WO2021193786A1 - 6-(fluoroalkyl)-3,4-dihydro-2h-pyran-5-carboxylic acid ester derivative, method for producing derivative, method for producing 2-(fluoroalkyl)nicotinic acid ester derivative, and method for producing 2-(fluoroalkyl)nicotinic acid derivative - Google Patents

Abstract

The present invention provides: a 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by a specific formula (3); a method for producing the same; a method for producing a 2-(fluoroalkyl) nicotinic acid derivative which is represented by a specific formula (5), and is characterized in that the 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative is reacted with an ammonium compound or ammonia, or is reacted with a base, an ammonium compound or ammonia, or after treating with acid or Lewis acid, is reacted with an ammonium compound or ammonia; and a method for producing an intermediate of the 2-(fluoroalkyl)nicotinic acid derivative.

Description

6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative, and a method for producing the derivative, and a method for producing 2- (fluoroalkyl) nicotinic acid ester derivative, and 2- ( Fluoroalkyl) Method for Producing Nicotinic Acid Derivative

The present invention relates to 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivatives useful as intermediates for the production of pesticides and methods for producing them.
The present invention also relates to a method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative and a method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which are useful as intermediates for producing pesticides.

It has been known that 2- (fluoroalkyl) nicotinic acid amide derivatives are useful as bactericidal agents in the field of agriculture and horticulture, and 2- (fluoroalkyl) nicotinic acid derivatives are intermediates for their production. Is known (Patent Documents 1 to 5).

By the way, as a method for producing a 2- (fluoroalkyl) nicotinic acid ester, it was prepared from acetoacetic ester and N, N-dialkylformamide in which the 4-position was substituted with fluorine in Patent Document 5, Patent Document 6, and Non-Patent Document 1. It is known that it can be produced by reacting a Vilsmeier reagent and an alkyl (vinyl) ether with a nitrogen source reagent such as ammonia.

Further, in Patent Document 7, Non-Patent Document 2 and Non-Patent Document 3, 2- (fluoroalkyl) nicotinic acid ester is obtained by reacting 2-halonicotinic acid ester with trifluoromethane, a fluorinated alkyl organometallic compound and the like. It is stated that it can be synthesized.

Further, Patent Document 8 and Non-Patent Document 4 describe that 2- (fluoroalkyl) nicotinic acid ester can be synthesized by the reaction of nicotinic acid ester and fluorinated alkylsulfinic acid.

Further, Non-Patent Document 5 describes that 2- (fluoroalkyl) nicotinic acid ester can be synthesized by reacting acrolein with an aminocrotonic acid ester in which the 4-position is fluorinated.

Further, as a method for producing 2- (fluoroalkyl) nicotinic acid, Patent Document 9 contains a Vilsmeier reagent prepared from an acetoacetic ester in which the 4-position is substituted with fluorine, an N, N-dialkylformamide, and an alkyl (vinyl) ether. It is known that 2- (fluoroalkyl) nicotinic acid can be produced by reacting with a nitrogen source reagent such as ammonia to obtain 2- (fluoroalkyl) nicotinic acid ester and then hydrolyzing. ing.

Further, a method for producing a similar compound of a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative is described in Non-Patent Document 6, but as in the present invention, 6 There is no example regarding the synthesis of a compound in which a fluoroalkyl group is substituted at the position.

International Publication No. 2006/097490 International Publication No. 2017/042142 International Publication No. 2016/131739 International Publication No. 2014/095675 International Publication No. 2015/197530 International Publication No. 2009/054742 U.S. Patent Application Publication No. 2015/0284341 International Publication No. 2013/082028 International Publication No. 2019/224174

[Correction under Rule 91 15.06.2021]
Organic Letters, Volume 10, Issue 9, pp. 1835-1837, 2008 Journal of Organic Chemistry, Vol. 78, No. 22, pp. 1126-1146, 2013 Organic Letters, No. 16, Volume 6, pp. 1744-1747, 2014 Journal of the American Chemical Society, Vol. 134, No. 3, pp. 1494-1497, 2012 Synthesis, No. 16, pp. 2751-2757, 2005 Tetrahedron Letters, Vol. 23, No. 17, pp. 1789-1792, 1982

The present invention provides a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative useful as an intermediate for producing pesticides and a production method for producing the ester compound easily and efficiently. The purpose is to do.
Further, in the present invention, a 2- (fluoroalkyl) nicotinic acid ester derivative useful as an intermediate for the production of pesticides is derived from a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative and the like. An object of the present invention is to provide a manufacturing method for manufacturing easily and efficiently.
Further, the present invention uses 6- (fluoroalkyl) -3,4-dihydro-2H-pyran as a 2- (fluoroalkyl) nicotinic acid derivative, which is an important intermediate in the production of bactericides and the like in the field of agriculture and horticultural fields. An object of the present invention is to provide a simple and efficient production method via a -5-carboxylic acid ester derivative or the like and a 2- (fluoroalkyl) nicotinic acid ester derivative.

The present inventor has made extensive studies to solve the above problems, and found that 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative, a method for producing the derivative, and 2- We have found a method for easily and efficiently producing a (fluoroalkyl) nicotinic acid derivative or the like via a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative or the like. The invention was completed.

That is, the present inventors have found that the above problem can be solved by the following configuration.

（式中、Ｒ¹、Ｒ^２はＣ_１－Ｃ_６アルキル基を表し、Ｒ_ｆはフッ素原子が置換しているＣ_１－Ｃ_４アルキル基を表し、Ｒ^３はＣ_１－Ｃ_８アルキル基、置換されていてもよいフェニル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基からなる群から選択される同一または異なった基によりモノ置換あるいはポリ置換されていてもよい。）、置換されていてもよいＣ_３－Ｃ_６シクロアルキル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基、Ｃ_１－Ｃ_６ハロアルキル基からなる群から選択される同一又は異なった基によりモノ置換あるいはポリ置換されていてもよい。）を表し、Ｘは酸素原子または硫黄原子を表す。）
で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体。 [1]
The following formula (3)

(In the formula, R ¹ and R ² represent a C _1- C ₆ alkyl group, R _{f represents a C 1 to} C ₄ alkyl group substituted with a fluorine atom, and R ³ represents a C _{1 to} C ₈ alkyl group. , a phenyl group (in which may be substituted are monosubstituted or polysubstituted by identical or different groups selected from halogen atom, C ₁ -C ₆ alkyl group, the group consisting of C ₁ -C ₆ alkoxy group _{C 3-} C ₆ cycloalkyl group which may be substituted (the group is a halogen atom, C _1- C ₆ alkyl group, C _1- C ₆ alkoxy group, C _1- C ₆ haloalkyl). It may be mono-substituted or poly-substituted by the same or different groups selected from the group consisting of groups), where X represents an oxygen atom or a sulfur atom.)
6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by.

[2]
R ³ is a C _1- C ₆ alkyl group (R ² and R ³ may be the same or different), X is an oxygen atom and R _f is a trifluoromethyl group or difluoro. The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to [1], which is a methyl group.

（式中、Ｒ¹、Ｒ^２はＣ_１－Ｃ_６アルキル基を表し、Ｒ_ｆはフッ素原子が置換しているＣ_１－Ｃ_４アルキル基を表す。）
で表されるフッ素化された２－（アルコキシメチリデン）－β－ケトエステル誘導体と、下記式（２）

（式中、Ｒ^３はＣ_１－Ｃ_８アルキル基、置換されていてもよいフェニル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基からなる群から選択される同一または異なった基によりモノ置換あるいはポリ置換されていてもよい。）、置換されていてもよいＣ_３－Ｃ_６シクロアルキル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基、Ｃ_１－Ｃ_６ハロアルキル基からなる群から選択される同一又は異なった基によりモノ置換あるいはポリ置換されていてもよい。）を表し、Ｘは酸素原子または硫黄原子を表す。）
で表されるビニル化合物を反応させることを特徴とする、［１］に記載の６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体の製造方法。 [3]
The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The method for producing a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to [1], which comprises reacting a vinyl compound represented by.

[4]
The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to [1] or [2] is reacted with an ammonium compound or ammonia, or the base is reacted with the ammonium compound or ammonia. After reacting with, or treating with an acid or Lewis acid, and then reacting with an ammonium compound or ammonia, the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A 2- (fluoroalkyl) nicotinic acid ester derivative represented by is obtained, and the obtained 2- (fluoroalkyl) nicotinic acid ester derivative is hydrolyzed to obtain the following formula (5).

(In the formula, R _f has the same meaning as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid derivative represented by.

[5]
It is characterized by reacting a base with a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the above formula (3) and then reacting with an ammonium compound or ammonia. The method for producing a 2- (fluoroalkyl) nicotinic acid derivative according to [4].

（式中、Ｒ¹及びＲ_ｆは前記と同じ意味を表す。）
で表される２－（フルオロアルキル）ニコチン酸エステル誘導体を得ることを特徴とする２－（フルオロアルキル）ニコチン酸エステル誘導体の製造方法。 [6]
The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to [1] or [2] is reacted with an ammonium compound or ammonia, or the base is reacted with the ammonium compound or ammonia. After reacting with, or treating with an acid or Lewis acid, and then reacting with an ammonium compound or ammonia, the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid ester derivative represented by.

