrations, so 40
~ 50% aqueous solution is commercially available. On the other hand, since N-fluoropyridinium (or N-fluoro-2,6-dichloro) tetrafluoroborate decomposes in the presence of excess water, water in the aqueous solution needs to be removed before the fluorination step. is there. Therefore, compared with the method of the present invention, the water removal step is increased, which is disadvantageous for mass production.

Example 3 Instead of 378 g of water (21 mol), 756 g of water (42 mol)
(Mole), and the same procedure as in Example 1 was carried out to obtain 3029 g (yield 55%) of white crystals of N-fluoro-2,6-dichloropyridinium tetrafluoroborate. The physical property values were the same as those obtained in Example 1.

In the method of the present invention, the presence of water is indispensable, but if it is present in excess, hydrolysis of the desired product occurs, which is not preferable.

Example 4 White crystalline N-fluoro-3,5-dichloropyridinium tetrafluoroborate was prepared in the same manner as in Example 1 except that 3,5-dichloropyridine was used instead of 2,6-dichloropyridine. 4131 g (yield 75%) of lat was obtained.
The physical property values are shown below.

Melting point; 208 to 209 ° C. Mass (m / e); 169, 167, 165 ¹⁹ F-NMR (CFCl ₃ internal standard in CD ₃ CN) δppm; -52.7 (bs, 1F, N
-F), 150.5 (s, 4F, BF ₄ )

Claims (2)

[Claims] 1. The following general formula (1): (In the formula, R ^{1 to} R ⁵ are the same or different and each is 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.) In an organic solvent in water. And hydrogen fluoride in the coexistence of boron trifluoride and fluorine gas, the general formula (2): (In the formula, R ^{1 to} R ⁵ are the same as above.) A method for producing N-fluoropyridinium tetrafluoroborate. 2. The amount of water is 1 to the pyridine compound.
The production method according to claim 1, which is 150 mol%.