Fluorine-containing pyridone compound and method for producing same

Abstract

Provided are a novel fluorine-containing pyridone compound and a method for producing the same. A fluorine-containing pyridone compound represented by general formula (1). In general formula (1), X represents CO (OmR2), Son (OmR2), PO (OmR2) (OlR3), CN or NO2, Y represents R4, OR4 or NR4R5, R1-R5 each independently represent a hydrocarbon group having 1-12 carbon atoms, l and m each independently represent 0 or 1, and n is 1 or 2. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to fluoropyridone compounds and methods for producing the same. Background Art

[0002] Compounds having a 2-pyridone ring are known to have various pharmacological effects. Among them, compounds having a 2-pyridone ring with a substituent introduced at the nitrogen atom in the 1-position have particularly excellent pharmacological effects and are thus widely used mainly in the fields of medicine and pesticides.

[0003] As examples of compounds having a 2-pyridone ring with a substituent introduced at the 1-position, as natural products, there can be mentioned Factumycin and Goldinomycin having a main protease inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Sambutoxin and Funiculosin having a pantothenol-cytochrome c reductase inhibitory effect, Heneicomycin and Efrotomycin having an elongation factor Tu inhibitory effect, Nudifloric acid having an inhibitory effect on transcription factors AP-1 and NF-κB, Nudiflorine suggesting an organophosphorus agent poisoning effect, Ricininine suggesting an inhibitory effect on casein kinase 1α, and Ricininic acid having a cytotoxic effect on cancer cells, etc.

[0004] In addition, as pharmaceuticals, there can be mentioned Ravoxertinib and Merestinib as anti-tumor agents, Fenebrutinib as an autoimmune disease therapeutic agent, Doravirine as an antiviral agent, Siremadlin and Pirfenidone as anti-fibrotic agents, Alvelestat as an anti-inflammatory agent, Eribaxaban as an anti-thrombotic agent, Perampanel as an anti-epileptic drug, and Embusartan, Emakalim, and Bimakalim as antihypertensive agents, etc.

[0005] In order to produce a compound having a 2-pyridone ring with a substituent introduced at the nitrogen atom at the 1-position, when attempting to introduce a substituent at the nitrogen atom at the 1-position of the 2-pyridone ring, it sometimes competes with the introduction of a substituent at the oxygen atom at the 2-position. This problem is particularly significant when the introduced substituent is a carbon substituent. Methods for introducing a carbon substituent at the nitrogen atom at the 1-position of the 2-pyridone ring are reported in Non-Patent Documents 1 to 3.

[0006] Prior Art Documents

[0007] Non-Patent Documents

[0008] Non-Patent Document 1: Organic Letters, 2021, Vol. 23, pp. 1038 - 1043;

[0009] Non-Patent Document 2: The Journal of Organic Chemistry, 2018, Vol. 83, pp. 6769 - 6775;

[0010] Non-Patent Document 3: Synthesis, 2018, Vol. 50, pp. 1699 - 1710. Summary of the Invention

[0011] Problems to be Solved by the Invention

[0012] However, a fluorinated pyridone compound having a substituent at the nitrogen atom at the 1-position and a trifluoromethyl group at the 5-position may be promising not only in the fields of medicine / pesticides but also in the field of organic electronic materials science. However, the reported examples of such compounds are extremely limited. In addition, when studying the manufacturing method of such a compound, in view of the method reported in Non-Patent Document 1, since ketosulfoxonium ylides are used, the introduced substituent is limited to a ketomethylene group; in the method reported in Non-Patent Document 2, it is considered difficult to introduce an aryl group at the 1-position, and due to the dislocation process caused by the acidic substance generated in the reaction system, it may not be suitable for introducing a substituent having an acid-sensitive moiety; in the method reported in Non-Patent Document 3, since the selectivity greatly depends on the structure of the introduced substituent, it may not be possible to quantitatively obtain the target product due to the structure of the substituent, etc. There is a need for a new manufacturing method with fewer restrictions.

[0013] The present invention provides a novel fluorinated pyridone compound and a method for producing the same.

