Method for producing pyridine compound

Abstract

To provide a new method for producing a pyridine compound useful as a precursor for a heterocyclic amide compound useful as a herbicide.SOLUTION: There is provided a method for producing a pyridine compound represented by the following formula (1), which comprises a step of purifying a reaction product, characterized by including a step of reacting a cyanoacetic acid ester compound represented by the following formula (2) with an enone compound represented by the following formula (3) in the presence of a base, followed by performing a cyclization reaction by acid treatment to produce a pyridine compound represented by formula (1); and a step of extracting the resulting reaction product into a water layer, followed by re-extracting into an organic layer. [R1 is an alkyl group having a carbon number of 1 to 3; R2 is an alkyl group having a carbon number of 1 to 4.]SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel method for producing a pyridine compound. [Background technology]

[0002] For example, Patent Document 1 discloses heterocyclic amide compounds useful as active ingredients of herbicides. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2014 / 192936 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a novel process for producing pyridine compounds which are useful as precursors of heterocyclic amide compounds which are useful as herbicides. [Means for solving the problem]

[0005] Means for Solving the Problems The present inventors have conducted intensive research to solve the above problems, and as a result have found that the desired pyridine compound can be obtained by reacting a cyanoacetate compound with an enone compound to obtain a crude product, and then carrying out a specific purification procedure, thereby completing the present invention.

[0006] That is, the present invention relates to the following [1]. [1] Formula (1):

[0007] [ka]

[0008] (In the formula, R 1represents an alkyl group having 1 to 3 carbon atoms, Formula (2):

[0009] [ka]

[0010] (In the formula, R 1 is as above.) A cyanoacetate compound represented by the formula: Formula (3):

[0011] [ka]

[0012] (In the formula, R 2 represents an alkyl group having 1 to 4 carbon atoms. in the presence of a base, followed by cyclization by treatment with an acid to produce a pyridine compound represented by formula (1); and purifying the reaction product after the producing step, The purification step includes extracting the reaction product into an aqueous layer and then re-extracting the product into an organic layer. A manufacturing method comprising: Effect of the Invention

[0013] According to the present invention, a novel method for producing a pyridine compound can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] [Method for producing a pyridine compound represented by formula (1)] The production method of the present invention is characterized in that a known cyanoacetate compound represented by formula (2) is reacted with a known enone compound represented by formula (3) in the presence of a base, followed by a cyclization reaction by acid treatment to produce a pyridine compound represented by formula (1), and then a purification step of the reaction product. When the cyanoacetate compound represented by formula (2) is reacted with the enone compound represented by formula (3), an adduct [2-cyano-6,6,6-trifluoro-5-hydroxy-2,4-hexadienoic acid ester compound] is obtained.

[0015] [ka]

[0016] In the above formula, R 1 represents an alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, or an i-propyl group; R 2 represents an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, or an n-butyl group.

[0017] 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 be used. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include polar solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile, dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolinone, 1-methyl-2-pyrrolidone, and water; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran (THF), diphenyl ether, and 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; and aliphatic hydrocarbon solvents such as n-pentane, n-hexane, and n-heptane. These solvents may be used alone or in combination of two or more.

[0018] Examples of the base include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonia, triethylamine, pyridine, 4-(dimethylamino)pyridine, etc. The amount of the base used is not particularly limited, but may be, for example, 0.5 to 50 equivalents relative to 1 equivalent of the cyanoacetic acid ester compound represented by formula (2).

[0019] The reaction temperature can be set at any temperature from −60° C. to the reflux temperature of the reaction mixture.

[0020] The reaction time 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.

[0021] Furthermore, an alcohol is also produced in the above reaction, and the alcohol may be removed by distilling off the solvent from the reaction mixture before the acid treatment of the above reaction.

[0022] After reacting the cyanoacetate compound represented by formula (2) with the enone compound represented by formula (3), the resulting reaction mixture is subjected to an acid treatment to carry out a cyclization reaction to produce the pyridine compound represented by formula (1).

[0023] The acid treatment can be carried out, for example, by adding an acid to the reaction mixture after the reaction, or by simultaneously adding the reaction mixture and the acid to a vessel other than the vessel in which the reaction mixture is contained. It is preferable to use a strong acid such as hydrogen halide such as hydrogen bromide or hydrogen chloride, or an aqueous solution thereof, as the acid. The amount of the acid used is not particularly limited, but can be, for example, 0.5 to 50 equivalents relative to 1 equivalent of the cyanoacetic ester compound represented by formula (2).

