Method for producing 2-fluorofuran ring-containing compounds

Abstract

To provide a method for producing 2-fluorofuran ring-containing compounds that are useful as final products of pharmaceuticals or pesticides, or as synthetic intermediates. [Solution] A method for producing a 2-fluorofuran ring-containing compound, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 1,1-difluoroalene compound (1) represented by the following formula (1) and an aldehyde compound (2) represented by the following formula (2). [C1] In formulas (1), (2), and (5) of TIFF2026070019000052.tif41170, R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

Description

[Technical Field]

[0001] This disclosure relates to a method for producing a 2-fluorofuran ring-containing compound. [Background technology]

[0002] Five-membered heterocycles are the central framework of biologically active compounds. In organic synthesis, the [2+3] cycloaddition reaction of allenes with heteroatom-containing compounds using transition metal catalysts is a promising approach for constructing heterocycles. However, this type of allene cycloaddition reaction has not been sufficiently investigated and is limited to only a few examples (Non-Patent Documents 1-4). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Li, G.-H.; Zhou, W.; Li, X.-X.; Bi, Q.-W.; Wang, Z.; Zhao, Z.-G.; Hu, W.-X.; Chen, Z. Gold Catalyzed Enantioselective Intermolecular [3+2] Dipolar Cycloaddition of N-Allenyl Amides with Nitrones. Chem. Commun. 2013, 49, 4770-4772 [Non-Patent Document 2] Zhou, W.; Li, X.-X.; Li, G.-H.; Wu, Y.; Chen, Z. Gold Catalyzed [3+2] Cycloaddition of N-Allenyl Amides with Azomethine Imines. Chem. Commun. 2013, 49, 3552-3554 [Non-Patent Document 3] Lin, T.-Y.; Zhu, C.-Z.; Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Regiodivergent Intermolecular [3+2] Cycloadditions of Vinyl Aziridines and Allenes: Stereospecific Synthesis of Chiral Pyrrolidines. Angew. Chem., Int. Ed. 2016, 55, 10844-10848. [Non-Patent Document 4] Wang, W.-Y.; Wu, J.-Y.; Liu, Q.-R.; Liu, X.-Y.; Ding, C.-H.; Hou, X.-L. Palladium / N-Heterocyclic Carbene (NHC)-catalyzed Asymmetric [3+2] Cycloaddition Reaction of Vinyl Epoxides with Allenic Amides. Org. Lett. 2018, 20, 4773-4776 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Furthermore, no method for producing 2-fluorofuran ring-containing compounds from 1,1-difluoroalene compounds has been reported to date. Fluorine-substituted aromatic heterocyclic compounds are highly valuable as substructures or synthetic intermediates for pharmaceuticals, agrochemicals, or organic electronic materials due to their properties that enhance the biological activity and reactivity of compounds, as well as their electron-donating ability due to the presence of heteroatoms. In particular, building blocks containing the 2-fluorofuran skeleton are rarely commercially available, and no synthetic routes have been established. This disclosure is made to solve the above-mentioned problems and aims to provide a method for producing a 2-fluorofuran ring-containing compound that is useful as a final product or synthetic intermediate of a pharmaceutical, agrochemical, or organic electronic material. [Means for solving the problem]

[0005] As a result of diligent research to solve the above problems, the present inventors have found that a 2-fluorofuran ring-containing compound can be produced by using a 1,1-difluoroarene compound or a 2,2-difluorodihydrofuran ring-containing compound that can be derived therefrom as a starting material. The gist of this disclosure is as follows: [1] to [7]. [1] A method for producing a 2-fluorofuran ring-containing compound, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 1,1-difluoroalene compound (1) represented by the following formula (1) and an aldehyde compound (2) represented by the following formula (2). [ka] In equations (1), (2), and (5), R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. [2] A method for producing a 2-fluorofuran ring-containing compound, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 2,2-difluorodihydrofuran ring-containing compound (4) represented by the following formula (4). [ka] In equations (4) and (5), R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. [3] A method for producing a 2-fluorofuran ring-containing compound according to [1], comprising, in obtaining the 2-fluorofuran ring-containing compound (5), a gold-containing compound and a silver-containing compound are used to carry out a cycloaddition reaction between the 1,1-difluoroarene compound (1) and the aldehyde compound (2) to obtain a 2,2-difluorodihydrofuran ring-containing compound (4) represented by (4) below. [ka] In formula (4), R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. [4] A method for producing a 2-fluorofuran ring-containing compound according to [2] or [3], comprising, in obtaining the 2-fluorofuran ring-containing compound (5), aromatizing the 2,2-difluorodihydrofuran ring-containing compound (4) in the presence of a base to obtain the 2-fluorofuran ring-containing compound (5). [5] A compound represented by the following chemical formula (5), produced by the method for producing a 2-fluorofuran ring-containing compound described in any one of items [1] to [4]. [ka] In formula (5), R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. [6] A synthetic intermediate for pharmaceuticals, agrochemicals, or organic electronic materials, comprising a 2-fluorofuran ring-containing compound, produced by a method for producing a 2-fluorofuran ring-containing compound described in any one of items [1] to [4]. [7] A pharmaceutical, agrochemical, or organic electronic material comprising a 2-fluorofuran ring-containing compound produced by a method for producing a 2-fluorofuran ring-containing compound described in any one of items [1] to [4]. [8] A pharmaceutical, agricultural chemical or organic electronic material containing a compound derived from a 2-fluorofuran ring-containing compound produced by the method for producing a 2-fluorofuran ring-containing compound according to any one of [1] to [4]. [9] After reacting the formyl group of the starting material with 1-bromo-2,2-difluorovinyllithium, reacting with acetic anhydride, and then eliminating lithium acetate by a 1,2-elimination reaction to convert to a 1,1-difluoroallene compound (1) represented by the following formula (1), and A method for producing a pharmaceutical, agricultural chemical or organic electronic material, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from the 1,1-difluoroallene compound (1) and an aldehyde compound (2) represented by the following formula (2).

Chemical formula

[10] Furthermore, a method for producing a pharmaceutical, agricultural chemical or organic electronic material according to [9], comprising eliminating the fluorine atom bonded to the carbon at the 2-position of the 2-fluorofuran ring-containing compound (5) to form a carbon-carbon bond, a carbon-oxygen bond, or a carbon-nitrogen bond.

[11] Furthermore, a method for producing a pharmaceutical, agricultural chemical or organic electronic material according to [9] or

[10] , comprising catalytic hydrogenation for reducing the furan ring to a tetrahydrofuran ring.

Advantages of the Invention

[0006] The manufacturing method disclosed herein has high industrial value because it allows for the production of 2-fluorofuran ring-containing compounds, which are useful as final products or synthetic intermediates of pharmaceuticals, agrochemicals, or organic electronic materials, using 1,1-difluoroarene compounds or 2,2-difluorodihydrofuran ring-containing compounds derived therefrom as starting materials, with a short reaction step and high yield. [Brief explanation of the drawing]

[0007] [Figure 1] This figure shows the 1H-NMR spectrum of compound 5a. [Figure 2] This figure shows the 13C-NMR spectrum of compound 5a. [Figure 3] This figure shows the 19F-NMR spectrum of compound 5a. [Figure 4] This figure shows the 1H-NMR spectrum of compound 5b. [Figure 5] This figure shows the 13C-NMR spectrum of compound 5b. [Figure 6] This figure shows the 19F-NMR spectrum of compound 5b. [Figure 7] This figure shows the 1H-NMR spectrum of compound 5c. [Figure 8] This figure shows the 13C-NMR spectrum of compound 5c. [Figure 9] This figure shows the 19F-NMR spectrum of compound 5c. [Figure 10] This figure shows the 1H-NMR spectrum of compound 5d. [Figure 11] This figure shows the 13C-NMR spectrum of compound 5d. [Figure 12] This figure shows the 19F-NMR spectrum of compound 5d. [Figure 13] This figure shows the 1H-NMR spectrum of compound 5e. [Figure 14] This figure shows the 13C-NMR spectrum of compound 5e. [Figure 15] This figure shows the 19F-NMR spectrum of compound 5e. [Figure 16] This figure shows the 1H-NMR spectrum of compound 5f. [Figure 17] This figure shows the 13C-NMR spectrum of compound 5f. [Figure 18] This figure shows the 19F-NMR spectrum of compound 5f. [Modes for carrying out the invention]

[0008] The following provides further details about this disclosure.

