JPH07233097A - Production of electrophilic fluorination agent - Google Patents

Abstract

PURPOSE:To obtain an electrophilic fluorination agent effective for improving the reaction yield and reaction rate and having excellent safety by spray-drying a solution of a specific compound to form fine powder of the compound. CONSTITUTION:This fluorination agent is produced by dissolving a compound of formula I (R<1> to R<5> each is H, a halogen, an alkyl, an aryl, an acyl, an alkoxycarbonyl, etc.; X<-> is a conjugated base of a Broensted acid excluding a halogen anion; R<1> to R<5> may form a cyclic structure by arbitrary combination) such as N-fluoropyridinium trifluoromethane sulfonate or N-fluoropyridinium pyridine heptafluorodiborate of formula II in a solvent such as water, an alcohol, acetone, acetonitrile, THF and DMF and spray-drying the obtained solution to effect the fine pulverization of the component of formula I or formula II. Preferably, the spray-drying treatment is carried out at 60-180 deg.C and the average particle diameter of the obtained fluorination agent is 10-50mum.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an electrophilic fluorinating agent. More specifically, the present invention relates to a fluorinating agent which has been finely pulverized by spray drying treatment and has improved reactivity.

[0002]

2. Description of the Related Art Fluorine causes a very violent reaction in the reaction with an organic substance, unlike chlorine, bromine, and iodine, so that the carbon-carbon bond of an organic substance is easily broken, and eventually, ignition or explosion occurs. , It is very difficult to control the reaction. Therefore, there has been a demand for a fluorinating agent capable of introducing fluorine into an organic substance under mild conditions.
For this purpose, the present applicants have found that an N-fluoropyridinium salt obtained by reacting a pyridine compound with a fluorine gas in the presence of a Bronsted acid or a Lewis acid is an excellent fluorine compound satisfying such a demand. It was found to be an agent (Japanese Patent Publication No. 2-33707). Also, Van Der Ruy et al. Have proposed N-fluoropyridinium pyridine heptafluorodiborate, which also has a pyridine-F bond (Japanese Patent Laid-Open No. Hei 4 (1999) -4242).
No. 501,424).

[0003]

However, the above-mentioned fluorinating agent has problems such as low reaction yield and long reaction time, and further improvement is needed. Such a problem is caused by the low solubility of the fluorinating agent in an organic solvent, particularly a halogen-based organic solvent which is said to be suitable for an electrophilic fluorination reaction. On the other hand, it has been reported that the reaction is difficult to proceed or does not proceed at all when a polar solvent having a high solubility of these fluorinating agents is used [J.Am.Chem.Soc.112 (J.Am.Chem.Soc.112 (J.Am.Chem.Soc.112)). 23), 1990 8563-857
Five)〕.

[0004]

The inventors of the present invention have conducted research to solve this problem, and as a result, surprisingly, a solution of a fluorinating agent was finely pulverized by a spray-drying treatment, so that the fluorinating agent was It has been found that the reactivity of can be improved. That is, the present invention provides a method for producing an electrophilic fluorinating agent having improved reactivity by finely pulverizing a solution of a compound represented by the following general formula by spray drying treatment.

[0005]

[Chemical 3]

Or

[Chemical 4]

[Wherein R ^{1 to} R ⁵ are hydrogen atoms, halogen atoms, alkyl groups, aryl groups, acyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, alkylsulfonyl groups, Arylsulfonyl group, hydroxyl group, alkoxy group,
An aryloxy group, an acyloxy group, an acylthio group, an amido group, an alkanesulfonyloxy group, or an arenesulfonyloxy group, and X ⁻ is a conjugated base of Bronsted acid (provided that F is a conjugated base of hydrogen halide).
^-, Cl ^-, Br ^- and I ^- is excluded). R ¹ , R ² ,
R ³ , R ⁴ and R ⁵ may have various combinations to form a cyclic structure with or without a heteroatom. X ⁻ may be bonded to R ¹ , R ² , R ³ , R ⁴ and R ⁵ in various combinations with or without a heteroatom.
H is a hydrogen atom. Furthermore, the present invention provides an electrophilic fluorinating agent having an average particle size of 10 to 50 μm.

The present invention will be described in more detail below. The electrophilic fluorinating agent used in the present invention is obtained by reacting a pyridine compound with fluorine gas in the presence of a Bronsted acid or a Lewis acid, as described in, for example, Japanese Patent Publication No. 2-33707. Obtained by N-
Fluoropyridinium salts can be used. Examples of the reaction for producing this include the following.

