JP2023132937A - Method for producing pyridine compound - Google Patents

Abstract

To provide a novel method for producing a pyridine compound useful as a precursor of a heterocyclic amide compound useful as a herbicide.SOLUTION: There is provided a method for producing a pyridine compound represented by the formula (1), which comprises: a step of reacting a cyanoacetate ester compound represented by the formula (2) with an enone compound represented by the formula (3) in the presence of a base, followed by cyclization reaction by acid treatment to form a pyridine compound represented by the formula (1); a step of extracting the resulting reaction product into an aqueous layer, followed by re-extracting into an organic layer; and a step of purifying the reaction product. (wherein, R1 represents an alkyl group having 1 to 3 carbon atoms and R2 represents an alkyl group having 1 to 4 carbon atoms.)SELECTED DRAWING: None

Description

The present invention relates to a novel method for producing pyridine compounds.

For example, Patent Document 1 discloses a heterocyclic amide compound useful as an active ingredient of a herbicide.

International Publication No. 2014/192936

An object of the present invention is to provide a novel method for producing pyridine compounds useful as precursors of heterocyclic amide compounds useful as herbicides.

As a result of extensive research to solve the above-mentioned problems, the present inventors obtained a crude product through the reaction of a cyanoacetate compound and an enone compound, and then carried out specific purification operations to achieve the objective. It was discovered that a pyridine compound can be obtained, and the present invention was completed.

That is, the present invention relates to the following [1].
[1]
Formula (1):

A method for producing a pyridine compound represented by (wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms),
Formula (2):

(In the formula, R ¹ is as described above.)
The cyanoacetate compound represented by
Formula (3):

(In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms.)
A step of reacting the enone compound represented by in the presence of a base and then performing a cyclization reaction by acid treatment to produce a pyridine compound represented by formula (1),
After the generation step, a step of purifying the reaction product,
The purification step includes a step of extracting the reaction product into an aqueous layer and then re-extracting it into an organic layer.
manufacturing method, including.

According to the present invention, a new method for producing a pyridine compound can be provided.

[Method for producing a pyridine compound represented by formula (1)]
The production method of the present invention involves reacting a known cyanoacetate compound represented by formula (2) with a known enone compound represented by formula (3) in the presence of a base, and then treating with an acid. It is characterized in that a cyclization reaction is performed to produce a pyridine compound represented by formula (1), and then the reaction product is purified. Note that when the cyanoacetate compound represented by formula (2) and the enone compound represented by formula (3) are reacted, an adduct [2-cyano-6,6,6-trifluoro-5-hydroxy- 2,4-hexadienoic acid ester compound] is estimated to be obtained.

In the above formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms, such as a methyl group, ethyl group, n-propyl group, or i-propyl group, and R ² represents an alkyl group having 1 to 4 carbon atoms. represents, for example, a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, etc.

The reaction between the cyanoacetate compound represented by formula (2) and the enone compound represented by formula (3) can be carried out without a solvent, but a solvent may also be used. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile, dimethylsulfoxide (DMSO), and 1,3-dimethylformamide (DMF). Polar solvents such as dimethyl-2-imidazolinone, 1-methyl-2-pyrrolidone, and water; alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, and ethylene glycol; diethyl ether, tetrahydrofuran (THF), and diphenyl ether , ethers such as 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; -Aliphatic hydrocarbon solvents such as pentane, n-hexane, n-heptane and the like. These solvents may be used alone or in combination of two or more of them.

Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonia, triethylamine, pyridine, 4-(dimethylamino)pyridine, etc. but not limited to. Further, the amount of the base used is not particularly limited, but can be, for example, 0.5 to 50 equivalents per equivalent of the cyanoacetate compound represented by formula (2).

The temperature of the above reaction can be set at any temperature from -60°C to the reflux temperature of the reaction mixture.
Further, the time for the above reaction varies depending on the concentration of the reaction substrate and the reaction temperature, but can usually be set arbitrarily within the range of 5 minutes to 100 hours.

After reacting the cyanoacetate compound represented by formula (2) with the enone compound represented by formula (3), a cyclization reaction is carried out by acid treatment to form a pyridine compound represented by formula (1). Generate.
The acid treatment can be carried out by adding an acid to the reaction mixture after the reaction, and it is preferable to use a strong acid such as a hydrogen halide such as hydrogen bromide or hydrogen chloride, or an aqueous solution thereof. The amount of the acid used is not particularly limited, but can be, for example, 0.5 to 50 equivalents per equivalent of the cyanoacetate compound represented by formula (2).
The temperature of the acid treatment can be set at any temperature from -60°C to the reflux temperature of the reaction mixture.
Further, the time for the acid treatment varies depending on the concentration of the reaction substrate and the temperature of the acid treatment, but can usually be set arbitrarily within the range of 5 minutes to 100 hours.