[0009] Method for producing 2-fluorofuran ring-containing compounds A method for producing a 2-fluorofuran ring-containing compound according to a first aspect of this disclosure includes obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 1,1-difluoroalene compound (1) represented by the following formula (1) and an aldehyde compound (2) represented by the following formula (2).

[0010] [ka]

[0011] In equations (1), (2), and (5), R 1 R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. 2 This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

[0012] R 1 In this, the number of carbon atoms in the hydrocarbon group is preferably 1 to 16, more preferably 3 to 14, and even more preferably 5 to 12. Examples of hydrocarbon groups include saturated hydrocarbon groups having 1 to 20 carbon atoms, which may have substituents; unsaturated hydrocarbon groups having 2 to 20 carbon atoms, which may have substituents; and aromatic hydrocarbon groups having 5 to 12 carbon atoms, which may have substituents. Examples of saturated hydrocarbon groups having 1 to 20 carbon atoms include straight-chain or branched-chain saturated hydrocarbon groups having 1 to 20 carbon atoms, and alicyclic groups having 1 to 20 carbon atoms. Examples of linear or branched saturated hydrocarbon groups having 1 to 20 carbon atoms include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and n-hexyl groups. Examples of alicyclic groups having 1 to 20 carbon atoms include cyclopropyl groups, cyclopentyl groups, and cyclohexyl groups. Examples of unsaturated hydrocarbon groups having 2 to 20 carbon atoms that may have substituents include vinyl groups and aryl groups. Examples of C5-C12 aromatic hydrocarbon groups that may have substituents include phenyl, naphthyl, anthranyl, furyl, and pyridyl groups. Examples of substituents include halogen atoms such as fluorine, chlorine, bromine, and iodine, hydroxyl groups, amino groups, carboxyl groups, alkyloxycarbonyl groups, amide groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and C5-C12 aromatic hydrocarbon groups. In particular, from the viewpoint of the stability of raw materials and synthetic intermediates, R 1 A 2-phenylethyl group (phenethyl group) is preferred.

[0013] R 2 In this context, the C1-C20 hydrocarbon group which may have substituents is R 1 The same items mentioned above can be cited. In particular, from the viewpoint of reducing side reactions, improving yield, and stability, R 2 Preferably, the substituents are aromatic hydrocarbon groups having 5 to 12 carbon atoms, such as phenyl groups, naphthyl groups, phenyl groups having halogen atoms such as fluorine, chlorine, bromine, or iodine as substituents, phenyl groups having alkyl groups having 1 to 6 carbon atoms as substituents, and phenyl groups having alkoxy groups having 1 to 6 carbon atoms as substituents.

[0014] The 1,1-difluoroalene compound (1) can be synthesized by known methods, for example, by the method described in the literature [Misaki Yokota, Kohei Fuchibe, Mikiko Ueda, Yuka Mayumi, and Junji Ichikawa, Org. Lett., Vol. 11, No. 17, 2009], using an aldehyde compound as a starting material. For example, the aldehyde group (formyl group) of the starting material is reacted with 1-bromo-2,2-difluorovinyllithium, followed by a reaction with acetic anhydride. Then, n-butyllithium is reacted to eliminate lithium acetate via a 1,2-elimination reaction, converting it to the 1,1-difluoroalene compound (1) represented by the following formula (1).

[0015] [ka]

[0016] 1-Bromo-2,2-difluorovinyllithium can be obtained by reacting 1,1-dibromo-2,2-difluoroethylene with n-butyllithium, thereby lithiating by eliminating one bromine atom from 1,1-dibromo-2,2-difluoroethylene. 1-Bromo-2,2-difluorovinyllithium is highly reactive and easily decomposed. Therefore, it is preferable to prepare 1-bromo-2,2-difluorovinyllithium each time, then add the aldehyde compound and react, followed by the addition of acetic anhydride, and then the addition of n-butyllithium to carry out 1,2-elimination. Thus, it is preferable to synthesize compound (1) in a one-pot reaction. Here, other acetylating agents such as acetyl chloride may be used instead of acetic anhydride. Reducing agents such as sec-butyllithium or t-butyllithium may be used instead of n-butyllithium.

[0017] [ka]

[0018] The aldehyde compound used as a starting material for the 1,1-difluoroalene compound (1) may be synthesized or a commercially available compound may be used. Examples of aldehyde compounds include aliphatic aldehydes which may have substituents, and aromatic aldehydes which may have substituents. Examples of substituents are the same as those described above. Examples of aliphatic aldehydes that may have substituents include acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, acrolein, and crotonaldehyde. Examples of aromatic aldehydes that may have substituents include salicylaldehyde, benzaldehyde, 2-chlorobenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2-methoxybenzaldehyde, and 3-nitrobenzaldehyde. Among these, 3-phenylpropionaldehyde, phenylacetaldehyde, and 3-naphthylpropionaldehyde are preferred because they are readily available.

[0019] Examples of 1,1-difluoroalene compounds (1) include the following compounds.

[0020] [ka]

[0021] In obtaining a 2-fluorofuran ring-containing compound, it is preferable to carry out a cycloaddition reaction using a 1,1-difluoroalene compound (1), a predetermined aldehyde compound (2), a gold-containing compound, and a silver-containing compound to obtain a 2,2-difluorodihydrofuran ring-containing compound (4) represented by (4) below.

[0022] [ka]

[0023] In formula (4), R 1 and R2 The same examples mentioned above can be cited.

[0024] In formula (4), R 1 Examples of such groups include the following. In the chemical formulas below, "*" indicates a bond position.

[0025] [ka]

[0026] In formula (4), R 2 Examples of such groups include the following. In the chemical formulas below, "*" indicates a bond position.

[0027] [ka]

[0028] Gold-containing compounds are used to selectively obtain α,γ adducts. Gold-containing compounds are used to increase the reactivity of 1,1-difluoroalene compounds (1). Examples of gold-containing compounds include chloro[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]gold(I) (hereinafter also referred to as AuCl(IPr)), gold(I) chloride (AuCl), and chloro(triphenylphosphine)gold(I) (AuCl(PPh3)). Among these, chloro[1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]gold(I) is preferred from the viewpoint of high product yield.

[0029] Silver-containing compounds are used to generate catalytically active species from gold-containing compounds. Examples of silver-containing compounds include silver antimonate hexafluoride (AgSbF6), silver hexafluoride phosphate (AgPF6), silver bis(trifluoromethanesulfonyl)imide (AgNTf2), silver tetrafluoroborate (AgBF4), silver trifluoromethanesulfonate (AgOTf), and silver fluoride (AgF). Among these, silver antimonate hexafluoride (AgSbF6), silver hexafluoride phosphate (AgPF6), and silver bis(trifluoromethanesulfonyl)imide (AgNTf2) are preferred from the viewpoint of high product yield.

[0030] From the viewpoint of reducing side reactions (reactions to produce oxetane ring-containing compounds, which are α,β adducts) and improving the yield of the product, the combinations of AuCl(IPr) and AgSbF6, AuCl(IPr) and AgPF6, and AuCl(IPr) and AgNTf2 are preferred as combinations of gold-containing compounds and silver-containing compounds. Among these, the combination of AuCl(IPr) and AgSbF6 is more preferred from the viewpoint of yield.

[0031] In obtaining the 2,2-difluorodihydrofuran ring-containing compound (4), the amount of 1,1-difluoroalene compound (1) used is preferably 0.8 to 1.3 moles, more preferably 1.0 to 1.2 moles, and even more preferably 1.1 to 1.2 moles per mole of aldehyde compound (2). If the amount of aldehyde compound (2) used is below the above upper limit, the burden of separating the excess 1,1-difluoroalene compound (1) from the product can be reduced, the purification of the product can be performed more easily, and productivity can be improved. In addition, it becomes easier to obtain a product of high purity, and the quality of the product can be improved. If the amount of 1,1-difluoroalene compound (1) used is above the above lower limit, the cyclization reaction can proceed sufficiently, and the yield can be improved without recovering unreacted aldehyde compound (2). In addition, productivity can be improved as the reaction proceeds more easily.

