JP2019182851A - Method for producing condensed-ring pyridine compound - Google Patents

Abstract

To provide a novel method for producing a condensed-ring pyridine compound, useful as a precursor of a heterocyclic amide compound useful as a herbicide.SOLUTION: The present invention provides a method for producing a condensed-ring pyridine compound represented by the formula (1), characterized by cyclizing a pyridine compound represented by the formula (2), in the presence of at least one selected from the group consisting of phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, diphosphorus pentoxide, thionyl chloride and oxalyl chloride (where R and Rindependently represent a C1-3 alkyl group, n is an integer of 0, 1 or 2).SELECTED DRAWING: None

Description

  The present invention relates to a novel process for producing a fused pyridine compound and a precursor thereof.

  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 process for producing a fused pyridine compound useful as a precursor of a heterocyclic amide compound useful as a herbicide, and a novel process for producing a pyridine compound which is a precursor of the fused pyridine compound. Is to provide.

  As a result of intensive studies to solve the above problems, the present inventors have found that the target compound can be easily obtained by cyclizing the precursor compound of the condensed pyridine compound. Further, the present inventors have found that the precursor compound can be obtained from an amidrazone compound and completed the present invention.

（式中、Ｒ及びＲ^１は、各々独立して炭素原子数１乃至３のアルキル基を表し、
ｎは０、１又は２の整数を表す。）
式（２）：

（式中、Ｒ、Ｒ^１及びｎは前記の通りである。）
で表されるピリジン化合物を、塩化ホスホリル、三塩化リン、五塩化リン、五酸化二リン、塩化チオニル及び塩化オキサリルからなる群から選択される少なくとも一種の存在下で環化させることを特徴とする製造方法。
〔２〕式（２）で表されるピリジン化合物の製造方法であって、

（式中、Ｒ及びＲ^１は、各々独立して炭素原子数１乃至３のアルキル基を表し、
ｎは０、１又は２の整数を表す。）
式（３）：

（式中、Ｒ、Ｒ^１及びｎは前記の通りである。）
で表されるアミドラゾン化合物と、
式（４）：

（式中、Ｒ^２は炭素原子数１乃至４のアルキル基を表す。）
で表される化合物を反応させることを特徴とする製造方法。 That is, the present invention relates to the following [1] to [2].
[1] A method for producing a condensed pyridine compound represented by the formula (1),

(Wherein R and R ¹ each independently represents an alkyl group having 1 to 3 carbon atoms,
n represents an integer of 0, 1 or 2. )
Formula (2):

(Wherein R, R ¹ and n are as described above.)
The pyridine compound represented by the formula is cyclized in the presence of at least one selected from the group consisting of phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, diphosphorus pentoxide, thionyl chloride and oxalyl chloride. Production method.
[2] A method for producing a pyridine compound represented by the formula (2),

(Wherein R and R ¹ each independently represents an alkyl group having 1 to 3 carbon atoms,
n represents an integer of 0, 1 or 2. )
Formula (3):

(Wherein R, R ¹ and n are as described above.)
An amidazone compound represented by
Formula (4):

(In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms.)
The manufacturing method characterized by making the compound represented by these react.

  ADVANTAGE OF THE INVENTION According to this invention, the new manufacturing method of a condensed pyridine compound and its precursor compound can be provided.

  The present invention relates to a method for producing a condensed pyridine compound represented by formula (1), and, as will be described later, a method for producing a pyridine compound represented by formula (2) which is a precursor of the condensed ring pyridine compound. Is also a subject of the present invention.

上記式中、Ｒ及びＲ^１は、各々独立して炭素原子数１乃至３のアルキル基を表し、例えばメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基を表し、ｎは０、１又は２の整数を表す。 [Method for producing condensed pyridine compound represented by formula (1)]
The condensed pyridine compound represented by the following formula (1) is produced by cyclizing the pyridine compound represented by the formula (2) in the presence of a dehydrating agent.

In the above formula, R and R ¹ each independently represents an alkyl group having 1 to 3 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, or an i-propyl group, and n is 0, 1 Or represents the integer of 2.

  This reaction can be carried out without solvent, but a solvent may be used. The solvent is not particularly limited as long as it is inert to the reaction. For example, polar solvents such as acetonitrile; ethers such as 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride Halogenated hydrocarbons such as chloroform, carbon tetrachloride and 1,2-dichloroethane, and aliphatic hydrocarbons such as n-pentane, n-hexane and n-heptane. These inert solvents may be used alone or as a mixture of two or more thereof.

  Examples of the dehydrating agent include at least one selected from the group consisting of phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, diphosphorus pentoxide, thionyl chloride, and oxalyl chloride. Among these, phosphoryl chloride is preferable. Moreover, the usage-amount of the said dehydrating agent is although it does not specifically limit, For example, it can be set as 0.5-50 equivalent with respect to 1 equivalent of pyridine compounds represented by Formula (2).

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

The fused ring pyridine compound represented by the above formula (1) and the pyridine compound represented by the formula (2) include known compounds.
Moreover, the pyridine compound represented by the said Formula (2) can be manufactured with the following method.

式中、Ｒ^２は炭素原子数１乃至４のアルキル基を表し、例えばメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基等を表し、Ｒ、Ｒ^１及びｎは上記したとおりである。 [Method for producing pyridine compound represented by formula (2)]
Precursor compound used in the production of the condensed pyridine compound represented by the above formula (1): the pyridine compound represented by the formula (2) is an amide razone compound represented by the formula (3) and the formula (4). It is produced by reaction with known compounds represented.