[7]
It is characterized by reacting a base with a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the above formula (3) and then reacting with an ammonium compound or ammonia. The method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative according to [6].

（式中、Ｒ¹、Ｒ^２はＣ_１－Ｃ_６アルキル基を表し、Ｒ_ｆはフッ素原子が置換しているＣ_１－Ｃ_４アルキル基を表す。）
で表されるフッ素化された２－（アルコキシメチリデン）－β－ケトエステル誘導体と、下記式（２）

（式中、Ｒ^３はＣ_１－Ｃ_８アルキル基、置換されていてもよいフェニル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基からなる群から選択される同一または異なった基によりモノ置換あるいはポリ置換されていてもよい。）、置換されていてもよいＣ_３－Ｃ_６シクロアルキル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基、Ｃ_１－Ｃ_６ハロアルキル基からなる群から選択される同一又は異なった基によりモノ置換あるいはポリ置換されていてもよい。）を表し、Ｘは酸素原子または硫黄原子を表す。）
で表されるビニル化合物を反応させ、下記式（３）

（式中、Ｒ¹、Ｒ^２、Ｒ^３、Ｒ_ｆ及びＸは前記と同じ意味を表す。）
で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体を得、このものをアンモニウム化合物若しくはアンモニアと反応させ、又は塩基とアンモニウム化合物若しくはアンモニアと反応させ、又は酸若しくはルイス酸で処理した後にアンモニウム化合物若しくはアンモニアと反応させ、下記式（４）

（式中、Ｒ¹及びＲ_ｆは前記と同じ意味を表す。）
で表される２－（フルオロアルキル）ニコチン酸エステル誘導体を得、得られた２－（フルオロアルキル）ニコチン酸エステル誘導体を加水分解し、下記式（５）

（式中、Ｒ_ｆは前記と同じ意味を表す。）
で表される２－（フルオロアルキル）ニコチン酸誘導体を得ることを特徴とする２－（フルオロアルキル）ニコチン酸誘導体の製造方法。 [8]
The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The vinyl compound represented by is reacted with the following formula (3).

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above.)
A 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by is obtained, and this is reacted with an ammonium compound or ammonia, or a base is reacted with an ammonium compound or ammonia. After being treated with an acid or Lewis acid, and then reacted with an ammonium compound or ammonia, the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A 2- (fluoroalkyl) nicotinic acid ester derivative represented by is obtained, and the obtained 2- (fluoroalkyl) nicotinic acid ester derivative is hydrolyzed to obtain the following formula (5).

(In the formula, R _f has the same meaning as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid derivative represented by.

（式中、Ｒ¹、Ｒ^２はＣ_１－Ｃ_６アルキル基を表し、Ｒ_ｆはフッ素原子が置換しているＣ_１－Ｃ_４アルキル基を表す。）
で表されるフッ素化された２－（アルコキシメチリデン）－β－ケトエステル誘導体と、下記式（２）

（式中、Ｒ^３はＣ_１－Ｃ_８アルキル基、置換されていてもよいフェニル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基からなる群から選択される同一または異なった基によりモノ置換あるいはポリ置換されていてもよい。）、置換されていてもよいＣ_３－Ｃ_６シクロアルキル基（該基はハロゲン原子、Ｃ_１－Ｃ_６アルキル基、Ｃ_１－Ｃ_６アルコキシ基、Ｃ_１－Ｃ_６ハロアルキル基からなる群から選択される同一又は異なった基によりモノ置換あるいはポリ置換されていてもよい。）を表し、Ｘは酸素原子または硫黄原子を表す。）
で表されるビニル化合物を反応させ、下記式（３）

（式中、Ｒ¹、Ｒ^２、Ｒ^３、Ｒ_ｆ及びＸは前記と同じ意味を表す。）
で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体を得、このものをアンモニウム化合物若しくはアンモニアと反応させ、又は、塩基とアンモニウム化合物又はアンモニアと反応させ、又は酸若しくはルイス酸で処理した後にアンモニウム化合物若しくはアンモニアと反応させ、下記式（４）

（式中、Ｒ¹及びＲ_ｆは前記と同じ意味を表す。）
で表される２－（フルオロアルキル）ニコチン酸エステル誘導体を得ることを特徴とする２－（フルオロアルキル）ニコチン酸エステル誘導体の製造方法。 [9]
The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The vinyl compound represented by is reacted with the following formula (3).

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above.)
A 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by is obtained and reacted with an ammonium compound or ammonia, or a base and an ammonium compound or ammonia. After reacting or treating with acid or Lewis acid, it is reacted with an ammonium compound or ammonia, and the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid ester derivative represented by.

[10]
R ³ is a C _1- C ₆ alkyl group (R ² and R ³ may be the same or different), X is an oxygen atom and R _f is a trifluoromethyl group or difluoro. The production method according to [8] or [9], which is a methyl group.

[11]
The production method according to any one of [4] to [10], wherein the base is sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
[12]
The production method according to any one of [4] to [11], wherein the ammonium compound is ammonium chloride, ammonium acetate, ammonium carbamate, ammonium carbonate, ammonium phosphate, ammonium sulfate, or ammonium formate. ..

According to the present invention, a production method for easily and efficiently producing a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative useful as an intermediate for producing a pesticide and the ester compound. Can be provided.
Further, according to the present invention, a 2- (fluoroalkyl) nicotinic acid ester derivative useful as an intermediate for the production of pesticides is a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative. It is possible to provide a manufacturing method for manufacturing easily and efficiently.
Further, according to the present invention, a 2- (fluoroalkyl) nicotinic acid derivative, which is an important intermediate in the production of bactericides and the like in the field of agriculture and horticultural fields, is a 6- (fluoroalkyl) -3,4-dihydro-2H. It is possible to provide a simple and efficient production method via a -pyran-5-carboxylic acid ester derivative or the like and a 2- (fluoroalkyl) nicotinic acid ester derivative.

で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体（以下、６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体（３）ともいう）について詳細に説明する。 The following equation (3) of the present invention

6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by (hereinafter, 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid) The acid ester derivative (3)) will be described in detail.

In the formula, R ¹ and R ² represent a C _1- C ₆ alkyl group, R _{f represents a C 1 to} C ₄ alkyl group substituted with a fluorine atom, and R ³ represents a C _{1 to} C ₈ alkyl group. optionally substituted phenyl (in which the group halogen atom, C ₁ -C ₆ alkyl group, optionally mono- substituted or polysubstituted by identical or different radicals selected from the group consisting of C ₁ -C ₆ alkoxy group _{C 3-} C ₆ cycloalkyl group which may be substituted (the group is a halogen atom, C _1- C ₆ alkyl group, C _1- C ₆ alkoxy group, C _1- C ₆ haloalkyl group). It may be mono-substituted or poly-substituted by the same or different groups selected from the group consisting of), where X represents an oxygen atom or a sulfur atom.

The _C 1 -C ₆ alkyl group represented by R ¹ or ^{R 2,} it may be straight-chain or branched, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec -Butyl group, isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group and the like can be exemplified and can be easily produced. , Preferably a methyl group, an ethyl group, or the like, and more preferably an ethyl group.
R ¹ and R ² may be the same or different.

The _C 1 -C ₈ alkyl group represented by R ^3, it may be straight-chain or branched, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec- butyl group , Isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like. is C ₁ -C ₆ alkyl group, more preferably may be exemplified an ethyl group, n- propyl group, n- butyl group, an isobutyl group.

The optionally ^{substituted phenyl group represented by R 3} includes a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, and a 4-chlorophenyl group. Group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group and the like can be exemplified, and a phenyl group is preferably used. It can be exemplified.

Examples of the optionally substituted C _3- C ₆ cycloalkyl group represented by R ³ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 4-methylcyclohexyl group and the like, which are preferable. Can exemplify a cyclohexyl group.

R ³ _is preferably a C 1 -C ₆ alkyl group.

The C ₁ -C ₄ alkyl group which fluorine atoms represented by R _f is substituted, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, pentafluoroethyl group, heptafluoro n- propyl group, hepta Fluoroisopropyl group, nonafluoro n-butyl group, nonafluorosec-butyl group, nonafluoroisobutyl group, nonafluorotert-butyl group and the like can be exemplified, and difluoromethyl group and trifluoro are preferable in that high pesticide activity can be expected. Methyl groups and the like can be exemplified.

X represents an oxygen atom or a sulfur atom, preferably an oxygen atom.

（式中、Ｒ¹、Ｒ^２、Ｒ^３、Ｒ_ｆ及びＸは、前記と同じ意味を表し、好ましい例も同様である。） Next, the method for producing the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) of the present invention shown in the following step-1 will be described in detail.

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above, and the same applies to preferred examples.)

Reaction-1 in step-1 is a fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the formula (1) (hereinafter, fluorinated 2- (alkoxymethylidene) -β-. 6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) by reacting the ketoester derivative (1) with the vinyl compound represented by the formula (2). Is the process of manufacturing.
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the formula (1) and the vinyl compound represented by the formula (2) are known, and commercially available products can be used. Further, the fluorinated 2- (alkoxymethylidene) -β-ketoester derivative (1) can be easily produced from available reagents according to a known method described in an experimental chemistry course, Organic Synthesis and the like. ..
In this reaction, the target product is obtained by reacting the fluorinated 2- (alkoxymethylidene) -β-ketoester derivative (1) with 0.1 to 30 equivalents of the vinyl compound (2). Obtainable. By using 1 equivalent or more of the equivalent of the vinyl compound (2), the desired product can be obtained in good yield.