[0032] The amount of gold-containing compound used is preferably 0.01 to 0.1 moles, more preferably 0.02 to 0.06 moles, and even more preferably 0.03 to 0.05 moles, per mole of aldehyde compound (2). If the amount of gold-containing compound used is below the above upper limit, it becomes easier to reduce the amount of expensive reagents used, thereby reducing manufacturing costs and resulting in superior productivity. If the amount of gold-containing compound used is above the above lower limit, the cyclization reaction proceeds more easily, and the yield can be improved without recovering unreacted 1,1-difluoroalene compound (1). In addition, the reaction proceeds more easily, which makes it easier to improve productivity.

[0033] The amount of silver-containing compound used is preferably 0.01 to 0.1 moles, more preferably 0.02 to 0.06 moles, and even more preferably 0.03 to 0.05 moles per mole of aldehyde compound (2). Using an amount of silver-containing compound below the above upper limit makes it easier to reduce the amount of expensive reagents used, thereby reducing manufacturing costs and resulting in superior productivity. Using an amount of silver-containing compound above the above lower limit makes it easier to allow the cyclization reaction to proceed sufficiently, making it easier to improve the yield without recovering unreacted 1,1-difluoroalene compound (1). Furthermore, since the reaction proceeds more easily, productivity is also easier to improve.

[0034] As for the organic solvent to be used, aprotic polar solvents are preferred from the viewpoint of reducing side reactions and improving yield, halogenated solvents are more preferred, and dichloroethane, chlorobenzene, and the like are even more preferred. The amount of organic solvent used is preferably 3 to 20 mL, more preferably 5 to 15 mL, and even more preferably 8 to 10 mL per mole of aldehyde compound (2). Using an amount of organic solvent below the upper limit prevents excessive dilution which hinders the reaction, thus reducing energy consumption and improving productivity. It also makes it easier to maintain the concentration necessary to suppress side reactions, thus improving yield and productivity. Using an amount of organic solvent above the lower limit allows for sufficient reaction between different molecules, suppressing the generation of side reactions and improving yield. Furthermore, suppressing side reactions makes product purification easier, thus improving productivity. This makes it easier to obtain a product of high purity and improve product quality.

[0035] The reaction temperature is preferably 0 to 50°C, more preferably 10 to 30°C, and even more preferably 15 to 25°C. If the reaction temperature is below the above upper limit, the decomposition of the product is more easily suppressed, and the yield is more easily improved. In addition, the energy consumption for heating is also more easily reduced, thus improving productivity. If the reaction temperature is above the above lower limit, the cycloaddition reaction proceeds more easily, and the yield is more easily improved without recovering the unreacted 1,1-difluoroalene compound (1). In addition, the reaction proceeds more easily, thus improving productivity.

[0036] The reaction time is preferably 0.1 to 3 hours, more preferably 0.25 to 2 hours, and even more preferably 0.5 to 1 hour. If the reaction time is below the above upper limit, the decomposition of the product is more easily suppressed, and the yield is more easily improved. In addition, the energy consumption for heating is also more easily reduced, thus improving productivity. If the reaction time is above the above lower limit, the cycloaddition reaction is more easily allowed to proceed sufficiently, and the yield is more easily improved without recovering the unreacted 1,1-difluoroalene compound (1). In addition, the reaction proceeds more easily, thus improving productivity.

[0037] In obtaining a 2-fluorofuran ring-containing compound, it is preferable to perform aromatization on the 2,2-difluorodihydrofuran ring-containing compound (4) in the presence of a base to obtain the 2-fluorofuran ring-containing compound (5). The 2,2-difluorodihydrofuran ring-containing compound (4) may be isolated and the reaction carried out in a multi-step manner, or it may be carried out as a one-pot reaction in which aromatization is performed immediately without isolation.

[0038] Aromaticization can be carried out using known methods. For example, aromaticization can be carried out in the presence of a base. Suitable bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydride, from the viewpoint of reducing side reactions by the base (e.g., aromatic nucleophilic substitution reactions by amine compounds); acetate salts such as sodium acetate and potassium acetate; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium n-butoxide, sodium n-butoxide, potassium n-butoxide, lithium t-pentoxide, sodium t-pentoxide, and potassium t-pentoxide; pyridine, 4-dimethylaminopyridine, 4-dimethylaminomethylpyridine, and 3,4-bis Nitrogen-containing aromatic compounds such as (dimethylamino)pyridine, picoline, 4-dimethylaminopyridine, 4-dimethylaminomethylpyridine, and 3,4-bis(dimethylamino)pyridine; triethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1-(3-aminopropyl)-2-pyrrolidone, N-(3-aminopropyl)-ε-caprolactam, 1,5,7-triazabicyclo[4.4.0]deca-5-ene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]deca-5-ene are preferred, and among these, tertiary amines such as 1,5,7-triazabicyclo[4.4.0]deca-5-ene (TBD) are preferred. From the viewpoint of improving the yield of the reaction product and reducing side reactions (e.g., decomposition of the reaction product), alkali metal alkoxides and tertiary amines are more preferred, and among these, potassium t-butoxide and 1,5,7-triazabicyclo[4.4.0]deca-5-ene (TBD) are even more preferred. In aromatization, Lewis acids such as AlCl3 and FeCl3 may be used, but it is preferable not to use them from the viewpoint of reducing side reactions (for example, the formation of by-products in which the fluorine at the 2-position is replaced by chlorine).

[0039] The amount of base used is preferably 1 to 3 moles, more preferably 1.1 to 2 moles, and even more preferably 1.2 to 1.5 moles, per mole of the 2,2-difluorodihydrofuran ring-containing compound (4). If the amount of base used is below the above upper limit, the decomposition of the product is more easily suppressed, and the yield is more easily improved. In addition, productivity is more easily improved because less base is used than necessary. If the amount of base used is above the above lower limit, aromatization is more easily allowed to proceed sufficiently, and the yield is more easily improved without recovering unreacted raw materials. In addition, productivity is more easily improved because the reaction proceeds more easily.

[0040] The reaction temperature during aromatization is preferably -20 to 10°C, more preferably -15 to 0°C, and even more preferably -10 to -5°C. If the reaction temperature is below the above upper limit, the decomposition of the product is more easily suppressed, and the yield is more easily improved. In addition, the energy consumption for heating is also more easily reduced, thus improving productivity. If the reaction temperature is above the above lower limit, aromatization is more easily carried out, and the yield is more easily improved without recovering unreacted raw materials. In addition, the reaction proceeds more easily, thus improving productivity.

[0041] The reaction time for aromatization is preferably 6 to 36 hours, more preferably 12 to 28 hours, and even more preferably 15 to 24 hours. If the reaction time is below the upper limit, the decomposition of the product is more easily suppressed, and the yield is more easily improved. In addition, the energy consumption for heating is also more easily reduced, thus improving productivity. If the reaction time is above the lower limit, aromatization is more easily allowed to proceed sufficiently, and the yield is more easily improved without recovering unreacted raw materials. In addition, the reaction proceeds more easily, thus improving productivity.

[0042] A method for producing a 2-fluorofuran ring-containing compound in a second aspect of this disclosure includes obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 2,2-difluorodihydrofuran ring-containing compound (4) represented by the following formula (4).

[0043] [ka]

[0044] In equations (4) and (5), R 1 and R 2 The same examples mentioned above can be cited.

[0045] In obtaining a 2-fluorofuran ring-containing compound, it is preferable to include aromaticizing the 2,2-difluorodihydrofuran ring-containing compound (4) in the presence of a base to obtain the 2-fluorofuran ring-containing compound.

[0046] The reaction conditions for aromatization are similar to those described above.

