Method for regioselectively constructing nitrogen aromatic compound C2 full-carbon quaternary carbon center and application

Abstract

The invention relates to the technical field of organic chemistry and medicinal chemistry, in particular to a method for regioselectively constructing a nitrogen aromatic compound C2 full-carbon quaternary carbon center and application. According to the specific technical scheme, N-amino salt of an electron-deficient aza-aromatic compound reacts with alpha-substituted aldehyde at the temperature of-78 DEG C to 150 DEG C in the presence of alkali, an oxidizing agent and an organic solvent, and then the C2-site quaternary carbon substituted aza-aromatic compound can be synthesized. According to the invention, the pyridine C2-position all-carbon quaternary carbon substituted product can be directly synthesized from pyridine, and the method has the advantages of few reaction steps, mild conditions, high yield, high regioselectivity, simple operation and the like. In addition, the compound shows significant inhibitory activity on gouty inflammatory factors and plant pathogens such as rice sheath blight disease and wheat scab, and can be used for development of drugs and / or pesticides.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry and medicinal chemistry, and particularly relates to a method for region-selectively constructing a C2 all-carbon quaternary carbon center of a nitrogen aromatic compound and application. BACKGROUND

[0002] Pyridine is the most common aromatic heterocyclic compound, and is a basic skeleton in pharmaceuticals, agrochemicals and material science. C2-substituted pyridine, especially C2-alkylated pyridine, is widely present in biologically active compounds and catalysts. For example, the analgesic drug oxycodone approved for marketing by FDA in 2020, the antiarrhythmic drug propylamine, interleukin 17 inhibitor, and the chiral bridged pyridine-oxazoline ligand (mepPyox) used in asymmetric catalysis all have quaternary carbon substitution skeleton at the C2 position of pyridine. Therefore, developing an efficient method for directly diversifying its structure is of great importance for obtaining complex and high-value derivatives. For this purpose, selective C-H functionalization provides a simplified approach to achieve region-selective modification at different positions (C2, C3 and C4), which is of great significance to molecular innovation in related fields.

[0003] At present, although the problem of site (C2, C4, C6) selectivity of pyridine has been solved, the problem of low region selectivity of such reactions has not been effectively solved when there is a substituent at the C3 position or C3, C5 position of pyridine. Especially for substituted pyridine compounds containing quaternary carbon centers (especially all-carbon substituted quaternary carbon centers) at the C2 / C6 position. The construction of such all-carbon substituted quaternary carbon centers relies on the traditional method of 2-halogenated pyridine aromatic nucleophilic substitution (S N Ar), 2-halogenated pyridine aromatic nucleophilic substitution can be used to synthesize the corresponding compounds, but there are still problems in the synthesis of such compounds when there is a substituent at the C3 position or C3, C5 position of pyridine, such as difficulty in controlling the region selectivity; there are also problems such as the use of toxic reagents and too harsh conditions. Therefore, in recent years, some other roundabout strategies have been developed. Most of them are constructed by specific substrates or synthesized from scratch, which have poor substrate universality and cannot synthesize pyridine derivatives with diverse structures, which is in sharp contrast to the wide application of pyridine in active drugs, natural products, pesticides and functional materials. Therefore, it is of great theoretical significance and application value to develop new strategies for region-selective functionalization modification of pyridine and to achieve efficient construction of pyridine with quaternary carbon center at the C2 position.

[0004] Therefore, developing greener and more efficient synthetic strategies, such as using simple starting materials like aldehydes and employing highly efficient, atom-economical catalytic processes to selectively construct these compounds, is crucial for enhancing their application in lead compound optimization and pharmacokinetic improvement. However, this still faces significant challenges, especially when pyridine has substituents at the C3 or C3 / C5 positions, often resulting in a mixture of C2 / C6 substituted pyridine compounds. The synthesis of these compounds still suffers from difficulties in controlling regioselectivity. This persistent regioselectivity challenge stands in stark contrast to the widespread use of these compounds in marketed drugs and lead compounds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen-containing aromatic compounds. Using an electron-deficient nitrogen-containing aromatic compound's N-amino salt and an α-substituted aldehyde as raw materials, the method involves stirring with a base in the presence of an oxidant to form a pyridine C2-position quaternary carbon substituted skeleton compound.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention discloses a method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen-containing aromatic compounds. The method involves reacting the N-amino salt of an electron-deficient nitrogen-containing aromatic compound with an α-substituted aldehyde in the presence of a base, an oxidant, and an organic solvent at a temperature of -78°C to 150°C to synthesize a nitrogen-containing aromatic compound with a C2-position quaternary carbon substitution.