This reaction can be carried out either in the absence of a solvent or in the presence of a solvent. As the solvent to be used, any solvent that does not harm the reaction can be used, and aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene, and aliphatic solvent such as pentane, hexane and octane can be used. , Diethyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethoxyethane, ether solvents such as 1,4-dioxane, ketone solvents such as acetone, methyl ethyl ketone, cyclohexanone, halogen solvents such as chloroform and dichloromethane, acetonitrile, pro. Nitrile-based solvents such as pionitrile, ester-based solvents such as ethyl acetate, propyl acetate, butyl acetate and methyl propionate, amide-based solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, Alcohol-based solvents such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol, dimethylsulfoxide, water, or a mixed solvent thereof can be used. Toluene and xylene are preferable in order to obtain the desired product in good yield.

Further, the target product can be obtained by reacting in a reaction temperature range of 0 to 200 ° C. Depending on the boiling point temperature of the fluorinated 2- (alkoxymethylidene) -β-ketoester derivative (1) or vinyl compound (2) to be reacted, or the solvent used in the reaction, the temperature may vary from 20 to 150 ° C. By reacting in the reaction temperature range, the desired product can be obtained in good yield.

In this reaction, a basic compound may coexist as a stabilizer of the vinyl compound represented by the formula (2). One kind or two or more kinds of basic compounds can be used. The basic compound is not particularly limited, and for example, alkali (earth) metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, and calcium hydroxide; hydrogen carbonate. Alkaline (earth) metal carbonates such as lithium, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate; Alkaline (earth) metal carboxylates such as lithium acetate, sodium acetate, potassium acetate, cesium acetate, magnesium acetate, calcium acetate; ammonium salts such as ammonium carbonate and ammonium carbamate, triethylamine, tripropylamine, tributylamine, tri Pentylamine, trihexylamine, N, N-diisopropylethylamine, 1-methylpyrrolidin, 1-methylpiperidin, 1-ethylpiperidin, 4-methylmorpholin, pyridine, picolin, N, N-dimethyl-p-toluidine, Examples thereof include amines such as rutidin, quinoline, isoquinolin, and collagen. These compounds are preferably present in the reaction solution at a concentration of 0.0001-5%.

Among these, alkaline (earth) metal hydroxides and amines can be mentioned as preferable basic compounds. Particularly preferred basic compounds include sodium hydroxide, potassium hydroxide, triethylamine, tripropylamine, tributylamine, tripentylamine and trihexylamine.

Regarding the order of adding the compounds in this reaction, the vinyl compound (2) was added to the fluorinated 2- (alkoxymethylidene) -β-ketoester derivative (1), or the vinyl compound (2) was fluorinated. Either 2- (alkoxymethylidene) -β-ketoester derivative (1) may be added.

After completion of the reaction, the desired product can be obtained by a normal post-treatment operation, but if necessary, it can also be purified by distillation, column chromatography or the like.

The method for producing the 2- (fluoroalkyl) nicotinic acid derivative (5) of the present invention (2- (fluoroalkyl) nicotinic acid derivative represented by the following formula (5)) will be described in detail.
As a preferred embodiment, a method for producing a 2- (fluoroalkyl) nicotinic acid derivative represented by the following formula (5), which is shown in the following step-2, will be described.

[Step-2]

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above, and the same applies to preferred examples.)

In reaction-1 in step 2, the fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the formula (1) is reacted with the vinyl compound represented by the formula (2), and the formula is changed. This is a reaction for obtaining a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by (3). The obtained 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) can be isolated if necessary, but the reaction-2 is not isolated. It can also be used for.

In reaction-2 in step-2, 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) is reacted with an ammonium compound or ammonia, or a base and an ammonium compound or A 2- (fluoroalkyl) nicotinic acid ester derivative represented by the formula (4) (hereinafter, 2- (fluoroalkyl) nicotine) is reacted with ammonia or treated with an acid or Lewis acid and then with an ammonium compound or ammonia. This is a reaction for obtaining an acid ester derivative (4)). The obtained 2- (fluoroalkyl) nicotinic acid ester derivative (4) can be isolated if necessary, but it can also be used in Reaction-3 without isolation.

Reaction-3 in step 2 is a 2- (fluoroalkyl) nicotinic acid derivative represented by the formula (5) by hydrolyzing the 2- (fluoroalkyl) nicotinic acid ester derivative (4) (hereinafter, 2). -(Also referred to as fluoroalkyl) nicotinic acid derivative (5)).

Reaction-1 in step-2 is the same as reaction-1 in step-1.

After completion of the reaction, the desired product can be obtained by a normal post-treatment operation and can be used for Reaction-2 without isolation, but if necessary, it should be isolated by distillation, column chromatography or the like. You can also.

Reaction-2 in step 2 is the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) prepared in reaction-1 (isolated in reaction-1). However, it may not be isolated in Reaction-1) is reacted with an ammonium compound or ammonia, or a base is reacted with an ammonium compound or ammonia, or is treated with an acid or Lewis acid and then reacted with an ammonium compound or ammonia. , A reaction for preparing a 2- (fluoroalkyl) nicotinic acid ester derivative represented by the formula (4).

Bases that can be used in Reaction-2 include sodium hydride, potassium hydride, lithium amide, sodium amide, lithium diisopropylamide (LDA), butyl lithium, tert-butyl lithium, trimethylsilyl lithium, and lithium hexamethyldisilazide. , Sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxydo, sodium ethoxide, sodium thiomethoxydo, sodium thioethoxydo, sodium-1-propanethiolate, sodium-2-propanethiolate, sodium-1-butane Thiorate, potassium-tert-butoxide, sodium-tert-butoxide, potassium-tert-butylthiolate, sodium-tert-butylthiolate, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, magnesium hydroxide, hydroxide Alkali metal bases such as barium and lithium hydroxide, dimethylamine, diethylamine, N-ethylmethylamine, dipropylamine, N-ethylisopropylamine, diisopropylamine, dibutylamine, diisobutylamine, pyrrolidine, piperidine, 2-methylpiperidin, Organic bases such as 3-methylpiperidin, 4-methylpiperidin, 2,2,6,6-tetramethylpiperidine, morpholin, dibenzylamine, N-methylaniline and the like can be used, and the desired product can be obtained in good yield. Therefore, it is preferable to use sodium methoxydo, sodium ethoxydo, sodium hydroxide, or potassium hydroxide.

The target product is obtained by using 0.1 to 20 equivalents of the base used in Reaction-2 with respect to the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3). By using 0.5 to 5 equivalents, the desired product can be obtained in good yield.

Ammonium compounds that can be used in Reaction-2 include ammonium benzoate, ammonium chloride, ammonium carbamate, ammonium formate, ammonium carbonate, ammonium oxalate, ammonium acetate, ammonium hydrogencarbonate, ammonium thiocyanate, ammonium iodide, and phosphorus. Ammonium salts such as ammonium acid, diammonium phosphate, and ammonium sulfate can be used.
Further, as ammonia, ammonia water or ammonia gas can also be used.
In order to obtain the desired product in good yield, it is preferable to use ammonium chloride, ammonium acetate, ammonium carbamate, ammonium carbonate, ammonium phosphate, ammonium sulfate, ammonium formate, or ammonia as the ammonium compound or ammonia. The desired product can be obtained by using 0.5 to 20 equivalents of the ammonium compound or ammonia with respect to the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3). By using 1 to 10 equivalents, the desired product can be obtained in good yield.

Examples of the acid or Lewis acid that can be used in Reaction-2 include hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, and chlorosulfonic acid. Perchloric acid, boron trifluoride, aluminum chloride, zinc chloride, titanium tetrachloride, tin tetrachloride, ferric chloride, ferric bromide, ethyl dichloride aluminum, copper bromide (II), etc. can be used. can. In order to obtain the desired product in good yield, it is preferable to use hydrogen chloride, methanesulfonic acid, zinc chloride, and copper (II) bromide. The desired product can be obtained by using 0.1 to 20 equivalents of the acid or Lewis acid with respect to the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3). By using 0.5 to 5 equivalents, the desired product can be obtained in good yield.

Reaction-2 can be carried out either in the absence of a solvent or in the presence of a solvent. As the solvent to be used, any solvent that does not harm the reaction can be used, and aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene, and aliphatic solvent such as pentane, hexane and octane can be used. , Diethyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethoxyethane, ether solvents such as 1,4-dioxane, ketone solvents such as acetone, methyl ethyl ketone, cyclohexanone, halogen solvents such as chloroform and dichloromethane, acetonitrile, pro. Nitrile-based solvents such as pionitrile, ester-based solvents such as ethyl acetate, propyl acetate, butyl acetate and methyl propionate, amide-based solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, Alcohol-based solvents such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, and ethylene glycol, dimethyl sulfoxide, water, or a mixed solvent thereof can be used. In order to obtain the desired product in good yield, it is preferable to use an alcohol solvent of methanol, ethanol, 2-propanol or tert-butanol, or an aromatic hydrocarbon solvent such as benzene, toluene, xylene and chlorobenzene.