[0047] Compounds containing a 2-fluorofuran ring The 2-fluorofuran ring-containing compound of this disclosure is a compound represented by the following chemical formula (5), which is produced by the method for producing the 2-fluorofuran ring-containing compound of this disclosure.

[0048] [ka]

[0049] In formula (5), R 1 and R 2 The same examples mentioned above can be cited.

[0050] The 2-fluorofuran ring-containing compounds of this disclosure can be used as synthetic intermediates for pharmaceuticals, agrochemicals, or organic electronic materials due to the high reactivity of the fluorine at the 2-position.

[0051] <<Synthetic intermediates for pharmaceuticals, pesticides, or organic electronic materials>> The synthetic intermediates for pharmaceuticals, agrochemicals, or organic electronic materials of this disclosure include 2-fluorofuran ring-containing compounds produced by the method for producing 2-fluorofuran ring-containing compounds of this disclosure. By using the synthetic intermediates of this disclosure, it becomes easier to produce final products having fluorine at the 2-position of the furan ring, final products with a substituent introduced at the 2-position of the furan ring, final products having fluorine at the 2-position of the tetrahydrofuran ring, and final products with a substituent introduced at the 2-position of the tetrahydrofuran ring.

[0052] Based on common technical knowledge, the 2-fluorofuran ring-containing compounds used as synthetic intermediates in this disclosure can be subjected to the following reactions.

[0053] <Reaction Example 1> Defluorinated coupling reaction with arylboronic acid

[0054] [ka]

[0055] In the above formula, R 1 and R 2 Examples include those similar to those mentioned above, and R a This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. R a In this context, the C1-C20 hydrocarbon group which may have substituents is R 1 The same items mentioned above can be cited.

[0056] The defluorination coupling reaction between the 2-fluorofuran ring-containing compound as a synthetic intermediate of this disclosure and an arylboronic acid can be carried out under known reaction conditions. For example, known catalysts such as palladium catalysts and nickel catalysts used in Suzuki-Miyaura couplings can be used as catalysts. The arylboronic acid may be synthesized or commercially available. Examples of arylboronic acids include the following:

[0057] [ka]

[0058] [ka]

[0059] From the viewpoint of reducing side reactions (e.g., nucleophilic aromatic substitution reactions by amino groups, etc.), it is preferable that arylboronic acids do not have polar functional groups such as amino groups or hydroxyl groups. When using arylboronic acids that have polar functional groups such as amino groups or hydroxyl groups, it is preferable to protect these polar functional groups with protecting groups before using them in the coupling reaction. From the viewpoint of reducing side reactions (e.g., unintended coupling reactions), it is preferable that arylboronic acids do not have leaving groups such as bromine on the aromatic ring. When the aromatic ring of an arylboronic acid has a fluorine atom, the fluorine atom at position 2 of the furan ring is more reactive, so the coupling reaction can be carried out regioselectively.

[0060] <Example of reaction 2> Aromatic nucleophilic substitution reaction with primary amine-containing compounds or secondary amine-containing compounds

[0061] [ka]

[0062] In the above formula, R 1 and R 2 Examples include those similar to those mentioned above, and R b and R c Each of these independently represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. R b and R c In this context, the C1-C20 hydrocarbon group which may have substituents is R 1 The same items mentioned above can be cited. R b and R c In this case, neither atom can be a hydrogen atom; if one atom is a hydrogen atom, the other is a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

[0063] The aromatic nucleophilic substitution reaction between a 2-fluorofuran ring-containing compound as a synthetic intermediate in this disclosure and a primary amine-containing compound or a secondary amine-containing compound can be carried out under known reaction conditions. For example, the reaction can be carried out by reacting the 2-fluorofuran ring-containing compound with a primary amine-containing compound or a secondary amine-containing compound in the presence of a base. The primary amine-containing compound or secondary amine-containing compound may be synthesized or commercially available. Examples of primary amine-containing compounds or secondary amine-containing compounds include the following:

[0064] [ka]

[0065] <Reaction Example 3> Aromatic nucleophilic substitution reaction with hydroxyl group-containing compounds

[0066] [ka]

[0067] In the above formula, R 1 and R 2 Examples include those similar to those mentioned above, and R d This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. R d In this context, the C1-C20 hydrocarbon group which may have substituents is R 1 The same items mentioned above can be cited.

[0068] The aromatic nucleophilic substitution reaction between a 2-fluorofuran ring-containing compound and a hydroxyl group-containing compound, as a synthetic intermediate in this disclosure, can be carried out under known reaction conditions. For example, the reaction can be carried out by reacting the 2-fluorofuran ring-containing compound with the hydroxyl group-containing compound in the presence of a base. The hydroxyl group-containing compound may be synthesized or commercially available. Examples of hydroxyl group-containing compounds include the following:

[0069] [ka]

[0070] <Reaction Example 4> Hydrolysis reaction with water

[0071] [ka]

[0072] The aromatic nucleophilic substitution reaction between a 2-fluorofuran ring-containing compound as a synthetic intermediate of this disclosure and water can be carried out under known reaction conditions. For example, a hydrolysis reaction can be carried out by reacting the 2-fluorofuran ring-containing compound with water in the presence of a base.

[0073] Furthermore, due to the high reactivity of the fluorine at the 2-position of 2-fluorofuran ring-containing compounds, various functional groups can be introduced at the 2-position. Examples include primary amino groups and alkyl groups (nucleophilic substitution reactions using alkyllithium).

[0074] Pharmaceuticals, pesticides, or organic electronic materials A first aspect of the pharmaceutical, agrochemical, or organic electronic material of the present disclosure comprises a 2-fluorofuran ring-containing compound produced by the method for producing a 2-fluorofuran ring-containing compound of the present disclosure. A second aspect of the pharmaceuticals, agrochemicals, or organic electronic materials of this disclosure includes compounds derived from 2-fluorofuran ring-containing compounds, produced by the method for producing 2-fluorofuran ring-containing compounds of this disclosure.

[0075] The 2-fluorofuran ring-containing compounds and compounds derived therefrom of this disclosure readily form intermolecular bonds with other molecules (e.g., hydrogen bonds) due to the highly electronegative oxygen atom, intermolecular bonds between the hydrocarbon constituting the ring and other molecules (e.g., hydrophobic bonds), and interactions with aromatic rings of other molecules (e.g., π-π stacking interactions). Furthermore, when a highly reactive fluorine is present at the 2-position of the ring, it decomposes during or after use as a pharmaceutical, agrochemical, or organic electronic material, and is converted to other functional groups such as carboxyl groups, thus making it usable as a prodrug or an environmentally friendly material. Moreover, when a substituent is present at the 2-position of the ring, the above-mentioned effects derived from the ring structure can be easily controlled.

[0076] Examples of pharmaceuticals, pesticides, or organic electronic materials of this disclosure include compounds having fluorine at the 2-position of the furan ring (5), compounds in which the 2-position of the furan ring is substituted (6), compounds having fluorine at the 2-position of the tetrahydrofuran ring (7), or compounds in which the 2-position of the tetrahydrofuran ring is substituted (8). Examples of compounds (5) to (8) include compounds represented by the following formulas (5) to (8).

[0077] [ka]

[0078] In formulas (5) to (8), R 1 and R 2 Examples include those similar to those mentioned above, and R 3 This represents a C1-C20 hydrocarbon group, a C1-C20 alkylamino group, a C2-C20 dialkylamino group, a C1-C20 alkoxy group, or a polar functional group, which may have substituents. R 3 In this context, the C1-C20 hydrocarbon group which may have substituents is R 1 You can use the same things as those listed above. R 3R is a group formed by removing fluorine at position 2 of compound (5), and is linked to the carbon atom at position 2 of the furan ring of compound (5) by a carbon-carbon bond, a carbon-oxygen bond, or a carbon-nitrogen bond. For example, R 3 This is a group that can be formed by the above reaction examples 1 to 4, etc.

[0079] Compound (7) can be synthesized by catalytic hydrogenation of compound (5). Catalytic hydrogenation can be carried out under known reaction conditions. Compound (8) can be synthesized by catalytic hydrogenation of compound (6). Catalytic hydrogenation can be carried out under known reaction conditions.