[0014] Means for Solving the Problems

[0015] The gist of the present invention is as follows.

[0016] [1] A fluoropyridone compound represented by the following general formula (1).

[0017] [Chemical Formula 1]

[0018]

[0019] (In the above general formula (1),

[0020] X represents CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN or NO2,

[0021] Y represents R 4 , OR 4 or NR 4 R 5 ,

[0022] R 1 ~R 5 each independently represents a hydrocarbon group having 1 to 12 carbon atoms,

[0023] l and m are each independently 0 or 1,

[0024] n is 1 or 2.)

[0025] [2] A fluoropyridone compound represented by the above general formula (1).

[0026] (In the above general formula (1),

[0027] X represents CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN or NO2,

[0028] Y represents a phenyl, benzyl, tolyl or naphthyl group capable of bonding to one or more alkoxy groups having 1 to 5 carbon atoms,

[0029] R 1 ~R 3 each independently represents a hydrocarbon group having 1 to 12 carbon atoms,

[0030] l and m are each independently 0 or 1,

[0031] n is 1 or 2.)

[0032] [3] A method for manufacturing a fluoropyridone compound, comprising: a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutene derivative represented by the following general formula (2) with a compound represented by the following general formula (3).

[0033] [Chemical formula 2]

[0034]

[0035] (In the above general formulas (1) to (3), X, Y and R 1 are as defined above.)

[0036] [4] A method for manufacturing a fluoropyridone compound, comprising: a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3).

[0037] [Chemical formula 3]

[0038]

[0039] (In the above general formulas (1), (3) and (4), X, Y and R 1 are as defined above,

[0040] Z represents a halogen atom, OCO(O k R 6 ) or O k SO i (O j R 6 ),

[0041] R 6 represents a hydrocarbon group having 1 to 10 carbon atoms,

[0042] j and k are each independently 0 or 1,

[0043] i is 1 or 2.)

[0044] Advantages of the Invention

[0045] According to the present invention, a novel fluoropyridone compound and a method for manufacturing the same can be provided. Detailed Embodiments

[0046] [Fluoropyridone Compound]

[0047] The fluoropyridone compound of the present invention is represented by the following general formula (1).

[0048] [Chemical formula 4]

[0049]

[0050] (In the above general formula (1),

[0051] X represents CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN or NO2,

[0052] Y represents R 4 , OR 4 or NR 4 R 5 ,

[0053] R 1 ~R 5 each independently represents a hydrocarbon group having 1 to 12 carbon atoms,

[0054] l and m are each independently 0 or 1,

[0055] n is 1 or 2.)

[0056] The fluoropyridone compound of the present invention has a substituent on the nitrogen atom at the 1-position and a trifluoromethyl group at the 5-position. It has been reported that similar pyridone compounds having a substituent on the nitrogen atom at the 1-position exhibit excellent activities in the pharmaceutical / pesticide fields. Therefore, the fluoropyridone compound of the present invention can be expected to have the same activities as its substitutes. In addition, the fluoropyridone compound of the present invention also contains multiple modifiable substitution sites (specifically, the 3-position, 4-position, and 6-position can be modified), and thus has high structural expandability. Therefore, the fluoropyridone compound of the present invention is expected to be an intermediate that can be converted into various compounds with high activities.

[0057] As R 1 ~R 5A hydrocarbon group having 1 to 12 carbon atoms, each independently represented, is not particularly limited as long as it is a hydrocarbon group composed of carbon atoms and hydrogen atoms having 1 to 12 carbon atoms, and examples thereof include a linear hydrocarbon group, an aromatic hydrocarbon group, and an alicyclic hydrocarbon group. The linear hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 1 to 12, and it may be a straight-chain hydrocarbon group or a branched-chain hydrocarbon group. The aromatic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 6 to 12, and it may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group not having a substituent. In addition, the aromatic hydrocarbon group may have a fused polycyclic structure. The alicyclic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 3 to 12, and it may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group not having a substituent. In addition, the alicyclic hydrocarbon group may have a bridged ring structure.

