JPH04124176A - Production of fluorine-substituted nitrogen-containing heterocyclic compound - Google Patents

Abstract

PURPOSE:To easily obtain the title high-purity compound by reaction between a chloro or bromonitrogen-contg. heterocyclic compound and fluoric anhydride under specified conditions. CONSTITUTION:A reaction is made between a chloro or bromonitrogen-contg. heterocyclic compound (e.g. 2-chloropyridine) and fluoric anhydride at 0-250 deg.C under normal pressures for 0.5-20hr. In this process, fluorination is carried out while expelling the hydrogen chloride or bromide out of the system. The reaction is made, if needed, in the presence of a basic compound (e.g. amine compound). The amount of the starting material to be used is such as to be 0.5-75mol% based on the fluoric anhydride.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an advantageous method for producing fluoro-nitrogen-containing heterocyclic compounds.

[Conventional technology and its issues]

As a method for producing fluoro nitrogen-containing heterocyclic compounds, a halogen exchange method is conventionally known in which a chloro or bromo nitrogen-containing heterocyclic compound is used as a starting material and is fluorinated using KF or KHF (Japanese Patent Application Laid-open No. 62-181257
However, this method requires a long reaction time under high temperature and pressure, and is not suitable for industrial implementation. In this case, it is also known to use highly reactive spray-dried KF, but this KF is expensive and therefore industrially disadvantageous.

In addition, the so-called Ziman method is also known, which uses the amino nitrogen-containing heterocyclic compound diazonium fluoride as an intermediate (
JP-A-60-130529, JP-A-61-63627
(No.), this method has the problem that it is difficult to control the decomposition reaction of the diazonium salt.

On the other hand, although hydrofluoric acid is the most common fluorinating agent, it was previously thought that chloro and bromo nitrogen-containing heterocyclic compounds could not be easily fluorinated with hydrofluoric acid. This is because hydrofluoric acid has a low boiling point (19° C.), so it was thought that raising the temperature would cause the hydrofluoric acid to evaporate, making it impossible to obtain the free hydrofluoric acid necessary for fluorination. For this purpose, a method of using a solid fluorination catalyst together with hydrofluoric acid (Japanese Unexamined Patent Publication No. 1275-1989)
No. 8) has been attempted, but this method has the problem that it is difficult to maintain the activity of the catalyst. In addition, in order to avoid evaporation of hydrofluoric acid, there is a method in which the reaction is carried out in a closed system under high temperature and pressure using an autoclave, and the reaction is carried out while maintaining the molar ratio of hydrofluoric acid and starting materials (Japanese Patent Publication No. 45-24780). Although this method is known, since it involves a closed system reaction under high pressure, it is difficult to control and continuous production is difficult.

[Knowledge that leads to problem resolution]

As a result of repeated studies on a complex compound consisting of hydrofluoric acid and a basic compound, the present inventors found that the complex compound has stable fluorination ability at high temperatures and atmospheric pressure.
When the emitting substance or product is a nitrogen-containing heterocyclic compound, the halogen exchange reaction can proceed by simply replenishing the consumed fluoric acid without applying pressure due to the reaction with the basic atom in the molecule. I was pissed. It was also confirmed that the above properties did not change even under high temperatures. It has also been confirmed that when the fluorination ability of the complex compound is weak, it is more effective to add another basic compound.

Based on the above findings, the present invention aims to provide a method for easily producing a fluoro nitrogen-containing heterocyclic compound using hydrofluoric acid under normal pressure.

[Means for solving the problem: Structure of the invention]

According to the present invention, a chloro or bromo nitrogen-containing heterocyclic compound is reacted with anhydrous hydrofluoric acid at a temperature of 0 to 250°C and under normal pressure, and fluorination is performed while the generated hydrogen chloride or hydrogen bromide is released from the system. A method for producing a fluoro nitrogen-containing heterocyclic compound is provided.

Furthermore, according to the present invention, as a preferred embodiment of the above production method, there is provided a production method in which a basic compound is added during the fluorination.

