JP7420583B2 - Method for producing carboxylic acid fluorides - Google Patents

Description

The present invention relates to a production method that uses an organic iodine compound in which an iodine atom is directly bonded to the carbon of a carbon-carbon double bond as a raw material and converts the iodine atom into a carboxylic acid fluoride. Carboxylic acid fluorides are compounds that can react with various nucleophiles and are useful as intermediates in the production of pharmaceuticals and agricultural chemicals and electronic materials.

Conventionally, methods for producing carboxylic acid fluoride include a method in which carboxylic acid chloride or carboxylic acid anhydride is used as a raw material and reacted with anhydrous hydrogen fluoride (for example, Non-Patent Document 1, etc.), and a method in which carboxylic acid is used as a raw material and reacted with anhydrous hydrogen fluoride (for example, Non-Patent Document 1), A method of reacting a hydrogen chloride-amine salt and N-bromosuccinimide (for example, Non-Patent Document 2) is known.
In addition, as a method for producing carboxylic acid fluoride using an organic iodine compound as a raw material, a method is known in which carbon monoxide is used and reacted in the presence of a catalyst such as palladium and an alkali metal fluoride (for example, Patent Document 3).
Furthermore, as a method for producing carboxylic acid fluoride using an organic iodine compound as a raw material and without using carbon monoxide, N-formylsaccharin is used as a carbon monoxide generating agent in the presence of a catalyst such as palladium and an alkali metal fluoride, Methods for causing the reaction are known (for example, Non-Patent Document 4).

The conventional method described in Non-Patent Document 1 or Non-Patent Document 2 is a method of deriving from carboxylic acid, and since anhydrous hydrogen fluoride or hydrogen fluoride-amine salt is used, complex In the case of production from a chemical compound, there is a problem that other functional groups may react with anhydrous hydrogen fluoride or hydrogen fluoride-amine salt, and the reaction substrate is limited.
The conventional method described in Non-Patent Document 3 uses highly toxic carbon monoxide and requires reaction at high pressure, so there is a problem that special high-pressure equipment such as an autoclave is required.
The conventional method described in Non-Patent Document 4 enables the reaction at normal pressure and does not require special high-pressure equipment; however, because the method generates carbon monoxide within the reaction system, Similarly, there is the issue that there may be carbon monoxide toxicity issues.

G. A. Olah et al., J. Org. Chem. 1961, 26, 237-238. K. Surya Prakash et al., Org. Lett. 2019, 21, 1659-1663. T. Sakakura et al., J. Organometaric Chem. 334, 205-211. Kei Manabe et al., Org. Lett. 2013, 15(20), 5370-5373.

An object of the present invention is to provide a method for converting an iodine atom of an organic iodine compound having an iodine atom directly connected to a carbon of a carbon-carbon double bond into a carboxylic acid fluoride using 2-difluoromethoxy-4-nitropyridine. There is a particular thing.

The present inventors conducted intensive studies on a method for converting the iodine atom directly connected to the carbon of the carbon-carbon double bond of an organic iodine compound into a carboxylic acid fluoride. It was discovered that formic acid fluoride, which is highly reactive with palladium catalysts, can be easily generated from fluoride, and furthermore, in the presence of palladium catalysts and ligands, organic iodine compounds having an iodine atom directly connected to the carbon of a carbon-carbon double bond were reacted. The inventors have discovered that iodine atoms can be converted into carboxylic acid fluoride by doing this, and have completed the present invention.

That is, the present invention provides an organic iodine compound containing an iodine atom directly connected to carbon forming a carbon-carbon double bond, and 2-(difluoromethoxy)-5 in the presence of a palladium catalyst, a phosphine ligand, and an alkali metal fluoride. - A method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond, characterized by reacting with nitropyridine.

（一般式（１）中、Ｒ^１は、水素原子、炭素数１～８の直鎖アルキル基、フェニル基、４－メトキシフェニル基を示し、Ｒ^２は水素原子又はフェニル基を示す）
で表されることを特徴とする、上記の炭素－炭素二重結合を形成する炭素に直結するカルボン酸フルオリド類の製造方法に係る。 Further, in the above invention, the present invention provides that the organic iodine compound has the following general formula (1).

(In general formula (1), R ¹ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a phenyl group, or a 4-methoxyphenyl group, and R ² represents a hydrogen atom or a phenyl group)
The present invention relates to a method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond as described above.

（一般式（３）中Ｒ^３は、水素原子、メチル基、メトキシ基、フッ素原子、塩素原子、臭素原子、トリフルオロメチル基、フェニル基、シアノ基、ニトロ基、（１，３－ジオキソイソインドリン－２－イル）メチル基、（１Ｓ，２Ｒ，５Ｓ）－２－イソプロピル－５－メチルシクロヘキシルオキシカルボニル基、４－（イソプロポキシカルボニル－イソプロピル－２－イルオキシ）ベンゾイル基、（（８Ｒ，９Ｓ，１３Ｓ，１４Ｓ）－１３－メチル－１７－オキソ－７，８，９，１１，１２，１３，１４，１５，１６，１７－デカヒドロ－６Ｈ－シクロペンタ［ａ］フェナントレン－３－イル）オキシカルボニル基、４－（フルオロカルボニル）ベンジルエステル ２－（１１－オキソ－６，１１－ジヒドロジベンゾ［ｂ，ｅ］オキセピン－２－イル）メチルカルボニルオキシメチル基、（Ａｌｌ－ｒａｃ）－４－（（（２，５，７，８－テトラメチル－２－（４，８，１２－トリメチルトリデシル）クロマン－６－イル）オキソ）メチル）基、（８Ｒ，９Ｓ，１０Ｒ，１３Ｓ，１４Ｓ，１７Ｒ）－１０，１３－ジメチル－３－オキソ－２，３，６，７，８，９，１０，１１，１２，１３，１４，１５，１６，１７－テトラデカヒドロ－１Ｈ－シクロペンタ［ａ］フェナントレン－１７－イル基、（１Ｒ）－（（２Ｓ，４Ｓ，５Ｒ）－４－（５－エチルキヌクリジン－２－イル）（６－メトキシキノリン－４－イル）メチルオキシカルボニル）基、又は４－（２－（ジエチルアミノ）エトキシカルボニル）基を示す）
で表されることを特徴とする、上記の炭素－炭素二重結合を形成する炭素に直結するカルボン酸フルオリド類の製造方法に係る。 Further, in the above invention, the present invention provides that the organic iodine compound has the following general formula (2).

(R ³ in general formula (3) is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a phenyl group, a cyano group, a nitro group, a (1,3-dioxo isoindolin-2-yl)methyl group, (1S,2R,5S)-2-isopropyl-5-methylcyclohexyloxycarbonyl group, 4-(isopropoxycarbonyl-isopropyl-2-yloxy)benzoyl group, ((8R, 9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy Carbonyl group, 4-(fluorocarbonyl)benzyl ester 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)methylcarbonyloxymethyl group, (All-rac)-4-( ((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl) group, (8R,9S,10R,13S,14S,17R )-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-17-yl group, (1R)-((2S,4S,5R)-4-(5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyloxycarbonyl) group, or 4-(2-(diethylamino)ethoxycarbonyl) group)
The present invention relates to a method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond as described above.

The present invention also provides the above invention in which the organic iodine compound is 2-iodothiophene, 2-iodobenzo[b]thiophene, 1-iodonaphthalene, 2-iodonaphthalene, 2-iodopyridine, 3-iodopyridine, or 4-iodopyridine. - A method for producing a carboxylic acid fluoride directly bonded to a carbon forming a carbon-carbon double bond, characterized in that it is iodopyridine.

であることを特徴とする上記の炭素－炭素二重結合を形成する炭素に直結するカルボン酸フルオリド類の製造方法に係る。 Further, in the above invention, the present invention provides that the organic iodine compound has the following formula (3).

The present invention relates to a method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond as described above.

であることを特徴とする上記の炭素－炭素二重結合を形成する炭素に直結するカルボン酸フルオリド類の製造方法に係る。 Further, in the above invention, the present invention provides that the organic iodine compound has the following formula (4).

The present invention relates to a method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond as described above.

According to the present invention, the iodine atom of organic iodine compounds having an iodine atom bonded to the carbon of various carbon-carbon double bonds can be converted into carboxylic acid fluoride, and further can be converted into various esters and amides. It became possible.
Additionally, compared to methods using carbon monoxide, which is highly toxic and requires a high-pressure container such as an autoclave, the reaction can be performed at normal pressure, making it a widely applicable carbonyl group introduction reaction.

The present invention will be explained in detail below.
Organic iodine compounds containing an iodine atom directly connected to carbon forming a carbon-carbon double bond that can be applied to the present invention are compounds in which an iodine atom is directly connected (directly bonded) to carbon forming various double bonds. If so, it is applicable without particular limitation. Furthermore, even if there are multiple carbon-carbon double bonds in one molecule, if an iodine atom is directly connected to the carbon that forms the carbon-carbon double bond, the reaction can be performed with multiple iodine atoms. be able to.
That is, as organic iodine compounds that can be applied to the production method of the present invention, compounds represented by the above-mentioned general formulas (1) and (2), 2-iodothiophene, 2-iodobenzo[b]thiophene, 1- Examples include iodonaphthalene, 2-iodonaphthalene, 2-iodopyridine, 3-iodopyridine, 4-iodopyridine, and the compounds represented by the above formulas (3) and (4).