[0008] Preferably, an electron-deficient nitrogen-containing aromatic compound is reacted with an electrophilic amination reagent to synthesize an N-amino salt of the electron-deficient nitrogen-containing aromatic compound in situ. Then, in the presence of a base, an oxidant, and an organic solvent, it is reacted with an α-substituted aldehyde at -78°C to 150°C for 0.5 h to 80 h to synthesize a nitrogen-containing aromatic compound with a quaternary carbon substitution at the C2 position.

[0009] Preferably, the base is one of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), tetramethylguanidine (TMG), Cs2CO3, K2CO3, Na2CO3, Li2CO3, K3PO4, K2HPO3, sodium methoxide (NaOMe), sodium ethoxide (NaOEt), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), lithium tert-butoxide (tBuOLi), lithium hexamethyldisilamide (LiHMDS), sodium hexamethyldisilamide (NaHMDS), and potassium hexamethyldisilamide (KHMDS).

[0010] The oxidant is one of peroxide, high-valent iodine reagent, organic nitrogen oxide, or a composite oxidant formed by organic nitrogen oxide and copper / iron salt;

[0011] The organic solvent is one of toluene, 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile (CH3CN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether (Et2O), methyl tert-butyl ether, and dimethyl glycol ether (DME);

[0012] The amount of the base used is 0.1 to 5 equivalents, the amount of the oxidant used is 0.01 to 2 equivalents, and the reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M.

[0013] Preferably, the peroxide is one of tert-butanol peroxide and hydrogen peroxide; the high-valent iodine reagent is one of 2-iodobenzoic acid, Dys-Martin oxidant, iodobenzene diacetate, and bis(trifluoroacetic)iodobenzene; the organic nitrogen oxide is tetramethylpiperidine oxide, 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide, 4-amino-2,2,6,6-tetramethylpiperidine oxide, and 9-azabicyclo[3.3.1]nonane-N-oxyalkylene oxide. One of the following: the copper salt / iron salt is one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, Fe(NO3)3·9H2O, FeCl2, and FeCl3, and the amount of the copper salt / iron salt is from 0.01 equivalents to 2 equivalents.

[0014] Preferably, the electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrophenylhydroxylamine and its substitutes;

[0015] The substitute for O-benzenesulfonyl hydroxylamine is one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine.

[0016] The alternative to the O-alkylsulfonyl hydroxylamine is one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine;

[0017] The alternative to the O-benzoyl hydroxylamine is one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine.

[0018] The alternative to O-nitrophenylhydroxylamine is one of O-2-nitrophenylhydroxylamine, O-4-nitrophenylhydroxylamine, O-o-nitrophenylhydroxylamine, O-m-nitrophenylhydroxylamine, O-p-nitrophenylhydroxylamine, and O-2,4-dinitrophenylhydroxylamine.

[0019] Preferably, the electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, and substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkylsulfonate, arylsulfonate, benzoic acid and its derivatives, phenol and its derivatives, halide, sulfate, and phosphate.

[0020] Accordingly, a method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen aromatic compounds produces pyridine C2-position quaternary carbon-substituted skeleton compounds, wherein the general structural formula of the pyridine C2-position quaternary carbon-substituted skeleton compound is any one of the following:

[0021]

[0022] Among them, R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

[0023] Preferably, when R 1 R 2 When each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs X Substituents of the substituents;

[0024] And / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent Rs X Substituents of the substituents;

[0025] R X It is any one of hydrogen atom, alkyl, fluoroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide;

[0026] Preferably, when R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7 Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 These atoms can form rings through carbon chains and heteroatoms.

[0027] Accordingly, a pharmaceutical composition comprises the pyridine C2-quaternary carbon-substituted skeleton compound, or a stereoisomer, tautomer, or salt thereof, or a prodrug molecule thereof, and a medically or pesticide-acceptable carrier.