[0058] As R 1 ~R 5 Examples of the linear hydrocarbon group represented by ~R

[0059] As R 1 ~R 5 Examples of the aromatic hydrocarbon group represented by ~R

[0060] As R 1 ~R 5 Examples of the alicyclic hydrocarbon group represented by ~R

[0061] As R 1 is preferably a linear hydrocarbon group or an aromatic hydrocarbon group, more preferably a linear hydrocarbon group, still more preferably a linear hydrocarbon group having 1 to 6 carbon atoms, particularly preferably methyl, ethyl, n-propyl or n-butyl, and most preferably methyl.

[0062] As R 2 and R 3, each independently is preferably a chain hydrocarbon group or an aromatic hydrocarbon group, more preferably a chain hydrocarbon group, still more preferably a chain hydrocarbon group having 1 to 6 carbon atoms, particularly preferably a methyl group, an ethyl group, a n-propyl group or a n-butyl group, and most preferably a methyl group.

[0063] As R 4 and R 5 , each independently is preferably a chain hydrocarbon group or an aromatic hydrocarbon group, more preferably a chain hydrocarbon group having 1 to 6 carbon atoms or an aromatic hydrocarbon group having 6 to 10 carbon atoms, particularly preferably a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a phenyl group, a benzyl group or a tolyl group, and most preferably a methyl group or a phenyl group.

[0064] X can be any group as long as it is selected from the group consisting of CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN and NO2. When X is CO(O m R 2 ), m is preferably 1. When X is SO n (O m R 2 ), m is preferably 0 and n is preferably 2. When X is PO(O m R 2 )(O l R 3 ), l is preferably 0 and m is preferably 1. Among them, X is preferably SO n (O m R 2 ), NO2, CO(O m R 2 ), or CN, more preferably CO(O m R 2 ), or CN, still more preferably CN.

[0065] Y can be any group as long as it is selected from the group consisting of R 4 , OR 4 and NR 4 R 5 . Among them, Y is preferably R 4 or OR 4 , more preferably R 4 .

[0066] [Method for manufacturing fluoropyridone compound]

[0067] As a specific example of the method for producing the fluoropyridone compound of the present invention, the following method (a) or (b) can be cited.

[0068] (a) A method having a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutene derivative represented by the following general formula (2) with a compound represented by the following general formula (3).

[0069] [Chemical formula 5]

[0070]

[0071] (In the above general formulas (1) to (3), X, Y and R 1 are as defined above.)

[0072] (b) A method having a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3).

[0073] [Chemical formula 6]

[0074]

[0075] (In the above general formulas (1), (3) and (4), X, Y and R 1 are as defined above,

[0076] Z represents a halogen atom, OCO (O k R 6 ) or O k SO i (O j R 6 ),

[0077] R 6 represents a hydrocarbon group having 1 to 10 carbon atoms,

[0078] j and k are each independently 0 or 1,

[0079] i is 1 or 2.)

[0080] Generally, the synthetic methods of fluorine-containing compounds can be roughly divided into methods starting from raw materials originally containing fluorine (modular method, building block approach) and methods for newly introducing fluorine into compounds. The former method is characterized in that the position of fluorine introduction depends on the raw materials. In addition, in the latter method, most of the raw materials can only use substituents that can coexist under the reaction conditions for fluorine introduction, and it is necessary to pre-introduce "labels" such as bromine and iodine at the position of fluorine introduction, resulting in poor efficiency. In the manufacturing method of the present invention, by adopting the method of (a) or (b) above, a novel fluorine-containing pyridone compound (the fluorine-containing pyridone compound of the present invention) in which fluorine is introduced at a position that is difficult to introduce in the existing methods can be obtained. The manufacturing method of the present invention is a modular method and can effectively obtain the fluorine-containing pyridone compound of the present invention.

