JP7021017B2 - Method for producing fluoroalkylpyridine - Google Patents

Description

The present invention relates to a method for producing a fluoroalkylpyridine, for example, a method for producing a fluoroalkylpyridine, which comprises reacting a propiolic acid ester with an aminocrotonic acid ester to obtain a fluoroalkylpyridine.

Fluoroalkylpyridines are important as intermediates for medical and agrochemicals and are used in the synthesis of various bioactive substances. For example, various reports have been made on the reaction, pharmacological activity, and use of 6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid ester.

As a method for producing fluoroalkylpyridine, a production method using acrylamide as a raw material (see Patent Documents 1 to 4) and a production method using acryloyl chloride have been proposed (see Patent Document 5). In all of these production methods, in the first-stage reaction, an addition cyclization reaction of acrylamide or acryloyl chloride as a raw material with an ester compound is carried out. Next, in the reaction of the second step, fluoroalkylpyridine (for example, 6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid ester) is obtained by carrying out an oxidation reaction of the addition cyclized product. ..
In the production method of Patent Document 1, the yield of the addition cyclized product in the first stage is 9%, and the final product of the second stage (6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid). The yield of the ester) is 70%, and the total yield of the 6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid ester is 6.3%.
In the production methods of Patent Documents 2 to 4, the yield of the addition cyclized product in the first stage is 25%, and the final product in the second stage (6-hydroxy-2-trifluoromethylpyridine-3-). The yield of carboxylic acid ester) is 92%, and the total yield of 6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid ester is 23%.
Further, in the production method of Patent Document 5, the yield of the cycloaddition cyclized product in the first stage is 35%, and the oxidation reaction in the second stage is carried out without isolating the cycloaddition cyclized product. Therefore, the total yield of the final product, fluoroalkylpyridine, is not described.

On the other hand, as another method for producing fluoroalkylpyridine, a method of first synthesizing an alkylpyridine which is a non-fluorinated product and then producing a fluoroalkylpyridine by a fluorination reaction has also been proposed (Patent Documents 6 to 10). reference). Regarding the production of alkylpyridine, in the method described in Patent Documents 6 to 9, the addition reaction between the propiolic acid ester and the aminocrotonic acid ester in the first step is carried out, and then the cyclization reaction in the second step is carried out. Alkyl pyridine is obtained. However, Patent Document 6 does not mention the position of the double bond in the adduct of the first stage. Further, in Patent Document 9, the yield of the adduct in the first stage is 93%, the yield of the cyclization reaction in the second stage is 60%, and the total yield of alkylpyridine is 56%. It is stated that there is. Subsequently, regarding the production of fluoroalkylpyridine by the fluorination reaction of alkylpyridine, in the method described in Patent Document 10, 2-methylpyridine is oxidized with chlorine gas in the presence of anhydrous hydrogen fluoride to form 2-tri. It is described that fluoromethylpyridine can be obtained.

International Publication No. 2011/020615 International Publication No. 2005/074939 International Publication No. 2004/0290227 International Publication No. 2004/0290226 U.S. Patent Application Publication No. 2009/0247588 International Publication No. 2006/0289558 International Publication No. 2008/085119 International Publication No. 2009/126863 International Publication No. 2013/056015 Japanese Unexamined Patent Publication No. 57-9762

Org. Process Res. Dev. , 1 (1), 370, 1997

In the synthesis of fluoroalkylpyridines using acrylamide as in Patent Documents 1 to 4, strict safety measures are indispensable due to the high harmfulness of acrylamide, so there is a problem of deterioration in operability, convenience and economy in work. Will be. In addition, since fluoroalkylpyridine is mainly used as an intermediate for medical and agricultural chemicals, the above-mentioned production method using a compound such as acrylamide, which is a concern for high toxicity, as a raw material may cause a problem from the viewpoint of reaction residue. rice field. Therefore, it is unavoidable that the removal step and the analysis step for preventing the residue of acrylamide and the like in the product are strict.

In the method for producing fluoroalkylpyridine using acryloyl chloride as in Patent Document 5, the acid chloride, acryloyl chloride, is easily hydrolyzed by moisture in the air such as humidity, and heat is generated and corrosive hydrogen chloride is produced. Can emit smoke. Therefore, the method for producing fluoroalkylpyridine using acryloyl chloride may require a strict anhydrous environment and anti-corrosion equipment. Further, since acryloyl chloride is more unstable to heat and light than acrylamide and causes a polymerization reaction extremely easily, it is indispensable to add a polymerization inhibitor for handling. Therefore, when acryloyl chloride is used, it is necessary to add a polymerization inhibitor to the raw material and remove the polymerization inhibitor from the product, which is inefficient.