[0009]

[Chemical 5]

Here, pyridine and trifluoromethanesulfonic acid are added to acetonitrile and cooled to -20 ° C. Then, while stirring, a mixed gas of fluorine and nitrogen is introduced and reacted. After the reaction, the solvent is distilled off, and N-fluoropyridinium trifluoromethanesulfonate can be obtained by crystallizing with ether.

The N-fluoropyridinium salt thus obtained is an excellent electrophilic fluorinating agent, but even if it is pulverized by a usual method, the average particle size is at most 200 μm, The activity in the fluorination reaction is still unsatisfactory. In the present invention, the electrophilic fluorinating agent refers to a reagent that generates a fluorine cation or a fluorine radical to introduce a fluorine atom into a compound serving as a substrate.

The fluorinating agent to be subjected to the spray-drying treatment of the present invention is obtained by distilling off the solvent (for example, acetonitrile in the above-mentioned production example) in the fluorinating agent production step as it is or finally as solid crystals. It may be a solution obtained by dissolving the above in a suitable solvent. In this case, the solvent used for re-dissolving the fluorinating agent crystals is not particularly limited as long as the fluorinating agent has a high solubility and the dissolved fluorinating agent does not decompose. Examples of the solvent that can be used include water, alcohol, acetone, acetonitrile, tetrahydrofuran, dimethylformamide and the like.

The spray dryer used for the spray dry treatment may be of the type conventionally used as shown in FIG. 1, and if the organic solvent can be used, the limited type spray dryer is used. do not have to. The spray dryer may be either an open system or a closed system, but it is desirable that it has a structure that does not discharge dust and the like to the outside. As a means for spraying the fluorinating agent solution into the spray dryer, a disk atomizer using a disk as shown in FIG. 2 can be exemplified, but it is not particularly limited thereto.

The processing temperature in the spray dryer is
It may be in a temperature range from around the boiling point of the solvent used to a temperature lower than the decomposition temperature of the fluorinating agent. For example, it is desirable to perform the treatment at an inlet temperature of the spray dryer of 60 ° C to 180 ° C. The particle size of the spray-dried fluorinating agent is preferably in the range of 10 μm to 50 μm. If the particle size is smaller than this, the recovery rate of the fluorinating agent at the time of spray-drying is lowered, and if it is larger than this, the effect of improving the reactivity is reduced.

The fluorinating agent of the present invention obtained by spray-drying treatment is collected by a cyclone attached to the spray-drying and collected in a container attached below the cyclone. When handling the recovered fluorinating agent, it is better to take measures to prevent the fluorinating agent from becoming fine powder and to wear it while wearing safety equipment such as a protective mask. .

[0016]

The effect of pulverization by the spray-drying treatment is that the solid is pulverized (the conventional method has an average particle size of 200 μm).
m is 20 μm in this method) and the increase of the specific surface area and the improvement of the solubility in an organic solvent due to the amorphization of solid crystals, etc., but the exact mechanism is not clear.

The present invention will be further described below with reference to examples.

Examples Reference Example 1 (Synthesis of N-fluoropyridinium tetrafluoroborate) 1.582 g (20.0 mmol) of pyridine and 4.084 g (20.0%) of 43% HBF ₄ aqueous solution equimolar thereto.
(Mmol) in 50 ml of acetonitrile,
The solvent was distilled off once. The white solid thus obtained was again dissolved in acetonitrile, 0.080 g (1.0 mmol) of pyridine was further added, and the mixture was cooled to -20 ° C. Then, while stirring, a mixed gas of fluorine and nitrogen (1: 9) was introduced at a flow rate of 50 ml / min. The amount of fluorine introduced was 40 mmol. Then 4
0.408 g (2.0 mmol) of 3% HBF ₄ aqueous solution was added. After the solvent was distilled off, ethyl acetate was added for crystallization, and 3.531 g of crystals of N-fluoropyridinium tetrafluoroborate were recovered. The recovery rate was 95.5%.

Reference Example 2 (N-fluoro-2,4,6-
Synthesis of trimethylpyridinium tetrafluoroborate) 2.517 g (20.20 g) of 2,4,6-trimethylpyridine in a solvent obtained by mixing 40 ml of acetonitrile and 10 ml of water.
4 mmol) was added and the mixture was cooled to -10 ° C. Then, while stirring, a mixed gas of fluorine and nitrogen (1: 9) is added to 50
It was introduced at a flow rate of ml / min. The amount of fluorine introduced is 40
It was millimole. Then, 3.104 g (21.9 mmol) of boron trifluoride diethyl ether complex was slowly added dropwise to the reaction solution. After the solvent was distilled off, ethyl acetate was added for crystallization to give N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate crystals 3.779.
g was obtained. The recovery rate was 81.8%.