[0028] Accordingly, the use of the pyridine C2-position quaternary carbon-substituted skeleton compound or the pharmaceutical composition in the preparation of drugs for treating gouty arthritis or preventing rice sheath blight or wheat scab.

[0029] The present invention has the following beneficial effects:

[0030] ① Under mild conditions, this invention efficiently converts the N-amino salt of an electron-deficient nitrogen-containing aromatic compound into a C2-position quaternary carbon-substituted pyridine nitrogen-containing aromatic compound in one step, thereby greatly shortening the synthesis steps of such compounds and improving the synthesis efficiency.

[0031] ② This type of reaction has high regioselectivity, which reduces the difficulty of separation and purification and further improves the reaction efficiency.

[0032] ③This method can be well applied to the synthesis of other polysubstituted nitrogen-containing aromatic compounds with quaternary carbon centers at the C2 position.

[0033] ④ This method can directly use electron-deficient nitrogen-containing aromatic compounds as raw materials to synthesize polysubstituted nitrogen-containing aromatic compounds with quaternary carbon centers at the C2 position through a two-step one-pot process.

[0034] ⑤ This method can be used to synthesize multiple active drug molecules, greatly simplifying the synthetic route. Attached Figure Description

[0035] Figure 1 EC for compound P2 50 curve;

[0036] Figure 2 EC for compound P3 50 curve. Detailed Implementation

[0037] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] Unless otherwise specified, the technical means used in the implementation examples are conventional means well known to those skilled in the art.

[0039] 1. This invention discloses a method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen-containing aromatic compounds. The method involves reacting the N-amino salt of an electron-deficient nitrogen-containing aromatic compound with an α-substituted aldehyde in the presence of a base, oxidant, and organic solvent at a temperature of -78°C to 150°C to synthesize a pyridine C2-position quaternary carbon-substituted skeleton compound. The reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M.

[0040] The general reaction formula is:

[0041]

[0042] 2. This invention also discloses another method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen-containing aromatic compounds. The method involves reacting an electron-deficient nitrogen-containing aromatic compound with an electrophilic amination reagent to synthesize the N-amino salt of the electron-deficient nitrogen-containing aromatic compound in situ. Then, in the presence of a base, oxidant, and organic solvent, the compound is reacted with an α-substituted aldehyde at -78°C to 150°C for 0.5 h to 80 h to synthesize a pyridine C2-position quaternary carbon-substituted skeleton compound. The reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M. The amount of the electron-deficient nitrogen-containing aromatic compound used is 0.5 equivalents to 1.5 equivalents, and the amount of the electrophilic amination reagent is 0.8 equivalents to 1.5 equivalents.

[0043] The general reaction formula is:

[0044]

[0045] In both methods described above, the alkali, oxidant, and organic solvent used are the same. Specifically, the alkali is an organic or inorganic alkali, including but not limited to triethylamine (TEA or Et3N), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,5-diazabicyclo[4.3.0]-5-nonene (DBN). The base is selected from the following: tetramethylguanidine (TMG), Cs₂CO₃, K₂CO₃, Na₂CO₃, Li₂CO₃, K₃PO₄, K₂HPO₃, sodium methoxide (NaOMe), sodium ethoxide (NaOEt), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), lithium tert-butoxide (tBuOLi), lithium hexamethyldisilamide (LiHMDS), sodium hexamethyldisilamide (NaHMDS), and potassium hexamethyldisilamide (KHMDS). The amount of the base used is from 0.1 equivalents to 5 equivalents.

[0046] The organic solvent is one of toluene, 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile (CH3CN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether (Et2O), methyl tert-butyl ether, and dimethyl glycol ether (DME).

[0047] The oxidant is one of the following: peroxide, high-valent iodine reagent, organic nitrogen oxide, or a composite oxidant formed by organic nitrogen oxide and copper / iron salt (such as CuBr+TEMPO+O2, CuBr+TEMPO+air, ​​etc.). The amount of the oxidant used is from 0.01 equivalents to 2 equivalents.