Further, in the method for producing a fluoroalkylpyridine using acrylamide or acryloyl chloride described in Patent Documents 1 to 5, an addition cyclized product as an intermediate (for example, 6-hydroxy-2-trifluoromethyl-4) is used. , 5-Dihydropyridine-3-carboxylic acid ester) requires an oxidation step. In this oxidation step, the atomic efficiency of N-bromosuccinimide (NBS) used as an oxidizing agent was low, the harmfulness of carbon tetrachloride used as a solvent, and the environmental load were high. In addition, these reactions are susceptible to impurities and the yield of the final product is not stable, and there is a problem that excessive oxidation competes as a side reaction (see Non-Patent Document 1).

Further, in the methods described in Patent Documents 6 to 9, an adduct of propiolic acid ester and aminocrotonic acid ester is obtained in the reaction of the first step, and then the adduct is cyclized in the reaction of the second step. Since it was necessary to form a pyridine ring and the reaction was in two stages, the operation was complicated and inefficient. Further, in the second stage cyclization reaction, it was necessary to carry out the reaction at a high temperature because the reaction was difficult to proceed. Therefore, in the methods of Patent Documents 6 to 9, the reaction is carried out by heating to at least 160 ° C., and it is necessary to input a large amount of energy. In addition, Patent Document 6 requires an operation of adding a strong basic reagent, and Patent Documents 7 and 8 require microwave heating equipment.

The method described in Patent Document 10 uses a gaseous reactant such as chlorine or anhydrous hydrogen fluoride as the gas phase reaction. Since these reactants are extremely toxic and corrosive gases, handling is extremely dangerous and strict safety management is essential. Further, in Patent Document 10, since the reaction progresses slowly, it is necessary not only to heat the mixture to about 400 ° C., but also the product is mixed with a by-product in which a plurality of chlorines are introduced on the aromatic ring. It is stated that. Therefore, the method of Patent Document 10 has problems such as low energy efficiency, selectivity, and functional group tolerance. Due to these restrictions, it can be determined that the method of first obtaining alkylpyridine by the method described in Patent Documents 6 to 9 and then converting to fluoroalkylpyridine by the method described in Patent Document 10 is not suitable for practical use.

The present invention has been made in view of such circumstances. That is, the present inventor has studied raw materials for fluoroalkylpyridine that can replace acrylamide and acryloyl chloride. As a result, it was found that propiolic acid ester and aminocrotonic acid ester having a specific structure are useful as raw materials and can solve the above-mentioned problems. That is, propiolic acid ester is less harmful to the human body than acrylamide, and unlike acryloyl chloride, it does not generate heat, smoke or hydrolyze in contact with water, and does not cause a violent polymerization reaction. Further, in the reaction with the propiolic acid ester, the fluoroaminorotonic acid ester is different from the amino crotonic acid ester in that it gives fluoroalkylpyridine in one step, so that it is not necessary to separately provide an oxidation reaction step, and it is a simple intermediate. Losses due to depurification and overreaction can also be avoided. As a result, the present inventor has found that fluoroalkylpyridine can be easily obtained in a one-step reaction step, and has completed the present invention.

That is, an object of the present invention is to provide a method for producing fluoroalkylpyridine, which can use a highly safe raw material and can easily obtain fluoroalkylpyridine in a one-step reaction step.

一般式（２）

一般式（３）

（上記一般式（１）～（３）において、Ｒ_１及びＲ_２はそれぞれ独立して炭素数１以上１０以下のアルキル基を表し、Ｒ_３は１以上のフッ素原子で置換された炭素数１以上１０以下のアルキル基を表す。）
［２］前記塩基が、１、５－ジアザビシクロ－［４．３．０］－ノネン、１，８－ジアザビシクロ－［５，４，０］－７－ウンデセン、メチルトリアザビシクロデセン、およびジアザビシクロオクタンからなる群から選択された少なくとも１種の塩基である、上記［１］に記載のフルオロアルキルピリジンの製造方法。
［３］上記一般式（１）で表されるプロピオール酸エステルと、上記一般式（２）で表されるアミノクロトン酸エステルとを、０～６０℃で反応させる、上記［１］または［２］に記載のフルオロアルキルピリジンの製造方法。
［４］前記プロピオール酸エステルが、下記式（４）で表される、上記［１］から［３］までのいずれか１つに記載のフルオロアルキルピリジンの製造方法。
式（４）