Reference Example 3 (Synthesis of N-fluoropyridinium trifluoromethanesulfonate) 1.592 g (20.1 mmol) of pyridine and 2.940 g (19.6 mmol) of trifluoromethanesulfonic acid were added to 40 ml of acetonitrile to give -20. Cooled to ° C.
Then, while stirring, a mixed gas of fluorine and nitrogen (1:
4) was introduced at a flow rate of 50 ml / min. The amount of fluorine introduced was 40 mmol. Then, the solvent was distilled off, ether was added to crystallize, and N-fluoropyridinium trifluoromethanesulfonate 4.716 g (1
9.1 mmol) was obtained. The recovery rate was 97.4%.
Example 1

[0020]

[Chemical 6]

The average particle size obtained in Reference Example 1 above was 2
75 g of 00 μm fluorinating agent (N-fluoropyridinium tetrafluoroborate) was added to acetonitrile 500
The solution dissolved in g is supplied at a flow rate of 2 liters / hour to a closed system spray dryer manufactured by Sakamoto Giken, which has a disk atomizer (φ70 mm, 10,000 rpm) whose outline is shown in FIG. did. Nitrogen gas is used as the drying gas, the hot air inlet temperature of the spray dryer is 80 ° C,
The operation was performed at an outlet temperature of 56 ° C. As a result of this treatment, a fluorinating agent having an average particle size of 20 μm was obtained. 10 ml capacity
0.4 mmol of zinc chloride was added to the eggplant-shaped flask of, and after heating and drying, 2 ml of dichloroethane as a solvent was added to the flask, and ethyl 2-oxocyclopentanecarboxylate as a substrate and a spray dry treatment were applied to the flask. The obtained fluorinating agent having an average particle size of 20 μm and 1 mmol of N-fluoropyridinium tetrafluoroborate were each added, and the mixture was set in a Dimroth cooler to replace the argon in the container. When this was set in an oil bath and reacted at 60 ° C. for 21 hours while stirring, ethyl 1-fluoro-2-oxocyclopentanecarboxylate was obtained in a yield of 76% from ¹⁹ F-NMR measurement. .

Example 2 A solution prepared by dissolving 75 g of a fluorinating agent (N-fluoropyridinium tetrafluoroborate) having an average particle size of 200 μm obtained in Reference Example 1 above in 500 g of acetonitrile was used in Example 1. The same disk atomizer and spray dryer as described above were used and fed at a flow rate of 2 liters / hour. At this time, the spray dryer was operated at a hot air inlet temperature of 150 ° C and an outlet temperature of 87 ° C. As a result of this treatment, a fluorinating agent having an average particle size of 20 μm was obtained. 0.4 mmol of zinc chloride was put in a 10 ml eggplant-shaped flask, and after heating and drying, 2 ml of dichloroethane as a solvent was put in this flask, and ethyl 2-oxocyclopentanecarboxylate as a substrate and spray-dry were added thereto. 1 mmol of the fluorinating agent (N-fluoropyridinium tetrafluoroborate) having an average particle diameter of 20 μm obtained by the treatment was added, and the fluorinating agent was set in a Dimroth cooler to replace the argon in the container. Set this in the oil bath, 6
When reacted at 0 ° C. for 21 hours with stirring, ¹⁹ F-
From the NMR measurement, ethyl 1-fluoro- was obtained with a yield of 59%.
2-Oxocyclopentanecarboxylate was obtained.

Comparative Example 1 0.4 mmol of zinc chloride was placed in an eggplant-shaped flask having a capacity of 10 ml, and after heating and drying, 2 ml of dichloroethane as a solvent was placed in this flask, and the substrate, ethyl, was added thereto.
1 mmol each of 2-oxocyclopentanecarboxylate and the fluorinating agent (N-fluoropyridinium tetrafluoroborate) obtained in Reference Example 1 and having an average particle diameter of 200 μm, which has not been subjected to the spray-drying treatment, were added, and a Dimroth condenser was used. Then, the inside of the container was replaced with argon. Set this in the oil bath, 60
When reacted with stirring at 21 ° C for 21 hours, ¹⁹ F-N
56% yield of ethyl 1-fluoro-2 from MR measurement
-Oxocyclopentanecarboxylate was obtained. Example 3

[0024]

[Chemical 7]