[0024] The temperature of the acid treatment can be set at any temperature within a range from −60° C. to the reflux temperature of the reaction mixture.

[0025] The time of 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.

[0026] After the pyridine compound represented by formula (1) is produced, a purification step of the reaction product is carried out. This step is characterized by including an unprecedented configuration in which the reaction product obtained in the above step is once extracted into an aqueous layer and then re-extracted into an organic layer. This step of extraction into an aqueous layer and re-extraction into an organic layer may be carried out repeatedly.

[0027] More specifically, after the above-mentioned reaction, a cyclization reaction is carried out by acid treatment to produce the pyridine compound represented by formula (1), and then the reaction mixture is separated. A basic aqueous solution is added to the obtained organic layer, and the reaction product is extracted into the aqueous layer as a salt of the pyridine compound represented by formula (1).

[0028] As the basic aqueous solution, an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate can be used.

[0029] An acidic solution is added to the resulting aqueous layer to neutralize the above salt, and then extraction is performed with an organic solvent, whereby the pyridine compound represented by formula (1) can be re-extracted into the organic layer.

[0030] The acid solution may be a strong acid such as hydrochloric acid.

[0031] Examples of the organic solvent that can be used include 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 n-pentane, n-hexane, and n-heptane; and ester solvents such as ethyl acetate.

[0032] Before the extraction into the aqueous layer and before re-extraction into the organic layer, the organic layer or the aqueous layer may be washed with water or an organic solvent, if necessary.

[0033] In each of the above-mentioned production methods, the reaction mixture after the cyclization reaction or the extract after extraction into the aqueous layer or organic layer may be appropriately subjected to a conventional post-treatment, such as direct concentration, dissolution in an organic solvent and washing with water followed by concentration, or pouring into ice water to extract with an organic solvent followed by concentration, as necessary.

[0034] 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, or liquid chromatography fractionation. EXAMPLES

[0035] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The measuring devices and the like used in the examples are as follows.

[0036] The proton nuclear magnetic resonance chemical shift values ​​of the examples (hereinafter 1H-NMR was measured in deuterated chloroform solvent at 300 MHz (model: ECX300 or ECP300, manufactured by JEOL) or 400 MHz (model: JNM-ECZ400S, manufactured by JEOL) using Me4Si (tetramethylsilane) as a standard substance. The symbols in the proton nuclear magnetic resonance chemical shift values ​​in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, br: broad. The products obtained in the following synthesis examples are 1 The product was analyzed by H-NMR.