［５］前記Ｒ_３は、炭素数１以上１０以下のパーフルオロアルキル基である、上記［１］から［４］までのいずれか１つに記載のフルオロアルキルピリジンの製造方法。
［６］前記アミノクロトン酸エステルが下記式（５）で表される、上記［１］から［５］までのいずれか１つに記載のフルオロアルキルピリジンの製造方法。
式（５）

The gist structure of the present invention is as follows.
[1] In the presence of a base, the propiolic acid ester represented by the following general formula (1) is reacted with the aminocrotonic acid ester represented by the following general formula (2) to react with the following general formula (3). A method for producing a fluoroalkylpyridine, which comprises the fluoroalkylpyridine represented by.
General formula (1)

General formula (2)

General formula (3)

(In the above general formulas (1) to (3), R ₁ and R ₂ each independently represent an alkyl group having 1 or more carbon atoms and 10 or less carbon atoms, and R ₃ has 1 or more carbon atoms substituted with 1 or more carbon atoms. It represents an alkyl group of 10 or more.)
[2] The bases are 1,5-diazabicyclo- [4.3.0] -nonene, 1,8-diazabicyclo- [5,4,0] -7-undecene, methyltriazabicyclodecene, and diaza. The method for producing fluoroalkylpyridine according to the above [1], which is at least one base selected from the group consisting of bicyclooctane.
[3] The propiolic acid ester represented by the general formula (1) and the aminocrotonic acid ester represented by the general formula (2) are reacted at 0 to 60 ° C., the above [1] or [2]. ]. The method for producing a fluoroalkylpyridine.
[4] The method for producing a fluoroalkylpyridine according to any one of the above [1] to [3], wherein the propiolic acid ester is represented by the following formula (4).
Equation (4)

[5] The method for producing a fluoroalkylpyridine according to any one of the above [1] to [ ₄ ], wherein R3 is a perfluoroalkyl group having 1 or more and 10 or less carbon atoms.
[6] The method for producing a fluoroalkylpyridine according to any one of the above [1] to [5], wherein the aminocrotonic acid ester is represented by the following formula (5).
Equation (5)

It is possible to provide a method for producing fluoroalkylpyridine, which can use a highly safe raw material and can easily obtain fluoroalkylpyridine in a one-step reaction step.

FIG. 1 is a diagram showing analysis results of the product obtained in Example 1 by a gas chromatograph. FIG. 2 is a diagram showing the results of mass spectrometry of the product obtained in Example 1.

Hereinafter, embodiments of the present invention will be described in detail. The present invention is not limited to the following embodiments.

一般式（２）

一般式（３）

（上記一般式（１）～（３）において、Ｒ_１及びＲ_２はそれぞれ独立して炭素数１以上１０以下のアルキル基を表し、Ｒ_３は１以上のフッ素原子で置換された炭素数１以上１０以下のアルキル基を表す。）。 In the method for producing fluoroalkylpyridine of one embodiment, a propiolic acid ester represented by the following general formula (1) and an aminocrotonic acid ester represented by the following general formula (2) are used in the presence of a base. The reaction is carried out to obtain a fluoroalkylpyridine represented by the following general formula (3).
General formula (1)

General formula (2)

General formula (3)

(In the above general formulas (1) to (3), R ₁ and R ₂ each independently represent an alkyl group having 1 or more carbon atoms and 10 or less carbon atoms, and R ₃ has 1 or more carbon atoms substituted with 1 or more carbon atoms. It represents an alkyl group of 10 or less.).

（なお、上記反応式（６）において、置換基Ｒ_１～Ｒ_３は、上記一般式（１）～（３）の置換基Ｒ_１～Ｒ_３と同義である。）
すなわち、上記式（６）で表されるように、プロピオール酸エステルと、アミノクロトン酸エステルとから環状のピリジン構造が形成されると共に、プロピオール酸エステルに由来するＲ_１ＯＨが生成する。 An example of the above reaction is represented by the following formula (6).
Equation (6)

(In the reaction formula (6), the substituents _R1 to R3 _are synonymous with the substituents _R1 to R3 of the general formulas (1) to ( ₃ ).)
That is, as represented by the above formula (6), a cyclic pyridine structure is formed from the propiolic acid ester and the aminocrotonic acid ester, and _R1 OH derived from the propiolic acid ester is produced.