In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and the like, and R, R ¹ and n are As described above.

This reaction can be carried out without solvent, but a solvent may be used. The solvent is not particularly limited as long as it is inert to the reaction. For example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), acetonitrile, dimethyl sulfoxide (DMSO), 1,3- Polar solvents such as dimethyl-2-imidazolinone, water; methanol,
Alcohols such as ethanol, 1-propanol, 2-propanol, and ethylene glycol; Ethers such as diethyl ether, tetrahydrofuran (THF), diphenyl ether, and 1,2-dimethoxyethane; Aromatic hydrocarbons such as benzene, toluene, and xylene Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; and aliphatic hydrocarbons such as n-pentane, n-hexane and n-heptane. These solvents may be used alone or as a mixture of two or more thereof.

  The reaction temperature can be set to any temperature from −60 ° C. to the reflux temperature of the reaction mixture. The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but it can be arbitrarily set in the range of usually 5 minutes to 100 hours.

  In each of the above production methods, the reaction mixture after completion of the reaction is directly concentrated or dissolved in an organic solvent, concentrated after washing with water, or poured into ice water, concentrated after extraction with an organic solvent, and then subjected to normal post-treatment, and the target compound Can be obtained. Moreover, when the necessity for purification arises, it can be separated and purified by any purification method such as recrystallization, column chromatograph, thin layer chromatograph, liquid chromatographic fractionation and the like.

上記式中、Ｒ^ａ及びＲ^ｂは、各々独立して炭素原子数１乃至８のアルキル基を表し、例えばメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、２−エチルヘキシル基等を表し、Ｒ、Ｒ^１及びｎは前記の通りである。 The amidrazon compound represented by the above formula (3) can be produced, for example, through the following two steps.

In the above formula, R ^a and R ^b each independently represents an alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, 2 -Represents an ethylhexyl group or the like, and R, R ¹ and n are as defined above.

[Step 1]
This step is a step of obtaining a hydrazide compound represented by the formula (6) by allowing hydrazine monohydrate to act on a known ester compound represented by the formula (5).
[Step 2]
Further, in this step, a 3-alkoxy-3-iminopropanoic acid alkyl ester, which is a known compound, is allowed to act on the hydrazide compound represented by the formula (6) obtained in [Step 1] to obtain the formula (3). Is a step of obtaining an amidrazon compound represented by the formula:
This reaction can be carried out in the presence of a base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, 4- (dimethylamino) pyridine, if necessary. Moreover, the usage-amount of the said base is although it does not specifically limit, For example, it can be set as 0.5-50 equivalent with respect to 1 equivalent of hydrazide compounds represented by Formula (6).

In any of the above steps, the reaction 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. For example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), acetonitrile, dimethyl sulfoxide (DMSO), 1,3- Polar solvents such as dimethyl-2-imidazolinone and water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; diethyl ether, tetrahydrofuran (THF), diphenyl ether, 1,2-dimethoxyethane and the like Ethers; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; n-pentane, n-hexane, n-heptane, etc. And aliphatic hydrocarbons. These solvents may be used alone or as a mixture of two or more thereof.
In any step, the reaction temperature can be set to any temperature from −60 ° C. to the reflux temperature of the reaction mixture. In addition, the reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can usually be arbitrarily set in the range of 5 minutes to 100 hours.

  After completion of each step of [Step 1] to [Step 2], the reaction mixture can be used as it is in the next step, and usual post-treatments such as washing, extraction and concentration are performed as necessary. Alternatively, the target compound may be separated and purified by any purification method and then used in the next step.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not limited to these Examples. In addition, each measuring apparatus etc. which were used in the Example are as follows.

In addition, the medium pressure preparative liquid chromatography described in the following synthesis examples and reference examples used Yamazen Corporation medium pressure preparative apparatus; YFLC-Wprep (flow rate 18 ml / min, silica gel 40 μm column).
Moreover, the proton nuclear magnetic resonance chemical shift value of the Example was measured at 300 MHz using Me ₄ Si (tetramethylsilane) as a reference material. Moreover, the solvent used for the measurement is described in the following synthesis examples. Moreover, the symbol in the proton nuclear magnetic resonance chemical shift value of an Example represents the following meaning: s: singlet, d: doublet, t: triplet, m: multiplet, q: quartet, br: broad.

Synthesis Example 1 Synthesis Step 1: 2 of Ethyl 3-{(methylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of-(methylthio) acetic acid (2-ethylhexyl) Mixture of 2-mercaptoacetic acid (2-ethylhexyl) 24.63 g (120.5 mmol), potassium carbonate 19.99 g (144.6 mmol) and N, N-dimethylformamide 75 g To the solution was added 18.24 g (144.6 mmol) of dimethyl sulfate at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 21 hours. After completion of stirring, 150 ml of water was added at room temperature to stop the reaction, and extraction with toluene (100 ml × 2 times) was performed. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 26.20 g of the desired product as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ): σ4.05 (d, J = 6.0 Hz, 2H), 3.19 (s, 2H), 2.21 (s, 3H), 1.63-1.57 ( m, 1H), 1.40-1.29 (m, 8H), 0.93-0.87 (m, 6H).

