Fluorine-containing pyridone compound and method for producing the 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 to R5 each independently represent a C1 to 12 hydrocarbon group, l and m each independently are 0 or 1, and n is 1 or 2.)

Description

[Technical Field]

[0001] The present invention relates to a fluorine-containing pyridone compound and a method for producing the same. [Background technology]

[0002] Compounds with a 2-pyridone ring are known to have various pharmacological effects. Among them, compounds with a 2-pyridone ring with a substituent at the 1-nitrogen atom have particularly excellent pharmacological effects and are therefore widely used, mainly in the pharmaceutical and agrochemical fields.

[0003] Examples of compounds with a 2-pyridone ring substituted at the 1-position include natural products such as factumycin and goldinomycin, which inhibit the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); sambutoxin and funiculosin, which inhibit ubiquinol-cytochrome c reductase; heneicomycin and efrotomycin, which inhibit elongation factor Tu; nudifloric acid, which inhibits the transcription factors AP-1 and NF-κB; nudiflorine, which has been suggested to have antidote effects for organophosphate poisoning; ricinine, which has been suggested to inhibit casein kinase 1α; and ricinic acid, which has a cytocidal effect on cancer cells.

[0004] In addition, examples of pharmaceuticals include antitumor agents such as ravoxertinib and merestinib, autoimmune disease treatment agent such as fenebrutinib, antiviral agent such as doravirine, antifibrotic agents such as siremadlin and pirfenidone, anti-inflammatory agent such as alvelestat, antithrombotic agent such as eribaxaban, antiepileptic drug such as perampanel, and antihypertensive agents such as embusartan, emakalim, and bimakalim.

[0005] When attempting to introduce a substituent onto the nitrogen atom at position 1 of a 2-pyridone ring to produce a compound having the 2-pyridone ring with a substituent introduced onto the nitrogen atom at position 1, the introduction of a substituent onto the nitrogen atom at position 1 may compete with the introduction of a substituent onto the oxygen atom at position 2. This problem is particularly pronounced when the substituent to be introduced is a carbon substituent. Methods for introducing a carbon substituent onto the nitrogen atom at position 1 of a 2-pyridone ring have been reported in Non-Patent Documents 1 to 3. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Organic Letters, 2021, Volume 23, Pages 1038-1043 [Non-patent document 2] The Journal of Organic Chemistry, 2018, Vol. 83, pp. 6769-6775 [Non-patent document 3] Synthesis, 2018, vol. 50, pp. 1699-1710 Summary of the Invention [Problem to be solved by the invention]

[0007] Although fluorine-containing pyridone compounds having a substituent on the nitrogen atom at position 1 and a trifluoromethyl group at position 5 may be promising not only in the fields of pharmaceuticals and agrochemicals but also in the field of organic electronic materials science, there have been very few reported examples of such compounds. Furthermore, in considering a method for producing such compounds, there is a need for a new production method with fewer constraints, considering that the method reported in Non-Patent Document 1 uses a ketosulfoxonium ylide, which limits the substituent to be introduced to a ketomethylene group; the method reported in Non-Patent Document 2 is thought to have difficulty in introducing an aryl group at position 1 and may not be suitable for introducing a substituent having an acid-sensitive site because it involves a rearrangement process caused by an acidic substance generated in the reaction system; and the method reported in Non-Patent Document 3 has selectivity that is highly dependent on the structure of the substituent to be introduced, which may prevent quantitative production of the target product depending on the structure of the substituent.

[0008] The present invention provides a novel fluorine-containing pyridone compound and a method for producing the same. [Means for solving the problem]

[0009] The gist and configuration of the present invention are as follows. [1] A fluorine-containing pyridone compound represented by the following general formula (1):

[0010] [ka]

[0011] (In the above general formula (1), X is CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN or NO2, Y is R 4 , OR4 or NR 4 R 5 represents 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 fluorine-containing pyridone compound represented by the above general formula (1). (In the above general formula (1), X is 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 a phenyl group, a benzyl group, a tolyl group, or a naphthyl group, which may have one or more alkoxy groups having 1 to 5 carbon atoms bonded thereto; 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 fluorine-containing pyridone compound, comprising a step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1):