[0080] Compounds (5) to (8) may also be pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesirable toxic effects. Examples of such salts include acid addition salts and base addition salts. Examples of acid addition salts include salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid, as well as non-toxic organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of base addition salts include salts derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, and non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0081] The molecular weight of compounds (5) to (8) as pharmaceuticals, pesticides, or organic electronic materials is preferably 300 to 800, more preferably 350 to 700, and even more preferably 400 to 600. When the molecular weight of compounds (5) to (8) is within the above range, they tend to exhibit favorable pharmacokinetics and are more easily metabolized in the body, thus reducing toxicity.

[0082] The pharmaceuticals of this disclosure may contain pharmaceutically acceptable antioxidants. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintenance of the required particle size in the case of dispersions, and the use of surfactants.

[0083] The pharmaceuticals of this disclosure, compounds (5) to (8), or their pharmaceutically acceptable salts, may also be useful in treating further disorders involving abnormal expression, ligand / receptor interactions, activation, or signaling events related to various kinases. These disorders include neuronal, glial, astrocyte, hypothalamic, and other glandular, macrophage, epithelial, stromal, and blastocoel disorders involving abnormal function, expression, activation, or signaling of tyrosine kinases. For example, they can be used as inhibitors of one or more kinases selected from the group consisting of MAPK, PDGFR, Src, PAK, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met. The pharmaceuticals of this disclosure can be used to treat or prevent abnormal cell proliferation such as cancer and neurodegenerative diseases. The term "cancer" means precancerous conditions, non-malignant cancers, low-grade cancers, high-grade cancers, and malignant cancers. Any histological type of cancer is envisioned for treatment or prevention with the compounds disclosed herein. Exemplary types of cancer include cell carcinoma, lymphoma, blastoma, sarcoma, leukemia, and lymphoid neoplasms. More specifically, in certain embodiments, cancers include lung cancers, including squamous cell carcinoma (e.g., squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancers, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (livercancer), bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer (hepatic carcinoma), anal cancer, penile cancer, and head and neck cancers. Examples of neurodegenerative diseases include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, which result from the neurodegenerative process. The pharmaceutical products disclosed herein may contain excipients, carriers, and other optional components.

[0084] The pesticides disclosed herein have desirable toxicity to warm-blooded animals, exhibit good environmental compatibility, are suitable for protecting plants and plant organs from biological and abiotic stressors, are suitable for increasing yields, are suitable for improving the quality of harvested products, and are suitable for controlling pests encountered in agriculture, horticulture, livestock farming, aquatic cultivation, forests, gardens and recreational facilities, in the protection of stored products and materials, and in the field of hygiene, particularly insects, arachnids, helminths, especially nematodes and mollusks. The pesticides disclosed herein may optionally be used as herbicides, phytotoxicity reducers, growth regulators, or plant property enhancers at specific concentrations or application rates, or as microbicides or gametocides, for example, as fungicides, antifungal agents, bactericidal agents, or virucidal agents (including those acting on viroids), or as agents acting on MLOs (mycoplasma-like organisms) and RLOs (rickettsia-like organisms). The pesticides disclosed herein may optionally contain surfactants, carriers, etc.

[0085] The organic electronic materials of this disclosure are polyfurans or oligofurans having conjugated chains, which can be used, for example, as materials for nanoscale devices used in solar cells, organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), organic light-emitting transistors (OLETs), batteries, electron-emitting materials, or sensors.

[0086] In the first embodiment of the pharmaceuticals, agrochemicals, or organic electronic materials of this disclosure, the content of the 2-fluorofuran ring-containing compound is preferably 80% by mass or more, more preferably 80-100% by mass, and even more preferably 90-100% by mass, based on the total mass of the pharmaceuticals, agrochemicals, or organic electronic materials. When the content of the 2-fluorofuran ring-containing compound is within the above range, the effects of the 2-fluorofuran ring-containing compound are more easily obtained. In a second embodiment of the pharmaceuticals, agrochemicals, or organic electronic materials of this disclosure, the content of the compound derived from the 2-fluorofuran ring-containing compound is preferably 80% by mass or more, more preferably 80-100% by mass, and even more preferably 90-100% by mass, based on the total mass of the pharmaceuticals, agrochemicals, or organic electronic materials. When the content of the compound derived from the 2-fluorofuran ring-containing compound is within the above range, the effects of the compound are more easily obtained.

[0087] ≪Methods for producing pharmaceuticals, pesticides, or organic electronic materials≫ The method for producing pharmaceuticals, pesticides, or organic electronic materials of this disclosure involves reacting the formyl group (aldehyde group) of the starting material with 1-bromo-2,2-difluorovinyllithium and acetic anhydride, then eliminating lithium acetate by a 1,2-elimination reaction to convert it into a 1,1-difluoroalene compound (1) represented by the following formula (1), and The present invention includes obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from the aforementioned 1,1-difluoroalene compound (1) and an aldehyde compound (2) represented by the following formula (2).

[0088] [ka]

[0089] [ka]

[0090] In equations (1), (2), and (5), R 1 and R 2 The same examples mentioned above can be cited.

[0091] The starting material having a formyl group is preferably a starting material or synthetic intermediate for pharmaceuticals, agrochemicals, or organic electronic materials. The formyl group can be formed, for example, by oxidation of a hydroxyl group or reduction of a carboxyl group. The molecular weight of the starting material having a formyl group is sufficient as long as the molecular weight of the final product is around 500. For example, 50 to 300 is preferred, 100 to 250 is more preferred, and 150 to 200 is even more preferred. When the molecular weight of the starting material is within the above range, it is easy to handle and the reaction conditions for conversion to the 1,1-difluoroalene compound (1) can be easily adjusted. The reaction conditions for converting to the 1,1-difluoroalene compound (1) are similar to those described above. Examples of aldehyde compounds (2) include those similar to those mentioned above. The reaction conditions for obtaining the 2-fluorofuran ring-containing compound (5) are similar to those described above.

[0092] The method for producing pharmaceuticals, pesticides, or organic electronic materials of this disclosure may further include removing the fluorine atom bonded to the carbon at position 2 of the 2-fluorofuran ring-containing compound (5) to form a carbon-carbon bond, a carbon-oxygen bond, or a carbon-nitrogen bond. Examples of reactions that form carbon-carbon bonds, carbon-oxygen bonds, or carbon-nitrogen bonds include those similar to those described in Reaction Examples 1 to 4 above.

[0093] The methods for producing pharmaceuticals, pesticides, or organic electronic materials of this disclosure may further include catalytic hydrogenation for reducing a furan ring to a tetrahydrofuran ring. [Examples]

[0094] The present disclosure will be specifically illustrated by the following examples, but this disclosure is not limited to these examples.

[0095] 1-1. Solvents and Reagents THF and DMF were passed through an activated alumina column, followed by drying through a Q-5 scavenger (Engelhard). Toluene was dried by passing it through an activated alumina column (Engelhard). 1,2-Dichloroethane was distilled from CaH2 and stored on molecular sieve 4A. AuCl, AuCl3, and AuCl(IPr) were purchased from MerckKGaA and used as received. AuCl(Johnphos) was prepared according to the method described in the literature [Mauleon, P.; Zeldin, RM; Gonzalez, AZ; Toste, FDJ Am. Chem. Soc. 2009, 131, 6348-6349.]. AgSbF6 was purchased from Tokyo Chemical Industry Co., Ltd. and used as received. Molecular sieves 4A were purchased from MerckKGaA, dried under microwave irradiation (3 minutes), and further flame-dried in the reaction vessel immediately before use. 1,5,7-Triazabicyclo[4.4.0]deca-5-ene (TBD) was purchased from Tokyo Chemical Industry Co., Ltd. and used as received. 1,1-Difluoroalene 1a was prepared by the method described in the literature [Fuchibe, K.; Abe, M.; Oh, K.; Ichikawa. J. Org. Synth. 2016, 93, 353-366]. α,α,α-Trifluorotoluene ( 19 The internal standard for F-NMR quantitative analysis was purchased from Tokyo Chemical Industry Co., Ltd. and used as is. The spectral data for 1,1-difluoroalene 1a is as described in the reference [Oh, K.; Fuchibe, K.; Ichikawa, J. Synthesis 2011, 2011, 881-886].