After the production of the pyridine compound represented by formula (1), a step of purifying the reaction product is performed. This step is characterized by including an unprecedented configuration in which the reaction product obtained in the step is once extracted into an aqueous layer and then re-extracted into an organic layer. This process of extraction into the aqueous layer and re-extraction into the organic layer may be repeated.

More specifically, after the above reaction, a cyclization reaction is performed by acid treatment to produce a pyridine compound represented by formula (1), and then the reaction mixture is separated, and the resulting organic layer is A basic aqueous solution is added to the solution, and the reaction product is extracted into the aqueous layer as a salt of the pyridine compound represented by formula (1).
As the basic aqueous solution, an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. can be used.

The pyridine compound represented by formula (1) can be re-extracted into the organic layer by adding an acidic solution to the obtained aqueous layer to neutralize the above salt, and then extracting with an organic solvent.
As the acidic solution, a strong acid such as hydrochloric acid can be used.
The organic solvents mentioned above include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; n-pentane, n-hexane; , aliphatic hydrocarbon solvents such as n-heptane; and ester solvents such as ethyl acetate.

In addition, before extraction into the above aqueous layer and before re-extraction into the organic layer, the organic layer or aqueous layer may be washed with water or an organic solvent if necessary. Good too.

In each of the above production methods, the reaction mixture after the cyclization reaction or the extract after extraction into the aqueous layer or organic layer may be directly concentrated, or dissolved in an organic solvent and concentrated after washing with water, as necessary. Alternatively, normal post-treatments such as pouring into ice water, extraction with an organic solvent, and concentration may be carried out as appropriate.
In addition to the above purification steps, the target compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography, etc.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. The measuring devices used in the examples are as follows.

The proton nuclear magnetic resonance chemical shift values (hereinafter referred to as ¹ H-NMR) of Examples were measured at 300 MHz in a deuterated chloroform solvent using Me ₄ Si (tetramethylsilane) as a reference material. Further, the symbols in the proton nuclear magnetic resonance chemical shift values in Examples have the following meanings.
s: singlet, d: doublet, t: triplet, q: quartet, br: broad. The products obtained in the following synthesis examples were analyzed by ¹ H-NMR.

[Synthesis Example 1] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one 10.23 g (60 To a mixed solution of 7.23 g (63.91 mmol) of ethyl 2-cyanoacetate and 51 g of toluene, 6.47 g (63.94 mmol) of triethylamine was added over 20 minutes at 10°C. After the addition was complete, the reaction mixture was stirred at 10° C. for 4 hours. After the stirring was completed, a mixed solution of 19 g of 12 mol/L hydrochloric acid and 10.2 g of water was added to the reaction mixture over 20 minutes at 40°C. After the addition was complete, the reaction mixture was stirred at 40° C. for 9 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated into layers. After washing the obtained organic layer with water, 133 g of water was added at 10° C., and then 24.5 g of a 13.9% by mass aqueous solution of potassium hydroxide was added over 10 minutes. After the addition was complete, the reaction mixture was separated at 10°C. After washing the obtained aqueous layer with 31 g of toluene, 6.34 g of 12 mol/L hydrochloric acid was added at 10° C., and extracted with toluene (51 g x 1 time). The solvent of the obtained organic layer was distilled off under reduced pressure to obtain 9.22 g of the target product as an orange solid.
^1H -NMR of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate: δ11.55 (s, 1H), 8.39 (d, 1H, J=7.8Hz), 7.31 (d, 1H, J=7.8 Hz), 4.50 (q, 2H, J=7.2Hz), 1.45 (t, 3H, J=7.2Hz).

[Synthesis Example 2] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one 8.35 g (42 4.53 g (44.77 mmol) of triethylamine was added over 15 minutes at 10° C. to a mixed solution of 5.06 g (44.73 mmol) of ethyl 2-cyanoacetate and 42 g of toluene. After the addition was complete, the reaction mixture was stirred at 10° C. for 4 hours. After the stirring was completed, a mixed solution of 13.3 g of 12 mol/L hydrochloric acid and 8.35 g of water was added to the reaction mixture over 15 minutes at 40°C. After the addition was complete, the reaction mixture was stirred at 40° C. for 24 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated into layers. After washing the obtained organic layer with water, 86.3 g of a 2.8% by mass aqueous solution of potassium hydroxide was added over 20 minutes at 15°C. After the addition was complete, the reaction mixture was separated at 15°C. After washing the obtained aqueous layer with 25 g of toluene, 3.55 g of 12 mol/L hydrochloric acid was added at 15° C., and extracted with toluene (42 g x 1 time). The solvent of the obtained organic layer was distilled off under reduced pressure to obtain 6.70 g of the target product as a pale red solid.