Specific examples of the organic iodine compounds represented by general formula (1) and general formula (2) include 2-iodothiophene, 2-iodobenzothiophene, 1-iodonaphthalene, 2-iodonaphthalene, 2-iodothiophene, and 2-iodobenzothiophene. Iodopyridine, 3-iodopyridine, 4-iodopyridine, iodoethylene, 1-iodo-1-propene, 1-iodo-1-butene, 1-iodo-1-pentene, 1-iodo-1-hexene, 1- Iodo-1-heptene, 1-iodo-1-octene, 1-iodo-1-nonene, 1-iodo-1-decene, β-iodostyrene, β-iodo-4-methoxystyrene, α-iodostyrene, iodo Benzene, 2-iodotoluene, 3-iodotoluene, 4-iodotoluene, 2-iodoanisole, 3-iodoanisole, 4-iodoanisole, 1-fluoro-2-iodobenzene, 1-fluoro-3-iodobenzene, 1-fluoro-4-iodobenzene, 1-chloro-2-iodobenzene, 1-chloro-3-iodobenzene, 1-chloro-4-iodobenzene, 1-bromo-2-iodobenzene, 1-bromo-3 -Iodobenzene, 1-bromo-4-iodobenzene, 2-iodobenzotrifluoride, 3-iodobenzotrifluoride, 4-iodobenzotrifluoride, 2-iodobiphenyl, 3-iodobiphenyl, 4-iodobiphenyl, 1 -Cyano-2-iodobenzene, 1-cyano-3-iodobenzene, 1-cyano-4-iodobenzene, 1-((1,3-dioxoisoindolin-2-yl)methyl)-4-iodobenzene , 4-iodobenzoic acid (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl ester, 4-(isopropoxycarbonyl-isopropyl-2-yloxy)-4'-iodobenzophenone, 4-iodobenzoic acid ( 8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl Ester, (11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid 4-iodobenzyl ester, 1-(All-rac)-4-(((2,5,7, 8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl)-4-iodobenzene, 4-iodobenzoic acid (8R,9S,10R,13S,14S, 17R)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a ] Phenanthren-17-yl ester, 4-iodobenzoic acid (1R)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)-(6-methoxyquinolin-4-yl))methyl Ester, 4-iodobenzoic acid 2-(diethylamino)ethyl ester, 1-benzyl-4-iodo-1H-pyrazole, (8R,9S,13S,14S)-13-methyl-17-oxo-3-iodo-7 , 8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene and the like.

Specific examples of acid fluorides that can be produced in the present invention include thiophene-2-carboxylic acid fluoride, benzo[b]thiophene-2-carboxylic acid fluoride, naphthalene-1-carboxylic acid fluoride, and naphthalene-2-carboxylic acid fluoride. Carboxylic acid fluoride, picolinic acid fluoride, nicotinic acid fluoride, isonicotinic acid fluoride, acrylic acid fluoride, crotonic acid fluoride, 2-pentenoic acid fluoride, 2-hexenoic acid fluoride, 2-heptenoic acid fluoride, 2-octenoic acid fluoride, 2 -Nonenic acid fluoride, 2-decenoic acid fluoride, 2-undecenoic acid fluoride, cinnamic acid fluoride, 4-methoxycinnamic acid fluoride, 2-phenylacrylic acid fluoride, benzoic acid fluoride, 2-methylbenzoic acid fluoride, 4- Methylbenzoic acid fluoride, 4-methylbenzoic acid fluoride, 2-methoxybenzoic acid fluoride, 3-methoxybenzoic acid fluoride, 4-methoxybenzoic acid fluoride, 2-fluorobenzoic acid fluoride, 3-fluorobenzoic acid fluoride, 4-fluoro Benzoic acid fluoride, 2-chlorobenzoic acid fluoride, 3-chlorobenzoic acid fluoride, 4-chlorobenzoic acid fluoride, 2-bromobenzoic acid fluoride, 3-bromobenzoic acid fluoride, 4-bromobenzoic acid fluoride, 2-(tribenzoic acid fluoride) fluoromethyl)benzoic acid fluoride, 3-(trifluoromethyl)benzoic acid fluoride, 4-(trifluoromethyl)benzoic acid fluoride, biphenyl-2-carboxylic acid fluoride, biphenyl-3-carboxylic acid fluoride, biphenyl-4-carboxylic acid fluoride Acid fluoride, 2-cyanobenzoic acid fluoride, 3-cyanobenzoic acid fluoride, 4-cyanobenzoic acid fluoride, 4-((1,3-dioxoisoindolin-2-yl)methyl)benzoic acid fluoride, ⁾ 4- (Fluorocarbonyl)benzoic acid (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl ester, 2-(4-(4-(fluorocarbonyl)benzoyl)phenoxy)-2-methylpropionic acid isopropyl ester, 4 -(Fluorocarbonyl)benzoic acid ((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Cyclopenta[a]phenanthren-3-yl) ester, (11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid 4-(fluorocarbonyl)benzyl ester, (All-rac) -4-(((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl)benzoic acid fluoride, (All-rac)- 4-(((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl)benzoic acid fluoride, 4-fluorocarbonylbenzoic acid ( 1R)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)-(6-methoxyquinolin-4-yl))methyl ester, 2-(diethylamino)ethyl 4-fluorocarbonylbenzoate Ester, 1-benzyl-1H-pyrazole-4-carboxylic acid fluoride, (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15, Examples include 16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-carbonyl fluoride.

The production of 2-difluoromethoxy-5-nitropyridine used as the fluorocarbonylating agent of the present invention can be carried out, for example, using 2-hydroxy-5-nitropyridine as a raw material in the presence of sodium hydride. It can be easily prepared by reacting -(fluorosulfonyl)acetic acid.
The amount of 2-difluoromethoxy-5-nitropyridine used in the present invention is preferably 1.0 mol to 3.0 mol per 1 mol of the organic iodine compound used in the reaction.

Specific examples of palladium catalysts to which the present invention can be applied include palladium (II) chloride (PdCl ₂ ), palladium (II) bromide (PdBr ₂ ), and palladium (II) acetate (Pd(OAc) ₂ ). , palladium(II) trifluoroacetate (Pd(TFA) ₂ ), bis(acetonitrile)palladium(II) dichloride (PdCl ₂ (NeCN) ₂ ), bis(dibenzylideneacetone)palladium(0) (Pd(dba) ₂ ), allylpalladium chloride (II) (dimer) ((PdCl(allyl)) ₂ ), bis(hexafluoroacetylacetone)palladium(0) (Pd(C ₅ HF ₆ O ₂ ) ₂ ), tris(dibenzylideneacetone) Examples include dipalladium (0) (Pd ₂ (dba) ₃ ), and it is preferably used in an amount of 0.001 mol to 0.300 mol per mol of the organic iodine compound used in the reaction.

Specific examples of the ligand applicable to the present invention include triphenylphosphine (PPh ₃ ), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), bis[2 -(diphenylphosphino)phenyl]ether (DPEphos), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP), bis[1,2-bis(diphenyl) phosphino)ethane] (DPPE), tri(2-furyl)phosphine (TFP), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (Xphos), tricyclohexylphosphine (PCy ₃ ), tri-o-tolylphosphine (P(o-Tol) ₃ ), tricyclopentylphosphine (Pcyp ₃ ), etc., and in terms of the number of phosphorus atoms contained per mol of the palladium catalyst used, It is preferable to use 1.0 mol to 5.0 mol.

Examples of the alkali metal fluoride applicable to the present invention include potassium fluoride and cesium fluoride, which are 1.0 mol to 5.0 mol per mol of the organic iodine compound used in the reaction. It is best to use the appropriate amount.

The solvent applicable to the present invention is not particularly limited as long as it is inert to the reaction, but preferably dimethyl sulfoxide (DMSO), acetonitrile (MeCN), N,N-dimethylformamide (DMF), N , N-dimethylacetamide (DMAc), preferably used in an amount of 5 times to 400 times the weight of the organic iodine compound used in the reaction.

The reaction temperature and time of the present invention vary depending on the type of organic iodine compound, the type of catalyst, the type of alkali metal fluoride, and the type of solvent, but are usually in the temperature range of 10°C to 120°C for 5 hours to 20 hours. Once the reaction is carried out, the reaction is complete.

The post-treatment after the production of the present invention can be carried out by a well-known method. For example, the desired carboxylic acid fluoride can be obtained by directly purifying the reaction product by silica gel column chromatography. In addition, the carboxylic acid fluoride obtained in the present invention has high reaction activity and can easily react with various nucleophiles. It can serve as an intermediate that can be derived into various compounds, such as into amides.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

The following equipment was used for the analysis.
¹ H-NMR (300 MHz), ¹⁹ F-NMR (282 MHz), ¹³ C-NMR (126 MHz): Buruker Avance 500, or Varian Mercury 300.
ESI-MS: Shimadzu LCMS-2020EV (SHIMADZU LCMS-2020EV).
EI-MS: JMS-Q1050GC Master-Quad GC/MS manufactured by JEOL.
HRMS (ESI-MS): Waters Synapt G2 HDMS.
HRMS (EI-MS): Shimadzu GCMS-QP5050A.
IR: JASCO FT/IR-4100 spectrometer.
Melting point: BUCHI M-565.

撹拌子を備えた１００ｍＬの丸底フラスコに、窒素気流下、２－ヒドロキシ－５－ニトロピリジン（Ｓ９）（０．７００ｇ，５．０ｍｍｏｌ）及び無水アセトニトリル（５０ｍＬ）を仕込んだ後、水素化ナトリウム（６０％－ミネラルオイル含侵品，５４０ｍｇ，１３．５ｍｍｏｌ）を添加し、室温下、１５分攪拌した。次いで２，２－ジフルオロ－２－（フルオロスルホニル）酢酸（Ｓ１０，０．８８ｍＬ，８．５ｍｍｏｌ）を滴下し、１５分攪拌した。
反応終了後、水（１０ｍＬ）をゆっくり添加した後、減圧下、アセトニトリルを留去し、得られた残査を酢酸エチルで抽出、飽和食塩水で洗浄、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物を、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１ ｖｏｌ／ｖｏｌ）で精製することにより目的物の２－（ジフルオロメトキシ）－５－ニトロピリジン（２）（０．８５５ｇ，収率９０％）を白色固体として得た。 Reference Example 1 Preparation of 2-(difluoromethoxy)-5-nitropyridine (2)

In a 100 mL round bottom flask equipped with a stirrer, 2-hydroxy-5-nitropyridine (S9) (0.700 g, 5.0 mmol) and anhydrous acetonitrile (50 mL) were charged under a nitrogen stream, and then sodium hydride was added. (60% mineral oil impregnated product, 540 mg, 13.5 mmol) was added and stirred at room temperature for 15 minutes. Then, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (S10, 0.88 mL, 8.5 mmol) was added dropwise and stirred for 15 minutes.
After the reaction was completed, water (10 mL) was slowly added, and the acetonitrile was distilled off under reduced pressure. The resulting residue was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. A crude product was obtained by doing this. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 9/1 vol/vol) to obtain the target product, 2-(difluoromethoxy)-5-nitropyridine (2) (0 .855 g, yield 90%) was obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.10 (d, J = 2.8 Hz, 1 H), 8.54 (dd, J = 9.0, 2.8 Hz, 1 H), 7.53 ( t, J = 71.6Hz, 1H), 7.05 (d, J = 9.0Hz 1H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: -90.122 (d, J=72.8 Hz, 2F) ppm.
^13C NMR (126MHz, _CDCl3 ) δ: 162.0 (t, J = 4.0Hz), 144.2, 141.6, 135.5, 113.7 (t, J = 258.9Hz), 111 .8ppm.
_HRMS (TOF/EI ⁺ ): _{Calculated for C6H4F2N2O3} ⁺ : 190.0190, found _: 190.0189.
IR (NaCl): 1527, 1346, 1346, 1268, 1134 ^{, 1076 cm −1} .
Melting point: 31.8-32.7°C.