Step 2: Synthesis of 2- (methylthio) acetohydrazide To a mixed solution of 2- (methylthio) acetic acid (2-ethylhexyl) 18.18 g (83.26 mmol) and ethanol 40 g, hydrazine monohydrate 8 was heated under reflux. .33 g (166.4 mmol) was added. After the addition was complete, the reaction mixture was stirred for 24 hours under heating to reflux. After completion of the stirring, 14 ml of a 12 mol / L hydrochloric acid aqueous solution was added at room temperature to stop the reaction, and the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 100 g of water was added at room temperature and washed with ethyl acetate (75 ml × 2 times). To the obtained aqueous layer, sodium hydrogen carbonate was added at room temperature to adjust the pH to 9, followed by extraction with ethyl acetate (200 ml × 3 times). The obtained organic layer was evaporated under reduced pressure to give 1.97 g of the desired product as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): σ 7.87 (brs, 1H), 3.92 (brs, 2H), 3.24 (s, 2H), 2.18 (s, 3H).

Step 3: Synthesis of ethyl 3-imino-3- [2- {2- (methylthio) acetyl} hydrazinyl] propanoate Mixing of 3.12 g (19.58 mmol) of ethyl 3-ethoxy-3-iminopropanoate and 20 ml of ethanol To the solution, a mixed solution of 1.81 g (15.06 mmol) of 2- (methylthio) acetohydrazide and 10 ml of ethanol was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 68 hours. After completion of the stirring, the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 30 ml of diisopropyl ether was added at room temperature, and the mixture was stirred at room temperature for 1 hour. After the completion of stirring, the precipitated solid was collected by filtration to obtain 2.96 g of the desired product as a pale yellow solid.
Melting point: 98-100 ° C

Step 4: Synthesis of ethyl 2- [2- {2- (methylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (methylthio) acetyl} hydrazinyl] To a mixed solution of 2.70 g (11.57 mmol) of ethyl propanoate and 30 ml of ethanol, 2.27 g of (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one at 80 ° C. A mixed solution of (11.57 mmol) and ethanol 5 ml was added. After completion of the addition, the reaction mixture was stirred at 80 ° C. for 2 hours, and then stirred for 1 hour under ice cooling. After the stirring, the precipitated solid was collected by filtration to obtain 1.96 g of the desired product as a white solid.
Melting point: 120-122 ° C

Step 5: Synthesis of ethyl 3-{(methylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 900 mg of phosphoryl chloride (5. 87 mmol) and 9 g of toluene were added 1.80 g (5.34 mmol) of ethyl 2- [2- {2- (methylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate at room temperature. . After completion of the addition, the reaction mixture was stirred at 100 ° C. for 8 hours. After completion of the stirring, 18 g of water was added at room temperature to stop the reaction, and the mixture was extracted with toluene (10 ml × 2 times). The obtained organic layer was washed with water and then with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate [gradient of 10: 1 to 3: 7 (volume ratio, hereinafter the same)] to obtain the desired product. 1.48 g was obtained as a brown solid.
Melting point: 83-84 ° C

Synthesis Example 2 Synthesis Step 1: 2 of Ethyl 3-{(ethylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of-(ethylthio) acetic acid (2-ethylhexyl) Mixture of 2-mercaptoacetic acid (2-ethylhexyl) 24.49 g (119.9 mmol), potassium carbonate 19.88 g (143.8 mmol) and N, N-dimethylformamide 75 g To the solution was added 22.43 g (143.8 mmol) of iodoethane at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After stirring, water 15 at room temperature
The reaction was stopped by adding 0 ml and extracted with toluene (100 ml × 2 times). The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 27.84 g of the desired product as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ): σ4.05 (d, J = 6.0 Hz, 2H), 3.23 (s, 2H), 2.66 (q, J = 7.5 Hz, 2H), 1. 61-1.54 (m, 1H), 1.42-1.27 (m, 11H), 0.93-0.87 (m, 6H).

Step 2: Synthesis of 2- (ethylthio) acetohydrazide To a mixed solution of 21.28 g (91.57 mmol) of 2- (ethylthio) acetic acid (2-ethylhexyl) and 45 g of ethanol, hydrazine monohydrate 9 was heated under reflux. .17 g (183.2 mmol) was added. After the addition was complete, the reaction mixture was stirred for 32 hours under heating to reflux. After completion of the stirring, 16 ml of a 12 mol / L hydrochloric acid aqueous solution was added at room temperature to stop the reaction, and the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 100 g of water was added at room temperature and washed with ethyl acetate (75 ml × 2 times). To the obtained aqueous layer, sodium hydrogen carbonate was added at room temperature to adjust the pH to 8 to 9, followed by extraction with ethyl acetate (100 ml × 3 times). The obtained organic layer was evaporated under reduced pressure to obtain 7.68 g of the desired product as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): σ 7.90 (brs, 1H), 3.89 (brs, 2H), 3.28 (s, 2H), 2.60 (q, J = 7.4 Hz, 2H) , 1.29 (t, J = 7.4 Hz, 3H).