[0037] The quantitative analyses described in the examples were quantitative analyses by the internal standard method using high performance liquid chromatography (hereinafter abbreviated as HPLC) under the conditions described below. [HPLC analysis conditions] Column: Inertsil ODS-4, 4.6×250 mm, 5 μm (GL Science) Eluent: acetonitrile: water: trifluoroacetic acid = 1:1:0.001 (volume ratio) Oven temperature: 40℃ Flow rate: 1.5ml / min Detection wavelength: 230 nm Internal standard: 2-ethoxynaphthalene [Synthesis Example 1] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 10.23g (60.88mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one, 7.23g (63.91mmol) of ethyl 2-cyanoacetate, and 51g of toluene, 6.47g (63.94mmol) of triethylamine was added at 10°C over 20 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 4 hours. After the stirring was completed, a mixed solution of 19g of 12mol / L hydrochloric acid and 10.2g of water was added to the reaction mixture at 40°C over 20 minutes. After the addition was completed, 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. The obtained organic layer was washed with water, and then 133g of water was added at 10°C, followed by the addition of 24.5g of a 13.9% by mass aqueous solution of potassium hydroxide over 10 minutes. After the addition was completed, the reaction mixture was separated at 10°C. The obtained aqueous layer was washed with 31 g of toluene, and then 6.34 g of 12 mol / L hydrochloric acid was added at 10° C., followed by extraction with toluene (51 g × 1 time). The solvent was distilled off from the obtained organic layer under reduced pressure, yielding 9.22 g of the target product as an orange solid. Ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate 1 H-NMR (300MHz): δ11.55 (s, 1H), 8.39 (d, 1H, J=7.8Hz), 7.31 (d, 1H, J=7.8Hz), 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 To a mixed solution of 10.00g (50.98mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one, 6.05g (53.53mmol) of ethyl 2-cyanoacetate and 50g of toluene, 5.42g (53.53mmol) of triethylamine was added at 10°C over 13 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 7 hours. After the stirring was completed, 10g of toluene was added to another reaction vessel, and then a mixed solution of 16g ​​of 12mol / L hydrochloric acid and 10.0g of water and the reaction mixture were added to toluene at the same time over 26 minutes at 40°C. After the addition was completed, the reaction mixture was stirred at 40°C for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated. The obtained organic layer was washed with water, and then 102.2g of a 2.8% by mass aqueous solution of potassium hydroxide was added over 18 minutes to adjust the pH to 12.7. After the addition was completed, the reaction mixture was separated at 10° C. The resulting aqueous layer was washed with 30 g of toluene, and then 5.31 g of 12 mol / L hydrochloric acid was added at 10° C., followed by extraction with toluene (50 g x 1). The solvent was distilled off from the resulting organic layer under reduced pressure to obtain 6.52 g of the target product as a brown oil. [Synthesis Example 3] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 2.71 g (26.78 mmol) of triethylamine, 3.03 g (26.79 mmol) of ethyl 2-cyanoacetate, and 5.00 g of N,N-dimethylformamide, 5.20 g (25.51 mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 0° C. over 49 minutes. After the addition was completed, the reaction mixture was stirred at 0° C. for 2 hours. After the stirring was completed, 5.24 g of the solvent was distilled off from the reaction mixture under reduced pressure, and 7.50 g of toluene was added. After the addition, a mixed solution of 7.5 g of toluene and 5.0 g of N,N-dimethylformamide was added to another container, and then the reaction mixture and 8 g of 12 mol / L hydrochloric acid were added simultaneously to the mixed solution of toluene and N,N-dimethylformamide over 70 minutes at 80° C. After the addition was completed, 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 separated. The obtained organic layer was washed twice with water, and the solvent was distilled off under reduced pressure. After adding 25 g of methanol, the solvent was distilled off, and 11.18 g of methanol and 3.81 g of water were added at room temperature. After the addition was completed, the reaction mixture was stirred at 10°C for 1 hour. After the precipitation of solids was visually confirmed, 5.33 g of water was added at 10°C over 90 minutes. After the addition was completed, the reaction mixture was cooled to 0°C and stirred for 1 hour. After the stirring was completed, the precipitated solid was filtered to obtain 4.22 g of the target product as a yellowish white solid. [Synthesis Example 4] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate A mixed solution of 20.00g (118.9mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one and 14.13g (124.9mmol) of ethyl 2-cyanoacetate was added to a mixed solution of 12.64g (124.9mmol) of triethylamine and 20.00g of N,N-dimethylformamide at 0°C over 30 minutes. After the addition was completed, the reaction mixture was stirred at 0°C for 4 hours. After the stirring was completed, 100.00g of toluene and 37.17g of 12mol / L hydrochloric acid were added to the reaction mixture at 80°C. After the addition was completed, 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 40.00g of water and 40.00g of toluene were added. After the addition was completed, 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 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 completed, the reaction mixture was separated at 0°C. 12.39 g of 12 mol / L hydrochloric acid was added to the obtained aqueous layer at 0°C to adjust the pH to 2.7, and then extracted with toluene (100 g x 1, 60 g x 1). 