[0081] When Z is a halogen atom, the halogen atom is F, Cl, Br or I, preferably F or Cl, more preferably F. When Z is OCO(O k R 6 ) or O k SO i (O j R 6 ), R 6 represents a hydrocarbon group having 1 to 10 carbon atoms. As the hydrocarbon group having 1 to 10 carbon atoms, for example, the hydrocarbon groups having 1 to 10 carbon atoms among the hydrocarbon groups listed in the above description of R 1 ~R 5 can be cited. When Z is OCO(O k R 6 ), k is preferably 0. When Z is O k SO i (O j R 6 ), i is preferably 2, j is preferably 0, and k is preferably 1.

[0082] The compounds represented by the above general formulas (2), (3) and (4) can use commercially available compounds or compounds manufactured by known methods and the like.

[0083] In the methods of (a) and (b) above, the reaction can be carried out in the presence of an organic solvent. As the organic solvents that can be used, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane, monoglyme, diglyme, triglyme, and tetraglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile; aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylpropyleneurea, tetramethylurea, dimethyl sulfoxide, and sulfolane can be cited.

[0084] In the methods of (a) and (b) above, the reaction can be carried out in the presence of a basic substance. Examples of the basic substance that can be used include alkali metal / alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, magnesium hydroxide, and barium hydroxide; alkali metal / alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; metal hydrides such as sodium hydride, potassium hydride, and calcium hydride; tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, diazabicycloundecene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 2-tert-butyl-1,1,3,3-tetramethylguanidine, and N,N-dimethylaniline; phosphazene bases such as 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, etc.

[0085] In the methods of (a) and (b) above, the reaction temperature is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 - 50°C, and further preferably 10 - 30°C. The reaction time in the methods of (a) and (b) above is preferably 0.5 - 48 hours, more preferably 1 - 36 hours, and further preferably 10 - 25 hours.

[0086] The embodiments of the present invention have been described above, but the present invention is not limited to the above embodiments, and various changes can be made within the scope of the present invention, including all modes included in the concept of the present invention and the claims.

[0087] Examples

[0088] Hereinafter, the present invention will be further specifically described by way of examples, etc., but the present invention is not limited by any of these examples, etc.

[0089] (Example 1)

[0090] [Preparation of 3-cyano-6-fluoro-4-methoxy-1-phenyl-5-(trifluoromethyl)pyridin-2-one]

[0091] Under ice-water cooling, 1.0 g (6.2 mmol) of N-phenyl-2-cyanoacetamide and 1.5 g (7.1 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene were added to 30 g of acetonitrile. Then, 5.1 g (19 mmol) of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine was added dropwise in such a manner that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature. After about 16 hours, the content was purified by column chromatography to obtain 0.1 g of the compound shown by the following formula (chemical formula: C 14 H8F4N2O2, molecular weight: 312.22 g / mol). The isolated yield was 5%.

[0092] [Chemical Formula 7]

[0093]

[0094] The analysis results are as follows.

[0095] Mass spectrometry (APCI, m / z): 312 ([M] + )

[0096] (Example 2)

[0097] [Preparation of 3-Cyano-6-fluoro-4-methoxy-1-methyl-5-(trifluoromethyl)pyridin-2-one]

[0098] Under ice-water cooling, 1.0 g (10 mmol) of N-methyl-2-cyanoacetamide and 2.8 g (12 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethylpropane were added to 30 g of acetonitrile. Then, 11 g (40 mmol) of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, column purification of the content was carried out to obtain 80 mg of the compound shown by the following formula (chemical formula: C9H6F4N2O2, molecular weight: 250.15 g / mol). The separation yield was 3%.

[0099] [Chemical Formula 8]

[0100]

[0101] The analysis results are as follows.

[0102] Mass spectrometry (APCI, m / z): 250 ([M] + )

[0103] 1 H-NMR (400 MHz, CDCl3) δ ppm: 4.01 (s, 3H), 3.49 (s, 3H)

[0104] (Example 3)

[0105] [Preparation of 3-Cyano-6-fluoro-4-methoxy-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridin-2-one]

[0106] To 15 g of acetonitrile were added 0.5 g (2.5 mmol) of 2-cyano-N-[(4-methoxyphenyl)methyl]acetamide and 0.6 g (2.8 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethylpropane. Subsequently, 1.7 g (7.4 mmol) of tert-butylimino-tris(dimethylamino)phosphine was added dropwise under an ice bath, and the mixture was warmed to room temperature. After 17 hours, the contents were purified by column chromatography to obtain a trace amount of a mixture of the compound represented by the following formula (chemical formula: C 16 H 12 F4N2O3, molecular weight: 356.28 g / mol).