Step 3: Synthesis of ethyl 3-imino-3- [2- {2- (ethylthio) acetyl} hydrazinyl] propanoate Mixture of 11.57 g (72.66 mmol) of ethyl 3-ethoxy-3-iminopropanoate and 30 ml of ethanol To the solution, a mixed solution of 7.50 g (55.89 mmol) of 2- (ethylthio) acetohydrazide and 20 ml of ethanol was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 69 hours. After completion of the stirring, the solvent in the reaction mixture was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with ethyl acetate: methanol (gradient of 100: 0 to 95: 5) to obtain 11.99 g of the desired product as a white solid.
Melting point: 77-79 ° C

Step 4: Synthesis of ethyl 2- [2- {2- (ethylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (ethylthio) acetyl} hydrazinyl] To a mixed solution of 5.00 g (20.22 mmol) of ethyl propanoate and 50 ml of ethanol, 3.97 g of (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one at 80 ° C. A mixed solution of (20.22 mmol) and 10 ml of ethanol was added. After completion of the addition, the reaction mixture was stirred at 80 ° C. for 2 hours, and then stirred for 1 hour under ice cooling. After the stirring, the precipitated solid was collected by filtration to obtain 3.99 g of the desired product as a white solid.
Melting point: 120-122 ° C

Step 5: Synthesis of ethyl 3-{(ethylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 1.68 g of phosphoryl chloride ( 10.96 mmol) and 18 g of toluene were mixed with 3.50 g (9.96 mmol) of ethyl 2- [2- {2- (ethylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate at room temperature. Added. After completion of the addition, the reaction mixture was stirred at 100 ° C. for 8 hours. After completion of the stirring, 35 g of water was added at room temperature to stop the reaction, and the mixture was extracted with toluene (20 ml × 2 times). The obtained organic layer was washed with water and then with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure. The residue obtained is n
-Purification by medium pressure preparative liquid chromatography eluting with hexane: ethyl acetate (gradient of 10: 1 to 3: 7) gave 2.91 g of the desired product as a brown solid.
Melting point: 91-92 ° C

Synthesis Example 3 Synthesis Step 1: Ethyl 3-{(isopropylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (isopropylthio) acetic acid (2-ethylhexyl) 2-mercaptoacetic acid (2-ethylhexyl) 24.62 g (120.5 mmol), potassium carbonate 19.99 g (144.6 mmol) and N, N-dimethylformamide 75 ml To this mixed solution, 17.78 g (144.6 mmol) of 2-bromopropane was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the stirring, 150 ml of water was added at room temperature to stop the reaction, and the mixture was extracted with toluene (100 ml × 2 times). The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 29.01 g of the desired product as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ): σ4.06 (d, J = 5.7 Hz, 2H), 3.27 (s, 2H), 3.13-3.03 (m, 1H), 1.49- 1.24 (m, 15H), 0.91 (t, J = 7.4 Hz, 6H).

Step 2: Synthesis of 2- (isopropylthio) acetohydrazide Hydrazine monohydrate under heating and reflux in a mixed solution of 29.01 g (117.7 mmol) of 2- (isopropylthio) acetic acid (2-ethylhexyl) and 90 g of ethanol 11.78 g (235.4 mmol) of product was added. After the addition was complete, the reaction mixture was stirred for 48 hours under heating to reflux. After the stirring, 20 ml of 12 mol / L hydrochloric acid aqueous solution was added under ice cooling to stop the reaction, and the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 100 g of water was added at room temperature and washed with ethyl acetate (75 ml × 2 times). To the obtained aqueous layer, sodium hydrogen carbonate was added at room temperature to adjust the pH to 8 to 9, followed by extraction with ethyl acetate (100 ml × 3 times). The obtained organic layer was evaporated under reduced pressure to obtain 13.42 g of the desired product as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ): σ7.89 (brs, 1H), 3.90 (brs, 2H), 3.29 (s, 2H), 3.02-2.91 (m, 1H), 1 .30 (d, J = 6.6 Hz, 6H).

Step 3: Synthesis of ethyl 3-imino-3- [2- {2- (isopropylthio) acetyl} hydrazinyl] propanoate 9.77 g (61.40 mmol) of ethyl 3-ethoxy-3-iminopropanoate and 30 ml of ethanol To the mixed solution, a mixed solution of 7.00 g (47.23 mmol) of 2- (isopropylthio) acetohydrazide and 20 ml of ethanol was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 70 hours. After completion of the stirring, the solvent in the reaction mixture was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (gradient of 50:50 to 0: 100) to obtain 9.68 g of the desired product as a white solid.
Melting point: 102-104 ° C

Step 4: Synthesis of ethyl 2- [2- {2- (isopropylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (isopropylthio) acetyl} (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one 2 in a mixed solution of 3.00 g (11.48 mmol) of ethyl hydrazinyl] propanoate and 30 ml of ethanol at 80 ° C. A mixed solution of .25 g (11.48 mmol) and ethanol 5 ml was added. After the addition was complete, the reaction mixture was stirred at 80 ° C. for 2 hours. After completion of the stirring, the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 10 ml of ethanol was added at room temperature. After completion of the addition, the reaction mixture was stirred for 1 hour under ice cooling. After the stirring, the precipitated solid was collected by filtration to obtain 2.55 g of the desired product as a white solid.
Melting point: 124-126 ° C

Step 5: Synthesis of ethyl 3-{(isopropylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 462 mg of phosphoryl chloride (3 .01 mmol) and 5 g of toluene at room temperature were mixed with 1.00 g (2.74 mmol) of ethyl 2- [2- {2- (isopropylthio) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate. Added. After completion of the addition, the reaction mixture was stirred at 100 ° C. for 8 hours. After completion of the stirring, 10 g of water was added at room temperature to stop the reaction, and the mixture was extracted with toluene (5 ml × 2 times). The obtained organic layer was washed with water and then with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (gradient of 10: 1 to 1: 1) to obtain 828 mg of the desired product as a brown solid.
Melting point: 101-103 ° C