窒素グローブボックス中で、撹拌子を備えた１０ｍＬのスクリューキャップ付きガラス容器に、トリフルオロ酢酸パラジウム（Ｐｄ（ＴＦＡ）_２，３．３ｍｇ，０．０１０ｍｍｏｌ，１０．０ｍｏｌ％）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（キサントホス，Ｘａｎｔｐｈｏｓ，８．７ｍｇ，０．０１５ｍｍｏｌ，１５．０ｍｏｌ％）、フッ化セシウム（３０．４ｍｇ，０．２０ｍｍｏｌ，２．０ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ，１．５ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（２）（３８．０ｍｇ，０．２０ｍｍｏｌ，２．０ｅｑ．）及び４－ヨードビフェニル（１ａ）（２８．０ｍｇ，０．１０ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却し、フルオロベンゼンを内部標準物質として用いた^１９Ｆ－ＮＭＲの測定で、収率は＞９９％であった。
反応生成物は、直接シリカゲルカラムクロマトグラフィー（内径２ｃｍ×高さ１０ｃｍ）（ｎ－ヘキサン／酢酸エチル＝５０／１ ｖｏｌ／ｖｏｌ）で精製することにより、目的物のビフェニル－４－カルボン酸フルオリド（３ａ）（１８．４ｍｇ，収率９２％）を白色固体として得た。 Example 1 Preparation of biphenyl-4-carboxylic acid fluoride (3a)

In a nitrogen glove box, palladium trifluoroacetate (Pd(TFA) ₂ , 3.3 mg, 0.010 mmol, 10.0 mol%), 4,5-bis (Diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 8.7 mg, 0.015 mmol, 15.0 mol%), cesium fluoride (30.4 mg, 0.20 mmol, 2.0 eq.) and anhydrous N,N-dimethylformamide (DMF, 1.5 mL) was charged, and after stirring for 10 minutes, 2-difluoromethoxy-5-nitropyridine (2) (38.0 mg, 0.20 mmol, 2.0 eq) was added to this. ) and 4-iodobiphenyl (1a) (28.0 mg, 0.10 mmol) were added, and the cap was closed to seal. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed, the reaction mixture was cooled to room temperature, and ¹⁹ F-NMR measurement using fluorobenzene as an internal standard showed that the yield was >99%.
The reaction product was directly purified by silica gel column chromatography (inner diameter 2 cm x height 10 cm) (n-hexane/ethyl acetate = 50/1 vol/vol) to obtain the target biphenyl-4-carboxylic acid fluoride ( 3a) (18.4 mg, yield 92%) was obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.13-8.10 (m, 2H), 7.76-7.73 (m, 2H), 7.65-7.63 (m, 2H) , 7.53-7.41 (m, 3H) ppm.
^19F -NMR (282MHz, CDCl3) δ: 17.65 (s, 1F) ppm.
MS (EI, m/z): 200 [M] ⁺ .

実施例１と同じ反応装置を用い、表１中に示した触媒（Ｃａｔ）、配位子（Ｌｉｇａｎｄ）及び塩基（Ｂａｓｅ）を替え、反応を行った。結果を表１中に示した。 Examples 2-21 Preparation of biphenyl-4-carboxylic acid fluoride (3a)

Using the same reaction apparatus as in Example 1, the reaction was carried out by changing the catalyst (Cat), ligand (Ligand), and base (Base) shown in Table 1. The results are shown in Table 1.

¹⁾ Indicates the molar ratio of palladium atoms and phosphorus atoms.
²⁾ Quantitative values obtained by ¹⁹ F-NMR using fluorobenzene of the reaction solution as an internal standard are shown. The numbers in parentheses indicate isolated yields.
³⁾ Indicates the abbreviation for palladium trifluoroacetate.
⁴⁾ Indicates the abbreviation for bis[2-(diphenylphosphino)phenyl]ether.
⁵⁾ Indicates the abbreviation for (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.
⁶⁾ Indicates the abbreviation for bis[1,2-bis(diphenylphosphino)ethane].
⁷⁾ Indicates the abbreviation for tri(2-furyl)phosphine.
⁸⁾ Indicates the abbreviation for 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl.
⁹⁾ Indicates the abbreviation for tricyclohexylphosphine.
¹⁰⁾ Indicates the abbreviation for tri-o-tolylphosphine.
¹¹⁾ Indicates the abbreviation for triphenylphosphine.
¹²⁾ Indicates the abbreviation for palladium acetate.
¹³⁾ Indicates the abbreviation for bis(acetonitrile)palladium(II) dichloride.
¹⁴⁾ Indicates the abbreviation for bis(dibenzylideneacetone)palladium(0).
¹⁵⁾ Indicates the abbreviation for allylpalladium chloride (II) (dimer).
¹⁶⁾ Indicates the abbreviation for tetrakis(triphenylphosphine)palladium(0).
¹⁷⁾ Indicates the abbreviation for bis(hexafluoroacetylacetone)palladium(0).
¹⁸⁾ Indicates the abbreviation for tris(dibenzylidene)dipalladium(0).

実施例１と同じ装置を用い、２－ジフルオロメトキシ－５－ニトロピリジン（２）（Ｘｅｑ．）、トリフルオロ酢酸パラジウム（Ｙｍｏｌ％）及びセシウムフルオリド（Ｚｅｑ．）の量を、表２に示した量に変更した以外、実施例１と同じ反応操作を行った。なお、キサントホスの使用量は、パラジウム原子：リン原子比が、１：３となる量添加し、反応を行い目的物のビフェニル－４－カルボン酸フルオリド（３ａ）を得た。また、実施例２７～３３は、４－ヨードビフェニル（１ａ）（８４．０ｍｇ，０．３０ｍｍｏｌ）及びＮ，Ｎ－ジメチルホルムアミド（４．５ｍＬ）を使用し反応を行った。結果を表２中に示した。 Examples 21-33 Preparation of biphenyl-4-carboxylic acid fluoride (3a)

Using the same apparatus as in Example 1, the amounts of 2-difluoromethoxy-5-nitropyridine (2) (Xeq.), palladium trifluoroacetate (Ymol%) and cesium fluoride (Zeq.) are shown in Table 2. The same reaction operation as in Example 1 was performed except that the amount was changed. The amount of xanthophos used was such that the ratio of palladium atoms to phosphorus atoms was 1:3, and the reaction was carried out to obtain the target product, biphenyl-4-carboxylic acid fluoride (3a). Furthermore, in Examples 27 to 33, reactions were carried out using 4-iodobiphenyl (1a) (84.0 mg, 0.30 mmol) and N,N-dimethylformamide (4.5 mL). The results are shown in Table 2.

実施例１と同じ反応装置を用い、４－ヨードビフェニル（１ａ）（８４．０ｍｇ，０．３０ｍｍｏｌ）、２－ジフルオロメトキシ－４－ニトロピリジン（２）（６８．０ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）、キサントホス（２．６ｍｇ，０．００１５ｍｍｏｌ，１．５ｍｏｌ％）及び表３に示した溶剤を４．５ｍＬ使用た以外、実施例１と同じ反応操作を行い、目的物のビフェニル－４－カルボン酸フルオリド（３ａ）を得た。結果を表３中に示した。

Examples 34-36 Preparation of biphenyl-4-carboxylic acid fluoride (3a)

Using the same reaction apparatus as in Example 1, 4-iodobiphenyl (1a) (84.0 mg, 0.30 mmol), 2-difluoromethoxy-4-nitropyridine (2) (68.0 mg, 0.36 mmol, 1. 4.5 mL of the solvents shown in Table 3 were used. Except for this, the same reaction operation as in Example 1 was performed to obtain the target product, biphenyl-4-carboxylic acid fluoride (3a). The results are shown in Table 3.

実施例１と同じ反応装置を用い、４－ヨードビフェニル（１ａ）（８４．０ｍｇ，０．３０ｍｍｏｌ）、２－ジフルオロメトキシ－４－ニトロピリジン（２）（６８．０ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）、キサントホス（２．６ｍｇ，０．００１５ｍｍｏｌ，１．５ｍｏｌ％）を使用し、Ｎ，Ｎ－ジメチルホルムアミドの使用量、反応温度及び反応時間を替えた以外、、実施例１と同じ反応操作を行った。結果を表４中に示した。

Examples 37-43 Preparation of biphenyl-4-carboxylic acid fluoride (3a)

Using the same reaction apparatus as in Example 1, 4-iodobiphenyl (1a) (84.0 mg, 0.30 mmol), 2-difluoromethoxy-4-nitropyridine (2) (68.0 mg, 0.36 mmol, 1. 2eq.), cesium fluoride (68.4mg, 0.45mmol, 1.5eq.), xanthophos (2.6mg, 0.0015mmol, 1.5mol%), and the amount of N,N-dimethylformamide used. The same reaction operation as in Example 1 was carried out except that the reaction temperature and reaction time were changed. The results are shown in Table 4.