[0012] [ka]

[0013] (In the above general formulas (1) to (3), X, Y and R 1 is as defined above.) [4] A method for producing a fluorine-containing pyridone compound, comprising a step of reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1):

[0014] [ka]

[0015] (In the above general formulas (1), (3) and (4), X, Y and R 1 is as defined above, Z is a halogen atom, OCO(O k R 6 ) or O k SO i (O j R 6 ) and R 6 represents a hydrocarbon group having 1 to 10 carbon atoms, j and k are each independently 0 or 1; i is 1 or 2.) [Effects of the Invention]

[0016] According to the present invention, a novel fluorine-containing pyridone compound and a method for producing the same can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0017] [Fluorine-containing pyridone compounds] The fluorine-containing pyridone compound of the present invention is represented by the following general formula (1).

[0018] [ka]

[0019] (In the above general formula (1), X is CO(O m R 2 ), SO n (Om R 2 ), PO(O m R 2 )(O l R 3 ), CN or NO2, Y is R 4 , OR 4 or NR 4 R 5 represents 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.

[0020] The fluorine-containing pyridone compound of the present invention has a substituent on the nitrogen atom at position 1 and a trifluoromethyl group at position 5. Similar pyridone compounds with a substituent on the nitrogen atom at position 1 have been reported to exhibit excellent activity in the pharmaceutical and agrochemical fields, and the fluorine-containing pyridone compound of the present invention is expected to have similar activity as a substitute. Furthermore, the fluorine-containing pyridone compound of the present invention has multiple substitution sites that can be further modified (specifically, the 3-, 4-, and 6-positions can be modified), thereby providing high structural flexibility. Therefore, the fluorine-containing pyridone compound of the present invention is also promising as an intermediate that can be converted into a variety of highly active compounds.

[0021] R 1 ~R 5The hydrocarbon group having 1 to 12 carbon atoms represented by each independently is not particularly limited as long as it is a hydrocarbon group having 1 to 12 carbon atoms and consisting of carbon atoms and hydrogen atoms, and examples thereof include a chain hydrocarbon group, an aromatic hydrocarbon group, and an alicyclic hydrocarbon group. The chain hydrocarbon group is not particularly limited as long as it has a total of 1 to 12 carbon atoms, and may be a straight-chain hydrocarbon group or a branched-chain hydrocarbon group. The aromatic hydrocarbon group is not particularly limited as long as it has a total of 6 to 12 carbon atoms, and may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group having no substituent. The aromatic hydrocarbon group may have a fused polycyclic structure. The alicyclic hydrocarbon group is not particularly limited as long as it has a total of 3 to 12 carbon atoms, and may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group having no substituent. The alicyclic hydrocarbon group may have a bridged ring structure.

[0022] R 1 ~R 5 Examples of the chain hydrocarbon group represented by include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, and dodecynyl.

[0023] R 1 ~R 5 Examples of the aromatic hydrocarbon group represented by include a phenyl group, a benzyl group, a tolyl group, and a naphthyl group. The tolyl group may be any of an o-tolyl group, an m-tolyl group, and a p-tolyl group. One or more alkoxy groups having 1 to 5 carbon atoms may be bonded to these aromatic hydrocarbon groups.

[0024] R 1 ~R5 The alicyclic hydrocarbon group represented by the formula (I) includes saturated or unsaturated cyclic hydrocarbon groups. Examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, and a norbornyl group.

[0025] R 1 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, an n-propyl group or an n-butyl group, and most preferably a methyl group.

[0026] R 2 and R 3 are each independently 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, an n-propyl group or an n-butyl group, and most preferably a methyl group.

[0027] R 4 and R 5 are each independently 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, ethyl group, n-propyl group, n-butyl group, phenyl group, benzyl group or tolyl group, and most preferably a methyl group or a phenyl group.