In one embodiment of the method for producing fluoroalkylpyridine, propiolic acid ester is used as a raw material. Therefore, unlike the conventional method, it is not necessary to use acrylamide which is harmful to the human body, and it is not necessary to use acryloyl chloride which generates heat, emits smoke and hydrolyzes in contact with water. Since the propiolic acid ester is an oxidant of acrylic acid, it is not necessary to provide an oxidation reaction step in the production method of one embodiment, and fluoroalkylpyridine can be obtained in one step, which simplifies the reaction step and simplifies the intermediate. Losses due to isolation and purification and overreaction can be avoided.
Further, in the conventional method for producing alkylpyridine using an acrylic acid derivative as a raw material, a polymer of the acrylic acid derivative can be formed. Since the polymer of this acrylic acid derivative releases a huge amount of energy and stabilizes when the main chain is polymerized to become a saturated hydrocarbon chain, the reaction system may become hot or explode. On the other hand, the propiole acid ester used as a raw material in the production method of one embodiment is difficult to form a polymer, and even when a polymer is formed, its main chain becomes an unsaturated hydrocarbon chain, so that the polymerization is carried out. The contribution of stabilization is small and the calorific value during polymerization is reduced. As a result, a chain polymerization reaction is less likely to occur, and safety is improved.
Therefore, in one embodiment, not only the reduction of waste, the simplification of the reaction process, the efficiency of work and the improvement of economy can be realized, but also highly safe raw materials can be used, and the reaction process can be simplified in one step. It is possible to realize a method for producing fluoroalkylpyridine, which can obtain fluoroalkylpyridine.

R ₁ in the above general formula (1) is not particularly limited as long as it is an alkyl group having 1 or more and 10 or less carbon atoms, but an alkyl group having 1 or more and 5 or less carbon atoms is preferable, and an alkyl group having 1 or more and 3 or less carbon atoms is preferable. More preferred. More specifically, R ₁ has a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, a t-butyl group or an n-pentyl group. Preferably, a methyl group, an ethyl group, an n-propyl group or an i-propyl group is more preferable, and a methyl group is further preferable.

R ₂ in the above general formulas (2) to (3) is not particularly limited as long as it is an alkyl group having 1 or more and 10 or less carbon atoms, but an alkyl group having 1 or more and 5 or less carbon atoms is preferable, and 1 or more and 3 or less carbon atoms. Alkyl group of is more preferred. More specifically, R ₂ has a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, a t-butyl group or an n-pentyl group. Preferably, a methyl group, an ethyl group, an n-propyl group or an i-propyl group is more preferable, and an ethyl group is further preferable.

R ₃ in the above general formulas (2) to (3) is not particularly limited as long as it is an alkyl group having 1 or more carbon atoms and 10 or less carbon atoms substituted with 1 or more fluorine atoms, but is substituted with 1 or more fluorine atoms. An alkyl group having 1 or more carbon atoms and 5 or less carbon atoms is preferable, and an alkyl group having 1 or more carbon atoms and 3 or less carbon atoms substituted with 1 or more fluorine atoms is more preferable. Further, in R ₃ , the number of fluorine atoms substituting an alkyl group is not particularly limited as long as it is 1 or more, but all hydrogen atoms in the alkyl group are substituted with fluorine atoms, and the number of carbon atoms is 1 or more and 10 or less. It is preferably a fluoroalkyl group. More specifically, a perfluoromethyl group, a perfluoroethyl group, a perfluoropropyl group, a perfluorobutyl group, and a perfluoropentyl group are preferable, and a perfluoromethyl group, a perfluoroethyl group, and a perfluoropropyl group are more preferable. , Perfluoromethyl group (trifluoromethyl group) is more preferable.

アミノクロトン酸エステルは、下記式（５）で表されるアミノクロトン酸エステルであることが特に好ましい。
式（５）

The propiolic acid ester is particularly preferably a propiolic acid ester represented by the following formula (4).
Equation (4)

The amino crotonic acid ester is particularly preferably an amino crotonic acid ester represented by the following formula (5).
Equation (5)

（上記一般式（７）において、Ｒ_２は炭素数１以上１０以下のアルキル基を表す。）。 Further, it is particularly preferable to produce a 6-hydroxy-2-trifluoromethylpyridine-3-carboxylic acid ester represented by the following general formula (7) as the fluoroalkylpyridine.
General formula (7)

(In the above general formula (7), R ₂ represents an alkyl group having 1 or more carbon atoms and 10 or less carbon atoms.)

