JP2023063618A - Method for producing 2-(fluoroalkyl) nicotinate derivative - Google Patents

Abstract

To provide a production method that makes it possible to readily and efficiently produce a 2-(fluoroalkyl) nicotinate derivative to be a production intermediate of a pest control agent.MEANS: A method for producing a 2-(fluoroalkyl) nicotinate derivative represented by formula (1a) includes reacting 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylate derivative (1) with an ammonium compound or ammonia, optionally in the presence of a base (where R1 and Rf are defined herein).SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a method for producing 2-(fluoroalkyl)nicotinate derivatives useful as intermediates for the production of agricultural chemicals.

It has been known that 2-(fluoroalkyl)nicotinamide derivatives are useful as fungicides in the agricultural and horticultural fields, and 2-(fluoroalkyl)nicotinic acid esters are intermediates for their production. are known (Patent Documents 1 to 5).

By the way, as a method for producing a 2-(fluoroalkyl)nicotinic acid ester, Patent Document 6, Patent Document 7, and Non-Patent Document 1 describe preparation from an acetoacetate having a fluorine-substituted 4-position and N,N-dialkylformamide. It is known that they can be prepared by reacting Vilsmeier reagents as well as alkyl (vinyl) ethers followed by reaction with nitrogen source reagents such as ammonia.

Further, in Patent Document 8, Non-Patent Document 2, and Non-Patent Document 3, a 2-(fluoroalkyl)nicotinate is produced by a reaction of a 2-halonicotinate with trifluoromethane, a fluorinated alkyl organometallic compound, or the like. It is stated that it can be synthesized

Further, Patent Document 9 and Non-Patent Document 4 describe that 2-(fluoroalkyl)nicotinate can be synthesized by reacting a nicotinic acid ester with a fluorinated alkylsulfinic acid.

In addition, Non-Patent Document 5 describes that a 2-(fluoroalkyl)nicotinate can be synthesized by reacting an aminocrotonate having a fluorinated position at the 4-position with acrolein.

WO2006/097490 WO2017/042142 WO2016/131739 WO2014/095675 WO2015/197530 WO2009/054742 WO2015/197530 WO2015/0284341 WO2013/082028

Organic Letters, Vol. 10, No. 9, pp. 1835-1837, 2008 Journal of Organic Chemistry, Vol.78, No.22, pp.11126-11146, 2013 Organic Letters, No. 16, Vol. 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

An object of the present invention is to provide a method for simply and efficiently producing 2-(fluoroalkyl)nicotinate derivatives, which are important intermediates in the production of fungicides and the like in the agricultural and horticultural fields.

In order to solve the above-described problems, the present inventors have made intensive studies and found that a 2-(fluoroalkyl)nicotinic acid ester derivative is converted into a 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester. The present inventors have found a simple and efficient production method from a derivative and completed the present invention.

（式中、Ｒ¹、Ｒ^２はＣ_１～Ｃ_６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、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基の群からなる同一又は異なった基がモノ置換あるいはポリ置換していてもよい）、置換されていてもよいＣ３－Ｃ６シクロアルキル基（該基はハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６ハロアルキル基の群からなる同一又は異なった基がモノ置換あるいはポリ置換していてもよい）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、Ｘは酸素原子又は硫黄原子を表す。）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）を、場合によっては塩基存在下に、アンモニウム化合物又はアンモニアと反応させることを特徴とする、下記式（１ａ）

（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）で示されるニコチン酸エステル誘導体の製造方法に関するものである。 That is, the invention according to the present application has the following formula (1)

(In the formula, R ¹ and R ² represent a C ₁ -C ₆ alkyl group, R ³ represents a C ₁ -C ₈ alkyl group, an optionally substituted phenyl group (the group is a halogen atom, a C1-C6 alkyl group, may be mono- or polysubstituted by the same or different groups consisting of the group of C1-C6 alkoxy groups), optionally substituted C3-C6 cycloalkyl group (the group is a halogen atom, C1- C6 alkyl group, C1-C6 alkoxy group, and C1-C6 haloalkyl group, which may be mono- or polysubstituted by the same or different groups), and R _f is a fluorine atom-substituted C ₁ to _C4 alkyl group, and X represents an oxygen atom or a sulfur atom.) is reacted with an ammonium compound or ammonia, optionally in the presence of a base, the following formula (1a)

(In the formula, R ¹ and R _f have the same meanings as described above).