窒素グローブボックス中で、撹拌子を備えた１０ｍＬのスクリューキャップ付きガラス容器に、トリフルオロ酢酸パラジウム（Ｐｄ（ＴＦＡ）_２，３．３ｍｇ，０．０１０ｍｍｏｌ，１０．０ｍｏｌ％）、キサントホス（８．７ｍｇ，０．０１５ｍｍｏｌ，１５．０ｍｏｌ％）、フッ化セシウム（９１．１ｍｇ，０．６０ｍｍｏｌ，２．０ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ，２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロベンゼン（２） （８５．１ｍｇ，０．４５ ｍｍｏｌ，１．５ ｅｑ．）及びヨードベンゼン（１ｂ） （６１．２ｍｇ，０．３ ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却し、フルオロベンゼンを内部標準物質として用いた^１９Ｆ－ＮＭＲの測定で、収率は＞９９％であった。
反応生成物は、直接シリカゲルカラムクロマトグラフィー（内径２ｃｍ×高さ１０ｃｍ）（ｎ－ヘキサン／酢酸エチル＝５０／１ ｖｏｌ／ｖｏｌ）で精製することにより、目的物の安息香酸フルオリド（３ｂ）（１０．１ｍｇ，収率２７％）を無色透明液体として得た。 Example 44 Preparation of benzoic acid fluoride (3b)

In a nitrogen glove box, palladium trifluoroacetate (Pd(TFA) ₂ , 3.3 mg, 0.010 mmol, 10.0 mol%), xanthophos (8.7 mg , 0.015 mmol, 15.0 mol%), cesium fluoride (91.1 mg, 0.60 mmol, 2.0 eq.) and anhydrous N,N-dimethylformamide (DMF, 2.0 mL), and stirred for 10 minutes. Then, 2-difluoromethoxy-5-nitrobenzene (2) (85.1 mg, 0.45 mmol, 1.5 eq.) and iodobenzene (1b) (61.2 mg, 0.3 mmol) were added to this. The solution was added and the cap was closed to seal the container. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed, the reaction mixture was cooled to room temperature, and ¹⁹ F-NMR measurement using fluorobenzene as an internal standard showed that the yield was >99%.
The reaction product was directly purified by silica gel column chromatography (inner diameter 2 cm x height 10 cm) (n-hexane/ethyl acetate = 50/1 vol/vol) to obtain the target product, benzoic acid fluoride (3b) (10 cm). .1 mg, yield 27%) was obtained as a colorless transparent liquid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.05 (d, J = 7.7 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.58-7.46 ( m, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.63 (s, 1F) ppm.
MS (EI, m/z): 124 [M] ⁺ .

窒素グローブボックス中で、撹拌子を備えた１０ｍＬのスクリューキャップ付きガラス容器に、トリフルオロ酢酸パラジウム（Ｐｄ（ＴＦＡ）_２，１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ，２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロベンゼン（２） （６８．０ｍｇ，０．３６ｍｍｏｌ，１．５ ｅｑ．）及び４－ヨードトルエン（１ｃ） （６５．４ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却し、フルオロベンゼンを内部標準物質として用いた^１９Ｆ－ＮＭＲの測定で、収率は９２％であった。
反応生成物は、直接シリカゲルカラムクロマトグラフィー（内径２ｃｍ×高さ１０ｃｍ）（ｎ－ヘキサン／酢酸エチル＝５０／１ ｖｏｌ／ｖｏｌ）で精製することにより、目的物の安息香酸フルオリド（３ｃ）（３１．９ｍｇ，収率７７％）を無色透明液体として得た。 Example 45 Preparation of 4-methylbenzoic acid fluoride (3c)

In a nitrogen glove box, palladium trifluoroacetate (Pd(TFA) ₂ , 1.0 mg, 0.003 mmol, 1.0 mol%), xanthophos (2.6 mg , 0.0045 mmol, 1.5 mol%), cesium fluoride (68.4 mg, 0.45 mmol, 1.5 eq.) and anhydrous N,N-dimethylformamide (DMF, 2.0 mL), and stirred for 10 minutes. Then, 2-difluoromethoxy-5-nitrobenzene (2) (68.0 mg, 0.36 mmol, 1.5 eq.) and 4-iodotoluene (1c) (65.4 mg, 0.3 mmol) were added to this. The solution was added and the cap was closed to seal the container. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed, the mixture was cooled to room temperature and measured by ¹⁹ F-NMR using fluorobenzene as an internal standard, and the yield was 92%.
The reaction product was directly purified by silica gel column chromatography (inner diameter 2 cm x height 10 cm) (n-hexane/ethyl acetate = 50/1 vol/vol) to obtain the target product, benzoic acid fluoride (3c) (31 .9 mg, yield 77%) was obtained as a colorless transparent liquid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.93 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 2.45 (s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 16.96 (s, 1F) ppm.
MS (EI, m/z): 138 [M] ⁺ .

Examples 46 to 71 Preparation of various carboxylic acid fluorides Using the same reaction apparatus as in Example 44, using the method (A) described in Example 45 or the method (B) described in Example 44, the raw materials were changed. Various carboxylic acid fluorides were prepared.
The results are shown in Table 5.

¹⁾ Quantitative values obtained by ¹⁹ F-NMR using fluorobenzene of the reaction solution as an internal standard are shown. The numbers in parentheses indicate isolated yields.
²⁾ 4-methoxybenzoic acid fluoride (3d)
Colorless transparent liquid.
1H-NMR (300 MHz, CDCl3) δ: 7.99 (d, J = 6.9 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H) ppm.
19F-NMR (282MHz, CDCl3) δ: 15.49 (s, 1F) ppm.
MS (EI, m/z): 154 [M] ⁺ .
³⁾ 4-fluorocarbonylbenzoic acid methyl ester (3e)
White crystal.
¹ H-NMR (300 MHz, CDCl3) δ: 8.20-8.11 (m, 4H), 3.98 (s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.61 (s, 1F) ppm.
MS (EI, m/z): 182 [M] ⁺ .
⁴⁾ 4-(trifluoromethyl)benzoic acid fluoride (3f)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.19 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.51 (s, 1F), -63.97 (s, 3F) ppm.
MS (EI, m/z): 192 [M] ⁺ .
⁵⁾ 4-chlorobenzoic acid fluoride (3g)
Pale yellow solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.01-7.79 (m, 2H), 7.53-7.50 (m, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.95 (s, 1F) ppm.
MS (EI, m/z): 157 [M] ⁺ .
⁶⁾ 4-bromobenzoic acid fluoride (3h)
White crystal.
¹ H-NMR (300 NHZ, CDCl ₃ ) δ: 7.91 (d, J=7.8 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H) ppm.
¹⁹ F-NMR (282 NHZ, CDCl ₃ ) δ: 17.93 (s, 1 F) ppm.
MS (EI, m/z): 202 [M] ⁺ .
⁷⁾ 4-fluorobenzoylbenzoic acid fluoride (3i)
Colorless transparent liquid.
1H-NMR (300Hz, CDCl3) δ: 8.11-8.07 (m, 2H), 7.25-7.19 (m.2H) ppm.
19F-NMR (282MHz, CDCl3) δ: 17.54 (s, 1F), -100.99--101.05 (m, 1F) ppm.
MS (EI, m/z): 142 [M] ⁺ .
⁸⁾ 3-fluorobenzoic acid fluoride (3j)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ; 7.87 (d, J = 7.7 Hz, 1H), 7.75-7.71 (m, 1H), 7.57-7.50 (m, 1H), 7.46-7.39 (m, 1H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 18.90 (d, J=4.5 Hz, 1F), -110.00--111.06 (m, 1F) ppm.
MS (EI, m/z): 142 [M] ⁺ .
⁹⁾ 3-Methylbenzoic acid fluoride (3k)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.87-7.85 (m, 2H), 7.51 (d, 1H), 7.42 (t, 1H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.77 (s, 1F) ppm.
MS (EI, m/z): 138 [M] ⁺ .
¹⁰⁾ 2-Methylbenzoic acid fluoride (3l)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.00 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H), 7.34 (d, J = 6.3Hz, 2H), 2.65(s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 28.77 (s, 1F) ppm.
MS (EI, m/z): 138 [M] ⁺ .
¹¹⁾ 2-naphthalenecarboxylic acid fluoride (3m)
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.62 (s, 1H), 8.01-7.90 (m, 4H), 7.70-7.58 (m, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.56 ppm.
MS (EI, m/z): 174 [M] ⁺ .
¹²⁾ 1-naphthalenecarboxylic acid fluoride (3n)
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ; 9.01 (d, J = 8.7 Hz, 1H), 8.34 (d, J = 7.4 Hz, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.93 (d, J = 8.2Hz, 1H), 7.70 (t, J = 7.4Hz, 1H), 7.62-7.52 (m, 2H) ppm .
¹⁹ F-NMR (282 NHZ, CDCl ₃ ) δ: 29.38 (s, 1 F) ppm.
MS (EI, m/z): 174 [M] ⁺ .
¹³⁾ (E)-Cinnamic acid fluoride (3o)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.84 (d, J = 16.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.51-7.41 (m, 3H), 6.37 (dd, J=16.0, 7.4Hz, 1H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 25.10 (d, J=7.4 Hz, 1F) ppm.
MS (EI, m/z): 150 [M] ⁺ .
¹⁴⁾ (E)-4-methoxycinnamic acid fluoride (3p)
White crystal.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.78 (d, J = 15.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.7Hz, 2H), 6.21 (dd, J=15.9, 7.4Hz, 1H), 3.86 (s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 23.19 (d, J=7.6 Hz, 1F) ppm.
MS (EI, m/z): 180 [M] ⁺ .
¹⁵⁾ Thiophene-2-carboxylic acid fluoride (3q)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.95-7.92 (m, 1H), 7.82-7.79 (m, 1H), 7.23-7.19 (m, 1H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 23.88 (s, 1F) ppm.
MS (EI, m/z): 130 [M] ⁺ .