Synthesis Example 4 Synthesis Step 1: Ethyl 3-{(methylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (methylsulfonyl) acetic acid (2-ethylhexyl) To a mixed solution of potassium peroxymonosulfate (CAS 37222-66-5) 32.94 g, water 10 ml and 1,4-dioxane 40 ml at room temperature A mixed solution of 7.80 g (35.72 mmol) of methylthio) acetic acid (2-ethylhexyl) and 10 ml of 1,4-dioxane was added dropwise over 1 hour. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours. After completion of the stirring, the reaction mixture was filtered, and 10 ml of a saturated aqueous sodium hydrogen sulfite solution was added to the obtained filtrate at room temperature. After completion of the addition, the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 20 ml of water was added at room temperature, followed by extraction with ethyl acetate (40 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.68 g of the desired product as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ): σ4.20-4.10 (m, 2H), 3.99 (s, 2H), 3.15 (s, 3H), 1.65 to 1.57 (m, 1H), 1.43-1.29 (m, 8H), 0.93-0.88 (m, 6H).

Step 2: Synthesis of ethyl 3-imino-3- [2- {2- (methylsulfonyl) acetyl} hydrazinyl] propanoate 5.10 g (20.37 mmol) 2- (methylsulfonyl) acetic acid (2-ethylhexyl) and ethanol To 6 ml of the mixed solution, 1.02 g (20.37 mmol) of hydrazine monohydrate was added at 60 ° C. After completion of the addition, the reaction mixture was stirred at 60 ° C. for 4 hours. After the completion of stirring, 4.22 g (26.48 mmol) of ethyl 3-ethoxy-3-iminopropanoate was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. After the stirring was completed, the precipitated solid was collected by filtration to obtain 4.11 g of the desired product as a white solid.
Melting point: 142-144 ° C

Step 3: Synthesis of ethyl 2- [2- {2- (methylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (methylsulfonyl) acetyl} (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one 2 at 80 ° C. in a mixed solution of 3.90 g (14.70 mmol) of ethyl hydrazinyl] propanoate and 60 ml of ethanol. A mixed solution of .88 g (14.70 mmol) and ethanol 5 ml was added. After completion of the addition, the reaction mixture was stirred at 80 ° C. for 3 hours and then under ice cooling for 1 hour. After completion of the stirring, the precipitated solid was collected by filtration to obtain 4.90 g of the desired product as a white solid.
Melting point: 194-196 ° C

Step 4: Synthesis of ethyl 3-{(methylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 2.09 g phosphoryl chloride 2.52 g of ethyl 2- [2- {2- (methylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate at room temperature in a mixed solution of (13.64 mmol) and 1,2-dichloroethane 7 ml (6.82 mmol) was added. After the addition was complete, the reaction mixture was stirred for 24 hours under heating to reflux. After completion of the stirring, 13 ml of water was added at room temperature. After completion of addition. The precipitated solid was collected by filtration to obtain 0.85 g of the desired product as a white solid.
Melting point: 218-220 ° C

Synthesis Example 5 Synthesis Step 1: Ethyl 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (ethylsulfonyl) acetic acid (2-ethylhexyl) To a mixed solution of potassium peroxymonosulfate (CAS 37222-66-5) 25.40 g, water 10 ml and 1,4-dioxane 40 ml at room temperature A mixed solution of 6.40 g (27.54 mmol) of ethylthio) acetic acid (2-ethylhexyl) and 10 ml of 1,4-dioxane was added dropwise over 1 hour. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours. After completion of the stirring, the reaction mixture was filtered, and 10 ml of a saturated aqueous sodium hydrogen sulfite solution was added to the obtained filtrate at room temperature. After completion of the addition, the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 20 ml of water was added at room temperature, followed by extraction with ethyl acetate (40 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.87 g of the desired product as a colorless liquid.
¹ H-NMR (CDCl ₃ ): σ 4.19-4.09 (m, 2H), 3.95 (s, 2H), 3.28 (q, J = 7.8 Hz, 2H), 1.65 1.56 (m, 1H), 1.47-1.29 (m, 11H), 0.93-0.88 (m, 6H).

Step 2: Synthesis of ethyl 3-imino-3- [2- {2- (ethylsulfonyl) acetyl} hydrazinyl] propanoate 4.88 g (18.46 mmol) of 2- (ethylsulfonyl) acetic acid (2-ethylhexyl) and ethanol To 6 ml of the mixed solution, 0.92 g (18.46 mmol) of hydrazine monohydrate was added at 60 ° C. After completion of the addition, the reaction mixture was stirred at 60 ° C. for 4 hours. After completion of the stirring, 3.82 g (24.00 mmol) of ethyl 3-ethoxy-3-iminopropanoate was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. After completion of the stirring, the precipitated solid was collected by filtration to obtain 3.55 g of the desired product as a white solid.
Melting point: 111-113 ° C

Step 3: Synthesis of ethyl 2- [2- {2- (ethylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (ethylsulfonyl) acetyl} (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one 2 at 80 ° C. in a mixed solution of 3.30 g (11.81 mmol) of ethyl hydrazinyl] propanoate and 40 ml of ethanol. A mixed solution of .32 g (11.81 mmol) and 5 ml of ethanol was added. After completion of the addition, the reaction mixture was stirred at 80 ° C. for 3 hours and then under ice cooling for 1 hour. After the completion of stirring, the precipitated solid was collected by filtration to obtain 1.75 g of the desired product as a white solid.
Melting point: 153-155 ° C