Further, in Reaction-2, the target product can be obtained by reacting in the reaction temperature range of 0 to 200 ° C., and the target product can be obtained in a higher yield by reacting in the range of 20 to 160 ° C. Can be done.
In Reaction-2, the order of adding the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) to be reacted and the reagent (base, ammonium compound or ammonia) is as follows. 6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) in the coexistence of ammonium compound or ammonia, 6- (fluoroalkyl) -3,4- A method of adding a base and an ammonium compound or ammonia to the dihydro-2H-pyran-5-carboxylic acid ester derivative (3), 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative ( A method of treating with an ammonium compound or ammonia after adding a base to 3), after adding the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) to the base. Examples thereof include a method of treating with an ammonium compound or ammonia.
In Reaction-2, a preferred embodiment is to react a base with a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative and then react with an ammonium compound or ammonia. Can be mentioned.

After completion of the reaction, the desired product can be obtained by a normal post-treatment operation and can be used for Reaction-3 without isolation, but if necessary, it should be isolated by distillation, column chromatography or the like. You can also.

Reaction-3 in step 2 is a 2- (fluoroalkyl) nicotinic acid ester derivative represented by the formula (4) prepared in reaction-2 (even if isolated in reaction-2, it is simple in reaction-2. This is a reaction for preparing a 2- (fluoroalkyl) nicotinic acid derivative (5) by hydrolyzing (which may not be separated).
Reaction-3 is preferably carried out in the presence of a base and water, and the bases that can be used include sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, magnesium hydroxide, barium hydroxide, and hydroxide. Lithium or the like can be used, and in order to obtain the desired product in good yield, it is preferable to use sodium hydroxide or potassium hydroxide.

The target product can be obtained by using 0.1 to 20 equivalents of the base used in Reaction-3 with respect to the 2- (fluoroalkyl) nicotinic acid ester derivative (4), and the yield is obtained by using 1 to 3 equivalents. You can get the desired product well.

Reaction-3 is preferably reacted in the presence of a solvent, and any solvent that does not harm the reaction can be used as the solvent, and aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene can be used. Solvents, aliphatic hydrocarbon solvents such as pentane, hexane and octane, ether solvents such as diethyl ether, diisopropyl ether, cyclopentylmethyl ether, tetrahydrofuran, dimethoxyethane and 1,4-dioxane, and ketones such as acetone, methyl ethyl ketone and cyclohexanone. System solvents, halogen solvents such as chloroform and dichloromethane, nitrile solvents such as acetonitrile and propionitrile, ester solvents such as ethyl acetate, propyl acetate, butyl acetate and methyl propionate, N, N-dimethylformamide, N, Use an amide solvent such as N-dimethylacetamide or N-methylpyrrolidone, an alcohol solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, or ethylene glycol, dimethyl sulfoxide, water, or a mixed solvent thereof. be able to. In order to obtain the desired product in good yield, it is preferable to use an alcohol solvent of methanol, ethanol, 2-propanol, or tert-butanol. When the reaction system is a two-layer system, it is better to use a so-called phase transfer catalyst such as tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium iodide to obtain the desired product in better yield.

Further, in Reaction-3, the target product can be obtained by reacting in the reaction temperature range of 0 to 200 ° C., and the target product can be obtained in a higher yield by reacting in the range of 0 to 160 ° C. Can be done. In Reaction-3 (hydrolysis reaction), the 2- (fluoroalkyl) nicotinic acid derivative (5) becomes a metal salt after the reaction is completed. Therefore, the purpose is to add an acid such as hydrochloric acid or sulfuric acid to the reaction solution. 2- (Fluoroalkyl) nicotinic acid derivative (5). The desired product can be obtained by a normal post-treatment operation, but if necessary, it can be purified by recrystallization, column chromatography, or the like.

According to the above step-2, the 2- (fluoroalkyl) nicotinic acid derivative (5), which is an important intermediate in the production of bactericides and the like in the field of agriculture and horticulture, can be produced easily and efficiently.

Further, as a preferred embodiment, the method for producing the 2- (fluoroalkyl) nicotinic acid derivative (5) shown below will be described.
The above manufacturing method is
The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the above formula (3) is reacted with an ammonium compound or ammonia, or a base and an ammonium compound or ammonia are used. After reacting or treating with an acid or Lewis acid, the reaction was carried out with an ammonium compound or ammonia to obtain a 2- (fluoroalkyl) nicotinic acid ester derivative represented by the above formula (4), and the obtained 2- (fluoroalkyl) was obtained. ) A method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which comprises hydrolyzing a nicotinic acid ester derivative to obtain a 2- (fluoroalkyl) nicotinic acid derivative represented by the above formula (5) (Method 1). ).
Method 1 is a method for producing a 2- (fluoroalkyl) nicotinic acid derivative (5), which obtains a 2- (fluoroalkyl) nicotinic acid derivative (5) by the reaction-2 and reaction-3 in the above step-2. .. Reaction-2 and Reaction-3 are as described above, respectively.

Moreover, the method for producing the 2- (fluoroalkyl) nicotinic acid ester derivative (4) of the present invention will be described in detail.
In a preferred embodiment, the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (3) is reacted with an ammonium compound or ammonia, or a base and an ammonium compound or ammonia are used. A 2- (fluoroalkyl) nicotinic acid ester derivative represented by the above formula (4) is obtained by reacting or treating with an acid or Lewis acid and then reacting with an ammonium compound or ammonia. Examples thereof include a method for producing an alkyl) nicotinic acid ester derivative (method 2).
Method 2 is a method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative (4), which obtains a 2- (fluoroalkyl) nicotinic acid ester derivative (4) by the reaction-2 in the above step-2. Reaction-2 is as described above.

Further, as a preferred embodiment, the 2- (fluoroalkyl) nicotinic acid ester derivative (4) is obtained by the reaction-1 and the reaction-2 in the above step-2, and the 2- (fluoroalkyl) nicotinic acid ester derivative (4) is obtained. ) Manufacturing method. Reaction-1 and Reaction-2 are as described above, respectively.

Representative examples of the 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the formula (3) are summarized in Table 1 below, and these compounds are exemplified. It is not limited to. These compounds also include mixtures of isomers. The compound number will be referred to in the following description.

In the table, "Me" is a methyl group, "Et" is an ethyl group, "nPr" is a normal propyl group, "iPr" is an isopropyl group, "nBu" is a normal butyl group, "sBu" is a sec-butyl group, and " "iBu" is an isobutyl group, "tBu" is a tert-butyl group, "nPen" is a normal pentyl group, "nHex" is a normal hexyl group, "cHex" is a cyclohexyl group, "nOct" is a normal octyl group, and "Ph" is a normal octyl group. Represents a phenyl group.

Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

[Example 1]
(1) Synthesis of Ethyl4-ethoxy-2-propoxy-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-120)
Add propyl (vinyl) ether (2.20 g, 25.0 mmol) to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol) and add 65 ° C. Was stirred for 2 hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound as a colorless oil (yield 3.00 g, Yield 75%) was obtained.

[Example 2]
(2) Synthesis of Ethyl4-ethoxy-2-isobutoxy-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-123)
Isobutyl (vinyl) ether (2.50 g, 25.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol), and the temperature was 83 ° C. Stirred for 7 and a half hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound as a colorless oil (yield 3.00 g, Yield 71%) was obtained.

[Example 3]
(3) Synthesis of Ethyl4-ethoxy-2-octoxy-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-126)
Add octyl (vinyl) ether (2.90 g, 18.7 mmol) to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol) and add 177 ° C. Was stirred for 6 and a half hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 2.10 g, The yield was 43%).

[Example 4]
(4) Synthesis of ethyl2- (cyclohexoxy) -4-ethoxy-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-128)
Cyclohexyl (vinyl) ether (3.20 g, 25.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol), and the temperature was 152 ° C. Was stirred for 6 and a half hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 4.20 g, Yield 92%) was obtained.

[Example 5]
(5) Synthesis of ethyl4-ethoxy-2-phenylsulfanyl-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-160)
Phenyl (vinyl) sulfide (3.40 g, 25.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol), and the temperature was 78 ° C. Was stirred for 6 and a half hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 2.10 g, Yield 45%) was obtained.

[Example 6]
(6) Synthesis of Ethyl4-ethoxy-2-ethylsulfanyl-6- (trifluoromethyl) -3,4-dihydro-2H-pyran-5-carboxylate (No. 1-154)
Ethyl (vinyl) sulfide (2.20 g, 25.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4,4-trifluoro-3-oxobutyrate (3.00 g, 12.5 mmol), and the temperature was 91 ° C. Stirred for 3.5 hours. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 3.50 g, The yield was 84%).

[Example 7]
(7) Synthesis of Ethyl6- (difluoromethyl) -2,4-diethoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-25)
Ethyl vinyl ether (649 mg, 9.00 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (1.00 g, 4.50 mmol), and the mixture was stirred at 50 ° C. for 8 hours. The obtained reaction solution was concentrated under reduced pressure to obtain a yellow oily title compound (yield 1.20 g, yield 91%).