[0096] 1-2. Reaction vessel and purification All reactions were carried out in flame-dried flasks under an argon atmosphere. The gold catalyst and silver salt were handled and weighed in a glove box. Column chromatography and preparative thin-layer chromatography were performed using silica gel or Florisil (60N silica gel and Florisil, Kanto Chemical, for column chromatography; Wakogel B-5F, Wako Pure Chemical Industries, for preparative thin-layer chromatography). Purification was also performed by preparative HPLC (GPC) using a JAILC-908 apparatus (Jaigel-2H column, CHCl3).

[0097] 1-3.Analysis IR spectra were recorded using Horiba FT-300S, Jasco FT / IR-4100, and Jasco FT / IR-4600 spectrometers. NMR spectra were recorded using Bruker Avance500 and Jeol JMNESC-400 spectrometers in CDCl3 at 500 or 400 MHz. 1 H-NMR), 126 or 101 MHz ( 13 ¹¹C-NMR), and 471 or 376MHz ( 19 The chemical shift was recorded by F-NMR. 1 For H-NMR: δ=0.00), CDCl3( 13 For C-NMR: δ=77.0), and C6F6( 19 For F-NMR: δ=0.0; C6F6 is -162.9 ppm relative to CFCl3. 19 The values ​​are shown in ppm for the F-NMR signal. High-resolution mass spectrometry (HRMS) was performed using a Jeol JMS-T100GCV instrument (EI, TOF).

[0098] 2. Synthesis of 2,2-difluorodihydrofuran ring-containing compounds <Manufacturing Example 1> Synthesis of 2,2-difluoro-5-phenyldihydrofuran ring-containing compounds

[0099] [ka]

[0100] Compounds containing a 2,2-difluoro-5-phenyldihydrofuran ring were synthesized by changing the type of metal catalyst. From the results obtained, it was found that gold-containing compounds were preferred in terms of high yield and low raw material recovery. [Table 1]

[0101] <Manufacturing Example 2> Synthesis of 2,2-difluoro-5-(p-methylphenyl)dihydrofuran ring-containing compounds

[0102] [ka]

[0103] Compounds containing a 2,2-difluoro-5-phenyldihydrofuran ring were synthesized by changing the type of reaction solvent. From the results obtained, it was found that 1,2-dichloroethane and chlorobenzene were preferred in terms of high yield and low raw material recovery.

[0104] [Table 2]

[0105] <Manufacturing Example 3> Synthesis of 2,2-difluoro-5-(p-methylphenyl)dihydrofuran ring-containing compounds

[0106] [ka]

[0107] Compounds containing a 2,2-difluoro-5-phenyldihydrofuran ring were synthesized by changing the type of silver-containing compound. From the results obtained, it was found that silver antimonate hexafluoride (AgSbF6), silver hexafluoride phosphate (AgPF6), and bis(trifluoromethanesulfonyl)imide silver (AgNTf2) were preferred in terms of high yield and low raw material recovery.

[0108] [Table 3]

[0109] 3. Synthesis of 2-fluorofuran ring-containing compounds <Example 1> Synthesis of 5-fluoro-3-(2-phenylethyl)-2-phenylfuran (5a)

[0110] [ka]

[0111] A 1,2-dichloroethane suspension (4 mL) containing AuCl(IPr) (9.3 mg, 15 μmol), AgSbF6 (5.2 mg, 15 μmol), and MS 4A (120 mg) was to be mixed with a 1,2-dichloroethane solution (3 mL) of 1,1-difluoroalene 1a (59 mg, 0.33 mmol) and benzaldehyde 2a (36 mg, 0.30 mmol) at room temperature. After stirring at room temperature for 0.5 hours, the reaction mixture was cooled to -10°C. To a solution containing difluorotetrahydrofuran 4a, a solution of 1,2-dichloroethane (3 mL) containing AlCl3 (40 mg, 0.30 mmol) and 1,5,7-triazabicyclo[4.4.0]deca-5-ene (TBD, 63 mg, 0.45 mmol) was added dropwise (for 5 minutes). After stirring at 10°C for 24 hours, the reaction was quenched by adding phosphate buffer (pH=7, 15 mL). The organic matter was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were washed with brine, dried on anhydrous Na2SO4, and filtered. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / toluene = 10:1) to obtain a mixture of 2-fluorofuran 5a and 2-chlorofuran 6a (46 mg, yield 50%, 5a / 6a = 83:17) as a colorless oil.

[0112] Spectral data of 5-fluoro-2-phenyl-3-(2-phenylethyl)furan (5a)

[0113] [ka]

[0114] Compound 5a 1 H-NMR spectrum, 13 1C NMR spectrum, and 19 The F-NMR spectra are shown in Figures 1-3, respectively. 1H-NMR (CDCl3,500MHz):δ 7.35(d,J=8.0Hz,2H),7.27(dd,J=7.7,7.7Hz,2H),7.24-7.09(m,6H),5.28(d,J HF =6.9Hz, 1H), 2.83(s, 4H). 13 C-NMR(CDCl3,126MHz):δ 156.9(d,J CF =276Hz),141.1,139.3,130.6,128.6,128.5,128.4,127.3,126.9,125.4,109.3,84.4(d,J CF =11Hz), 35.9, 28.2. 19 F-NMR(CDCl3,471MHz):δ 47.1(d,J FH (=7Hz). IR (mixture of KBr, 5a and 6a): 2928, 1638, 1604, 1494, 1314, 1002, 694 cm³ -1 . HRMS(EI): m / z calcd. for C 18 H 15 FO[M] + :266.1105;found:266.1116.

[0115] Spectral data of 5-chloro-2-phenyl-3-(2-phenylethyl)furan (6a)

[0116] [ka]

[0117] 1 H-NMR (CDCl3,500MHz): δ 7.40(d,J=8.0Hz,2H),7.28(dd,J=7.1,7.1Hz,2H),7.24-7.19(m,6H),6.03(s,1H),2.83(s,4H). 13C-NMR(CDCl3,126MHz):δ 148.6,135.1,130.5,128.6,128.5,127.3,125.6,125.6,122.8,109.6,35.9,27.8. IR (mixture of KBr, 5a and 6a): 2928, 1638, 1604, 1494, 1314, 1002, 694 cm³ -1 . HRMS(EI): m / z calcd. for C 18 H 15 ClO[M] + :282.0809;found:282.0809.

[0118] <Example 2> Synthesis of 5-fluoro-2-(naphthalene-1-yl)-3-(2-phenylethyl)furan (5b)

[0119] [ka] Except for replacing benzaldehyde 2a with 1-naphthalenealdehyde 2b, and changing the amounts of each reagent used to 1,1-difluoroalene 1a (60 mg, 0.33 mmol), 1-naphthalenealdehyde 2b (47 mg, 0.30 mmol), AuCl(IPr) (9.4 mg, 15 mmol), AgSbF6 (5.3 mg, 15 mmol), MS 4A (120 mg), AlCl3 (40 mg, 0.30 mmol), and TBD (62 mg, 0.45 mmol), and purifying by silica gel column chromatography (SiO2, hexane / toluene = 10:1), a mixture of 2-fluorofuran 5b and 2-chlorofuran 6b (78 mg, yield 82%, 5b / 6b = 93:7) was obtained as a colorless oil in the same manner as in Example 1.