In one embodiment of the method for producing fluoroalkylpyridine, the reaction between the propiolic acid ester and the aminocrotonic acid ester is carried out in the presence of a base. Examples of the base used in the above reaction include 1,5-diazabicyclo- [4.3.0] -nonene (DBN) and 1,8-diazabicyclo- [5,4,0] -7-undecene (DBU). , Methyltriazabicyclodecene, diazabicyclooctane and other organic nitrogen derivatives, phosphazene base and the like. The amount of the base used is preferably (propiolic acid ester): (base) = 1: 0.1 to 5, more preferably 1: 0.2 to 3, and 1: 0.5 to 1.5 in terms of molar ratio. More preferred.

Since the reaction can be efficiently carried out in the method for producing fluoroalkylpyridine of one embodiment, the reaction temperature can be preferably set low. The propiolic acid ester represented by the general formula (1) and the aminocrotonic acid ester represented by the general formula (2) are preferably reacted at 0 to 100 ° C., and are reacted at 0 to 80 ° C. It is more preferable, and it is further preferable to react at 0 to 60 ° C.

The reaction time between the propiolic acid ester and the aminocrotonic acid ester is preferably 30 minutes or more and 72 hours or less, more preferably 1 hour or more and 48 hours or less, and further preferably 2 hours or more and 36 hours or less.

Examples of the solvent for reacting the propiole acid ester with the aminocrotonic acid ester include tetrahydrofuran (THF), monoglime, jigglime, triglime, tetraglime, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethyleneurea, and the like. Aprotic polar solvents such as dimethylpropylene urea, tetramethylurea, dimethylsulfoxide, and sulfolane are used.

In the method for producing fluoroalkylpyridine of one embodiment, the amino crotonic acid ester is preferably added so as to have an excess molar equivalent with respect to the propiolic acid ester. As a result, the anionic polymerization reaction between the base used in the reaction and the propiolic acid ester represented by the above general formula (1) can be suppressed, and the yield of fluoroalkylpyridine is improved. The ratio (molar ratio) of propiolic acid ester and aminocrotonic acid ester used (propiolic acid ester): (aminochromic acid ester) is preferably more than 1: 1 and 5 or less, preferably 1: 1.3 to 3. More preferably, 1: 1.5 to 2.5 is even more preferable.

In the method for producing fluoroalkylpyridine of one embodiment, it is preferable to add the aminocrotonic acid ester to the solution in which the base is dissolved, and then add the propiolic acid ester to the solution. As a result, the anionic polymerization reaction between the base used in the reaction and the propiolic acid ester can be suppressed, so that the yield of fluoroalkylpyridine can be improved.

The fluoroalkylpyridine obtained by the production method of one embodiment is dried over anhydrous sodium sulfate, filtered, and then the formation of fluoroalkylpyridine can be confirmed by GC-MS.

As described above, in the method for producing fluoroalkylpyridine of one embodiment, since propiolic acid ester is used as a raw material, it is not necessary to use acrylamide which is harmful to the human body. Further, it becomes possible to obtain fluoroalkylpyridine without using acryloyl chloride which generates heat, emits smoke and hydrolyzes in contact with water as a raw material. In the production method of one embodiment, since the raw material propiolic acid ester is an oxidant of acrylic acid, fluoroalkylpyridine can be obtained in one step without requiring an oxidation reaction step, which simplifies the reaction step. Losses due to isolation and purification of intermediates and overreaction can also be avoided.
Further, in the conventional method for producing alkylpyridine using an acrylic acid derivative as a raw material, a polymer of the acrylic acid derivative can be formed. Since the polymer of this acrylic acid derivative releases a huge amount of energy and stabilizes when the main chain is polymerized to become a saturated hydrocarbon chain, the reaction system may become hot or explode. On the other hand, the propiole acid ester used as a raw material in the production method of one embodiment is difficult to form a polymer, and even when a polymer is formed, its main chain becomes an unsaturated hydrocarbon chain, so that the polymerization is carried out. The contribution of stabilization is small, and the calorific value during polymerization is reduced. As a result, a chain polymerization reaction is less likely to occur, and safety is improved.
As a result, according to the method for producing fluoroalkylpyridine of the above embodiment, it is possible to realize reduction of waste, simplification of reaction process, efficiency of work and improvement of economy, as well as highly safe raw material. It becomes possible to realize a method for producing fluoroalkylpyridine, which can easily obtain fluoroalkylpyridine in a one-step reaction step.