[Example 8]
(8) Synthesis of Ethyl6- (difluoromethyl) -4-ethoxy-2-propoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-26)
Propyl (vinyl) ether (2.30 g, 27.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and the mixture was added at 65 ° C. for 2 hours. Semi-stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 3.70 g, (Yield 88%) was obtained.

[Example 9]
(9) Synthesis of Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-28)
Butyl (vinyl) ether (271 g, 2.70 mol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (500 g, 2.30 mol), and the mixture was stirred at 94 ° C. for 1 and a half hours. The obtained reaction solution was concentrated under reduced pressure to obtain a yellow oily title compound (yield 747 g, yield 100%).

[Example 10]
(10) Synthesis of Ethyl6- (difluoromethyl) -4-ethoxy-2-isobutoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-29)
Isobutyl (vinyl) ether (2.70 g, 27.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and the mixture was added at 83 ° C. for 5 hours. Stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound as a colorless oil (yield 4.10 g, Yield 94%) was obtained.

[Example 11]
(11) Synthesis of Ethyl6- (difluoromethyl) -4-ethoxy-2-octoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-32)
Add octyl (vinyl) ether (3.20 g, 20.3 mmol) to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and add octyl (vinyl) ether (3.20 g, 20.3 mmol) at 160 ° C. for 5 hours. Stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 4.20 g, Yield 82%) was obtained.

[Example 12]
(12) Synthesis of Ethyl2- (Cyclohexoxy) -6- (Difluoromethyl) -4-ethoxy-3,4-dihydro-2H-Pyran-5-carboxylate (No. 1-34)
Cyclohexyl (vinyl) ether (3.40 g, 27.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and the mixture was added at 152 ° C. for 5 hours. Stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 4.10 g, (Yield 88%) was obtained.

[Example 13]
(13) Synthesis of Ethyl6- (difluoromethyl) -4-ethoxy-2-phenylsulfanyl-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-66)
Phenyl (vinyl) sulfide (3.70 g, 27.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and the mixture was added at 78 ° C. for 8 hours. Stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 2.20 g, Yield 46%) was obtained.

[Example 14]
(14) Synthesis of Ethyl6- (difluoromethyl) -4-ethoxy-2-ethylsulfanyl-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-60)
Ethyl (vinyl) sulfide (2.40 g, 27.0 mmol) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (3.00 g, 13.5 mmol), and the temperature was 91 ° C. for 3 hours. Stirred. The obtained reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 5) to obtain the title compound of yellow oil (yield 3.30 g, Yield 80%) was obtained.

[Example 15]
(15) Synthesis of Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-28)
Toluene (75 mL) was added to ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (146 g, 657 mmol), and the mixture was heated to 110 ° C. Butyl vinyl ether (73.9 g, 723 mmol, purity 98%) was added dropwise to the reaction solution over 30 minutes, and the mixture was stirred at 110 ° C. for 6 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 9) to obtain the title compound of yellow oil (yield 191 g, yield 90%). ) Was obtained.

[Example 16]
(16) Synthesis of Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-28)
A reaction solution prepared by adding toluene (75.0 mL) to butyl vinyl ether (75.9 g, 743 mmol, purity 98%) was heated to 110 ° C. and ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate. (150 g, 675 mmol) was added dropwise over 30 minutes, and the mixture was stirred at 110 ° C. for 6 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 9) to obtain the title compound of yellow oil (yield 216 g, yield 99%). ) Was obtained.

[Example 17]
(17) Synthesis of Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (No. 1-28)
Butyl vinyl ether (75.9 g, 743 mmol, purity 98%) was heated to 94 ° C., and ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (150 g, 675 mmol) was added dropwise over 90 minutes. , 90-94 ° C. for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane = 1: 9) to obtain the title compound of yellow oil (yield 212 g, yield 97%). ) Was obtained.

[Example 18]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.00 g, 3.10 mmol) with acetate Ammonium (478 mg, 6.21 mmol) and a 20% sodium ethoxide ethanol solution (1.58 g, 4.65 mmol) were added, and the mixture was stirred at 78 ° C. for 2 hours. After confirming the completion of the reaction by TLC (Thin-Layer Chromatography), ethyl acetate and water were added to the reaction solution, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 370 mg, yield 60%) in an orange transparent liquid.
^{1 1} HNMR spectrum (CDCl ₃ ) σ: 8.87 (1H, d, J = 4.8 Hz), 8.33 (1H, d, J = 8.0 Hz), 7.52 (1H, dd, J1 = 8) 0.0Hz, J2 = 4.8Hz), 7.43 (1H, t, J = 54.2Hz), 4.45 (2H, q, J = 7.2Hz), 1.43 (3H, t, J = 7.2Hz).

[Example 19]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.00 g, 3.10 mmol) with acetic acid Ammonium (837 mg, 10.9 mmol) was added, and the mixture was stirred at 160 ° C. for 9 hours. Ethyl acetate and water were added to the reaction solution, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 300 mg, yield 48%) in an orange transparent liquid.

[Example 20]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (500 mg, 1.70 mmol) with piperidine (604 mg) , 8.50 mmol) and ammonium acetate (458 mg, 5.95 mmol) were added, and the mixture was heated under reflux at 90 ° C. for 8 hours. Water (5.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 180 mg, yield 53%) in an orange transparent liquid.

[Example 21]
Synthesis of 2-difluoromethylnicotinic acid Ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (21.0 g, 94.5 mmol) was added to butyl vinyl ether (10.6 g, 104 mmol, purity 98%). In addition, the mixture was stirred at 25 ° C. for 3 hours and then at 90 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g). ..
The crude product of ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g) obtained was added to ammonium acetate (9.97 g, 123 mmol, purity 95%), 20% sodium ethoxide ethanol solution (35.4 g, 104 mmol) and ethanol (20.0 mL) were added, and the mixture was reacted under heating and reflux for 4 hours. After allowing to cool to 25 ° C., water (20.0 mL) was added, and a 48% aqueous sodium hydroxide solution (15.8 g, 189 mmol) was added dropwise while cooling in an ice bath. Then, the mixture was stirred at 25 ° C. for 1 hour, and the reaction solution was concentrated under reduced pressure. Toluene (30.0 mL) was added to the obtained reaction solution for washing, and 35% hydrochloric acid (29.5 g, 284 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (30.0 mL), and dried under reduced pressure to give the title compound (yield 10.0 g, yield 61%) as a white solid.
^{1 1} HNMR spectrum (DMSO-d ₆ ) σ: 8.85 (1H, d, J = 4.6Hz), 8.33 (1H, d, J = 7.8Hz), 7.69 (1H, dd, J1) = 7.8Hz, J2 = 4.6Hz), 7.50 (1H, t, J = 54.2Hz).

[Example 22]
Synthesis of 2-difluoromethylnicotinic acid Ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (21.0 g, 94.5 mmol) was added to butyl vinyl ether (10.6 g, 104 mmol, purity 98%). In addition, the mixture was stirred at 25 ° C. for 3 hours and then at 90 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g).
The ethyl obtained above is added to a separately prepared mixed solution of ammonium acetate (9.97 g, 123 mmol, purity 95%), 20% sodium ethoxide ethanol solution (35.4 g, 104 mmol), and ethanol (20.0 mL). A crude product of 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g) was added, and the mixture was reacted under heating and reflux for 4 hours. After allowing to cool to 25 ° C., water (20.0 mL) was added, and a 48% aqueous sodium hydroxide solution (15.8 g, 189 mmol) was added dropwise while cooling in an ice bath. Then, the mixture was stirred at 25 ° C. for 1 hour, and the reaction solution was concentrated under reduced pressure. Toluene (30.0 mL) was added to the obtained reaction solution for washing, and 35% hydrochloric acid (29.5 g, 284 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (30.0 mL), and dried under reduced pressure to give the title compound (yield 7.90 g, yield 48%) as a white solid.

[Example 23]
Synthesis of ethyl 2-difluoromethylnicotinate Ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (21.0 g, 94.5 mmol) in butyl vinyl ether (10.6 g, 104 mmol, purity 98%) Was added, and the mixture was stirred at 25 ° C. for 3 hours and then at 90 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g). ..
The crude product of ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (30.1 g) obtained was added to ammonium acetate (9.97 g, 123 mmol, purity 95%), 20% sodium ethoxide ethanol solution (35.4 g, 104 mmol) and ethanol (20.0 mL) were added, and the mixture was reacted under heating and reflux for 4 hours. The reaction solution is concentrated under reduced pressure, water (35.0 mL) and ethyl acetate (35.0 mL) are added for extraction, the organic layer is washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. bottom. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 12.9 g, yield 68%) in an orange transparent liquid.

[Example 24]
Synthesis of 2-difluoromethylnicotinic acid A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene) -4. , 4-Difluoro-3-oxobutyrate ethyl (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). ..
A 20% sodium ethoxide ethanol solution in the crude product of the obtained ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). (3.54 g, 10.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour, and then an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL) was added, and 25 The mixture was stirred at ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, 48% aqueous sodium hydroxide solution (1.58 g, 18.9 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and the mixture was stirred at 25 ° C. for 1 hour. .. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (3.00 mL), 35% hydrochloric acid (2.95 g, 28.4 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (3.00 mL), and dried under reduced pressure to give the title compound (yield 1.25 g, yield 76%) as a white solid.