[0107] [Chemical formula 9]

[0108]

[0109] The analysis results are as described below.

[0110] Mass spectrometry (APCI, m / z): 355.7 ([M] + )

[0111] (Example 4)

[0112] [Preparation of 3-cyano-6-fluoro-4-methoxy-(phenylmethyl)-5-(trifluoromethyl)pyridin-2-one]

[0113] To 15 g of acetonitrile were added 0.5 g (2.9 mmol) of N-benzyl-2-cyanoacetamide and 0.7 g (3.3 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethylpropane. Subsequently, 2.0 g (8.7 mmol) of tert-butylimino-tris(dimethylamino)phosphine was added dropwise under an ice bath, and the mixture was warmed to room temperature. After 18 hours, the contents were purified by column chromatography to obtain a trace amount of a mixture of the compound represented by the following formula (chemical formula: C 15 H 10 F4N2O2, molecular weight: 326.25 g / mol).

[0114] [Chemical formula 10]

[0115]

[0116] The analysis results are as described below.

[0117] Mass spectrometry (APCI, m / z): 325.9 ([M] + )

[0118] As described above, the novel fluorinated pyridone compound of the present invention can be produced without problems.

[0119] Industrial applicability

[0120] The fluoropyridone compound of the present invention can be applied to the fields of medicine / pesticide and organic electronic materials science.

Claims

1. A fluoropyridone compound represented by the following general formula (1), wherein: [Chemical formula 1] In the above general formula (1), X represents CO(O m R 2 )、SO n (O m R 2 )、PO(O m R 2 )(O l R 3 )、CN or NO2, Y represents R 4 、OR 4 or NR 4 R 5 , R 1 ~R 5 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, l and m are each independently 0 or 1, n is 1 or 2.

2. A fluoropyridone compound represented by the following general formula (1), wherein: [Chemical formula 2] In the above general formula (1), X represents CO(O m R 2 )、SO n (O m R 2 )、PO(O m R 2 )(O l R 3 )、CN or NO2, Y represents phenyl, benzyl, tolyl or naphthyl which can be bonded to one or more alkoxy groups having 1 to 5 carbon atoms, R 1 ~R 3 each independently represents a hydrocarbon group having 1 to 12 carbon atoms l and m are each independently 0 or 1, n is 1 or 2.

3. A method for producing a fluoropyridone compound, comprising: a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutene derivative represented by the following general formula (2) with a compound represented by the following general formula (3), [Chemical formula 3] In the above general formulas (1) to (3), X represents CO(O m R 2 )、SO n (O m R 2 )、PO(O m R 2 )(O l R 3 )、CN or NO2, Y represents R 4 , OR 4 or NR 4 R 5 , R 1 ~R 5 Each independently represents a hydrocarbon group having 1 to 12 carbon atoms, l and m are each independently 0 or 1, n is 1 or 2.

4. A method for producing a fluoropyridone compound, comprising: a step of obtaining a fluoropyridone compound represented by the following general formula (1) by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3), [Chemical formula 4] In the above general formulas (1), (3) and (4), X represents CO(O m R 2 )、SO n (O m R 2 )、PO(O m R 2 )(O l R 3 )、CN or NO2, Y represents R 4 , OR 4 or NR 4 R 5 , Z represents a halogen atom, OCO(O k R 6 ) or O k SO i (O j R 6 ) R 1 ~R 5 each independently represents a hydrocarbon group having 1 to 12 carbon atoms R 6 represents a hydrocarbon group having 1 to 10 carbon atoms, j, k, l and m are each independently 0 or 1, i and n are each independently 1 or 2.

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