¹⁶⁾ Benzo[b]thiophene-2-carboxylic acid fluoride (3r)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.21 (s, 1H), 7.96-7.89 (m, 2H), 7.58-7.45 (m, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 24.58 (s, 1F) ppm.
MS (EI, m/z): 180 [M] ⁺ .
¹⁷⁾ 4-((1,3-dioxoisoindolin-2-yl)methyl)benzoic acid fluoride (3s)
Pale yellow solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.03-7.99 (m, 2H), 7.90-7.86 (m, 2H), 7.78-7.74 (m, 2H) , 7.59-7.55 (m, 2H), 4.93 (s, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.63 ppm.
^13C -NMR (126MHz, _CDCl3 ) δ: 167.7, 156.9 (d, J = 344.1Hz), 143.9, 134.2, 131.83, 131.79, 128.9, 124 .3 (d, J=61.4Hz), 123.5, 41.1ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₁₆ H ₁₀ FNO ₃ ⁺ : 283.0645, found: 283.0638.
IR (NaCl): 1805, 1718, 1610, 1429, 1392, 1333, 1292, 1242, 1186, 1105, 1088, 1028, 1007, 943, 781, 723 ^{, 586 cm -1} .
Melting point: 152.5-153.5°C.
¹⁸⁾ 1-benzyl-1H-pyrazole-4-carboxylic acid fluoride (3t)
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.01 (s, 1H), 7.94 (s, 1H), 7.40-7.37 (m, 3H), 7.29-7.27 (m, 2H), 5.33 (s, 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 26.09 (s, 1F) ppm.
^13C -NMR (126Hz, CDCl ₃ ) δ: 152.8 (d, J = 329.4 Hz), 142.7 (d, J = 3.6 Hz), 134.6 (d, J = 3.8 Hz) , 134.3, 129.2, 128.9, 128.2, 109.3 (d, J = 73.8 Hz), 56.8 ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₁₁ H ₉ FN ₂ O ⁺ : 204.0699, found: 204.0692.
IR (NaCl): 1807, 1547, 1496, 1455, 1392, 1360, 1205, 1173, 1063, 989, 955, 879, 748, 729, 704, 609, 517, ^{496 cm −1} .
Melting point: 43.9-45.1°C.
¹⁹⁾ 2-phenylacrylic acid fluoride (3u)
Colorless transparent liquid.
1H-NMR (300MHz, CDCl3) δ: 7.47-7.45 (m, 2H), 7.41-7.39 (m, 2H), 6.60 (s, 1H), 6.28 (d , J=1.5Hz, 1H), ppm.
19F-NMR (282MHz, CDCl3) δ: 22.47 (s, 1F) ppm.
13C-NMR (126MHz, CDCl3) δ: 156.3 (d, J = 350.6Hz), 136.7 (d, J = 56.3Hz), 134.4 (d, J = 3.3Hz), 133 .0, 129.1, 128.5, 128.1 (d, J = 1.8 Hz) ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₉ H ₇ FO ⁺ : 150.0481, found: 150.0482.
IR (NaCl): 1811, 1275, 1261, 750, 480, 463, 440, 428, 413, ^{401 cm −1} .
²⁰⁾ (E)-2-nonenoic acid fluoride (3v)
Colorless transparent liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.19 (dd, J = 15.6, 7.0 Hz, 1H), 5.80 (ddd. J = 15.7, 8.4, 1.7 Hz , 1H), 2.28 (dq, J = 7.2, 1.6Hz, 2H), 1.49 (dd, J = 10.2, 4.5Hz, 2H), 1.33-1.28 ( m, 6H), 0.89 (t, J=6.0Hz, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 24.48 (d, J=8.5 Hz, 1F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 157.8 (d, J = 5.7 Hz), 156.5 (d, J = 340.7 Hz), 116.0 (d, J = 64.9 Hz) , 32.7, 31.5, 28.8, 27.5, 22.5, 14.0 ppm.
HRMS (TOF/EI): Calculated for _C9H15FO ⁺ : _158.1107 , found: 158.1104.
IR (NaCl): 3901, 3869, 3820, 3749, 3647, 2925, 2854, 1811, 1649, 1541, 669, 577, 490, 442 ^{cm −1} .
²¹⁾ 4-(fluorocarbonyl)benzoic acid (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl ester (3w)
Colorless transparent viscous liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.20-8.10 (m, 4H), 4.98 (ddd, J=10.9, 4.3Hz, 1H), 2.16-2. 08 (m, 1H), 1.97-1.88 (m, 1H), 1.78-1.69 (m, 2H), 1.63-1.51 (m, 2H), 1.20- 1.10 (m, 3H), 0.98-0.90 (m, 6H), 0.80 (d, J=7.0Hz, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ; 19.53 (s, 1F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 164.6, 156.6 (d, J = 345.7 Hz), 136.7, 131.3 (d, J = 3.5 Hz), 130.0, 128.3 (d, J=61.5Hz), 75.9, 47.2, 40.8, 34.2, 31.4, 26.5, 23.6, 22.0, 20.7, 16 .5ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₁₈ H ₂₃ FO ₃ ⁺ : 306.1631, found: 306.1624.
IR (NaCl): 2956, 2871, 1819, 1720, 1238, 1107, 1034, 1011, 982, 779, 721, 519, 503, 455 ^{cm -1} .
²²⁾ 2-(4-(4-(fluorocarbonyl)benzoyl)phenoxy)-2-methylpropionic acid isopropyl ester (3x)
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.16 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.6Hz, 2H), 6.89-6.86 (m, 2H), 5.09 (septet, J=6.3Hz, 1H), 1.67 (s, 6H), 1.21 (d, J=6.3Hz, 6H)ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.28 (s, 1F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 194.0, 172.9, 160.3, 156.6 (d, J = 345.2 Hz), 144.2, 132.1, 131.3 (d , J = 3.5 Hz), 129.7, 129.3, 127.3 (d, J = 61.7 Hz), 79.5, 69.4, 25.3, 21.5 ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₂₁ H ₂₁ FO ₅ ⁺ : 372.1373, found: 372.1373.
IR (NaCl): 2986, 2939, 1815, 1730, 1650, 1597, 1284, 1250, 1178, 1146, 1103, 1031, 1009, 930, 704, 488, 461, 449 ^{, 440 cm -1} .
Melting point: 107.3-108.4°C.

²³⁾ (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene -3-carbonyl fluoride (3y)
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.82-7.77 (m, 2H), 7.44 (d, J=8.1Hz, 1H), 3.01-2.95 (m, 2H), 2.58-2.43 (m, 2H), 2.41-2.33 (m, 1H), 2.23-2.14 (m, 1H), 2.12-1.98 ( m, 3H) 1.70-1.45 (m, 6H), 0.93 (s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.30 (s, 1F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 157.5 (d, J = 343.2 Hz), 148.0, 137.6, 132.0 (d, J = 3.8 Hz), 128.6 ( d, J = 3.5 Hz), 126.1, 122.1 (d, J = 60.5 Hz), 50.4, 47.8, 44.7, 37.5, 35.7, 31.4, 29.0, 26.0, 25.4, 21.5, 13.7ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₁₉ H ₂₁ FO ₂ ⁺ : 300.1526, found: 300.1532.
IR (NaCl): 2927, 2860, 1801, 1735, 1606, 1241, 1086, 1032, 1009, 787, 739, 490, 480, 465, 449 ^{cm −1} .
Melting point: 206.5-207.6°C.
²⁴⁾ 4-(Fluorocarbonyl)benzoic acid ((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthren-3-yl) ester (3z).
White solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.34 (d, J=8.7 Hz, 2H), 8.20-8.17 (m, 2H), 7.36 (d, J=8. 4Hz, 1H), 7.02-6.96 (m, 2H), 2.97-2.93 (m, 2H), 2.57-2.41 (m, 2H), 2.33 (dt, J=10.4, 4.0Hz, 1H), 2.19-2.16 (m, 1H), 2.11-1.96 (m, 3H), 1.70-1.44 (m, 6H ), 0.93 (s, 3H) ppm.
¹⁹ F-NMR (282 NHZ, CDCl ₃ ) δ: 9.86 (s, 1 F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 164.0, 156.4 (d, J = 345.8 Hz), 148.4, 138.3, 138.0, 135.5, 131.5 (d , J=3.1Hz), 130.6, 129.1 (d, J=61.9Hz), 126.6, 121.4, 118.6, 50.4, 47.9, 44.2, 38 .0, 35.8, 31.5, 29.4, 26.3, 25.8, 21.6, 13.8ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₂₆ H ₂₅ FO ₄ ⁺ : 420.1737, found: 420.1725.
IR (NaCl): 2931, 2870, 1813, 1738, 1493, 1410, 1265, 1238, 1149, 1074, 1032, 1009, 897, 714, 540 ^{, 476 cm −1} .
Melting point: 198.1-199.3°C.
²⁵⁾ (11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid 4-(fluorocarbonyl)benzyl ester (3za)
Pale yellow solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.15 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.88 (dd, J = 7.6, 1.5Hz, 1H), 7.57 (dt, J = 7.4, 1.6Hz, 1H), 7.50-7.41 (m, 4H), 7.37 (dd, J =7.4, 1.4Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 3.73 (s , 2H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 18.01 (s, 1F) ppm.
^13C -NMR (126MHz, _CDCl3 ) δ: 190.7, 170.9, 160.5, 157.0 (d, J = 344.1Hz), 143.5, 140.3, 136.2, 135 .4, 132.8, 132.4, 131.6 (d, J=3.9Hz), 129.4, 129.3, 128.0, 127.8, 127.2, 124.5 (d, J=61.4Hz), 124.2, 121.1, 73.6, 65.5, 40.0ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₂₄ H ₁₇ FO ₅ ⁺ : 404.1060, found 404.1038.
IR (NaCl): 1807, 1739, 1647, 1612, 1489, 1414, 1300, 1242, 1140, 1120, 1032, 1009, 827, 760, 741, 692, 640 ^{, 457 cm -1} .
Melting point: 107.7-108.6°C.
²⁶⁾ (All-rac)-4-(((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl)benzoic acid fluoride (3zb)
Colorless transparent viscous liquid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.07 (d, J = 7.7 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 4.80 (s, 2H) , 2.59 (s, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 1.80 (q, J = 7.4Hz, 2H ), 1.58-1.06 (m, 24H), 0.88-0.84 (m, 12H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 17.68 (s, 1F), ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 157.2 (d, J = 343.7 Hz), 148.1, 147.7, 146.2, 131.6 (d, J = 3.8 Hz), 127.7, 127.4, 127.3, 125.7, 124.0 (d, J = 60.9Hz), 123.1, 117.7, 73.4, 40.0, 39.9, 39 .40, 37.60, 37.60, 37.54, 37.47, 37.44, 37.40, 37.37, 37.31, 37.27, 32.78, 32.76, 32.67 , 32.65, 31.24, 31.19, 28.00, 24.81, 24.80, 24.40, 23.9, 22.70, 22.62, 22.59, 21.03, 21 .02, 21.02, 20.70, 19.74, 19.69, 19.67, 19.65, 19.62, 19.59, 12.80, 11.90, 11.80ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₃₇ H ₅₅ FO ₃ ⁺ : 566.4135, found: 566.4158.
IR (NaCl): 2927, 2868, 1813, 1612, 1460, 1409, 1375, 1254, 1174, 1090, 1032, 1011, 741, 507 ^{cm −1} .
²⁷⁾ 4-(Fluorocarbonyl)benzoic acid ((8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11 , 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl) ester (3zc).
White solid.
¹ H-NMR (300 NHZ, CDCl ₃ ) δ: 8.17-8.10 (m, 4 H), 5.75 (d, J = 1.8 Hz, 1 H), 5.11 (d, J = 6. 2Hz, 1H), 2.50-2.28 (m, 5H), 2.08-1.85 (m, 3H), 1.84-1.27 (m, 10H), 1.21 (s, 3H), 1.10-0.92 (m, 1H), 0.89 (s, 3H) ppm.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.61 (s, 1F) ppm.
¹³ C-NMR (126 MHz, CDCl ₃ ) δ: 199.4, 170.8, 164.6, 156.5 (d, J = 345.6 Hz), 136.5, 131.4 (d, J = 3 .4Hz), 130.0, 128.5 (d, J=61.5Hz), 123.9, 83.2, 53.5, 50.0, 45.0, 38.6, 35.8, 35 .7, 33.9, 32.8, 32.2, 31.9, 30.1, 24.7, 20.4, 17.4, 16.6 ppm.
HRMS (TOF/EI ⁺ ): Calculated for C ₂₇ H ₃₁ FO ₄ ⁺ : 438.2206, found: 438.2221.
IR (NaCl): 2943, 2879, 1814, 1720, 1674, 1410, 1277, 1238, 1107, 1032, 1011, 870, 721, 511, ^{494 cm -1} .
Melting point: 80.6-81.8°C.