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 completed, 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 solid precipitation was visually confirmed, and then 20.62 g of water was added at 15°C over 30 minutes. After the addition was completed, 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 5] Synthesis of ethyl 2-cyano-6,6,6-trifluoro-5-oxo-3-hexanoate triethylamine salt To a mixed solution of 4.33g (42.79mmol) of triethylamine, 4.84g (42.79mmol) of ethyl 2-cyanoacetate and 8.00g of N,N-dimethylformamide, 8.24g (40.83mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 40°C. After the addition was completed, the reaction mixture was stirred at 40°C for 2 hours to obtain 25.23g of N,N-dimethylformamide solution containing the target substance. Quantitative analysis of the obtained N,N-dimethylformamide solution confirmed that it contained 13.46g of the target substance (retention time: 3.54 minutes). [Synthesis Example 6] Synthesis of methyl 2-hydroxy-6-(trifluoromethyl)nicotinate A mixed solution of 5.00g (29.7mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one and 3.09g (31.2mmol) of methyl 2-cyanoacetate was added to a mixed solution of 3.16g (31.2mmol) of triethylamine and 5g of N,N-dimethylformamide at 0°C over 20 minutes. After the addition was completed, the reaction mixture was stirred at 0°C for 4 hours. After the stirring was completed, 25.00g of toluene and 9.30g of 12mol / L hydrochloric acid were added to the reaction mixture at 80°C. After the addition was completed, 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 10.00g of water and 10.00g of toluene were added. After the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then separated. The obtained organic layer was washed with water, and 220.00g 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 completed, the reaction mixture was separated at 0° C. 3.10 g of 12 mol / L hydrochloric acid was added to the obtained aqueous layer at 0° C. to adjust the pH to 2.8, and then extracted with toluene (25 g x 1, 15 g x 1). The obtained organic layer was washed with water, and 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 completed, 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 the precipitation of solids was visually confirmed, and then 7.75 g of water was added at 15° C. over 30 minutes. After the addition was completed, the reaction mixture was cooled to 0° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was filtered to obtain 4.35 g of the target product as a white solid. Methyl 2-hydroxy-6-(trifluoromethyl)nicotinate 1 H-NMR(300MHz):δ11.45 (brs, 1H), 8.39 (d, 1H, J=7.8Hz), 7.32 (d, 1H, J=7.8Hz), 4.05 (s, 3H) [Synthesis Example 7] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate A mixed solution of 5.00g (25.62mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one and 3.04g (26.90mmol) of ethyl 2-cyanoacetate was added to a mixed solution of 2.72g (26.90mmol) of triethylamine and 25.00g of toluene at 0°C. After the addition was completed, the reaction mixture was stirred at 0°C for 3 hours. After the stirring was completed, 3.12g of the reaction mixture (35.05g) was transferred to another reaction vessel, and 0.7g of 12mol / L hydrochloric acid was added to the 3.12g of the reaction mixture at 40°C. After the addition was completed, the reaction mixture was stirred at 40°C for 3 hours, and then stirred at room temperature overnight. After the stirring was completed, the reaction mixture was cooled to room temperature, and water and acetonitrile were added to obtain a toluene solution containing the target product. The entire amount of the obtained toluene solution was quantitatively analyzed, and it was confirmed that the solution contained 0.35 g of the target product (retention time: 7.61 minutes). [Synthesis Example 8] Synthesis of ethyl 2-cyano-6,6,6-trifluoro-5-oxo-3-hexanoate triethylamine salt To a mixed solution of 31.14g (307.8mmol) of triethylamine, 34.81g (307.8mmol) of ethyl 2-cyanoacetate and 300.0g of toluene, 60.00g (293.1mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 0°C. After the addition was completed, the reaction mixture was stirred at 0°C for 6 hours. After the stirring was completed, the solvent was distilled off under reduced pressure, 147.9g of diisopropyl ether was added, the mixture was cooled to 0°C, and stirred for 2 hours. After the stirring was completed, the precipitated solid was filtered to obtain 94.22g of the target product as a brown solid. Ethyl 2-cyano-6,6,6-trifluoro-5-oxo-3-hexanoate triethylamine salt 1 H-NMR(400MHz):δ11.08 (brs, 1H), 8.34 (d, 1H, J=12.8Hz), 5.96 (d, 1H, J=12.8Hz), 4.22 (q, 2H, J=7.2Hz), 3.13 (q, 6H, J=7.2Hz), 1.36 (t, 9H, J=7.2Hz), 1.31 (t, 3H, J=7.2Hz) [Synthesis Example 9] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 10.00g (59.48mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one, 7.06g (62.46mmol) of ethyl 2-cyanoacetate and 50g of toluene, 6.32g (62.46mmol) of triethylamine was added at 10°C over 13 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 24 hours. After the stirring was completed, 12.78g of the solvent was distilled off from the reaction mixture under reduced pressure, and a mixed solution of 19g of 12mol / L hydrochloric acid and 10.0g of water was added at 