[0048] The peroxides include, but are not limited to, one of tert-butanol peroxide (TBHP) and hydrogen peroxide; the high-valent iodine reagents include, but are not limited to, one of 2-iodobenzoic acid (IBX), Dysmartin oxidant (DMP), iodobenzene diacetate (PIDA), and bis(trifluoroacetic)iodobenzene (PIFA); the organic nitrogen oxides include, but are not limited to, tetramethylpiperidine oxide (TEMPO), 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide (4-Oxo-TEMPO), and 4-amino-2,2,6,6-tetramethylpiperidine oxide (4-A The copper / iron salt is one of mino-TEMPO, 9-azabicyclo[3.3.1]nonane-N-oxygen radical (ABNO); the copper / iron salt includes, but is not limited to, one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, Fe(NO3)3·9H2O, FeCl2, and FeCl3, and the amount of the copper / iron salt is 0.01 equivalents to 2 equivalents.

[0049] In the two synthetic methods described above, the electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, or substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkyl sulfonate (such as trifluoromethanesulfonic acid, methanesulfonic acid, p-methylbenzenesulfonic acid, p-nitrobenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, p-bromobenzenesulfonic acid, etc.), aryl sulfonate, benzoic acid and its derivatives (such as p-nitrobenzoic acid, o-nitrobenzoic acid, etc.), phenol and its derivatives (such as o-nitrophenol, p-nitrophenol, m-nitrophenol, 2,4-dinitrophenol, etc.), halide, sulfate, or phosphate.

[0050] The N-amino salts of the aforementioned electron-deficient nitrogen-containing aromatic compounds can undergo displacement reactions with inorganic acids to form corresponding inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, persulfate, and sulfate. Therefore, the corresponding N-amino inorganic acid salts of electron-deficient aromatic compounds are also within the scope of protection of this invention.

[0051] The electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrobenzenesulfonyl hydroxylamine and its substitutes; specifically, the substitutes for O-benzenesulfonyl hydroxylamine include, but are not limited to, one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine; the O-alkyl... The substitutes for benzoyl hydroxylamine include, but are not limited to, one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine; the substitutes for O-benzoyl hydroxylamine include, but are not limited to, one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine; the substitutes for O-nitrophenyl hydroxylamine include, but are not limited to, one of O-2-nitrophenyl hydroxylamine, O-4-nitrophenyl hydroxylamine, O-o-nitrophenyl hydroxylamine, O-m-nitrophenyl hydroxylamine, O-p-nitrophenyl hydroxylamine, and O-2,4-dinitrophenyl hydroxylamine.

[0052] 3. The general structural formula of pyridine C2-position quaternary carbon substituted skeleton compounds constructed by the above-disclosed method for regioselectively constructing nitrogen aromatic compounds with an all-carbon quaternary carbon center at C2 is any one of the following:

[0053]

[0054] Among them, R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

[0055] Furthermore, when R 1 R 2 When each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs XSubstituents of the substituents;

[0056] And / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent Rs X Substituents of the substituents;

[0057] R X It is any one of hydrogen atom, alkyl, fluoroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide;

[0058] Furthermore, when R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 Between them, they can form carbon rings, heterocycles, and aromatic carbon rings and heterocycles through carbon chains, heteroatoms, etc. At the same time, after cyclic formation, they can be substituted by substituents such as halogens.

[0059] 4. A pharmaceutical composition comprising the pyridine C2-quaternary carbon-substituted skeleton compound, or a stereoisomer, tautomer, or salt thereof, or a prodrug molecule thereof, and a medically or pesticide-acceptable carrier.

[0060] 5. The use of the above-mentioned pyridine C2-position quaternary carbon-substituted skeleton compounds or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating gouty arthritis or preventing rice sheath blight or wheat scab.

[0061] The present invention will be further described below with reference to specific embodiments.

[0062] Example 1 Synthesis of 2-(5-acetylpyridin-2-yl)-2-phenylpropionitrile

[0063] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), TEMPO (1.8 mg, 7.5% mmol), Cu(CH3CN)4BF4 (3.3 mg, 7% mmol), sodium methoxide (16.2 mg, 0.3 mmol, 2.0 equiv.), and 1,4-dioxane (1.5 mL) were added to a reaction tube. Then, 2-phenylpropanal (40.3 mg, 0.3 mmol, 2.0 equiv.) was added to the reaction system using a microsyringe. The reaction was placed in an ice-water bath or cooled to 0°C, and an oxygen bulb was inserted. The resulting mixture was heated to 40°C and stirred. TLC was used to monitor the reaction during the process. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane / ethyl acetate = 5:1) to give 2-(5-acetylpyridine-2-yl)-2-phenylpropionitrile P1 (30.4 mg, yield 81%).