[Synthesis Example 3] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate Add ( E) A mixed solution of 20.00 g (118.9 mmol) of -4-butoxy-1,1,1-trifluoro-3-buten-2-one and 14.13 g (124.9 mmol) of ethyl 2-cyanoacetate was added to 30 g of ethyl 2-cyanoacetate. Added in portions. After the addition was complete, the reaction mixture was stirred at 0° C. for 4 hours. After the stirring was completed, 100.00 g of toluene and 37.17 g of 12 mol/L hydrochloric acid were added to the reaction mixture at 80°C. After the addition was complete, the reaction mixture was stirred at 80° C. for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature, and 40.00 g of water and 40.00 g of toluene were added. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes and then separated. After washing the obtained organic layer with water, 440.00 g of water was added at 0°C. After the addition was completed, 101.50 g of an 8% by mass aqueous solution of potassium hydroxide was added at 0° C. over 25 minutes to adjust the pH to 9.3. After the addition was complete, the reaction mixture was separated at 0°C. To the obtained aqueous layer, 12.39 g of 12 mol/L hydrochloric acid was added at 0° C. to adjust the pH to 2.7, and then extracted with toluene (100 g x 1 time, 60 g x 1 time). After washing the obtained organic layer with water, the solvent was distilled off under reduced pressure. After the distillation was completed, 47.14 g of methanol was added at room temperature. After the addition was complete, the reaction mixture was cooled to 15° C. and 14.73 g of water was added. After the addition was completed, the reaction mixture was stirred at 15° C. for 10 minutes, and after visually confirming the precipitation of solid, 20.62 g of water was added at 15° C. over 30 minutes. After the addition was complete, the reaction mixture was cooled to 0° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration to obtain 18.01 g of the target product as a white solid.

[Synthesis Example 4] Synthesis of methyl 2-hydroxy-6-(trifluoromethyl)nicotinate Add (E) to a mixed solution of 3.16 g (31.2 mmol) of triethylamine and 5 g of N,N-dimethylformamide at 0°C. A mixed solution of 5.00 g (29.7 mmol) of -4-butoxy-1,1,1-trifluoro-3-buten-2-one and 3.09 g (31.2 mmol) of methyl 2-cyanoacetate was added over 20 minutes. and added. After the addition was complete, the reaction mixture was stirred at 0° C. for 4 hours. After the stirring was completed, 25.00 g of toluene and 9.30 g of 12 mol/L hydrochloric acid were added to the reaction mixture at 80°C. After the addition was complete, the reaction mixture was stirred at 80° C. for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature, and 10.00 g of water and 10.00 g of toluene were added. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes and then separated. After washing the obtained organic layer with water, 220.00 g of water was added at 0°C. After the addition was completed, 25.40 g of an 8% by mass aqueous solution of potassium hydroxide was added at 0° C. over 20 minutes to adjust the pH to 10.3. After the addition was complete, the reaction mixture was separated at 0°C. To the obtained aqueous layer, 3.10 g of 12 mol/L hydrochloric acid was added at 0° C. to adjust the pH to 2.8, and then extracted with toluene (25 g x 1 time, 15 g x 1 time). After washing the obtained organic layer with water, the solvent was distilled off under reduced pressure. After the distillation was completed, 15.00 g of methanol was added at room temperature. After the addition was complete, the reaction mixture was cooled to 15° C. and 3.50 g of water was added. After the addition was completed, the reaction mixture was stirred at 15° C. for 10 minutes, and after visually confirming the precipitation of solid, 7.75 g of water was added at 15° C. over 30 minutes. After the addition was complete, the reaction mixture was cooled to 0° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration to obtain 4.35 g of the target product as a white solid.
^1H -NMR of methyl 2-hydroxy-6-(trifluoromethyl)nicotinate: δ11.45 (brs, 1H), 8.39 (d, 1H, J=7.8Hz), 7.32 (d, 1H, J=7.8 Hz), 4.05 (s, 3H)