[0028] X is CO(O m R 2 ), SO n (O m R 2 ), PO(O m R 2 )(O l R 3 ), CN, and NO2. X may be any group selected from the group consisting of CO(O m R 2 ), the preferred m is 1. n (Om R 2 ), the preferred m is 0 and the preferred n is 2. m R 2 )(O l R 3 ), the preferred l is 0, and the preferred m is 1. Among them, X is SO n (O m R 2 ), NO2, CO(O m R 2 ) or CN, and CO(O m R 2 ) or CN, more preferably CN.

[0029] Y is R 4 , OR 4 and N.R. 4 R 5 Among them, Y may be any group selected from the group consisting of R 4 OR 4 Preferably, R 4 It is more preferable that:

[0030] [Method of producing fluorine-containing pyridone compound] Specific examples of the method for producing the fluorine-containing pyridone compound of the present invention include the following method (a) or (b).

[0031] (a) A method comprising the step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1):

[0032] [ka]

[0033] (In the above general formulas (1) to (3), X, Y and R 1 is as defined above.)

[0034] (b) A method comprising the step of reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1):

[0035] [ka]

[0036] (In the above general formulas (1), (3) and (4), X, Y and R 1 is as defined above, Z is a halogen atom, OCO(O k R 6 ) or O k SO i (O j R 6 ) and R 6 represents a hydrocarbon group having 1 to 10 carbon atoms, j and k are each independently 0 or 1; i is 1 or 2.)

[0037] In general, methods for synthesizing fluorine-containing compounds can be broadly divided into methods starting from raw materials that originally contain fluorine (building block methods) and methods for newly introducing fluorine into a compound. The former method is characterized by the fact that the position at which fluorine is introduced depends on the raw material. The latter method is less efficient because it can only use raw materials having substituents that are compatible with the reaction conditions for introducing fluorine, and it often requires the prior introduction of a "marker" such as bromine or iodine at the position at which fluorine is introduced. In the production method of the present invention, by employing the above method (a) or (b), a novel fluorine-containing pyridone compound (the fluorine-containing pyridone compound of the present invention) can be obtained in which fluorine is introduced at a position that was difficult to introduce using conventional methods. The production method of the present invention is a building block method, and can efficiently obtain the fluorine-containing pyridone compound of the present invention.

[0038] 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 ), then R 6 represents a hydrocarbon group having 1 to 10 carbon atoms. Examples of the hydrocarbon group having 1 to 10 carbon atoms include the above-mentioned R 1 ~R 5 Among the hydrocarbon groups mentioned in the explanation of the above, hydrocarbon groups having 1 to 10 carbon atoms can be mentioned. k R 6 ), the preferred k is 0. k SO i (O j R 6 ), preferably i is 2, preferably j is 0, and preferably k is 1.

[0039] The compounds represented by the above general formulas (2), (3) and (4) may be commercially available compounds or compounds produced by known methods.

[0040] In the above methods (a) and (b), the reaction may be carried out in the presence of an organic solvent. Examples of the organic solvent that can be used include ethers such as tetrahydrofuran, diethyl ether, dioxane, monoglyme, diglyme, triglyme, and tetraglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile; and aprotic polar solvents such as dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethyleneurea, tetramethylurea, dimethyl sulfoxide, and sulfolane.

[0041] In the above methods (a) and (b), the reaction may 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; and phosphazene bases such as 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine.

[0042] The reaction temperature in the above methods (a) and (b) is preferably −20° C. or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50° C., and even more preferably 10 to 30° C. The reaction time in the above methods (a) and (b) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.

[0043] Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, but includes all aspects encompassed by the concept of the present invention and the scope of the claims, and can be modified in various ways within the scope of the present invention. [Example]

[0044] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0045] Example 1 [Production of 3-cyano-6-fluoro-4-methoxy-1-phenyl-5-(trifluoromethyl)pyridin-2-one] 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. Subsequently, 5.1 g (19 mmol) of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After approximately 16 hours, the contents were purified with a column to obtain the compound represented by the following formula (chemical formula: C 14 0.1 g of H8F4N2O2 (molecular weight: 312.22 g / mol) was obtained in an isolated yield of 5%.