In the production method of the present invention, a chloro or bromo nitrogen-containing heterocyclic compound is used as a starting material. Specifically, a pyridine compound in which at least one position at 2.4 or 6 is substituted with chlorine or bromine, or a pyrimidine compound in which at least one position at 2.4 or 6 is substituted with chlorine or bromine. A substituted compound, or a compound in which at least one of the 3.4.5 or 6 positions of a pyridazine compound is substituted with chlorine or bromine, or at least one of the 2.3.5 or 6 positions of a pyrazine compound Compounds in which is substituted with chlorine or bromine are preferably used. The position to which chlorine or bromine is bonded is likely to be activated due to the electron-withdrawing property of nitrogen in the heterocycle, and is likely to undergo fluorine substitution. Note that the above-mentioned pyridine compound, pyrimidine compound, pyridazine compound, and pyrazine compound may contain any substituent other than chlorine or bromine.

The following compounds are known as typical pyridine compounds: 2-chloropyridine, 2-bromopyridine 2-chloro-5-trihalomethylpyridine 2-bromo-5-trihalomethylpyridine 2-chloro-3-trihalomethyl Pyridine 2-bromo-3-trihalomethylpyridine 2-chloro-5-nitropyridine 2-bromo-5-nitropyridine 2-chloro-3-nitropyridine 2-bromo-3-nitropyridine Also representative pyrimidine compounds, pyridazine The following compounds are known as compounds and pyrazine compounds.

2-chloropyrimidine, 2-bromopyrimidine 4-
Chloropyrimidine, 4-bromopyrimidine 2-chloro-4-nitropyrimidine 2-bromo-4-nitropyrimidine 2,4-dichloro-5-nitropyrimidine 2,4-chlorobromo-5-nitropyrimidine 2,4-dibromo- 5
-nitropyrimidine 2.4.6-dolichloro5-nitropyrimidine 2.4.6-dolibromo5-nitropyrimidine 4-chloro-6-dolihalomethylpyrimidine 4-
Bromo-6-trihalomethylpyrimidine 3.4.5-Trichloropyridazine 3.6-cyclopyridazineChloropyrazine, 2.6-dichloropyrazine
The pyridine compound, pyrimidine compound, pyridazine compound, and pyrazine compound used in the present invention are not limited to the above-listed compounds. Furthermore, hydrochlorides, hydrofluorates, etc. of these can also be used.

When the above starting material and hydrofluoric acid react to perform halogen exchange, as shown in the linear equation,
A 5alt type complex compound is formed as an intermediate, and the halogen exchange reaction proceeds via the complex compound.

At the same time, liberated chlorine or bromine combines with hydrogen to produce hydrogen chloride or hydrogen bromide.

In a closed system reaction using a conventional autoclave, the generated hydrogen chloride or hydrogen bromide reacts with the fluoro-nitrogen compound to form the above intermediate, a reverse reaction that progresses and inhibits the halogen exchange reaction. .

Therefore, in the method of the present invention, the fluorination reaction is carried out under normal pressure, and the generated hydrogen chloride and hydrogen bromide are actively expelled from the system to promote the fluorination reaction.

The reaction temperature of the method of the present invention is 0 to 250°C, preferably 20 to 250°C.
The temperature is 200°C. If the reaction temperature is lower than 0°C, the progress of the reaction will be extremely slow, which is not preferable. Further, the starting material forms a complex with hydrofluoric acid due to its basicity, but if the temperature exceeds 250°C, the starting material or the complex will flow out of the system, which is not preferable.

Also, the amount of starting material for anhydrous hydrofluoric acid is 0.5 to 15 m
oQ%, preferably 1 to 50 IIOQ%. The reaction time can be adjusted as appropriate, but is preferably 0.5 to 20 hours, preferably 1 hour.
~10 hours.

In the method of the present invention, the fluorination reaction is promoted by adding a basic compound. This is because by adding a basic compound, the basic compound forms a complex with hydrofluoric acid.
This is to generate active F- that is effective for fluorination.

Examples of the basic compound include the following compounds that form a complex with hydrofluoric acid, such as ether compounds, ketone compounds, aldehyde compounds, ester compounds, alcohol compounds, carboxylic acid compounds, water, thioether compounds, thioketone compounds, thioaldehyde compounds, thioester compound,
Thiol compounds, sulfoxide compounds, sulfone compounds, amine compounds, amide compounds, N-oxide compounds, nitrile compounds, isonitrile compounds, phosphine compounds, phosphite compounds, phosphate compounds, etc. are used. Among these compounds, amine compounds are most preferred.