40°C over 26 minutes. After the addition was completed, the reaction mixture was stirred at 40°C for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated. The obtained organic layer was washed with water, and then 130 g of water was added at 10° C., followed by the addition of 24.0 g of a 13.9% by mass aqueous solution of potassium hydroxide over 10 minutes to adjust the pH to 10.4. After the addition was completed, the reaction mixture was separated at 10° C. The obtained aqueous layer was washed with 30 g of toluene, and then 6.20 g of 12 mol / L hydrochloric acid was added at 10° C., followed by extraction with toluene (50 g x 1 time). The solvent was distilled off from the obtained organic layer under reduced pressure to obtain 7.10 g of the target product as a brown oil. [Synthesis Example 10] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 32.40g (320.19mmol) of triethylamine, 36.40g (321.78mmol) of ethyl 2-cyanoacetate, and 120.00g of N,N-dimethylformamide, 60.00g (305.86mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 2-8°C. After the addition was completed, the reaction mixture was stirred at 2-3°C for 1.5 hours. After the stirring was completed, 79.70g of 12mol / L hydrochloric acid was added to the reaction mixture at 50-58°C. After the addition was completed, 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 180.00g of water and 180.00g of toluene were added. After the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes, and then separated. The resulting organic layer was washed with water, and the solvent was then distilled off under reduced pressure to obtain 71.10 g of a brown oil containing the target compound. [Synthesis Example 11] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 10.00g (50.98mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one, 6.05g (53.53mmol) of ethyl 2-cyanoacetate and 50g of toluene, 5.42g (53.53mmol) of triethylamine was added at 10°C over 10 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 22 hours. After the stirring was completed, 11.16g of the solvent was distilled off from the reaction mixture under reduced pressure, and a mixed solution of 16g ​​of 12mol / L hydrochloric acid and 10.0g of water was added at 40°C over 19 minutes. After the addition was completed, the reaction mixture was stirred at 40°C for 7 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated. The obtained organic layer was washed with water, and then 102.2g of a 2.8% by mass aqueous solution of potassium hydroxide was added at 10°C over 11 minutes to adjust the pH to 10.9. After the addition was completed, the reaction mixture was separated at 10° C. The resulting aqueous layer was washed with 30 g of toluene, and then 5.31 g of 12 mol / L hydrochloric acid was added at 10° C., followed by extraction with toluene (50 g x 1). The solvent was distilled off from the resulting organic layer under reduced pressure to obtain 8.03 g of the target product as a brown solid. [Synthesis Example 12] Purification of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 18.10 g of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate obtained in Synthesis Example 10 and 31.60 g of methanol, 9.89 g of water was added at 50°C. After the addition was completed, the mixture was cooled to 10°C, and the precipitation of a 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 at 10°C over 1.5 hours. After the addition was completed, the mixture was stirred at -14 to -10°C for 1 hour. After the stirring was completed, the precipitated solid was filtered and washed with a mixed solution of 6.60 g of methanol and 6.60 g of water, thereby obtaining 12.40 g of the target product as a light brown solid. [Synthesis Example 13] Synthesis of ethyl 2-cyano-6,6,6-trifluoro-5-oxo-3-hexanoate triethylamine salt To a mixed solution of 4.34g (42.89mmol) of triethylamine, 4.85g (42.87mmol) of ethyl 2-cyanoacetate and 8.00g of N,N-dimethylformamide, 8.24g (40.82mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 20°C. After the addition was completed, the reaction mixture was stirred at 20°C for 3 hours to obtain 25.33g of N,N-dimethylformamide solution containing the target substance. Quantitative analysis of the obtained N,N-dimethylformamide solution confirmed that it contained 13.50g of the target substance. [Synthesis Example 14] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 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 at room temperature. After the addition was completed, 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 completed, 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 completed, the reaction mixture was stirred at room temperature for 15 minutes, and then separated. The obtained organic layer was washed with water, and the solvent was distilled off under reduced pressure. To the resulting residue, 50 ml of methanol was added at room temperature, and 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 completion of addition, the reaction mixture was stirred at 11 to 14°C for 1 hour, and then 23.9 g of water was added at 11 to 14°C over 1.5 hours. After completion of addition, the reaction mixture was cooled to 1 to 2°C and stirred for 1 hour. After completion of stirring, the precipitated solid was filtered and 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. [Synthesis Example 15] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 10.00g (59.48mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one, 7.06g (62.46mmol) of ethyl 2-cyanoacetate and 50g of toluene, 6.32g (62.46mmol) of