[0120] Spectral data of 5-fluoro-2-(naphthalene-1-yl)-3-(2-phenylethyl)furan (5b)

[0121] [ka]

[0122] For compound 5b 1 the 1H-NMR spectrum, 13 the 13C-NMR spectrum, and 19 the 19F-NMR spectrum are shown in FIGS. 4 to 6, respectively. 1 1H-NMR(CDCl3, 500 MHz): δ 7.79 - 7.69(m, 3H), 7.39 - 7.32(m, 2H), 7.28(t, J = 7.6 Hz, 1H), 7.15 - 6.99(m, 4H), 6.93(d, J HF = 6.8 Hz, 1H), 2.69(t, J = 7.7 Hz, 2H), 2.55(t, J = 7.7 Hz, 2H). 13 13C-NMR(CDCl3, 126 MHz): δ 157.4(d, J CF = 276 Hz), 141.0, 139.1, 129.2, 128.6, 128.4, 128.3, 128.2, 126.4, 125.99, 125.98, 125.8, 125.0, 123.7, 108.5, 83.1(d, J CF = 11 Hz), 36.0, 27.6. 19 19F-NMR(CDCl3, 471 MHz): δ 47.3(d, J FH = 7 Hz). IR(KBr): 2940, 1639, 1601, 1305, 1002, 802, 776 cm -1 . HRMS(EI): m / z calcd. for C 22 H 17 FO[M] + : 316.1261; found: 316.1277.

[0123] <Example 3> Synthesis of 2-(4-chlorophenyl)-5-fluoro-3-(2-phenylethyl)furan (5c)

[0124]

Chemical Structure

[0125] Benzaldehyde 2a was changed to p-chlorobenzaldehyde 2c, and the amounts of each reagent used were changed to 1,1-difluoroarene 1a (70 mg, 0.39 mmol), p-chlorobenzaldehyde 2c (42 mg, 0.30 mmol), AuCl(IPr) (9.4 mg, 15 μmol), AgSbF6 (5.2 mg, 15 μmol), MS 4A (120 mg), AlCl3 (40 mg, 0.30 mmol), and TBD (63 mg, 0.45 mmol). A mixture of 2-fluorofuran 5c and 2-chlorofuran 6c (49 mg, yield 53%, 5c / 6c = 66:34) was obtained as a colorless oil in the same manner as in Example 1, except that it was purified by silica gel column chromatography (SiO2, hexane / toluene = 10:1).

[0126]

Chemical formula

[0127] Spectral data of 2-(4-chlorophenyl)-5-fluoro-3-(2-phenylethyl)furan (5c) For compound 5c 1 1H-NMR spectrum, 13 13C-NMR spectrum, and 19 19F-NMR spectrum are shown in Figures 7 to 9, respectively. 1 1H-NMR (CDCl3, 500 MHz): δ 7.26 - 7.19 (m, 6H), 7.16 - 7.18 (m, 3H), 5.31 (d, J HF = 6.9 Hz, 1H), 2.81 (s, 4H). 13 13C-NMR (CDCl3, 126 MHz): δ 156.9 (d, J CF = 277 Hz), 140.9, 128.8, 128.7, 128.5, 128.4, 126.7, 126.5, 126.3, 122.6, 109.7, 84.6 (d, J CF = 10 Hz), 35.8, 28.2. 19 19F-NMR (CDCl3, 471 MHz): δ 47.8 (d, J FH = 7 Hz). IR(KBr):2933,1638,1487,1314,1093,1009,829,698cm -1 . HRMS(EI):m / z calcd. forC 18 H 14 ClFO[M] + :300.0715;found:300.0721.

[0128] <Example 4> Synthesis of 5-fluoro-2-(4-methylphenyl)-3-(2-phenylethyl)furan (5d)

[0129] [ka]

[0130] Except for replacing benzaldehyde 2a with p-methylbenzaldehyde 2d, and changing the amounts of each reagent used to 1,1-difluoroalene 1a (59 mg, 0.33 mmol), p-methylbenzaldehyde 2d (36 mg, 0.30 mmol), AuCl(IPr) (9.3 mg, 15 mmol), AgSbF6 (5.3 mg, 15 mmol), MS 4A (120 mg), AlCl3 (40 mg, 0.30 mmol), and TBD (63 mg, 0.45 mmol), and purifying by silica gel column chromatography (SiO2, hexane / toluene = 10:1), a mixture of 2-fluorofuran 5d and 2-chlorofuran 6d (68 mg, yield 81%, 5d / 6d = 90:10) was obtained as a colorless oil in the same manner as in Example 1.

[0131] Spectral data of 5-fluoro-2-(4-methylphenyl)-3-(2-phenylethyl)furan (5d)

[0132] [ka]

[0133] Compound 5d 1 H-NMR spectrum,13 13C-NMR spectrum, and 19 19F-NMR spectrum are shown in FIGS. 10 to 12, respectively. 1 1H-NMR (CDCl3, 500 MHz): δ 7.23 - 7.12 (m, 2H), 7.15 - 6.95 (m, 2H), 7.10 - 7.00 (m, 5H), 5.20 (d, J HF = 6.9 Hz, 1H), 2.75 (s, 4H), 2.20 (s, 3H). 13 13C-NMR (CDCl3, 126 MHz): δ 156.6 (d, J CF = 276 Hz), 141.1, 139.5, 136.6, 129.2, 128.4, 128.3, 126.1, 125.4, 121.3, 109.5, 84.2 (d, J CF = 11 Hz), 35.8, 28.1, 21.1. 19 19F-NMR (CDCl3, 471 MHz): δ 45.6 (d, J FH = 7 Hz). IR (KBr): 2923, 2357, 1639, 1313, 1084, 818, 698 cm -1 . HRMS (EI): m / z calcd. for C 19 H 17 FO[M] + : 280.1261; found: 280.1265.

[0134] <Example 5> Synthesis of 5-Fluoro-2-(2-methoxyphenyl)-3-(2-phenylethyl)furan (5e)

[0135]

Chemical formula

[0136] Benzaldehyde 2a was changed to o-methoxybenzaldehyde 2e, and the amounts of each reagent used were changed to 1,1-difluoroarene 1a (60 mg, 0.33 mmol), o-methoxybenzaldehyde 2e (41 mg, 0.30 mmol), AuCl(IPr) (9.1 mg, 15 mmol), AgSbF6 (5.3 mg, 15 mmol), MS 4A (120 mg), AlCl3 (40 mg, 0.30 mmol), and TBD (63 mg, 0.45 mmol). A mixture of 2-fluorofuran 5e and 2-chlorofuran 6e (74 mg, yield 82%, 5e / 6e = 97:3) was obtained as a colorless oil in the same manner as in Example 1, except that it was purified by silica gel column chromatography (SiO2, hexane / toluene = 10:1).

[0137] Spectral data of 5-fluoro-2-(2-methoxyphenyl)-3-(2-phenylethyl)furan (5e)

[0138]

Chemical formula

[0139] For compound 5e 1 1H-NMR spectrum, 13 13C-NMR spectrum, and 19 19F-NMR spectrum are shown in Figures 13 to 15, respectively. 1 1H-NMR (CDCl3, 500 MHz): δ 7.20 (ddd, J = 7.9, 7.9, 1.7 Hz, 1H), 7.18 - 7.12 (m, 2H), 7.11 - 7.03 (m, 4H), 7.11 - 7.03 (m, 2H), 5.27 (d, J HF = 6.8 Hz, 1H), 3.70 (s, 3H), 2.73 (t, J = 7.9 Hz, 2H), 2.58 (t, J = 7.9 Hz, 2H). 13 13C-NMR (CDCl3, 126 MHz): δ 157.2 (d, J CF=275Hz),156.9,141.6,136.7,131.0,129.6,128.3,128.2,125.9,123.5,120.4,119.2,111.1,83.2(d,J CF (=11Hz), 55.5, 35.9, 27.9. 19 F-NMR(CDCl3,471MHz):δ 47.4(d,J FH (=7Hz). IR(KBr):2935,1642,1494,1094,1026,752,698cm -1 . HRMS(EI): m / z calcd. for C 19 H 17 FO2[M] + :296.1211;found:296.1206.

[0140] <Example 6> Synthesis of 5-fluoro-2-(3-methoxyphenyl)-3-(2-phenylethyl)furan (5f)

[0141] [ka]

[0142] Except for replacing benzaldehyde 2a with m-methoxybenzaldehyde 2f, and changing the amounts of each reagent used to 1,1-difluoroalene 1a (60 mg, 0.33 mmol), m-methoxybenzaldehyde 2f (41 mg, 0.40 mmol), AuCl(IPr) (9.1 mg, 15 mmol), AgSbF6 (5.4 mg, 15 mmol), MS 4A (120 mg), AlCl3 (40 mg, 0.30 mmol), and TBD (63 mg, 0.45 mmol), and purifying by silica gel column chromatography (SiO2, hexane / toluene = 10:1), a mixture of 2-fluorofuran 5f and 2-chlorofuran 6f (56 mg, yield 63%, 5f / 6f = 88:12) was obtained as a colorless oil in the same manner as in Example 1.