[Example 25]
Synthesis of 2-difluoromethylnicotinic acid A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene) -4. , 4-Difluoro-3-oxobutyrate ethyl (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). ..
Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5 obtained above in a 20% sodium ethoxide ethanol solution (3.54 g, 10.4 mmol) A crude product of -carboxylate (3.04 g) was added and stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, 48% aqueous sodium hydroxide solution (1.58 g, 18.9 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and the mixture was stirred at 25 ° C. for 1 hour. .. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (3.00 mL), 35% hydrochloric acid (2.95 g, 28.4 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (3.00 mL), and dried under reduced pressure to give the title compound (yield 1.14 g, yield 70%) as a white solid.

[Example 26]
Synthesis of 2-difluoromethylnicotinic acid A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene) -4. , 4-Difluoro-3-oxobutyrate ethyl (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.00 g). ..
A 20% sodium ethoxide ethanol solution in the crude product of the obtained ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.00 g). (3.54 g, 10.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, and a 48% aqueous sodium hydroxide solution (1.58 g, 18.9 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then at 25 ° C. for 1 hour. Stirred. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (3.00 mL), 35% hydrochloric acid (2.95 g, 28.4 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (3.00 mL), and dried under reduced pressure to give the title compound (yield 1.16 g, yield 71%) as a white solid.

[Example 27]
Synthesis of 2-difluoromethylnicotinic acid A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene) -4. , 4-Difluoro-3-oxobutyrate ethyl (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.03 g). ..
Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5 obtained above in a 20% sodium ethoxide ethanol solution (3.54 g, 10.4 mmol) -A crude product of carboxylate (3.03 g) was added, and the mixture was stirred at 25 ° C. for 1 hour, and then an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mol, purity 95%) in water (1.00 mL) was added. In addition, the mixture was stirred at 25 ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, 48% aqueous sodium hydroxide solution (1.58 g, 18.9 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and the mixture was stirred at 25 ° C. for 1 hour. .. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (3.00 mL), 35% hydrochloric acid (2.95 g, 28.4 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (3.00 mL), and dried under reduced pressure to give the title compound (yield 1.21 g, yield 74%) as a white solid.

[Example 28]
Synthesis of ethyl 2-difluoromethylnicotinate A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene)- Ethyl 4,4-difluoro-3-oxobutyrate (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). ..
A 20% sodium ethoxide ethanol solution in the crude product of the obtained ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). (3.54 g, 10.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. Then, an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL) was added, and the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 1.30 g, yield 68%) in an orange transparent liquid.

[Example 29]
Synthesis of ethyl 2-difluoromethylnicotinate A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene)- Ethyl 4,4-difluoro-3-oxobutyrate (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.04 g). ..
Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5 obtained above in a 20% sodium ethoxide ethanol solution (3.54 g, 10.4 mmol) A crude product of -carboxylate (3.04 g) was added and stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 1.50 g, yield 79%) in an orange transparent liquid.

[Example 30]
Synthesis of ethyl 2-difluoromethylnicotinate A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene)- Ethyl 4,4-difluoro-3-oxobutyrate (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.03 g). ..
A 20% sodium ethoxide ethanol solution in the crude product of the obtained ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.03 g). (3.54 g, 10.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 1.49 g, yield 78%) in an orange transparent liquid.

[Example 31]
Synthesis of ethyl 2-difluoromethylnicotinate A reaction solution prepared by adding toluene (1.00 mL) to butyl vinyl ether (1.06 g, 10.4 mmol, purity 98%) was heated to 110 ° C. and 2- (ethoxymethylene)- Ethyl 4,4-difluoro-3-oxobutyrate (2.10 g, 9.45 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (3.03 g). ..
Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5 obtained above in a 20% sodium ethoxide ethanol solution (3.54 g, 10.4 mmol) -A crude product of carboxylate (3.03 g) was added, and the mixture was stirred at 25 ° C. for 1 hour, and then an aqueous solution prepared by dissolving ammonium acetate (997 mg, 12.3 mmol, purity 95%) in water (1.00 mL) was added. In addition, the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 1.46 g, yield 77%) in an orange transparent liquid.

[Example 32]
Synthesis of 2-difluoromethylnicotinic acid Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (29.1 g, 90.3 mmol) with ammonium acetate (9.52 g, 117 mmol, purity 95%), 20% sodium ethoxide ethanol solution (33.8 g, 99.3 mmol) and ethanol (20.0 mL) were added, and the mixture was reacted under heating and reflux for 4 hours. After allowing to cool to 25 ° C., water (20.0 ml) was added, and a 48% aqueous sodium hydroxide solution (15.0 g, 181 mmol) was added dropwise while cooling in an ice bath. Then, the mixture was stirred at 25 ° C. for 1 hour, and the reaction solution was concentrated under reduced pressure. After washing by adding toluene (30.0 mL), 35% hydrochloric acid (28.2 g, 271 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (30.0 mL), and dried under reduced pressure to give the title compound (yield 10.3 g, yield 66%) as a white solid.

[Example 33]
Synthesis of 2-difluoromethylnicotinic acid 20% to ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (29.1 g, 90.3 mmol) Sodium ethoxide ethanol solution (33.8 g, 99.3 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour, and then ammonium acetate (9.52 g, 117 mmol, purity 95%) was dissolved in water (10.0 mL). An aqueous solution was added, and the mixture was stirred at 25 ° C. for 7 hours. Then, water (10.0 mL) was added to the reaction solution, 48% aqueous sodium hydroxide solution (15.0 g, 181 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and the mixture was stirred at 25 ° C. for 1 hour. .. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (30.0 mL), 35% hydrochloric acid (28.2 g, 270 mmol) was added to the aqueous layer at 10 to 30 ° C. while cooling in an ice bath. The precipitated solid was filtered, washed with water (30.0 mL), and dried under reduced pressure to give the title compound (yield 12.4 g, yield 79%) as a white solid.

[Example 34]
Synthesis of 2-difluoromethylnicotinic acid Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran in a 20% sodium ethoxide ethanol solution (3.48 g, 10.2 mmol) -5-carboxylate (3.00 g, 9.31 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared separately in ammonium acetate (982 mg, 12.1 mmol, purity 95%) in water (1.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, and a 48% aqueous sodium hydroxide solution (1.55 g, 18.6 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then at 25 ° C. for 1 hour. Stirred. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (3.00 mL), 35% hydrochloric acid (2.91 g, 27.9 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (1.00 mL), and dried under reduced pressure to give the title compound (yield 1.27 g, yield 79%) as a white solid.

[Example 35]
Synthesis of 2-difluoromethylnicotinic acid 20% sodium ethoxide ethanol in ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (148 g, 459 mmol) The solution (171 g, 503 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (48.1 g, 593 mmol, purity 95%) in water (150 mL), and the mixture was stirred at 25 ° C. for 3 hours. Then, a 48% aqueous sodium hydroxide solution (76.0 g, 912 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and after washing by adding toluene (100 mL), 35% hydrochloric acid (141 g, 135 mol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (150 mL), and then dried under reduced pressure to give the title compound (yield 66.8 g, yield 82%) as a white solid.

[Example 36]
Synthesis of 2-difluoromethylnicotinic acid Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran in a 20% sodium ethoxide ethanol solution (3.38 g, 9.93 mmol) -5-carboxylate (2.91 g, 9.03 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. Then, an aqueous solution prepared by dissolving ammonium acetate (952 mg, 11.7 mmol, purity 95%) in water (1.00 mL) was added, and the mixture was stirred at 25 ° C. for 2 hours. Then, water (1.00 mL) was added to the reaction solution, and a 48% aqueous sodium hydroxide solution (1.50 g, 18.1 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then at 25 ° C. for 1 hour. Stirred. The reaction solution was concentrated under reduced pressure, toluene (3.00 mL) was added to separate the solutions, and then 35% hydrochloric acid (2.82 g, 27.1 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (1.00 mL), and dried under reduced pressure to give the title compound (yield 1.25 g, yield 80%) as a white solid.

[Example 37]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.0 g, 31.0 mmol) with ethanol A 20% sodium ethoxide ethanol solution (18.5 g, 54.3 mmol) was added to the reaction solution to which (10.0 mL) was added, and the mixture was stirred at 25 ° C. for 1 hour. Then, an aqueous solution prepared by dissolving ammonium acetate (8.81 g, 109 mmol, purity 95%) in water (10.0 mL) was added, and the mixture was stirred at 25 ° C. for 2 hours. Water (10.0 mL) and ethyl acetate (30.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 4.37 g, yield 70%) in an orange transparent liquid.

[Example 38]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H- in a 20% sodium ethoxide ethanol solution (11.6 g, 34.1 mmol) Piran-5-carboxylate (10.0 g, 31.0 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.27 g, 40.3 mmol, purity 95%) in water (2.50 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (17.5 mL) and ethyl acetate (17.5 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 5.28 g, yield 85%) in an orange transparent liquid.

[Example 39]
Synthesis of Ethyl 2-Difluoromethylnicotinate 20 to ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.0 g, 31.0 mmol) % Sodium ethoxide ethanol solution (11.6 g, 34.1 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.27 g, 40.3 mmol, purity 95%) in water (2.50 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (17.5 mL) and ethyl acetate (17.5 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 5.47 g, yield 88%) in an orange transparent liquid.