Step 4: Synthesis of ethyl 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 1.24 g of phosphoryl chloride 1.58 g of ethyl 2- [2- {2- (ethylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate in a mixed solution of (8.08 mmol) and 1,2-dichloroethane 4 ml at room temperature (4.04 mmol) was added. After the addition was complete, the reaction mixture was stirred for 24 hours under heating to reflux. After completion of the stirring, 8 ml of water was added at room temperature to stop the reaction, followed by extraction with 1,2-dichloroethane (30 ml × 2 times). The obtained organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (gradient 5: 5 to 0:10) to obtain 0.85 g of the desired product as a pale yellow solid.
Melting point: 191-192 ° C

Synthesis Example 6 Synthesis Step 1: Ethyl 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (isopropylsulfonyl) acetic acid (2-ethylhexyl) To a mixed solution of potassium peroxymonosulfate (CAS 37222-66-5) 28.07 g, water 10 ml and 1,4-dioxane 40 ml at room temperature A mixed solution of 7.50 g (30.44 mmol) of isopropylthio) acetic acid (2-ethylhexyl) and 10 ml of 1,4-dioxane was added dropwise over 1 hour. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours. After completion of the stirring, the reaction mixture was filtered, and 10 ml of a saturated aqueous sodium hydrogen sulfite solution was added to the obtained filtrate at room temperature. After completion of the addition, the solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, 20 ml of water was added at room temperature, followed by extraction with ethyl acetate (40 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.21 g of the desired product as a colorless liquid.
¹ H-NMR (CDCl ₃ ): σ 4.18-4.08 (m, 2H), 3.97 (s, 2H), 3.61-3.52 (m, 1H), 1.66-1. 56 (m, 1H), 1.45-1.29 (m, 14H), 0.93-0.87 (m, 6H).

Step 2: Synthesis of ethyl 3-imino-3- [2- {2- (isopropylsulfonyl) acetyl} hydrazinyl] propanoate 2- (isopropylsulfonyl) acetic acid (2-ethylhexyl) 5.35 g (19.22 mmol) and ethanol To 6 ml of the mixed solution, 0.96 g (19.22 mmol) of hydrazine monohydrate was added at 60 ° C. After completion of the addition, the reaction mixture was stirred at 60 ° C. for 4 hours. After completion of the stirring, 3.98 g (24.99 mmol) of ethyl 3-ethoxy-3-iminopropanoate was added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. After completion of the stirring, the precipitated solid was collected by filtration to obtain 3.50 g of the desired product as a white solid.
Melting point: 129-130 ° C

Step 3: Synthesis of ethyl 2- [2- {2- (isopropylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate 3-Imino-3- [2- {2- (isopropylsulfonyl) acetyl} (E) -4-butoxy-1,1,1-trifluoro-3-buten-2-one 2 at 80 ° C. in a mixed solution of 3.20 g (10.91 mmol) of ethyl hydrazinyl] propanoate and 30 ml of ethanol. A mixed solution of .14 g (10.91 mmol) and ethanol 5 ml was added. After the addition was complete, the reaction mixture was stirred at 80 ° C. for 3 hours. After completion of the stirring, the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (9: 1 to 4: 6 gradient) to obtain 1.22 g of the desired product as a pale yellow solid.
Melting point: 133-135 ° C

Step 4: Synthesis of ethyl 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 0.85 g phosphoryl chloride 1.55 g of ethyl 2- [2- {2- (isopropylsulfonyl) acetyl} hydrazinyl] -6- (trifluoromethyl) nicotinate at room temperature in a mixed solution of (5.54 mmol) and 2 ml of 1,2-dichloroethane (2.77 mmol) was added. After the addition was complete, the reaction mixture was stirred for 9 hours under heating to reflux. After completion of the stirring, 8 ml of water was added at room temperature to stop the reaction, followed by extraction with 1,2-dichloroethane (20 ml × 2 times). The obtained organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (gradient 8: 2-1: 9) to obtain 0.52 g of the objective product as a white solid.
Melting point: 195-197 ° C

[Reference Example 1] Synthesis step of 2- (isopropylthio) acetohydrazide 1: Synthesis of ethyl 2- (isopropylthio) acetate 15.8 g (131.5 mmol) of ethyl 2-mercaptoacetate, 19.1 g of potassium carbonate (138. 2mmol) and 31.6 g of N, N-dimethylformamide were added 17.0 g (138.2 mmol) of 2-bromopropane at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After completion of the stirring, 150 ml of water was added at room temperature to stop the reaction, and the mixture was extracted with ethyl acetate (100 ml × 2 times). The obtained organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with n-hexane: ethyl acetate (gradient of 95: 5 to 50:50) to obtain 19.28 g of the desired product as a colorless liquid. . ¹ H-NMR (CDCl ₃ ): σ 4.19 (q, J = 7.2 Hz, 2H), 3.25 (s, 2H), 3.15-3.07 (m, 1H), 1.32- 1.26 (m, 9H).