[0143] Spectral data of 5-fluoro-2-(3-methoxyphenyl)-3-(2-phenylethyl)furan (5f)

[0144] [ka]

[0145] Compound 5f 1 H-NMR spectrum, 13 1C NMR spectrum, and 19 The F-NMR spectra are shown in Figures 16-18, respectively. 1 H-NMR (CDCl3,500MHz):δ 7.23-7.15(m,3H),7.14-7.08(m,3H),6.96-6.90(m,2H),6.71(dd,J=8.3,1.7Hz,1H),5.27(d,J HF =6.9Hz,1H),3.71(s,3H),2.82(s,4H). 13 C-NMR(CDCl3,126MHz):δ 159.7,156.8(d,J CF =276Hz),141.1,139.1,131.8,129.6,128.5,128.4,126.2,122.4,117.8,110.8,109.7,84.5(d,J CF (=11Hz), 55.2, 35.8, 28.2. 19 F-NMR(CDCl3,471MHz):δ 47.2(d,J FH (=7Hz). IR(KBr):2931,1638,1494,1316,1218,781,698cm -1 . HRMS(EI): m / z calcd. for C 19 H 17 FO2[M] + :296.1211;found:296.1211.

[0146] <Example 7> Synthesis of 5-fluoro-2-(4-methylphenyl)-3-(2-phenylethyl)furan (5d)

[0147] [Chemical formula]

[0148] To a suspension of AuCl(IPr) (8.3 mg, 13 μmol), AgSbF6 (4.1 mg, 12 μmol), and MS 4A (140 mg) in 1,2-dichloroethane (3.5 mL) was added a solution of 1,1-difluoroarene 1a (54 mg, 0.3 mmol) and p-methylbenzaldehyde 2d (36 mg, 0.3 mmol) in 1,2-dichloroethane (3 mL) at room temperature. After stirring at room temperature for 0.5 h, it was filtered through silica gel (eluent: dichloromethane). To a solution containing difluorotetrahydrofuran 4d was added a solution of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 63 mg, 0.45 mmol) in N,N-dimethylformamide (2 mL). After heating to 35 °C and stirring for 39 h, phosphate buffer (pH = 7, 10 mL) was added to quench the reaction. The organic matter was extracted with hexane / ethyl acetate = 5:1 (3 × 10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and filtered. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / toluene = 10:1) to obtain 2-fluorofuran 5d (21 mg, yield 25%, 5d / 6d = 100:0) as a colorless oil.

[0149] <Example 8> Synthesis of 5-fluoro-3-(2-phenylethyl)-2-phenylfuran (5a)

[0150] [Chemical formula]

[0151] A 10 mL suspension of 1,2-dichloroethane containing AuCl(IPr) (16 mg, 25 μmol), AgSbF6 (16 mg, 45 μmol), and MS 4A (1.8 g) was to be mixed with a 10 mL solution of 1,1-difluoroalene 1a (978 mg, 5.4 mmol) and benzaldehyde 2a (480 mg, 4.5 mmol) in 1,2-dichloroethane at room temperature. After stirring at room temperature for 0.5 hours, the reaction mixture was filtered through silica gel (eluent: ethyl acetate / triethylamine = 100:3). Potassium t-butoxide (563 mg, 5.0 mmol) was added to a tetrahydrofuran solution (18 mL) containing difluorotetrahydrofuran 4d. After stirring at 0°C for 0.5 hours, the reaction was quenched with saturated ammonium chloride aqueous solution (40 mL). The organic matter was extracted with CH2Cl2 (3 × 40 mL). The combined extracts were washed with brine, dried on anhydrous Na2SO4, and filtered. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / toluene = 10:1) to obtain 2-fluorofuran 5a (247 mg, yield 71%, 5a / 6a = 100:0) as a colorless oil. [Industrial applicability]

[0152] The method for producing 2-fluorofuran ring-containing compounds according to this disclosure is of high industrial value because it allows for the production of 2-fluorofuran ring-containing compounds, which are useful as final products of pharmaceuticals or agrochemicals, or as synthetic intermediates, using 1,1-difluoroarene compounds or 2,2-difluorodihydrofuran ring-containing compounds derived therefrom as starting materials, with a short reaction process and high yield.

Claims

1. A method for producing a 2-fluorofuran ring-containing compound, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 1,1-difluoroalene compound (1) represented by the following formula (1) and an aldehyde compound (2) represented by the following formula (2). 【Chemistry 1】 In equations (1), (2), and (5), R １ R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. ２ This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

2. A method for producing a 2-fluorofuran ring-containing compound, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from a 2,2-difluorodihydrofuran ring-containing compound (4) represented by the following formula (4). 【Chemistry 2】 In equations (4) and (5), R １ R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. ２ This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

3. A method for producing a 2-fluorofuran ring-containing compound according to claim 1, comprising, in obtaining the 2-fluorofuran ring-containing compound (5), a gold-containing compound and a silver-containing compound are used to carry out a cycloaddition reaction between the 1,1-difluoroalene compound (1) and the aldehyde compound (2) to obtain a 2,2-difluorodihydrofuran ring-containing compound (4) represented by (4) below. 【Transformation 3】 In formula (4), R １ R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. ２ This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

4. A method for producing a 2-fluorofuran ring-containing compound according to claim 2, comprising, in obtaining the 2-fluorofuran ring-containing compound (5), aromatizing the 2,2-difluorodihydrofuran ring-containing compound (4) in the presence of a base to obtain the 2-fluorofuran ring-containing compound (5).

5. A compound represented by the following chemical formula (5), produced by the method for producing a 2-fluorofuran ring-containing compound described in any one of claims 1 to 4. 【Chemistry 4】 In formula (5), R １ R represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents. ２ This represents a hydrocarbon group having 1 to 20 carbon atoms, which may have substituents.

6. A synthetic intermediate for pharmaceuticals, agrochemicals, or organic electronic materials, comprising a 2-fluorofuran ring-containing compound produced by the method for producing a 2-fluorofuran ring-containing compound according to any one of claims 1 to 4.

7. A pharmaceutical, agrochemical, or organic electronic material comprising a 2-fluorofuran ring-containing compound produced by the method for producing a 2-fluorofuran ring-containing compound described in any one of claims 1 to 4.

8. A pharmaceutical, agrochemical, or organic electronic material comprising a compound derived from a 2-fluorofuran ring-containing compound, produced by the method for producing a 2-fluorofuran ring-containing compound according to any one of claims 1 to 4.

9. The process involves reacting the formyl group of the starting material with 1-bromo-2,2-difluorovinyllithium, then reacting it with acetic anhydride, and subsequently eliminating lithium acetate by a 1,2-elimination reaction to convert it into a 1,1-difluoroarene compound (1) represented by the following formula (1), and A method for producing pharmaceuticals, pesticides, or organic electronic materials, comprising obtaining a 2-fluorofuran ring-containing compound (5) represented by the following formula (5) from the 1,1-difluoroalene compound (1) and an aldehyde compound (2) represented by the following formula (2). 【Transformation 5】 In formulas (1), (2) and (5), R １ represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, and R ２ represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent.

10. Furthermore, the method for producing a pharmaceutical, agrochemical, or organic electronic material according to claim 9, comprising removing the fluorine atom bonded to the carbon at position 2 of the 2-fluorofuran ring-containing compound (5) to form a carbon-carbon bond, a carbon-oxygen bond, or a carbon-nitrogen bond.

11. Furthermore, the method for producing a pharmaceutical, agrochemical, or organic electronic material according to claim 9 or 10, comprising catalytic hydrogenation for reducing a furan ring to a tetrahydrofuran ring.

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