triethylamine was added at 10°C over 23 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 17 hours. After the stirring was completed, 10g of toluene was added to another reaction vessel, and then a mixed solution of 19g of 12mol / L hydrochloric acid and 10.0g of water and the reaction mixture were simultaneously added to toluene over 30 minutes at 40°C. After the addition was completed, the reaction mixture was stirred at 40°C for 3 hours. After the stirring was completed, the reaction mixture was cooled to room temperature and separated. The obtained organic layer was washed with water, and then 130 g of water was added at 10° C., followed by the addition of 24.0 g of a 13.9% by mass aqueous solution of potassium hydroxide over 5 minutes to adjust the pH to 10.9. After the addition was completed, the reaction mixture was separated at 10° C. The obtained aqueous layer was washed with 30 g of toluene, and then 6.20 g of 12 mol / L hydrochloric acid was added at 10° C., followed by extraction with toluene (50 g x 1 time). The solvent was distilled off from the obtained organic layer under reduced pressure to obtain 7.78 g of the target product as a brown oil. [Synthesis Example 16] Synthesis of ethyl 2-cyano-6,6,6-trifluoro-5-oxo-3-hexanoate triethylamine salt To a mixed solution of 4.33g (42.79mmol) of triethylamine, 4.84g (42.79mmol) of ethyl 2-cyanoacetate and 8.00g of N,N-dimethylformamide, 8.23g (40.78mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one was added at 60°C. After the addition was completed, the reaction mixture was stirred at 60°C for 2 hours to obtain 25.07g of N,N-dimethylformamide solution containing the target substance. Quantitative analysis of the obtained N,N-dimethylformamide solution confirmed that it contained 13.44g of the target substance. [Synthesis Example 17] 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 were added at 0°C. After the addition was completed, 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 completed, 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 completed, the reaction mixture was stirred at room temperature for 15 minutes and then separated. The obtained organic layer was washed with water, and 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 completed, the reaction mixture was separated at 0° C. After the obtained aqueous layer was washed 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 times). The obtained organic layer was washed with water, and the solvent was distilled off under reduced pressure. After the distillation was completed, 29.00 g of methanol and 7.25 g of water were added at 50° C. After the addition was completed, 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 the precipitation of solids 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 solids were filtered to obtain 13.50 g of the target product as a white solid. [Synthesis Example 18] Purification of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 17.60 g of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate obtained in Synthesis Example 10 and 25.70 g of methanol, 8.09 g of water was added at 50° C. After the addition was completed, the mixture was cooled to 10° C., and the precipitation of solids 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 completed, the mixture was stirred at 2° C. for 1 hour. After the stirring was completed, the precipitated solid was filtered, and the obtained solid was washed with a mixed solution of 9.60 g of methanol and 9.60 g of water, thereby obtaining 11.60 g of the target product as a light brown solid. [Synthesis Example 19] Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)nicotinate To a mixed solution of 8.35g (42.57mmol) of (E)-4-butoxy-1,1,1-trifluoro-3-buten-2-one, 5.06g (44.73mmol) of ethyl 2-cyanoacetate and 42g of toluene, 4.53g (44.77mmol) of triethylamine was added at 10°C over 15 minutes. After the addition was completed, the reaction mixture was stirred at 10°C for 4 hours. After the stirring was completed, a mixed solution of 13.3g of 12mol / L hydrochloric acid and 8.35g of water was added to the reaction mixture at 40°C over 15 minutes. After the addition was completed, 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. The obtained organic layer was washed with water, and then 86.3g of a 2.8% by mass aqueous solution of potassium hydroxide was added at 15°C over 20 minutes. After the addition was completed, the reaction mixture was separated at 15°C. The obtained aqueous layer was washed with 25 g of toluene, and then 3.55 g of 12 mol / L hydrochloric acid was added at 15° C., followed by extraction with toluene (42 g × 1 time). The solvent was distilled off from the obtained organic layer under reduced pressure, yielding 6.70 g of the target product as a pale red solid.

Claims

[Claim 1] Formula (1): 【Chemistry 1】 (In the formula, R １ represents an alkyl group having 1 to 3 carbon atoms, Formula (2): 【Chemistry 2】 (In the formula, R １ is as stated above.) A cyanoacetate compound represented by the formula: Formula (3): 【Chemistry 3】 (In the formula, R ２ represents an alkyl group having 1 to 4 carbon atoms. in the presence of a base, followed by cyclization by treatment with an acid to produce a pyridine compound represented by formula (1); and purifying the reaction product after the producing step, The purification step includes extracting the reaction product into an aqueous layer and then re-extracting the product into an organic layer. Manufacturing method.

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