Step 2: Synthesis of 2- (isopropylthio) acetohydrazide To a mixed solution of ethyl 2- (isopropylthio) acetate 15.0 g (92.4 mmol) and ethanol 20 ml, hydrazine monohydrate 5.08 g (101 0.7 mmol) was added. After completion of the addition, the reaction mixture was stirred for 17 hours under heating to reflux. After completion of the stirring, the solvent in the reaction mixture was distilled off under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography eluting with ethyl acetate: methanol (gradient of 100: 0 to 93: 7) to obtain 12.02 g of the desired product as a colorless liquid.
¹ H-NMR (CDCl ₃ ): σ7.89 (brs, 1H), 3.90 (brs, 2H), 3.29 (s, 2H), 3.02-2.91 (m, 1H), 1 .30 (d, J = 6.6 Hz, 6H).

Reference Example 2 Synthesis of ethyl 3-{(methylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 2-hydrazinyl In a mixed solution of 498 mg (2.00 mmol) of ethyl-6- (trifluoromethyl) nicotinate, 276 mg (2.00 mmol) of 2- (methylsulfonyl) acetic acid and 4.0 g of anisole, 920 mg (6. 00 mmol) was added. After completion of the addition, the reaction mixture was stirred at 60 ° C. for 0.5 hour and then at 100 ° C. for 3 hours. After completion of the stirring, 10 ml of water was added at room temperature to stop the reaction, and the mixture was extracted with 70 ml of 1,2-dichloroethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with 20 ml of ethyl acetate to obtain 484 mg of the desired product as a pale yellow solid.
Melting point: 224-225 ° C

Reference Example 3 Synthesis Step 1: Ethyl 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (ethylsulfonyl) acetic acid 3.00 g (24.96 mmol) of 2- (ethylthio) acetic acid, 82 mg (0.25 mmol) of sodium tungstate dihydrate, 510 mg (12.37 mmol) of 97% by weight sodium hydroxide Then, 2.43 g (25.01 mmol) of a 35 mass% aqueous solution of hydrogen peroxide was added to the mixed solution of 6.0 g of water at room temperature over 1 hour. After completion of the addition, 2.67 g (27.5 mmol) of a 35 mass% aqueous solution of hydrogen peroxide was added at 40 ° C. over 1 hour. After the addition was complete, the reaction mixture was stirred at 40 ° C. for 1 hour. After completion of the stirring, 2.5 ml of a 10% by weight aqueous solution of sodium bisulfite and 1.22 g (12.44 mmol) of sulfuric acid were added to stop the reaction, and the mixture was extracted with ethyl acetate (30 ml × twice). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.62 g of the desired product as a colorless liquid.
¹ H-NMR (CDCl ₃ ): σ 6.73 (brs, 1H), 4.02 (s, 2H), 3.32 (q, J = 1.5 Hz, 2H), 1.46 (t, J = 1.5Hz, 3H).

Step 2: Synthesis of ethyl 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 2-hydrazinyl-6 920 mg (6.00 mmol) of phosphoryl chloride at room temperature in a mixed solution of 498 mg (2.00 mmol) of ethyl (trifluoromethyl) nicotinate, 304 mg (2.00 mmol) of 2- (ethylsulfonyl) acetic acid and 2.5 g of anisole Was added. After completion of the addition, the reaction mixture was stirred at 60 ° C. for 0.5 hour and then at 100 ° C. for 3 hours. After completion of stirring, 10 ml of water was added at room temperature to stop the reaction, and the mixture was extracted with 30 ml of 1,2-dichloroethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from 20 ml of ethyl acetate to obtain 515 mg of the desired product as a pale yellow solid.
Melting point: 190-191 ° C

Reference Example 4 Synthesis Step 1: Ethyl 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Synthesis of 2- (isopropylsulfonyl) acetic acid 3.00 g (22.36 mmol) of 2- (isopropylthio) acetic acid, 74 mg (0.22 mmol) of sodium tungstate dihydrate, 450 mg (10.91 mmol of 97% by weight sodium hydroxide) ) And 12 g of water were added at room temperature with 5.32 g (46.93 mmol) of a 30% by weight aqueous solution of hydrogen peroxide. After the addition was complete, the reaction mixture was stirred at 40 ° C. for 3 hours. After completion of the stirring, 900 mg (8.64 mmol) of sodium bisulfite and 1.10 g (11.2 mmol) of sulfuric acid were added to stop the reaction, and the mixture was extracted with ethyl acetate (12 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.23 g of the desired product as a white solid.
¹ H-NMR (CDCl ₃ ): σ6.36 (brs, 1H), 4.03 (s, 2H), 3.62-3.50 (m, 1H), 1.44 (d, 6H, J = 6.0 Hz).

Step 2: Synthesis of ethyl 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 2-hydrazinyl-6 -To a mixed solution of ethyl (trifluoromethyl) nicotinate 600 mg (2.41 mmol), 2- (isopropylsulfonyl) acetic acid 400 mg (2.41 mmol) and anisole 1.2 g at 60 ° C., 961 mg (6.27 mmol) phosphoryl chloride. ) Was added. After the addition is complete, the reaction mixture is stirred at 60 ° C. for 0.5 hour, then 10
Stir at 0 ° C. for 7 hours. After completion of the stirring, 6 ml of water was added at room temperature to stop the reaction, followed by extraction with 1,2-dichloroethane (3 ml × 2 times). The obtained organic layer was washed with 3 ml of a 2% by weight aqueous solution of sodium bicarbonate and then with water, and the solvent was distilled off under reduced pressure to obtain 773 mg of the desired product as a pale yellow solid.