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（２０．０ｍｇ，０．１ｍｍｏｌ）とＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ，１．０ｍＬ）を仕込んだ後、次いでこれにトリエチルアミン（４２μＬ，０．３ｍｍｏｌ，３．０ｅｑ．）及びアニリン（１８μＬ，０．２ｍｍｏｌ，２．０ｅｑ．）を添加し、室温下、一夜、反応を行った。
反応終了後、水（１０ｍＬ）を添加、酢酸エチルで抽出（１０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニル （１，１´－ビフェニル）－４－カルボン酸アミド（７ａ）（２５．９ｍｇ、収率９５％）を白色固体として得た。 Reference Example 2 Preparation of N-phenyl (1,1'-biphenyl)-4-carboxylic acid amide

Biphenyl-4-carboxylic acid fluoride (3a) (20.0 mg, 0.1 mmol) and N,N-dimethylformamide (DMF, 1.0 mL) were placed in a 25 mL eggplant-shaped flask equipped with a stirrer under a nitrogen stream. After charging, triethylamine (42 μL, 0.3 mmol, 3.0 eq.) and aniline (18 μL, 0.2 mmol, 2.0 eq.) were added thereto, and the reaction was carried out overnight at room temperature.
After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product, N-phenyl (1,1'-biphenyl)-4-carboxylic acid amide. (7a) (25.9 mg, yield 95%) was obtained as a white solid.

The analysis results are shown below.
^1H -NMR (300MHz, DMSO- _d6 ) δ: 10.29 (s, 1H), 8.06 (d, J=8.4Hz, 2H), 7.85-7.74 (m, 6H) , 7.54-7.33 (m, 5H), 7.11 (t, J = 7.3Hz, 1H) ppm.
MS (ESI, m/z): 272 [MH] ^- .

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（２０．０ｍｇ，０．１ｍｍｏｌ）、フェノール（１１．３ｍｇ，０．１２ｍｍｏｌ，１．２ｅｑ．）及びＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ，１．０ｍＬ）を仕込んだ後、次いでこれにトリエチルアミン（２８μＬ，０．２ｍｍｏｌ，２．０ｅｑ．）を添加し、室温下、一夜、反応を行った。
反応終了後、水（１０ｍＬ）を添加、酢酸エチルで抽出（１０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／クロロホルム＝１／５ ｖｏｌ／ｖｏｌ）で精製し、目的物の（１，１´－ビフェニル）－４－カルボン酸 フェニルエステル（８ａ）（２３．４ｍｇ，収率８５％）を白色固体として得た。
^１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：８．２８（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．７４（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．６６（ｄｄ，Ｊ＝７．１，１．６Ｈｚ，２Ｈ）。７．５２－７．３９（ｍ，５Ｈ），７．３１－７．２２（ｍ，３Ｈ）ｐｐｍ。
ＭＳ（ＥＳＩ，ｍ／ｚ）：２７５［Ｍ＋Ｈ］^＋。 Reference Example 3 Preparation of (1,1′-biphenyl)-4-carboxylic acid phenyl ester (8a)

Biphenyl-4-carboxylic acid fluoride (3a) (20.0 mg, 0.1 mmol) and phenol (11.3 mg, 0.12 mmol, 1.2 eq) were placed in a 25 mL eggplant-shaped flask equipped with a stirrer under a nitrogen stream. ) and N,N-dimethylformamide (DMF, 1.0 mL), then triethylamine (28 μL, 0.2 mmol, 2.0 eq.) was added thereto, and the reaction was carried out overnight at room temperature. .
After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/chloroform = 1/5 vol/vol) to obtain the target product (1,1'-biphenyl)-4-carboxylic acid phenyl ester (8a). (23.4 mg, yield 85%) was obtained as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.28 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.66 (dd, J = 7.1, 1.6Hz, 2H). 7.52-7.39 (m, 5H), 7.31-7.22 (m, 3H) ppm.
MS (ESI, m/z): 275 [M+H] ⁺ .

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（２０．０ｍｇ，０．１ｍｍｏｌ）、ｐ－トルエンチオール（１４．９ｍｇ，０．１２ｍｍｏｌ，１．２ｅｑ．）及びＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ，１．０ｍＬ）を仕込んだ後、次いでこれにトリエチルアミン（２８μＬ，０．２ｍｍｏｌ，２．０ｅｑ．）を添加し、室温下、一夜、反応を行った。
反応終了後、水（１０ｍＬ）を添加、酢酸エチルで抽出（１０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１０ ｖｏｌ／ｖｏｌ）で精製し、目的物の（１，１´－ビフェニル）－４－カルボン酸 （４－メチルフェニルチオ）エステル（９ａ）（２３．１ｍｇ，収率７６％）を白色固体として得た。 Reference Example 4 Preparation of (1,1′-biphenyl)-4-carboxylic acid (4-methylphenylthio)ester (9a)

Biphenyl-4-carboxylic acid fluoride (3a) (20.0 mg, 0.1 mmol), p-toluenethiol (14.9 mg, 0.12 mmol, After charging 1.2 eq.) and N,N-dimethylformamide (DMF, 1.0 mL), triethylamine (28 μL, 0.2 mmol, 2.0 eq.) was added thereto, and the reaction was allowed to proceed overnight at room temperature. I did it.
After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/10 vol/vol) to obtain the target product (1,1'-biphenyl)-4-carboxylic acid (4-methyl Phenylthio)ester (9a) (23.1 mg, yield 76%) was obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.09 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 6.9Hz, 2H), 7.52-7.36 (m, 5H), 7.27 (d, J = 7.9Hz, 2H), 2.40 (s, 3H) ppm.
MS (ESI, m/z): 305 [M+H] ⁺ .

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（４０．０ｍｇ，０．２ｍｍｏｌ）、酢酸パラジウム（１．１ｍｇ，０．００５ｍｍｏｌ，２．５ｍｏｌ％）、トリシクロヘキシルホスフィン（５．６ｍｇ，０．０２ｍｍｏｌ，１０．０ｍｏｌ％）、フッ化カリウム（１７．４ｍｇ，０．３ｍｍｏｌ，１．５ｅｑ，）及び無水トルエン（０．５ｍＬ）を仕込み、室温下、１分攪拌した後、次いでこれにフェニルボロン酸（３６．６ｍｇ，０．３ｍｍｏｌ，１．５ｅｑ．）を添加し、１２０℃で１６時間反応を行った。
反応終了後、水（１０ｍＬ）を添加、酢酸エチルで抽出（１０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／クロロホルム＝５／１ ｖｏｌ／ｖｏｌ）で精製し、目的物の４－フェニルベンゾフェノン（１０ａ）（２４．３ｍｇ，収率４７％）を白色固体として得た。 Reference Example 5 Preparation of 4-phenylbenzophenone (10a)

Biphenyl-4-carboxylic acid fluoride (3a) (40.0 mg, 0.2 mmol) and palladium acetate (1.1 mg, 0.005 mmol, 2.0 mmol) were placed in a 25 mL eggplant-shaped flask equipped with a stirrer under a nitrogen stream. 5 mol%), tricyclohexylphosphine (5.6 mg, 0.02 mmol, 10.0 mol%), potassium fluoride (17.4 mg, 0.3 mmol, 1.5 eq,) and anhydrous toluene (0.5 mL), After stirring for 1 minute at room temperature, phenylboronic acid (36.6 mg, 0.3 mmol, 1.5 eq.) was then added thereto, and the reaction was carried out at 120° C. for 16 hours.
After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/chloroform = 5/1 vol/vol) to obtain the target product 4-phenylbenzophenone (10a) (24.3 mg, yield 47%). Obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.90 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.9Hz, 2H), 7.66 (d, J = 7.7Hz, 2H), 7.60 (d, J = 7.1Hz, 1H), 7.50 (q, J = 7.0Hz, 1H ), 7.43-7.39 (m, 1H) ppm.
MS (ESI, m/z): 259 [M+H] ⁺ .

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（６０．０ｍｇ，０．３ｍｍｏｌ）及びイソプロパノール（１．０ｍＬ）を仕込んだ後、水素化ホウ素ナトリウム（１１．３ｍｇ，０．３ｍｍｏｌ，１．０ｅｑ．）を添加し、室温下、３０分反応を行った。
反応終了後、水（１０ｍＬ）を添加、酢酸エチルで抽出（１０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、再結晶で精製し、目的物の（１，１´－ビフェニル－４－イル）メタノール（１１ａ）（５１．４ｍｇ，収率９３％）を白色固体として得た。 Reference Example 6 Preparation of (1,1′-biphenyl-4-yl)methanol (11a)

Biphenyl-4-carboxylic acid fluoride (3a) (60.0 mg, 0.3 mmol) and isopropanol (1.0 mL) were charged into a 25 mL eggplant-shaped flask equipped with a stirrer under a nitrogen stream, and then hydrogenated. Sodium boron (11.3 mg, 0.3 mmol, 1.0 eq.) was added, and the reaction was carried out at room temperature for 30 minutes.
After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by recrystallization to obtain the target product (1,1'-biphenyl-4-yl)methanol (11a) (51.4 mg, yield 93%) as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ³ ) δ: 7.59 (d, J=7.8 Hz, 4H), 7.46-7.37 (m, 4H), 7.34 (q, J=7. 3Hz, 1H), 4.73 (s, 2H), 1.79 (s, 1H) ppm.
MS (ESI, m/z): 185 [M+H] ⁺ .