The hydrofluoric acid consumed in the halogen exchange reaction or the evaporated hydrofluoric acid is replenished intermittently or continuously.

In this case, the evaporated hydrofluoric acid may be cooled and recovered through a condenser and reused. Furthermore, continuous production can be carried out by continuously supplying hydrofluoric acid and starting materials during the progress of the reaction, and at the same time distilling the product by utilizing the difference in boiling points and expelling it from the system and recovering it. After the reaction is completed, the temperature may be raised to carry out simple distillation of the reaction product, and the remaining basic compound may be reused.

A fluoro nitrogen-containing heterocyclic compound in which at least one of the 2 or 6 positions of the starting material pyridine compound is substituted with fluorine by the above halogen exchange reaction, or a pyrimidine compound in which at least one of the 2, 4, or 6 positions of the pyrimidine compound is substituted with fluorine. A fluoro-nitrogen-containing heterocyclic compound is obtained. Also, a fluoro nitrogen-containing heterocyclic compound in which at least one of the 3.4.5 or 6 positions of the pyridazine compound is substituted with fluorine, and a pyrazine compound in which at least one of the 2.3.5 or 6 positions of the pyrazine compound is substituted with fluorine. A fluoro nitrogen-containing heterocyclic compound is obtained.

〔Effect of the invention〕

According to the production method of the present invention, fluorination can be carried out at a sufficiently lower reaction temperature and normal pressure than in conventional methods, so unlike conventional methods, high-pressure reaction using an autoclave is not required, making it suitable for industrial implementation. In addition, since the method of the present invention does not require a catalyst such as aluminum fluoride,
The reaction system is easy to manage and is easy to carry out, and since hydrofluoric acid is used as the fluorinating agent, unlike methods using potassium fluoride, there is no problem of contamination with impurities such as potassium, and a highly pure product can be obtained.

[Examples and comparative examples]

Example 1 100ml of anhydrous hydrofluoric acid was added to a 100ml Teflon reaction vessel cooled to 0°C. After 1 mol of 2-chloropyrimidine was gradually added without stirring, the reaction vessel was transferred to a 100° C. oil bath and reacted for 10 minutes while heating. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel. Thereafter, 100 mmol of anhydrous hydrofluoric acid was added and reacted for 10 minutes (total reaction time 20 minutes). After the reaction, the reaction vessel was cooled, extracted with ether, and solid sodium bicarbonate was added to gradually neutralize it. After neutralization, the product was obtained by dehydration with magnesium sulfate. Analysis of the product by gas chromatography etc. confirmed that it was 2-fluoropyrimidine. Also, the yield is 90
%Met.

Comparative Example 1 200ml of anhydrous hydrofluoric acid was added to a 100mm iron autoclave cooled to 0°C! After 10 mmol of 2-chloropyrimidine was gradually added without stirring, the autoclave was transferred to a 100° C. oil bath and reacted in a closed system for 1 hour while heating. After the reaction, the reaction vessel was cooled, extracted with ether, and solid sodium bicarbonate was added to gradually neutralize it. After neutralization, the product was obtained by dehydration with magnesium sulfate.

Analysis of the product by gas chromatography etc. confirmed that it was 2-fluoropyrimidine. The yield is 20
It stopped at %.

Example 2 Anhydrous hydrofluoric acid was added to a Teflon reaction vessel (cooled to 0°C), 0f) a+1 at 100 μm! Add 1 mole and stir without stirring.
- 50 mmol of chloropyridine and 50 mmol of γ-collidine
After gradually adding mmol, one reaction vessel was transferred to a 150° C. oil bath and heated gradually. 2.5 hours later, 20
The reaction was terminated when the temperature reached 0°C. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel. During the reaction, 200 mmol of anhydrous hydrofluoric acid (gaseous) was continuously added. During the reaction, the product was distilled out due to the difference in boiling points, and 83% of 2-fluoropyridine was obtained as a distillate and 11% as a residue (total yield: 94%).

Example 3 50 mmol of anhydrous hydrofluoric acid was placed in a 100 ml Teflon reaction vessel cooled to 0°C, and 2-chloro-
After 10 mmol of 5-nitropyridine was gradually added, the reaction vessel was transferred to a 120° C. oil bath and reacted for 2 hours while heating. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel. Anhydrous fluoride a during the reaction
75 mmol (gaseous) was added continuously.