[Reference Example 5] Synthesis of 3-{(methylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-{( 5. Methylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 291 mg (1.00 mmol), sodium tungstate dihydrate To a mixed solution of 6 mg (0.020 mmol) and 1,2-dichloroethane 10 g, 243 mg (2.50 mmol) of a 35 mass% aqueous solution of hydrogen peroxide was added at 40 ° C. After the addition was complete, the reaction mixture was stirred at 40 ° C. for 2 hours. After completion of the stirring, the reaction was stopped by adding 1 ml of a 10% by weight aqueous solution of sodium bisulfite and 5 ml of water, followed by extraction with 1,2-dichloroethane (30 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 85 mg of the desired product as a white solid.
Melting point: 233-234 ° C

[Reference Example 6] Synthesis of 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-{( 5. Ethylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 305 mg (1.00 mmol), sodium tungstate dihydrate To a mixed solution of 6 mg (0.020 mmol) and 1,2-dichloroethane 4 g, 243 mg (2.50 mmol) of a 35 mass% aqueous solution of hydrogen peroxide was added at 40 ° C. After the addition was complete, the reaction mixture was stirred at 40 ° C. for 2 hours. After completion of the stirring, 1 ml of a 10% by weight aqueous solution of sodium bisulfite and 5 ml of water were added to stop the reaction, and the mixture was extracted with 1,2-dichloroethane (10 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 259 mg of the desired product as a white solid.
Melting point: 191-192 ° C

[Reference Example 7] Synthesis of 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-{( Isopropylthio) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 300 mg (0.940 mmol), sodium tungstate dihydrate 6 To a mixed solution of .2 mg (0.019 mmol) and 1,2-dichloroethane 3 g, 228 mg (2.35 mmol) of a 35 mass% aqueous solution of hydrogen peroxide was added at 40 ° C. After the addition was complete, the reaction mixture was stirred at 40 ° C. for 3 hours. After completion of the stirring, 1 ml of a 10% by weight aqueous solution of sodium bisulfite and 5 ml of water were added to stop the reaction, and the mixture was extracted with 1,2-dichloroethane (10 ml × 2 times). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 318 mg of the desired product as a white solid.
Melting point: 162-164 ° C

[Reference Example 8] Synthesis of ethyl 3-{(methylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 3- ( To a mixed solution of 308 mg (1.00 mmol) of ethyl chloromethyl) -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate and 5 ml of ethanol at room temperature. 112 mg (1.10 mmol) of sodium methanesulfinate was added. After completion of the addition, the reaction mixture was stirred for 3 hours under heating to reflux. After completion of the stirring, 10 ml of water was added at room temperature to stop the reaction, and the mixture was extracted with 20 ml of 1,2-dichloroethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with ethyl acetate to obtain 258 mg of the desired product as a white solid.
Melting point: 222-223 ° C

[Reference Example 9] Synthesis of ethyl 3-{(ethylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate 3- ( To a mixed solution of 200 mg (0.65 mmol) of ethyl chloromethyl) -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate and 3 ml of ethanol at room temperature. Then, 83 mg (0.71 mmol) of sodium ethanesulfinate was added. After completion of the addition, the reaction mixture was stirred for 3 hours under heating to reflux. After completion of the stirring, the reaction was stopped by adding 10 ml of water at room temperature, and extracted with 15 ml of 1,2-dichloroethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with ethyl acetate to obtain 139 mg of the desired product as a white solid.
Melting point: 186-187 ° C

[Reference Example 10] Synthesis of ethyl 3-{(isopropylsulfonyl) methyl} -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate Sodium sulfite 1 To a mixed solution of .68 g (13.33 mmol), sodium bicarbonate 1.23 g (14.64 mmol) and water 5 ml, isopropylsulfonyl chloride 1.00 g (7.01 mmol) was added at 50 ° C. After the addition was complete, the reaction mixture was stirred at 50 ° C. for 1 hour. After completion of stirring, 137 mg (1.40 mmol) of sulfuric acid was added. After completion of the addition, the reaction mixture was stirred at 70 ° C. for 1 hour. After completion of the stirring, at 70 ° C., 614 mg (2.00 mmol) of ethyl 3- (chloromethyl) -5- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine-8-carboxylate ) Was added. After the addition was complete, the reaction mixture was stirred at 70 ° C. for 3 hours. After stirring, the mixture was cooled to room temperature, and the precipitated solid was collected by filtration to obtain 260 mg of the desired product as a pale yellow solid.

Claims (2)

Formula (1):

(Wherein R and R ¹ each independently represents an alkyl group having 1 to 3 carbon atoms,
n represents an integer of 0, 1 or 2. And a method for producing a condensed pyridine compound represented by:
Formula (2):

(Wherein R, R ¹ and n are as described above.)
The pyridine compound represented by the formula is cyclized in the presence of at least one selected from the group consisting of phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, diphosphorus pentoxide, thionyl chloride and oxalyl chloride. Production method. Formula (2):

(Wherein R and R ¹ each independently represents an alkyl group having 1 to 3 carbon atoms,
n represents an integer of 0, 1 or 2. A method for producing a pyridine compound represented by:
Formula (3):

(Wherein R, R ¹ and n are as described above.)
An amidazone compound represented by
Formula (4):

(In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms.)
The manufacturing method characterized by making the compound represented by these react.