撹拌子を備えた、２５ｍＬのナス型フラスコに、窒素気流下、ビフェニル－４－カルボン酸フルオリド（３ａ）（４０．０ｍｇ，０．２ｍｍｏｌ）及び水（１．０ｍＬ）を仕込み、還流下、２時間反応を行った。
反応終了後、室温まで冷却し、ジエチルエーテルで抽出（１０ｍＬ×３回）、抽出した有機層を合わせて水酸化ナトリウム水溶液で抽出（１Ｍ溶液、１０ｍＬ×２回）、次いで抽出した水層を塩酸（１Ｍ溶液）でｐＨ＝２とした後、酢酸エチルで抽出（１０ｍＬ×３回）した。得られた有機層を、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより、粗製物を得た。
得られた粗製物は、再結晶で精製し、目的物のビフェニル－４－カルボン酸（１２ａ）（２５．０ｍｇ，収率６３％）を白色固体として得た。 Reference Example 7 Preparation of biphenyl-4-carboxylic acid (12a)

Biphenyl-4-carboxylic acid fluoride (3a) (40.0 mg, 0.2 mmol) and water (1.0 mL) were charged into a 25 mL eggplant-shaped flask equipped with a stirrer under a nitrogen atmosphere, and the mixture was heated under reflux for 2 hours. A time reaction was performed.
After the reaction was completed, it was cooled to room temperature, extracted with diethyl ether (10 mL x 3 times), the extracted organic layers were combined and extracted with an aqueous sodium hydroxide solution (1M solution, 10 mL x 2 times), and then the extracted aqueous layer was extracted with hydrochloric acid. (1M solution) to adjust the pH to 2, and then extracted with ethyl acetate (10 mL x 3). The obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
The obtained crude product was purified by recrystallization to obtain the target biphenyl-4-carboxylic acid (12a) (25.0 mg, yield 63%) as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.21-8.17 (m, 2H), 7.72-7.63 (m, 4H), 7.49-7.41 (m, 3H) ppm.
MS (ESI, m/z): 197 [MH] ^- .

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、ビフェニル－４－カルボン酸フルオリド（３ａ）（６０．０ｍｇ，０．３ｍｍｏｌ）、酢酸パラジウム（１．６ｍｇ，０．００７５ｍｍｏｌ，２．５ｍｏｌ％）、トリシクロヘキシルホスフィン（６．３ｍｇ，０．０２２５ｍｍｏｌ，７．５ｍｏｌ％）及び無水トルエン（０．３ｍＬ）を仕込み、１分攪拌の後、トリエチルシラン（４８．９ｍｇ，０．４２ｍｍｏｌ，１．４ｅｑ．）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、１００℃で２０時間反応を行った。
反応終了後、反応生成物をシリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１９ ｖｏｌ／ｖｏｌ）で精製し、目的物のビフェニル－４－カルボキシアルデヒド（１３ａ）（４６．７ｍｇ，収率８５％）を白色固体として得た。 Reference Example 8 Preparation of biphenyl-4-carboxaldehyde (13a)

In a nitrogen glove box, in a 5 mL screw-capped container equipped with a stir bar were added biphenyl-4-carboxylic acid fluoride (3a) (60.0 mg, 0.3 mmol), palladium acetate (1.6 mg, 0.0075 mmol, 2.5 mol%), tricyclohexylphosphine (6.3 mg, 0.0225 mmol, 7.5 mol%) and anhydrous toluene (0.3 mL), and after stirring for 1 minute, triethylsilane (48.9 mg, 0.42 mmol) was added. , 1.4 eq.) was added, and the cap was closed and sealed. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 100° C. for 20 hours.
After completion of the reaction, the reaction product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/19 vol/vol) to obtain the target product biphenyl-4-carboxaldehyde (13a) (46.7 mg, yield 85%) was obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 10.05 (s, 1H), 7.95 (d, J = 8.3Hz, 2H), 7.76 (d, J = 8.3Hz, 2H) , 7.65-7.62 (m, 2H), 7.51-7.39 (m, 3H) ppm.
MS (ESI, m/z): 183 [M+H] ⁺ .

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、ビフェニル－４－カルボン酸フルオリド（３ａ）（６０．０ｍｇ，０．３ｍｍｏｌ）、酢酸パラジウム（１．６ｍｇ，０．００７５ｍｍｏｌ，２．５ｍｏｌ％）、ビス（ジシクロヘキシルホスフィノ）エタン（４．８ｍｇ，０．０１４４ｍｍｏｌ，３．８ｍｏｌ％）及び無水トルエン（０．３ｍＬ）を仕込み、１分攪拌の後、トリエチルシラン（４８．９ｍｇ，０．４２ｍｍｏｌ，１．４ｅｑ．）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、１００℃で２０時間反応を行った。
反応終了後、反応生成物をシリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン）で精製し、目的物のビフェニル－４－カルボキシアルデヒド（１４ａ）（３０．５ｍｇ，収率６０％）を白色固体として得た。 Reference Example 9 Preparation of biphenyl (14a)

In a nitrogen glove box, in a 5 mL screw-capped container equipped with a stir bar were added biphenyl-4-carboxylic acid fluoride (3a) (60.0 mg, 0.3 mmol), palladium acetate (1.6 mg, 0.0075 mmol, 2.5 mol%), bis(dicyclohexylphosphino)ethane (4.8 mg, 0.0144 mmol, 3.8 mol%) and anhydrous toluene (0.3 mL), and after stirring for 1 minute, triethylsilane (48.9 mg) was added. , 0.42 mmol, 1.4 eq.) was added, and the cap was closed and sealed. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 100° C. for 20 hours.
After the reaction was completed, the reaction product was purified by silica gel flash chromatography (n-hexane) to obtain the target biphenyl-4-carboxaldehyde (14a) (30.5 mg, yield 60%) as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.62-7.57 (m, 4H), 7.48-7.41 (m, 4H), 7.38-7.31 (m, 2H) ppm.
MS (ESI, m/z): 154 [M] ⁺ .

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び４－ニトロヨードベンゼン（７４．７ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩攪拌した。
一晩攪拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニル ４－ニトロ安息香酸アミド（７ｚｄ）（４９．４ｍｇ，収率６８％）を淡黄色固体として得た。 Example 72 One-step preparation of N-phenyl 4-nitrobenzoic acid amide (7zd)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and 4-nitroyodobenzene (74.7 mg, 0.3 mmol) were added, and the mixture was sealed with a cap. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight.
After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product N-phenyl 4-nitrobenzoic acid amide (7zd) (49.4 mg). , yield 68%) as a pale yellow solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, DMSD-d ₆ ) δ: 10.57 (s, 1H), 8.40-8.36 (m, 2H), 8.20-8.17 (m, 2H), 7 .78 (d, J = 7.3 Hz, 2H), 7.41-7.35 (m, 2H), 7.13 (t, J = 8.4 Hz, 1H) ppm.
MS (ESI, m/z): 241 [MH] ^- .

The yield of the intermediate 4-nitrobenzoic acid fluoride (3zd) was determined to be 76% by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 20.96 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び４－シアノベンゼン（６８．７ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩攪拌した。
一晩攪拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニル ４－シアノ安息香酸アミド（７ｚｅ）（６１．２ｍｇ，収率９２％）を無色透明液体として得た。 Example 73 One-step preparation of N-phenyl 4-cyanobenzoic acid amide (7ze)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and 4-cyanobenzene (68.7 mg, 0.3 mmol) were added, and the mixture was sealed with a cap. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight.
After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product N-phenyl 4-cyanobenzoic acid amide (7ze) (61.2 mg). , yield 92%) was obtained as a colorless transparent liquid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.98 (d, J = 8.4 Hz, 2H), 7.90 (s, 1H), 7.78 (d, J = 8.3Hz, 1H) , 7.63 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 2H) ppm.
MS (ESI, m/z): 221 [MH] ^- .

The yield of the intermediate 4-cyanobenzoic acid fluoride (3ze) was determined to be 96% by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.87 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び２－ヨードピリジン（６１．５ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩撹拌した。一晩撹拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニルピコリンアミド（７ｚｆ）（４１．６ｍｇ，収率７０％）を白色固体として得た。 Example 74 One-step preparation of N-phenylpicolinamide (7zf)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and 2-iodopyridine (61.5 mg, 0.3 mmol) were added, and the mixture was sealed with a cap. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight. After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product N-phenylpicolinamide (7zf) (41.6 mg, yield 70 %) as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.03 (s, 1H), 8.63-8.61 (m, 1H), 8.33-8.29 (m, 1H), 7.95 -7.88 (m, 1H), 7.81-7.77 (m, 2H), 7.51-7.46 (m, 1H), 7.44-7.36 (m, 2H), 7 .18-7.12 (m, 1H).
MS (EI, m/z): 199 [M+H] ⁺ .

The yield of the intermediate 2-fluorocarbonylpyridine (3zf) was 76% as determined by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 16.54 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び３－ヨードピリジン（６１．５ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩撹拌した。一晩撹拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニルニコチンアミド（７ｚｇ）（３６．８ｍｇ，収率６２％）を白色固体として得た。 Example 75 One-step preparation of N-phenylnicotinamide (7zg)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and 3-iodopyridine (61.5 mg, 0.3 mmol) were added, and the mixture was sealed with a cap. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight. After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product N-phenylnicotinamide (7zg) (36.8mg, yield 62 %) as a white solid.

The analysis results are shown below.
¹ H-NMR (300 NHZ, CDCl ₃ ) δ: 9.06 (s, 1 H), 8.70 (d, J = 4.6 Hz, 1 H), 8.51 (s, 1 H), 8.18 (d , J=8.1Hz, 1H), 7.63 (d, J=8.0Hz, 2H), 7.40-7.33 (m, 3H), 7.17 (t, J=7.4Hz, 1H)ppm.
MS (ESI, m/z): 199 [M+H] ⁺ .

The yield of the intermediate 3-fluorocarbonylpyridine (3zg) was determined to be 66% by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 30.31 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び４－ヨードピリジン（６１．５ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩攪拌した。
一晩攪拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物のＮ－フェニルイソニコチンアミド（７ｚｈ）（１１．９ｍｇ，収率２０％）を白色固体として得た。 Example 76 One-step preparation of N-phenylisonicotinamide (7zh)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and 4-iodopyridine (61.5 mg, 0.3 mmol) were added and the cap was closed. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight.
After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product N-phenylisonicotinamide (7zh) (11.9 mg, yield 20%) was obtained as a white solid.