[Example 40]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H- in a 20% sodium ethoxide ethanol solution (3.48 g, 10.2 mmol) Piran-5-carboxylate (3.00 g, 9.31 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. Then, an aqueous solution prepared by dissolving ammonium acetate (982 mg, 12.1 mmol, purity 95%) in water (1.00 mL) was added, and the mixture was stirred at 25 ° C. for 2 hours. After confirming the disappearance of the raw material by TLC, water (3.00 mL) and ethyl acetate (10.0 mL) are added for extraction, the organic layer is washed with saturated brine (5.00 mL), dried over sodium sulfate, and then dried. Concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 1.54 g, yield 82%) in an orange transparent liquid.

[Example 41]
Synthesis of 2-trifluoromethylnicotinic acid 20% to ethyl2-butoxy-6- (trifluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (52.2 g, 153 mmol) A sodium ethoxide ethanol solution (57.5 g, 169 mmol) was added, and the mixture was stirred at 25 ° C. for 1.5 hours. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (16.2 g, 200 mmol, purity 95%) in water (50.0 mL), and the mixture was stirred at 25 ° C. for 3 hours. Then, a 48% aqueous sodium hydroxide solution (25.7 g, 308 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, toluene (40.0 mL) and water (50.0 mL) were added for washing, and then 35% hydrochloric acid (49.0 g, 470 mmol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (50.0 mL), and then dried under reduced pressure to give the title compound (yield 14.5 g, yield 47%) as a white solid.
^{1 1} HNMR spectrum (DMSO-d ₆ ) σ: 8.84 (1H, d, J = 4.8 Hz), 8.25 (1H, d, J = 7.8 Hz), 7.81 (1H, dd, J1) = 7.8Hz, J2 = 4.8Hz).

[Example 42]
Synthesis of ethyl 2-difluoromethylnicotinate Add ethanol (10.0 mL) to potassium hydroxide (2.24 g, 34.1 mmol, purity 85.5%), stir at 45 ° C to dissolve, and then bring to 25 ° C. After cooling, add ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.0 g, 31.0 mmol) and add at 25 ° C. for 2 hours. Stirred. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.27 g, 40.3 mmol, purity 95%) in water (10.0 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 4.18 g, yield 67%) in an orange transparent liquid.

[Example 43]
Synthesis of ethyl 2-difluoromethylnicotinate Add ethanol (10.0 mL) to sodium hydroxide (1.37 g, 34.1 mmol), stir at 45 ° C. to dissolve, and then ethyl 2-butoxy-6- (difluoro). Methyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.0 g, 31.0 mmol) was added, and the mixture was stirred at 25 ° C. for 2 hours. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.27 g, 40.3 mmol, purity 95%) in water (5.00 mL), and the mixture was stirred at 25 ° C. for 2 hours. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 3.60 g, yield 58%) in an orange transparent liquid.

[Example 44]
Synthesis of Ethyl 2-Difluoromethylnicotinate 20 to ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.1 g, 31.2 mmol) A solution of% sodium ethoxide ethanol (11.7 g, 34.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium carbonate (6.50 g, 20.3 mmol, purity 30%) in water (30.0 mL), and the mixture was stirred at 25 ° C. for 6 hours. Then, water (3.00 mL) and ethyl acetate (10.0 mL) were added to the reaction solution for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 5.11 g, yield 81%) in an orange transparent liquid.

[Example 45]
Synthesis of Ethyl 2-Difluoromethylnicotinate 20 to ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.1 g, 31.2 mmol) A solution of% sodium ethoxide ethanol (11.4 g, 33.4 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium sulfate (2.61 g, 19.8 mmol) in water (10.0 mL), and the mixture was stirred at 25 ° C. for 4 hours. Then, water (3.00 mL) and ethyl acetate (10.0 mL) were added to the reaction solution for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 4.88 g, yield 80%) in an orange transparent liquid.

[Example 46]
Synthesis of Ethyl 2-Difluoromethylnicotinate 20 to ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.1 g, 31.2 mmol) % Sodium ethoxide ethanol solution (11.6 g, 34.1 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared by dissolving ammonium chloride (2.17 g, 40.3 mmol) in water (10.0 mL), and the mixture was stirred at 25 ° C. for 4 hours. Then, water (3.00 mL) and ethyl acetate (10.0 mL) were added to the reaction solution for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 3.01 g, yield 48%) in an orange transparent liquid.

[Example 47]
Synthesis of ethyl 2-difluoromethylnicotinate Toluene (10.6 mL) was added to sodium ethoxide (2.45 g, 34.1 mmol, purity 95%), and the mixture was stirred at 25 ° C. for 10 minutes. Ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (10.0 g, 31.0 mmol) was added dropwise over 5 minutes and 1 at 25 ° C. Stirred for hours. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.27 g, 40.3 mmol, purity 95%) in water (10.0 mL), and the mixture was stirred at 25 ° C. for 5 hours and then at 120 ° C. for 2 hours. The mixture was heated under reflux. Water (3.00 mL) and ethyl acetate (10.0 mL) were added for extraction, and the organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 5.23 g, yield 88%) in an orange transparent liquid.

[Example 48]
Synthesis of 2-difluoromethylnicotinic acid Toluene (138 g) was added to sodium ethoxydo (36.7 g, 512 mmol, purity 95%) at 0 ° C., and ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3 was added. , 4-Dihydro-2H-pyran-5-carboxylate (150 g, 465 mmol) was added dropwise over 30 minutes, stirred at 25 ° C. for 1 hour, and then separately adjusted ammonium acetate (49.1 g, 605 mmol, purity 95%). Was added to an aqueous solution dissolved in water (150 mL), stirred at 25 ° C. for 3 hours, and then heated to reflux at 120 ° C. for 1 hour. After adding an aqueous solution of tetrabutylammonium bromide (7.66 g, 23.3 mmol, purity 98%) and water (70.0 mL) to a 48% aqueous sodium hydroxide solution (58.1 g, 698 mmol) at 110 ° C. The mixture was heated under reflux for 6 hours. The organic layer of the reaction solution was removed, toluene (100 mL) was added to the aqueous layer for washing, and then 35% hydrochloric acid (148 g, 1442 mmol) was added at 25-40 ° C. while cooling in an ice bath. The precipitated solid was filtered, washed with water (100 mL), and dried under reduced pressure to give the title compound (yield 56.3 g, yield 68%) as a white solid.

[Example 49]
Synthesis of Ethyl 2-Trifluoromethylnicotinate Ethyl 2-butoxy-6- (trifluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (9.80 g, 28.8 mmol) A 20% sodium ethoxide ethanol solution (10.8 g, 31.7 mmol) was added dropwise over 5 minutes in the range of 21 to 24 ° C., and then the mixture was stirred at 40 ° C. for 3 hours. This reaction solution was added to an aqueous solution prepared by dissolving ammonium acetate (3.00 g, 37.8 mmol, purity 95%) in water (10.0 mL), stirred at 30 ° C. for 3 hours, and then 3 at 78 ° C. Stirred for hours. After concentration under reduced pressure to distill off ethanol, water (80.0 mL) and ethyl acetate (80.0 mL) were added for extraction, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 3.90 g, yield 61%) in an orange transparent liquid.
^{1 1} HNMR spectrum (CDCl ₃ ) σ: 8.81 (1H, d, J = 4.6Hz), 8.12 (1H, d, J = 7.8Hz), 7.56 (1H, dd, J1 = 7) 0.8Hz, J2 = 4.6Hz), 4.43 (2H, q, J = 7.2Hz), 1.41 (3H, t, J = 7.2Hz).

[Example 50]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.10 g, 3.35 mmol) with ethanol (1.00 mL) and methanesulfonic acid (322 mg, 3.35 mmol) were added, and the mixture was reacted at 50 ° C. for 2 hours. The reaction solution was allowed to cool to 25 ° C., ammonium acetate (905 mg, 11.7 mmol) was added, and the mixture was stirred at 25 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and then reduced under reduced pressure. Lower concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 350 mg, yield 52%) in an orange transparent liquid.

[Example 51]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.11 g, 3.45 mmol) with ethanol (1.00 mL) and 35% hydrochloric acid (359 mg, 3.45 mmol) were added, and the mixture was reacted at 50 ° C. for 2 hours. The reaction solution was allowed to cool to 25 ° C., ammonium acetate (930 mg, 12.1 mmol) was added, and the mixture was stirred at 25 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and then reduced under reduced pressure. Lower concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 273 mg, yield 39%) in an orange transparent liquid.

[Example 52]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g, 3.19 mmol) with ethanol (1.00 mL) and zinc chloride (130 mg, 0.96 mmol) were added, and the mixture was reacted at 50 ° C. for 2 hours. The reaction solution was allowed to cool to 25 ° C., ammonium acetate (860 mg, 11.2 mmol) was added, and the mixture was stirred at 25 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and then reduced under reduced pressure. Lower concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 280 mg, yield 35%) in an orange transparent liquid.