In the method for producing fluoroalkylpyridine of one embodiment, one of the causes of the simple one _- step fluoroalkylpyridine production reaction is that R3 in the aminocrotonic acid ester used as a raw material contains a fluorine atom. It is thought that this is because it has. That is, since the fluorine atom has a high electronegativity, R ₃ is an electron-withdrawing substituent. Then, an adduct of propiole acid ester and aminocrotonic acid ester, which is an intermediate of the reaction for producing fluoroalkylpyridine from propiole acid ester and aminocrotonic acid ester, was donated by a base at the time of cyclization. It is considered that the electron passes through the negatively charged carboanion. Here, since R ₃ contained in the transition state carbanion is an electron-withdrawing group, it is presumed that the carbanion is stabilized by attracting a negative charge in the carbanion. As a result, it is considered that the activation energy of a series of reactions is reduced and fluoroalkylpyridine can be easily produced. Further, as the number of fluorine atoms bonded to one carbon atom increases, the electron-withdrawing property of R ₃ increases. Therefore, when R ₃ is a perfluoroalkyl group, fluoroalkyl pyridine is most easily produced. Presumed.

Hereinafter, the present invention will be described in more detail based on examples. The present invention is not limited to the following examples.

(Example 1)
In a 100 mL three-necked flask, 6.25 g of tetrahydrofuran (THF), 25 g of ethyl 3-amino-4,4,4-trifluorocrotonate (136 mmol), diazabicyclo- [5,4,0] -7-undecene (DBU). 11.5 g (75.5 mmol) was added with stirring. Next, under ice-water cooling, 6.25 g (74.3 mmol) of methyl propiolate was added dropwise so that the internal temperature did not exceed 20 ° C., and the mixture was stirred for 1 hour and then heated to 60 ° C. After stirring for 24 hours, the contents are separated, dried and filtered over anhydrous sodium sulfate, and then GC-MS (model number: QP2010, manufactured by Shimadzu Corporation, column: DB-1MS, manufactured by Agilent Technologies, Inc.). Moving layer: He) was used for analysis. The results are shown in FIGS. 1 and 2. As shown by the arrows in FIGS. 1 and 2, it was confirmed that ethyl 6-hydroxy-2-trifluoromethylpyridine-3-carboxylate was obtained.

Claims (6)

In the presence of a base, the propiolic acid ester represented by the following general formula (1) is reacted with the aminocrotonic acid ester represented by the following general formula (2) and represented by the following general formula (3). A method for producing a fluoroalkylpyridine to obtain a fluoroalkylpyridine.
General formula (1)

General formula (2)

General formula (3)

(In the above general formulas (1) to (3), R ₁ and R ₂ each independently represent an alkyl group having 1 or more carbon atoms and 10 or less carbon atoms, and R ₃ has 1 or more carbon atoms substituted with 1 or more carbon atoms. It represents an alkyl group of 10 or more.) The base is from 1,5-diazabicyclo- [4.3.0] -nonene, 1,8-diazabicyclo- [5,4,0] -7-undecene, methyltriazabicyclodecene, and diazabicyclooctane. The method for producing fluoroalkylpyridine according to claim 1, which is at least one base selected from the group. The fluoroalkyl according to claim 1 or 2, wherein the propiolic acid ester represented by the general formula (1) and the aminocrotonic acid ester represented by the general formula (2) are reacted at 0 to 60 ° C. Method for producing pyridine. The method for producing a fluoroalkylpyridine according to any one of claims 1 to 3, wherein the propiolic acid ester is represented by the following formula (4).
Equation (4)

The method for producing a fluoroalkylpyridine according to any one of claims 1 to ₄ , wherein R3 is a perfluoroalkyl group having 1 or more and 10 or less carbon atoms. The method for producing a fluoroalkylpyridine according to any one of claims 1 to 5, wherein the aminocrotonic acid ester is represented by the following formula (5).
Equation (5)

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