[Synthesis Example 5] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 3.74 g (90.70 mmol) of 97% by mass sodium hydroxide and 29.00 g of N,N-dimethylformamide, 10.25 g (90.61 mmol) of ethyl 2-cyanoacetate and 14.50 g (86.26 mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one at 0°C. was added. After the addition was complete, the reaction mixture was stirred at 0° C. for 3.5 hours. After the stirring was completed, 16.17 g of 12 mol/L hydrochloric acid was added to the reaction mixture at 0°C. After the addition was complete, the reaction mixture was stirred at 60° C. for 2 hours. After the stirring was completed, the reaction mixture was cooled to room temperature, and 43.50 g of water and 43.50 g of toluene were added. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes and then separated. After washing the obtained organic layer with water, 217.50 g of water was added at room temperature. After the addition was completed, 96.80 g of a 5% by mass aqueous solution of potassium hydroxide was added at 0° C. over 20 minutes to adjust the pH to 10.4. After the addition was complete, the reaction mixture was separated at 0°C. After washing the obtained aqueous layer with 43.50 g of toluene, 8.99 g of 12 mol/L hydrochloric acid was added at 0°C to adjust the pH to 2.4, and then extracted with toluene (43.50 g x 2). After washing the obtained organic layer with water, the solvent was distilled off under reduced pressure. After completion of distillation, 29.00 g of methanol and 7.25 g of water were added at 50°C. After the addition was complete, the reaction mixture was cooled to 15° C. and 14.50 g of methanol and 29.00 g of water were added. After the addition was completed, the reaction mixture was stirred at 15° C. for 10 minutes, and precipitation of solid was visually confirmed, and then the reaction mixture was cooled to 0° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration to obtain 13.50 g of the target product as a white solid.

[Synthesis Example 6] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate 32.40 g (320.19 mmol) of triethylamine, 36.40 g (321.78 mmol) of ethyl 2-cyanoacetate, and N,N-dimethyl 60.00 g (305.86 mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added to a mixed solution of 120.00 g of formamide at 2 to 8°C. . After the addition was complete, the reaction mixture was stirred at 2-3° C. for 1.5 hours. After the stirring was completed, 79.70 g of 12 mol/L hydrochloric acid was added to the reaction mixture at 50 to 58°C. After the addition was complete, the reaction mixture was stirred at 50° C. for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature, and 180.00 g of water and 180.00 g of toluene were added. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes and then separated. After washing the obtained organic layer with water, the solvent was distilled off under reduced pressure to obtain 71.10 g of a brown oil containing the target product.

[Synthesis Example 7] Purification of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate 17.60 g of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate obtained in Synthesis Example 6 and 25.70 g of methanol. 8.09 g of water was added to the mixed solution at 50°C. After the addition was completed, the mixture was cooled to 10°C, and precipitation of solid was visually confirmed, and then the mixture was stirred at 10°C for 1 hour. After the stirring was completed, 11.20 g of water was added at 10° C. over 1.5 hours. After the addition was complete, the mixture was stirred at 2° C. for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solution of 9.60 g of methanol and 9.60 g of water to obtain 11.60 g of the target product as a light brown solid.

[Synthesis Example 8] Purification of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate 18.10 g of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate obtained in Synthesis Example 6 and 31.60 g of methanol 9.89 g of water was added to the mixed solution at 50°C. After the addition was completed, the mixture was cooled to 10°C, and precipitation of solid was visually confirmed, and then the mixture was stirred at 10°C for 1 hour. After the stirring was completed, 13.80 g of water was added over 1.5 hours at 10°C. After the addition was complete, the mixture was stirred at -14 to -10°C for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solution of 6.60 g of methanol and 6.60 g of water to obtain 12.40 g of the target product as a light brown solid.

[Synthesis Example 9] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate 13.0 g (128.47 mmol) of triethylamine, 14.2 g (125.53 mmol) of ethyl 2-cyanoacetate, and 40.10 g of dimethyl sulfoxide. 20.00 g (118.96 mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one was added to the mixed solution at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1.5 hours. After the stirring was completed, 31.10 g of 12 mol/L hydrochloric acid was added to the reaction mixture at 47 to 63°C. After the addition was complete, the reaction mixture was stirred at 52° C. for 2 hours. After the stirring was completed, the reaction mixture was cooled to room temperature, and 60.00 g of water and 60.00 g of toluene were added. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes and then separated. After washing the obtained organic layer with water, the solvent was distilled off under reduced pressure. After adding 50 ml of methanol to the obtained residue at room temperature, the solvent was distilled off under reduced pressure. After completion of distillation, 54.50 g of methanol and 17.00 g of water were added at 50°C. After the addition was completed, the reaction mixture was stirred at 11-14°C for 1 hour, and then 23.9 g of water was added at 11-14°C over 1.5 hours. After the addition was complete, the reaction mixture was cooled to 1-2° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solution of 13.7 g of methanol and 13.7 g of water to obtain 19.30 g of the target product as a white solid.

Claims (1)

Formula (1):

A method for producing a pyridine compound represented by (wherein R ¹ represents an alkyl group having 1 to 3 carbon atoms),
Formula (2):

(In the formula, R ¹ is as described above.)
The cyanoacetate compound represented by
Formula (3):

(In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms.)
A step of reacting the enone compound represented by in the presence of a base and then performing a cyclization reaction by acid treatment to produce a pyridine compound represented by formula (1),
After the generation step, a step of purifying the reaction product,
The purification step includes a step of extracting the reaction product into an aqueous layer and then re-extracting it into an organic layer.
Production method.