INDUSTRIAL APPLICABILITY The present invention can provide a method for producing a 2-(fluoroalkyl)nicotinate derivative useful as an intermediate for agricultural chemical production.

（式中、Ｒ¹、Ｒ^２、Ｒ^３、Ｒ_ｆ及びＸは、前記と同じ意味を表す。） The method for producing the 2-(fluoroalkyl)nicotinate derivative (1a) of the present invention will be described in detail.

(In the formula, R ¹ , R ² , R ³ , R _f and X have the same meanings as above.)

The C ₁ -C ₆ alkyl group represented by R ¹ or R ² may be linear or branched and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -Butyl group, isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group, etc., and can be easily produced. , preferably a methyl group or an ethyl group.

The C ₁ -C ₈ alkyl group represented by R ³ may be linear or branched, and includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and 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, etc., and preferably can be exemplified by ethyl group, n-propyl group, n-butyl group, isobutyl group and the like.

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.

Examples of the optionally substituted C3-C6 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.

The fluorine atom-substituted C ₁ -C ₄ alkyl group represented by R _f includes a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, and a nonafluorobutyl group. groups and the like, preferably difluoromethyl group, trifluoromethyl group and the like.

Step-1 comprises reacting 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (1) represented by formula (1) with an ammonium compound or ammonia, This is a step of producing a 2-(fluoroalkyl)nicotinic acid ester derivative (1a). 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (1) represented by formula (1) is a fluorinated 2-(alkoxymethylidene)-β- It can be prepared by reacting a ketoester derivative with a vinyl compound.

This reaction can proceed in the presence of a base, and usable bases include sodium hydride, potassium hydride, lithium amide, sodium amide, lithium diisopropylamide (LDA), butyllithium, and tert-butyllithium. , trimethylsilyllithium, lithium hexamethyldisilazide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium thiomethoxide, sodium thioethoxide, potassium-tert-butoxide and other alkali metals Base, dimethylamine, diethylamine, N-ethylmethylamine, dipropylamine, N-ethylisopropylamine, diisopropylamine, dibutylamine, diisobutylamine, pyrrolidine, piperidine, 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine , 2,2,6,6-tetramethylpiperidine, morpholine, dibenzylamine and N-methylaniline. The target product can be obtained by using 0.1 to 20 equivalents of the base relative to the substrate, and the target product can be obtained in good yield by using 0.5 to 5 equivalents of the base.

Ammonium compounds used in this reaction include ammonium benzoate, ammonium chloride, ammonium carbamate, ammonium formate, ammonium carbonate, ammonium oxalate, ammonium acetate, ammonium hydrogencarbonate, ammonium thiocyanate, ammonium iodide, ammonium phosphate, Ammonium salts such as ammonium and ammonium sulfate, or ammonia water or ammonia gas can be used for phosphoric acid. The target product can be obtained by using 0.5 to 20 equivalents of the ammonium compound relative to the substrate, and the target product can be obtained in good yield by using 1 to 10 equivalents of the ammonium compound. ammonium

This reaction can be carried out either in the absence of a solvent or in the presence of a solvent. Any solvent can be used as long as it does not harm the reaction, and aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene, and aliphatic hydrocarbon solvents such as pentane, hexane and octane can be used. , diethyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethoxyethane, 1,4-dioxane and other ether solvents, acetone, methyl ethyl ketone, cyclohexanone and other ketones, chloroform, dichloromethane and other halogen solvents, acetonitrile, propio Nitrile solvents such as nitrile, ester solvents such as ethyl acetate, propyl acetate, butyl acetate and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, methanol , ethanol, 1-propanol, 2-propanol, tert-butanol, ethylene glycol, dimethylsulfoxide, water or a mixed solvent thereof can be used.