[Example 53]
Synthesis of Ethyl 2-Difluoromethylnicotinate Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g, 3.20 mmol) with ethanol (1.00 mL), copper (II) bromide (716 mg, 3.20 mmol) was added, and the mixture was reacted at 50 ° C. for 2 hours. The reaction solution was allowed to cool to 25 ° C., ammonium acetate (864 mg, 11.2 mmol) was added, and the mixture was stirred at 25 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and then reduced under reduced pressure. Lower concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/3) to obtain the title compound (yield 163 mg, yield 25%) in an orange transparent liquid.

[Example 54]
Synthesis of 2-difluoromethylnicotinic acid Ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (2.00 g, 6.21 mmol) with ethanol ( 2.00 mL) and methanesulfonic acid (596 mg, 6.21 mmol) were added, and the mixture was reacted at 50 ° C. for 2 hours. The reaction solution was allowed to cool to 25 ° C., ammonium acetate (1.67 g, 21.7 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. Then, a 48% aqueous sodium hydroxide solution (2.59 g, 31.0 mmol) was added at 10 to 30 ° C. while cooling in an ice bath, and then the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, water (5 mL) and toluene (5 mL) were added for washing, and then 35% hydrochloric acid (3.88 g, 37.2 mol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (5 mL), and then dried under reduced pressure to give the title compound (yield 310 mg, yield 29%) as a white solid.

^{1 1} HNMR of 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative compound represented by the formula (3) according to the present invention produced based on the above synthesis example and the above production method. Table 2 shows the spectrum (CDCl ₃ ) σ (ppm) values and properties. ^{1 1} HNMR data was measured by JNM-ECS400 Spectrometer (manufactured by JEOL Ltd.).

[Reference Example 1]
Synthesis of 2-difluoromethylnicotinic acid Triethyl orthoformate (177 g, 1.17 mol, purity 98%), acetic anhydride (123 g, 1.17 mol,) in ethyl 4,4-difluoroacetoacetate (100 g, 586 mmol, purity 97%) Purity (97%) was added, and the mixture was stirred at 110 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxobutyrate (136 g). A reaction solution prepared by adding toluene (50.0 mL) to butyl vinyl ether (67.6 g, 662 mmol, purity 98%) was heated to 110 ° C., and the above-mentioned 2- (ethoxymethylene) -4,4-difluoro-3 was obtained. A crude product of ethyl oxobutyrate (136 g) was added dropwise over 15 minutes and stirred at 110 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure to give a crude product of ethyl2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (187 g).
A 20% sodium ethoxide ethanol solution (217 g) was added to the crude product of the obtained ethyl 2-butoxy-6- (difluoromethyl) -4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (187 g). , 639 mmol) was added, and the mixture was stirred at 25 ° C. for 1 hour. This reaction solution was added to an aqueous solution prepared separately in ammonium acetate (61.3 g, 755 mmol purity 95%) in water (43.0 mL), and the mixture was stirred at 25 ° C. for 4 hours. Then, a 48% aqueous sodium hydroxide solution (96.8 g, 1.16 mol) was added at 10 to 30 ° C. while cooling in an ice bath, and then stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, water (300 mL) and toluene (100 mL) were added for washing, and then 35% hydrochloric acid (182 g, 1.74 mol, 35%) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (300 mL), and dried under reduced pressure to give the title compound (yield 76.0 g, yield 76%) as a white solid.

According to the present invention, a production method for easily and efficiently producing a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative useful as an intermediate for producing a pesticide and the ester compound. Can be provided.
Further, according to the present invention, a 2- (fluoroalkyl) nicotinic acid ester derivative useful as an intermediate for the production of pesticides is a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative. It is possible to provide a manufacturing method for manufacturing easily and efficiently.
Further, according to the present invention, a 2- (fluoroalkyl) nicotinic acid derivative, which is an important intermediate in the production of bactericides and the like in the field of agriculture and horticultural fields, is a 6- (fluoroalkyl) -3,4-dihydro-2H. It is possible to provide a simple and efficient production method via a -pyran-5-carboxylic acid ester derivative or the like and a 2- (fluoroalkyl) nicotinic acid ester derivative.

Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
This application is a Japanese patent application filed on March 27, 2020 (Japanese Patent Application No. 2020-057804), a Japanese patent application filed on March 27, 2020 (Japanese Patent Application No. 2020-057805), and an application filed on November 25, 2020. It is based on a Japanese patent application (Japanese Patent Application No. 2020-195023) and a Japanese patent application filed on November 25, 2020 (Japanese Patent Application No. 2020-195024), the contents of which are incorporated herein by reference.

Claims (12)

The following formula (3)

(In the formula, R ¹ and R ² represent a C _1- C ₆ alkyl group, R _{f represents a C 1 to} C ₄ alkyl group substituted with a fluorine atom, and R ³ represents a C _{1 to} C ₈ alkyl group. , a phenyl group (in which may be substituted are monosubstituted or polysubstituted by identical or different groups selected from halogen atom, C ₁ -C ₆ alkyl group, the group consisting of C ₁ -C ₆ alkoxy group _{C 3-} C ₆ cycloalkyl group which may be substituted (the group is a halogen atom, C _1- C ₆ alkyl group, C _1- C ₆ alkoxy group, C _1- C ₆ haloalkyl). It may be mono-substituted or poly-substituted by the same or different groups selected from the group consisting of groups), where X represents an oxygen atom or a sulfur atom.)
6- (Fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by. R ³ is a C _1- C ₆ alkyl group (R ² and R ³ may be the same or different), X is an oxygen atom and R _f is a trifluoromethyl group or difluoro. The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to claim 1, which is a methyl group. The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The method for producing a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to claim 1, which comprises reacting a vinyl compound represented by. The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to claim 1 or 2 is reacted with an ammonium compound or ammonia, or a base is reacted with an ammonium compound or ammonia. After being treated with an acid or Lewis acid, it was reacted with an ammonium compound or ammonia to formulate the following formula (4).

(In the formula, R ¹ and R _f have the same meanings as described above.)
A 2- (fluoroalkyl) nicotinic acid ester derivative represented by is obtained, and the obtained 2- (fluoroalkyl) nicotinic acid ester derivative is hydrolyzed to obtain the following formula (5).

(In the formula, R _f has the same meaning as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid derivative represented by. It is characterized by reacting a base with a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the above formula (3) and then reacting with an ammonium compound or ammonia. The method for producing a 2- (fluoroalkyl) nicotinic acid derivative according to claim 4. The 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative according to claim 1 or 2 is reacted with an ammonium compound or ammonia, or a base is reacted with an ammonium compound or ammonia. After being treated with an acid or Lewis acid, it was reacted with an ammonium compound or ammonia to formulate the following formula (4).

(In the formula, R ¹ and R _f have the same meanings as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid ester derivative represented by. It is characterized by reacting a base with a 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by the above formula (3) and then reacting with an ammonium compound or ammonia. The method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative according to claim 6. The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The vinyl compound represented by is reacted with the following formula (3).

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above.)
A 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by is obtained, and this is reacted with an ammonium compound or ammonia, or a base is reacted with an ammonium compound or ammonia. After being treated with an acid or Lewis acid, and then reacted with an ammonium compound or ammonia, the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A 2- (fluoroalkyl) nicotinic acid ester derivative represented by is obtained, and the obtained 2- (fluoroalkyl) nicotinic acid ester derivative is hydrolyzed to obtain the following formula (5).

(In the formula, R _f has the same meaning as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid derivative represented by. The following formula (1)

(Wherein, R ^{1, R 2} represents a _C 1 -C ₆ alkyl group, and _{R f} represents a _C 1 -C ₄ alkyl group in which a fluorine atom is substituted.)
The fluorinated 2- (alkoxymethylidene) -β-ketoester derivative represented by the following formula (2)

(Select wherein, ^{R 3} is _C 1 -C ₈ alkyl group, an optionally substituted phenyl group (in which a halogen _atom, C 1 -C ₆ alkyl _group, from the group consisting of C 1 -C ₆ alkoxy group Mono-substituted or poly-substituted with the same or different groups to be made, C _3- C ₆ cycloalkyl groups which may be substituted (the groups are halogen atoms, C _1- C ₆ alkyl groups, It may be mono- or poly-substituted with the same or different groups selected from the group consisting of C _1- C ₆ alkoxy groups and C _1- C _{6 haloalkyl groups), where X is an oxygen atom or a sulfur atom.} Represents.)
The vinyl compound represented by is reacted with the following formula (3).

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as described above.)
A 6- (fluoroalkyl) -3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative represented by is obtained and reacted with an ammonium compound or ammonia, or a base and an ammonium compound or ammonia. After reacting or treating with acid or Lewis acid, it is reacted with an ammonium compound or ammonia, and the following formula (4)

(In the formula, R ¹ and R _f have the same meanings as described above.)
A method for producing a 2- (fluoroalkyl) nicotinic acid ester derivative, which comprises obtaining a 2- (fluoroalkyl) nicotinic acid ester derivative represented by. R ³ is a C _1- C ₆ alkyl group (R ² and R ³ may be the same or different), X is an oxygen atom and R _f is a trifluoromethyl group or difluoro. The production method according to claim 8 or 9, which is a methyl group. The production method according to any one of claims 4 to 10, wherein the base is sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide. The production method according to any one of claims 4 to 11, wherein the ammonium compound is ammonium chloride, ammonium acetate, ammonium carbamate, ammonium carbonate, ammonium phosphate, ammonium sulfate, or ammonium formate.