After the reaction, the mixture was cooled and extracted with ether. The extract was washed with saturated brine, neutralized with sodium bicarbonate, and then dehydrated with magnesium sulfate to obtain a product. When the product was analyzed by gas chromatography, it was confirmed to be 2-fluoro-5-nitropyridine. Moreover, the yield was 77%.

Example 4 100 mmol of anhydrous hydrofluoric acid was placed in a 100 ml Teflon reaction vessel cooled to 0°C, and while stirring, 10 mmol of 2-chloro-3-trifluoromethylpyridine and 10 ml of γ-collidine were added. After the gradual addition, one reaction vessel was transferred to a 120° C. oil bath and reacted for 1 hour while being heated. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel. During the reaction, 100 mmol of anhydrous hydrofluoric acid (gaseous) was continuously added. After the reaction, the temperature of the oil bath was raised to 200°C and the product was subjected to simple distillation to obtain 2-fluoro-3-trifluoromethylpyridine in a yield of 80%.

Example 5 In a 100a+1 Teflon reaction vessel cooled to 0°C, 2
-After adding 10 mmol of chloro-5-trifluoromethylpyridine and 10 mmol of γ-collidine, the reaction vessel was transferred to a 120°C oil bath and heated, while 75 mlJ mol of anhydrous hydrofluoric acid (gaseous) was added continuously. The reaction was allowed to proceed for 1 hour while bubbling. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel.

After the reaction, analysis according to Example 3 revealed that the desired 2-fluoro-5-trifluoromethylpyridine was obtained in a yield of 66%.

Example 6 In a 100+*L Teflon reaction vessel cooled to 0°C, 2
- After adding 10 mmol of chloro-5-ditropyridine, the reaction vessel was transferred to a 120°C oil bath and heated, while 100 mmol of anhydrous hydrofluoric acid (gaseous) was continuously added at 1 h.
The reaction was allowed to take place over time. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel.

After the reaction, the product was analyzed according to Example 3, and as a result, the desired 2-fluoro-5-nitropyridine was obtained in a yield of 68%.

Comparative Example 2 Ioo mmol of anhydrous hydrofluoric acid was placed in a lot) ml of iron autoclave cooled to 0°C, and 10 mmol of 2-chloro-5-nitropyridine was gradually added without stirring. The mixture was transferred to a bath and allowed to react in a closed system for 1 hour. After the reaction, the product was analyzed according to Example 3, and as a result, the desired 2-fluoro-5-nitropyridine was obtained in a yield of only 9%.

Example 7 In a 100ml Teflon reaction vessel cooled to 0°C, 2-
After adding 10 mlJ mol of bromopyridine, the reaction vessel was transferred to a 150° C. oil bath and heated, and 100 mlJ mol of anhydrous hydrofluoric acid (gaseous) was continuously blown into the reactor for 2 hours for reaction. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel.

After the reaction, the product was analyzed according to Example 3, and the desired 2-fluoropyridine was obtained in a yield of 53%.

Example 8 10Oi'J mol of anhydrous hydrofluoric acid was placed in a 100+I11 Teflon reaction vessel cooled to 0°C, and 2-
After gradually adding 10 mmol of bromopyridine and lo milJ moles of γ-collidine, the reaction vessel was transferred to a 1.50°C oil bath and heated while adding anhydrous hydrofluoric acid (gaseous).
The reaction was carried out while continuously blowing in 100 mmol for 1 hour. Hydrogen chloride generated during the reaction was released into the atmosphere through a thin tube in the upper lid of the reaction vessel. After the reaction, analysis according to Example 3 revealed that the desired 2-fluoropyridine was obtained in a yield of 79.
Obtained in %.

Patent applicant: Tochem Products Co., Ltd. Agent: Masahiro Matsui (1 other person)

Claims (2)

[Claims] (1) A chloro or bromo nitrogen-containing heterocyclic compound is reacted with anhydrous hydrofluoric acid at a temperature of 0 to 250°C under normal pressure, and fluorination is performed while the generated hydrogen chloride or hydrogen bromide is released from the system. A method for producing a fluoro nitrogen-containing heterocyclic compound. (2) The first step of adding a basic compound during the above fluorination
Claimed manufacturing method.