Further, the desired product can be obtained by reacting at a reaction temperature of 0 to 200°C, and the desired product can be obtained in a higher yield by reacting at a reaction temperature of 20 to 160°C.

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

EXAMPLES Next, the present invention will be specifically described with reference to Examples, but the scope of the present invention is not limited to these.

エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．００ｇ，３．１０ｍｍｏｌ）に酢酸アンモニウム（４７８ｍｇ，６．２１ｍｍｏｌ）、２０％ナトリウムエトキシドエタノール溶液（１．５８ｇ，４．６５ｍｍｏｌ）を加え、７８℃で２時間撹拌した。ＴＬＣで反応の終了を確認した後、反応溶液に酢酸エチル、水を加えて、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量３７０ｍｇ、収率６０％）を得た。
^１ＨＮＭＲスペクトル（ＣＤＣｌ_３） σ：８．８７（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５２（１Ｈ，ｄｄ，Ｊ１＝８．０Ｈｚ，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 1]
Synthesis of ethyl 2-difluoromethylnicotinate

To ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.00 g, 3.10 mmol) ammonium acetate (478 mg, 6.21 mmol), A 20% sodium ethoxide ethanol solution (1.58 g, 4.65 mmol) was added, and the mixture was stirred at 78°C for 2 hours. After confirming the completion of the reaction by TLC, ethyl acetate and water were added to the reaction solution, and 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 (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (yield: 370 mg, yield: 60%).
¹ H NMR spectrum (CDCl ₃ ) σ: 8.87 (1H, d, J = 4.8 Hz), 8.33 (1H, d, J = 8.0 Hz), 7.52 (1H, dd, J = 8 .0Hz, J2 = 4.8Hz), 7.43 (1H, t, J = 54.2Hz), 4.45 (2H, q, J = 7.2Hz), 1.43 (3H, t, J = 7.2 Hz).

エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．００ｇ，３．１０ｍｍｏｌ）に酢酸アンモニウム（８３７ｍｇ，１０．９ｍｍｏｌ）を加え、１６０℃で９時間撹拌した。反応溶液に酢酸エチル、水を加えて、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量３００ｍｇ、収率４８％）を得た。 [Example 2]
Synthesis of ethyl 2-difluoromethylnicotinate

Ammonium acetate (837 mg, 10.9 mmol) was added to ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.00 g, 3.10 mmol). and stirred at 160° C. for 9 hours. Ethyl acetate and water were added to the reaction solution, and 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 (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (yield: 300 mg, yield: 48%).

２－（エトキシメチレン）－４，４－ジフルオロ－３－オキソ酪酸エチル（５００ｇ，２．３０ｍｏｌ）にブチル（ビニル）エーテル（２７１ｇ，２．７０ｍｏｌ）を加え、９４℃で１時間半撹拌した。得られた反応溶液を減圧濃縮して、黄色油状の標記化合物（収量７４７ｇ、収率１００％）で得た。
^１ＨＮＭＲスペクトル（ＣＤＣｌ_３） σ：７．１４（０．７Ｈ，ｔ，Ｊ＝５４．２Ｈｚ），７．０８（０．３Ｈ，ｔ，Ｊ＝５４．２Ｈｚ），５．３３（０．７Ｈ，ｔ，Ｊ＝２．６Ｈｚ），５．１４（０．３Ｈ，ｄｄ，Ｊ１＝１０．０Ｈｚ，Ｊ２＝２．４Ｈｚ），４．３５－４．１５（３Ｈ，ｍ），４．０２（０．３Ｈ，ｄｔ，Ｊ１＝９．６Ｈｚ，Ｊ２＝６．６Ｈｚ）， ３．８７（０．７Ｈ，ｄｔ，Ｊ１＝１０．０Ｈｚ，Ｊ２＝６．６Ｈｚ），３．７０－３．６０（１Ｈ，ｍ）， ３．５７－３．４４（２Ｈ，ｍ），２．３６（０．７Ｈ， ｄｔ，Ｊ１＝１４．４Ｈｚ，Ｊ２＝２．７Ｈｚ）， ２．２１（０．３Ｈ， ｄｔ，Ｊ１＝１４．０Ｈｚ，Ｊ２＝２．５Ｈｚ），１．９２（０．７Ｈ，ｄｄｄ， Ｊ１＝１４．５Ｈｚ，Ｊ２＝５．７Ｈｚ，Ｊ３＝３．３Ｈｚ），１．７７－１．７０（０．３Ｈ，ｍ），１．６３－１．５０（２Ｈ，ｍ），１．４３－１．３４（２Ｈ，ｍ），１．４４－１．３０（３Ｈ，ｍ），１．２２－１．１７（３Ｈ，ｍ），０．９６－０．８９（３Ｈ，ｍ）． [Reference Example 1]
Synthesis of ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate

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 1.5 hours. The resulting reaction solution was concentrated under reduced pressure to obtain the title compound as a yellow oil (yield: 747 g, yield: 100%).
¹ H NMR spectrum (CDCl ₃ ) σ: 7.14 (0.7H, t, J = 54.2 Hz), 7.08 (0.3H, t, J = 54.2 Hz), 5.33 (0.7H , t, J = 2.6 Hz), 5.14 (0.3H, dd, J1 = 10.0 Hz, J2 = 2.4 Hz), 4.35-4.15 (3H, m), 4.02 ( 0.3H, dt, J1 = 9.6Hz, J2 = 6.6Hz), 3.87 (0.7H, dt, J1 = 10.0Hz, J2 = 6.6Hz), 3.70-3.60 ( 1H, m), 3.57-3.44 (2H, m), 2.36 (0.7H, dt, J1 = 14.4Hz, J2 = 2.7Hz), 2.21 (0.3H, dt , J1 = 14.0 Hz, J2 = 2.5 Hz), 1.92 (0.7H, ddd, J1 = 14.5 Hz, J2 = 5.7 Hz, J3 = 3.3 Hz), 1.77-1.70 (0.3H, m), 1.63-1.50 (2H, m), 1.43-1.34 (2H, m), 1.44-1.30 (3H, m), 1.22 -1.17 (3H, m), 0.96-0.89 (3H, m).

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to efficiently produce and provide a 2-(fluorine-substituted alkyl) nicotine ester derivative that is an intermediate of a fungicide for agricultural and horticultural use.

Claims (2)

Formula (1) below

(In the formula, R ¹ and R ² represent a C ₁ -C ₆ alkyl group, R ³ represents a C ₁ -C ₈ alkyl group, an optionally substituted phenyl group (the group is a halogen atom, a C1-C6 alkyl group, may be mono- or polysubstituted by the same or different groups consisting of the group of C1-C6 alkoxy groups), optionally substituted C3-C6 cycloalkyl group (the group is a halogen atom, C1- C6 alkyl group, C1-C6 alkoxy group, and C1-C6 haloalkyl group, which may be mono- or polysubstituted by the same or different groups), and R _f is a fluorine atom-substituted C ₁ to _C4 alkyl group, and X represents an oxygen atom or a sulfur atom.) is reacted with an ammonium compound or ammonia, the following formula (1a)

(1a)
A method for producing a 2-(fluoroalkyl)nicotinic acid ester derivative represented by (wherein R ¹ and R _f have the same meanings as defined above). A method for producing a 2-(fluoroalkyl)nicotinate derivative represented by the general formula (1a), comprising: 6-(fluoroalkyl)-3,4-dihydro- represented by the general formula (1) 2. The method for producing a 2-(fluoroalkyl)nicotinic acid ester derivative according to claim 1, wherein the 2H-pyran-5-carboxylic acid ester derivative is reacted with an ammonium compound or ammonia in the presence of a base.