The analysis results are shown below.
^1H -NMR (300MHz, CDCl ₃ ) δ: 10.49 (s, 1H), 8.79 (d, J = 4.9Hz, 2H), 7.86 (d, J = 4.9Hz, 2H) , 7.77 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.14 (t, J = 7.3 Hz, 2H) ppm.
MS (ESI, m/z): 199 [M+H] ⁺ .

The yield of the intermediate 4-fluorocarbonylpyridine (3zh) was determined to be 27% by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 20.62 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び（１Ｒ）－（（２Ｓ，４Ｓ，５Ｒ）－５－エチルキヌクリジン－２－イル）（６－メトキシキノリン－４－イル）メチル ４－ヨード安息香酸エステル（１ｚｉ）（１６６．９ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩撹拌した。一晩撹拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー）（ジクロロメタン／メタノール＝１９／１ ｖｏｌ／ｖｏｌ）で精製し、目的物の（１Ｒ）－（（２Ｓ，４Ｓ，５Ｒ）－５－エチルキヌクリジン－２－イル）（６－メトキシキノリン－４－イル）メチル ４－（フェニルカルバモイル）安息香酸エステル（７ｚｉ）（１１７．０ｍｇ，収率７１％）を白色固体として得た。 Example 77 4-(phenylcarbamoyl)benzoic acid (1R)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)-(6-methoxyquinolin-4-yl)) methyl ester ( One-stage preparation of 7zi)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and (1R)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinoline -4-yl)methyl 4-iodobenzoic acid ester (1zi) (166.9 mg, 0.3 mmol) was added, and the mixture was sealed with a cap. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight. After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (dichloromethane/methanol = 19/1 vol/vol) to obtain the target product (1R)-((2S,4S,5R)-5-ethylquinuclidine). -2-yl)(6-methoxyquinolin-4-yl)methyl 4-(phenylcarbamoyl)benzoic acid ester (7zi) (117.0 mg, yield 71%) was obtained as a white solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.67 (d, J = 4.6 Hz, 1H), 8.63 (s, 1H), 8.11 (d, J = 7.9Hz, 2H) , 7.97 (dd, J = 17.1, 8.6 Hz, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.41-7. 30 (m, 4H), 7.14 (t, J = 7.4Hz, 1H), 6.73 (d, J = 6.5Hz, 1H), 3.96 (s, 3H), 3.51- 3.43 (m, 1H), 3.24-3.16 (m, 1H), 3.12-3.01 (m, 1H), 2.72-2.62 (m, 1H), 2. 56 (s, 1H). 2.39-2.34 (m, 1H), 1.86 (s, 2H), 1.75-1.66 (m, 2H), 1.49-1.44 (m, 2H), 1. 37-1.34 (m, 1H), 0.86 (t, J=7.1Hz, 3H) ppm.
¹³ C-NMR (126 Hz, CDCl ₃ ) δ: 164.9, 164.7, 158.0, 147.2, 144.5, 143.6, 139.4, 137.7, 132.2, 131. 6,129.8,129.0,127.4,126.8,124.8,121.9,120.4,118.5,101.3,75.0,59.2,58.3, 55.6, 42.6, 37.3, 28.5, 27.7, 25.2, 23.9, 12.1 ppm.
HRMS (ESI): Calculated for C ₃₄ H ₃₆ N ₃ O ₄ [M+H] ⁺ :550.2703, found: 550.2703.
IR (NaCl): 3298, 3060, 2933, 2870, 1724, 1657, 1620, 1601, 1539, 1508, 1441, 1323, 1267, 1103, 1031, 1018, 754, 727, 692 ^{, 586 cm -1} .
Melting point: 100.5-101.4°C.

In addition, the intermediate benzoic acid (1R)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl 4-(fluorocarbonyl) ester (3zi The yield of ) was 71% as determined by ¹⁹ F-NMR using fluorobenzene as an internal standard. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.96 (s, 1F) ppm.

窒素グローブボックス中で、撹拌子を備えた５ｍＬのスクリューキャップ付き容器に、トリフルオロ酢酸パラジウム（１．０ｍｇ，０．００３ｍｍｏｌ，１．０ｍｏｌ％）、キサントホス（２．６ｍｇ，０．００４５ｍｍｏｌ，１．５ｍｏｌ％）、フッ化セシウム（６８．４ｍｇ，０．４５ｍｍｏｌ，１．５ｅｑ．）及び無水Ｎ，Ｎ－ジメチルホルムアミド（２．０ｍＬ）を仕込み、１０分攪拌の後、次いでこれに、２－ジフルオロメトキシ－５－ニトロピリジン（６８．４ｍｇ，０．３６ｍｍｏｌ，１．２ｅｑ．）及び
（ジエチルアミノ）エチル ４－ヨード安息香酸エステル（１ｚｊ）（１０４．２ｍｇ，０．３ｍｍｏｌ）を添加し、キャップを閉め密栓した。次いで、反応器を窒素グローブより取り出し、７０℃で１５時間反応を行った。
反応終了後、室温まで冷却した後、トリエチルアミン（４１８μＬ，３．０ｍｍｏｌ，１０．０ｅｑ．）及びアニリン（８１μＬ，０．９ｍｍｏｌ，３．０ｅｑ．）を添加し、室温下、一晩攪拌した。一晩攪拌後、水（２０ｍＬ）を添加、酢酸エチルで抽出（２０ｍＬ×３回）し、有機層を合わせて、硫酸ナトリウム上で乾燥、ろ過、減圧濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルフラッシュクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物の２－（ジエチルアミノ）エチル ４－（フェニルカルバモイル）安息香酸エステル（７ｚｊ）（４３．９ｍｇ，収率４３％）を黄色の半固体として得た。 Example 78 One-step preparation of 4-(phenylcarbamoyl)benzoic acid 2-(diethylamino)ethyl ester (7zz)

In a nitrogen glove box, palladium trifluoroacetate (1.0 mg, 0.003 mmol, 1.0 mol %), xanthophos (2.6 mg, 0.0045 mmol, 1. 2-difluoro Add methoxy-5-nitropyridine (68.4 mg, 0.36 mmol, 1.2 eq.) and (diethylamino)ethyl 4-iodobenzoate (1zz) (104.2 mg, 0.3 mmol) and close the cap. It was sealed tightly. Next, the reactor was taken out from the nitrogen glove, and the reaction was carried out at 70° C. for 15 hours.
After the reaction was completed and the mixture was cooled to room temperature, triethylamine (418 μL, 3.0 mmol, 10.0 eq.) and aniline (81 μL, 0.9 mmol, 3.0 eq.) were added, and the mixture was stirred at room temperature overnight. After stirring overnight, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate = 1/1 vol/vol) to obtain the target product, 2-(diethylamino)ethyl 4-(phenylcarbamoyl)benzoate (7zz ) (43.9 mg, yield 43%) was obtained as a yellow semi-solid.

The analysis results are shown below.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.14 (m, 2H), 7.93-7.91 (m, 3H), 7.65 (d, J = 7.9Hz, 2H), 7 .38 (t, J=7.8Hz, 2H), 7.18 (t, J=7.5Hz, 1H), 4.43 (t, J=6.3Hz, 2H), 2.87 (t, J=6.2Hz, 2H), 2.64 (q, J=7.2Hz, 4H), 1.08 (t, J=7.2Hz, 6H) ppm.
¹³ C-MNR (126 MHz, CDCl ₃ ) δ: 165.7, 164.9, 138.8, 137.6, 133.1, 130.0, 129.1, 127.1, 124.9, 120. 3, 63.8, 50.9, 47.8, 12.0 ppm.
HRMS (ESI): Calculated for C20H25N2O3+: 341.1865, found: 341.1865.
IR (NaCl): 3313, 2970, 2810, 1722, 1658, 1601, 1537, 1500, 1442, 1381, 1323, 1273, 1180, 1122, 1018, 870, 754, 727, 692, 511, ^{492 cm -1} .

The yield of the intermediate 2-(diethylamino)ethyl 4-(fluorocarbonyl)benzoate (7zz) 4-(phenylcarbamoyl)benzoic acid fluoride (3zz) was calculated using fluorobenzene as an internal standard ^. The yield was 76% as determined by F-NMR. Moreover, the shift value was as follows.
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ: 19.83 (s, 1F) ppm.

The carboxylic acid fluorides obtained by the method of the present invention can further easily react with nucleophiles, and are useful in the fields of medicine, agrochemicals, and electronic materials as a method for synthesizing esters and amides.

Claims (6)

In the presence of a palladium catalyst, a phosphine ligand, and an alkali metal fluoride, an organic iodine compound containing an iodine atom directly connected to carbon forming a carbon-carbon double bond is reacted with 2-(difluoromethoxy)-5-nitropyridine. A method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond. In claim 1, the organic iodine compound has the following general formula (1):
(In general formula (1), R ¹ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a phenyl group, or a 4-methoxyphenyl group, and R ² represents a hydrogen atom or a phenyl group)
A method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond according to claim 1, characterized in that: In claim 1, the organic iodine compound has the following general formula (2):
(R ³ in general formula (3) is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a phenyl group, a cyano group, a nitro group, a (1,3-dioxo isoindolin-2-yl)methyl group, (1S,2R,5S)-2-isopropyl-5-methylcyclohexyloxycarbonyl group, 4-(isopropoxycarbonyl-isopropyl-2-yloxy)benzoyl group, ((8R, 9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy Carbonyl group, 4-(fluorocarbonyl)benzyl ester 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)methylcarbonyloxymethyl group, (All-rac)-4-( ((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxo)methyl) group, (8R,9S,10R,13S,14S,17R )-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-17-yl group, (1R)-((2S,4S,5R)-4-(5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyloxycarbonyl) group, or 4-(2-(diethylamino)ethoxycarbonyl) group)
A method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond according to claim 1, characterized in that: In claim 1, the organic iodine compound is 2-iodothiophene, 2-iodobenzo[b]thiophene, 1-iodonaphthalene, 2-iodonaphthalene, 2-iodopyridine, 3-iodopyridine, or 4-iodopyridine. The method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond according to claim 1. In claim 1, the organic iodine compound is represented by the following formula (3):
The method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond according to claim 1. In claim 1, the organic iodine compound is represented by the following formula (4):
The method for producing a carboxylic acid fluoride directly bonded to carbon forming a carbon-carbon double bond according to claim 1.