The average particle size obtained in Reference Example 1 is 200 μm.
Of the fluorinating agent (N-fluoropyridinium tetrafluoroborate) of 500 g of acetonitrile was dissolved in 500 g of acetonitrile using the same disk atomizer and spray dryer as used in Example 1, and a flow rate of 2 liter / hour was used. Supplied by. At this time, the spray dryer was operated at a hot air inlet temperature of 80 ° C and an outlet temperature of 56 ° C. As a result of this treatment, the average particle size is 20
A μm fluorinating agent was obtained. Into a round-bottomed flask having a capacity of 10 ml, 2 ml of dichloroethane as a solvent was placed, and 3,17-β-diacetoxy-3,5-androstadiene as a substrate and fluorine having an average particle size of 20 μm obtained by a spray drying treatment were added thereto. 1 mmol of each of the agents (N-fluoropyridinium tetrafluoroborate) was added, and they were set in a Dimroth condenser to replace the argon in the container. Set this in the oil bath,
When the reaction was carried out at 80 ° C. for 6 hours with stirring, ¹⁹ F-
From the NMR measurement, 6-fluoro-4-androsterone-17-β-ol-3-one was produced in a yield of 32%.

Comparative Example 2 2 ml of a solvent, dichloroethane, was placed in an eggplant type flask having a volume of 10 ml, and 3,17-β-diacetoxy-3,5-androstadiene as a substrate and the product obtained in Reference Example 1 were obtained. 1 mmol of a fluorinating agent (N-fluoropyridinium tetrafluoroborate) having an average particle diameter of 200 μm, which has not been spray-dried, was added to each, and it was set in a Dimroth cooler to replace the argon in the container. Set this in the oil bath, 80 ℃
When reacted with stirring for 6 hours, ¹⁹ F-NMR
From the measurement, 6-fluoro-4-androsterone-17-β-ol-3-one was produced in a yield of 15%. Example 4

[0027]

[Chemical 8]

The average particle size obtained in Reference Example 1 was 200.
A solution of 75 g of a μm fluorinating agent (N-fluoropyridinium tetrafluoroborate) in 500 g of acetonitrile was used, using the same disk atomizer and spray dryer as used in Example 1, to which 2 l / h It was supplied at a flow rate. At this time, the hot air inlet temperature of the spray dryer is 80 ° C and the outlet temperature is 5
The operation was performed at 6 ° C. As a result of the treatment, a fluorinating agent having an average particle size of 20 μm was obtained. 2 ml of a solvent, dichloroethane, was placed in an eggplant-shaped flask having a capacity of 10 ml, and 1- (trimethylsiloxy) cyclohexene as a substrate and a fluorinating agent (N-fluoro) having an average particle size of 20 μm obtained by the above spray drying treatment were added to the flask. 1 mmol each of pyridinium tetrafluoroborate),
It was set in a Dimroth condenser and the inside of the container was replaced with argon. Place this in an oil bath and keep it at 40 ° C for 8
When the reaction was carried out with stirring for 2 hours, 2-fluorocyclohexanone was produced in a yield of 60% from ¹⁹ F-NMR measurement.

Comparative Example 3 2 ml of a solvent, dichloroethane, was placed in an eggplant-shaped flask having a volume of 10 ml, and 1- (trimethylsiloxy) cyclohexene as a substrate and the spray-dried average obtained in Reference Example 1 were not added. 1 mmol of a fluorinating agent (N-fluoropyridinium tetrafluoroborate) having a particle diameter of 200 μm was charged, and the fluorinating agent was set in a Dimroth condenser to replace the argon in the container. When this was set in an oil bath and reacted at 40 ° C. for 8 hours with stirring, 2-fluorocyclohexanone was produced in a yield of 45% from ¹⁹ F-NMR measurement. Example 5

[0030]

[Chemical 9]

The average particle size obtained in Reference Example 2 was 200 μm.
The fluorinating agent (N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate) of 75 g was dissolved in 500 g of acetonitrile using the same disc atomizer and spray dryer as used in Example 1, This was fed at a flow rate of 2 liters / hour. At this time, the spray dryer was operated at a hot air inlet temperature of 80 ° C and an outlet temperature of 56 ° C. As a result of the treatment, a fluorinating agent having an average particle size of 20 μm was obtained. Capacity 1
0.4 mmol of zinc chloride was placed in a 0 ml eggplant-shaped flask, and after heating and drying, 2 ml of dichloroethane as a solvent was placed in this flask, and ethyl 2-oxocyclopentanecarboxylate as a substrate and the above-mentioned spray 1 mmol of each fluorinating agent (N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate) having an average particle size of 20 μm obtained by the dry treatment was charged, and the fluorinating agent was set in a Dimroth cooler, and argon in the container was set. Substitution was made. Set this in the oil bath,
When reacted at 60 ° C. for 6 hours with stirring, ¹⁹ F-
52% yield of ethyl 1-fluoro-
2-Oxocyclopentanecarboxylate was obtained.