[0046] [ka]

[0047] The analysis results were as follows: Mass spectrum (APCI, m / z): 312 ([M] + )

[0048] Example 2 [Production of 3-cyano-6-fluoro-4-methoxy-1-methyl-5-(trifluoromethyl)pyridin-2-one] 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. Subsequently, 11 g (40 mmol) of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine was added dropwise, ensuring that the internal temperature did not exceed 10°C, and the mixture was allowed to warm to room temperature. After approximately 16 hours, the contents were purified using a column chromatography to obtain 80 mg of the compound represented by the following formula (chemical formula: CHFNO, molecular weight: 250.15 g / mol). The isolation yield was 3%.

[0049] [ka]

[0050] The analysis results were as follows: Mass spectrum (APCI, m / z): 250 ([M] + ) 1 H-NMR(400MHz,CDCl3)δppm:4.01(s,3H),3.49(s,3H)

[0051] Example 3 [Production of 3-cyano-6-fluoro-4-methoxy-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridin-2-one] 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 were added to 15 g of acetonitrile. Subsequently, 1.7 g (7.4 mmol) of tert-butylimino-tris(dimethylamino)phosphorane was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature. After 17 hours, the contents were purified by column chromatography to obtain a mixture of compounds represented by the following formula (chemical formula: C 16 H 12 Trace amounts of F4N2O3 (molecular weight: 356.28 g / mol) were obtained.

[0052] [ka]

[0053] The analysis results were as follows: Mass spectrum (APCI, m / z): 355.7 ([M] + )

[0054] Example 4 [Production of 3-cyano-6-fluoro-4-methoxy-1-(phenylmethyl)-5-(trifluoromethyl)pyridin-2-one] To 15 g of acetonitrile, 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 were added. Subsequently, 2.0 g (8.7 mmol) of tert-butylimino-tris(dimethylamino)phosphorane was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature. After 18 hours, the contents were purified by column chromatography to obtain a mixture of compounds represented by the following formula (chemical formula: C 15 H 10 Trace amounts of F4N2O2 (molecular weight: 326.25 g / mol) were obtained.

[0055] [ka]

[0056] The analysis results were as follows: Mass spectrum (APCI, m / z): 325.9 ([M] + )

[0057] From the above, it is clear that the novel fluorine-containing pyridone compound of the present invention can be produced without any problems. [Industrial Applicability]

[0058] The fluorine-containing pyridone compound of the present invention can be suitably used in the fields of medicine and agrochemicals and organic electronic materials science.

Claims

1. A fluorine-containing pyridone compound represented by the following general formula (1): 【Chemical 1】 (In the above general formula (1), X is CO(O ｍ R ２ ), SO ｎ (O ｍ R ２ ), PO(O ｍ R ２ ) (O ｌ R ３ ), CN or NO ２ represents Y represents R 4 ; R １ R to R 4 each independently represent 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 fluorine-containing pyridone compound represented by the following general formula (1): 【Chemistry 2】 (In the above general formula (1), X is CO(O ｍ R ２ ), SO ｎ (O ｍ R ２ ), PO(O ｍ R ２ ) (O ｌ R ３ ), CN or NO ２ represents Y represents a phenyl group, a benzyl group, a tolyl group, or a naphthyl group, which may have one or more alkoxy groups having 1 to 5 carbon atoms bonded thereto; 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 fluorine-containing pyridone compound, comprising a step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1): 【Chemistry 3】 (In the above general formulas (1) to (3), X is CO(O ｍ R ２ ), SO ｎ (O ｍ R ２ ), PO(O ｍ R ２ ) (O ｌ R ３ ), CN or NO ２ represents Y represents R 4 ; R １ R to R 4 each independently represent 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 fluorine-containing pyridone compound, comprising a step of reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (3) to obtain a fluorine-containing pyridone compound represented by the following general formula (1): 【Chemistry 4】 (In the above general formulas (1), (3) and (4), X is CO(O ｍ R ２ ), SO ｎ (O ｍ R ２ ), PO(O ｍ R ２ ) (O ｌ R ３ ), CN or NO ２ represents Y represents R 4 ; Z is a halogen atom, OCO(O ｋ R ６ ) or O ｋ SO ｉ (O ｊ R ６ ) and R １ R to R 4 each independently represent 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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