Comparative Example 4 2 ml of dichloroethane as a solvent was placed in an eggplant-shaped flask having a volume of 10 ml, and the substrate, ethyl 2-oxocyclopentanecarboxylate, and the spray-drying treatment obtained in Reference Example 2 were not carried out. Average particle size 200μ
1 mmol of the fluorinating agent of m (N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate) was added, and the mixture was set in a Dimroth condenser and the inside of the container was replaced with argon. This was set in an oil bath, it was reacted with stirring for 6 hours at 60 ° C., ¹⁹
From the F-NMR measurement, ethyl 1-fluoro-2-oxocyclopentanecarboxylate was obtained in a yield of 46%. Example 6

[0033]

[Chemical 10]

The average particle size obtained in Reference Example 3 is 200 μm.
Fluorinating agent (N-fluoropyridinium trifluoromethanesulfonate) 75 g, acetonitrile 500 g
Using the same disk atomizer and spray dryer as used in Example 1,
This was fed at a flow rate of 2 liters / hour. At this time, the spray dryer was operated at a hot air inlet temperature of 80 ° C and an outlet temperature of 56 ° C. As a result of treatment, average particle size is 20μ
m fluorinating agent was obtained. Into a round-bottomed flask having a capacity of 10 ml, 0.4 mmol of zinc chloride was put, and after heating and drying, 2 ml of dichloroethane as a solvent was put in this flask, and ethyl 2-oxocyclopentanecarboxylate as a substrate and the above-mentioned substrate were added to the flask. Fluorinating agent (N-fluoropyridinium trifluoromethanesulfonate) having an average particle size of 20 μm obtained by spray drying treatment
1 mmol of each was charged and set in a Dimroth condenser, and the inside of the container was replaced with argon. When this was set in an oil bath and reacted at 60 ° C. for 6 hours while stirring, ethyl 1-fluoro-2-oxocyclopentanecarboxylate was obtained in a yield of 70% from ¹⁹ F-NMR measurement. .

Comparative Example 5 Into a round-bottomed flask having a volume of 10 ml was placed 2 ml of the solvent dichloroethane, and the substrate, ethyl 2-oxocyclopentanecarboxylate, and the spray-drying treatment obtained in Reference Example 3 were not carried out. Average particle size 200μ
1 mmol of each fluorinating agent (m-N-fluoropyridinium trifluoromethanesulfonate) was added,
It was set in a Dimroth condenser and the inside of the container was replaced with argon. Set this in an oil bath and run at 60 ° C for 2
When the reaction was carried out while stirring for an hour, ethyl 1-fluoro-2-oxocyclopentanecarboxylate was obtained in a yield of 64% from ¹⁹ F-NMR measurement.

[0036]

Since the present invention is constructed as described above, the activity of the electrophilic fluorinating agent can be remarkably enhanced by a simple operation.

[Brief description of drawings]

FIG. 1 is a diagram showing an example of a spray dryer that can be used in the present invention.

FIG. 2 is a diagram showing an example of a disk used in a spray dryer that can be used in the present invention.

[Explanation of symbols]

 1 Raw material inlet 2 Hot air inlet 3 Hot air outlet 4 Disc atomizer

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tsunesa Kawada 2-4 Daisaku 2-chome, Sakura City, Chiba Prefecture Onoda Cement Co., Ltd. Central Research Laboratory

Claims (3)

[Claims] 1. A method for producing an electrophilic fluorinating agent, which comprises finely pulverizing a solution of a compound represented by the following general formula by spray-drying treatment: Or [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,
Aryloxycarbonyl group, carbamoyl group, nitro group, cyano group, alkylsulfonyl group, arylsulfonyl group, hydroxyl 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 (provided that the conjugate base of the hydrogen halide F ^-, Cl ^-, B
r ⁻ and I ⁻ are excluded). R < ¹ >, R < ² >, R < ³ >, R < ⁴ > and R < ⁵ > may have a cyclic structure with or without a heteroatom in various combinations. X ⁻ is R ¹ , R ² ,
It may be bonded to R ³ , R ⁴ and R ⁵ in various combinations via a hetero atom or not. H is a hydrogen atom. ] 2. A spray-drying treatment from 60.degree. C. to 180.
The method for producing an electrophilic fluorinating agent according to claim 1, wherein the method is performed in the range of ° C. 3. An electrophilic fluorinating agent having an average particle size of 10 to 50 μm.