[0064] The reaction equation is:

[0065]

[0066] The obtained product P1 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0067] 1H NMR (400MHz, CDCl3) δ9.15 (d, J=2.2Hz, 1H), 8.21 (dd, J=8.2, 2.3Hz, 1H), 7.55 (d ,J=8.3Hz,1H),7.49–7.43(m,2H),7.40–7.28(m,3H),2.63(s,3H),2.21(s,3H). 13 C NMR (101MHz, CDCl3) δ196.00,163.17,149.64,139.52,136.88,131.34,129.11 ,128.33,126.33,122.42,121.64,48.93,26.81,26.65.ESI-HRMS(m / z):[M+H] + calcd for C 16 H 15 N2O:251.1184; found:251.1170.

[0068] Example 2: Yield of P1 when screening different types of alkali

[0069] Screening of bases revealed that organic bases performed better than inorganic bases. Among them, 1,8-diazabicyclo[5,4,0]undecene-7 (DBU) and sodium methoxide (CH3ONa) showed the best results, yielding the target product in 33% and 46% yields, respectively (Table 1, Entries 2, 6). Other organic bases, including DIPEA, triethylamine (TEA), 4-dimethylaminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO), all had yields below 30% (Table 1, Entries 1, 3, 4, 7). Therefore, sodium methoxide was determined as the optimal base for further screening of other conditions.

[0070] Table 1 Screening of bases

[0071]

[0072] a Reaction conditions: under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), Base (0.30 mmol), TEMPO (0.18 mmol), toluene (1.5 mL).

[0073] Add alkali at 0°C and then raise the temperature to 50°C to react; b Separation yield

[0074] Example 3: Yield of P1 when screening different solvents

[0075] Following the synthesis method described in Example 1, after determining the optimal base, a simple screening of solvents was conducted (Table 2). Toluene, which performed well, was considered (Table 2, Entry 1), while highly polar solvents such as trifluoroethanol (TFE) were also tried. The results showed that when TFE was used as the solvent, only trace amounts of product were detected (Table 2, Entry 2). When dioxane was used as the solvent, the reaction time was shortened from 30 h to 18 h, and the separation yield reached 54% (Table 2, Entry 3). When dimethyl sulfoxide (DMSO) was used as the solvent, although the separation yield reached 64% (Table 2, Entry 4), considering the long reaction time, the high boiling point of DMSO, and the difficulty of post-processing, dioxane was chosen as the optimal solvent for the reaction.

[0076] Table 2 Solvent Screening

[0077]

[0078]

[0079] Reaction conditions: Under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), CH3ONa (0.30 mmol), Solvent (1.5 mL)

[0080] Add alkali at 0°C, then raise the temperature to 50°C to react; b Separation yield

[0081] Example 4: Yield of P1 when screening oxidants or co-catalysts

[0082] Referring to the synthesis method in Example 1, for the screening of oxidants or co-catalysts, this invention first screened for tert-butanol peroxide (TBHP) and H2O2, which are relatively common and environmentally friendly oxidants in the laboratory. The results showed that although the reaction yielded the target product in high yields in the presence of both TBHP and H2O2, both required relatively long reaction times (Table 3, Entries 1-2). Simultaneously, commonly used oxidants, high-valent iodine reagents, were also screened, and it was found that the target product was obtained with a 67% separation yield in the presence of 2-iodobenzoic acid (IBX) (Table 3, Entry 3). Recent studies have shown that catalytic amounts of iron or copper salts can act as oxidants to oxidize alcohols to form carbonyl compounds. Therefore, this invention further screened the effects of ferric(III) nitrate nonahydrate (Fe(NO3)3·9H2O) and tetracopper tetrafluoroborate (Cu(CH3CN)4BF4) on the reaction. Surprisingly, both metal salts could catalyze the reaction. When Fe(NO3)3·9H2O was used as a catalyst, the product was obtained in 30% yield (Table 3, Entry 4); while with the combined action of catalytic amounts of Cu(CH3CN)4BF4 and TEMPO, the reaction could obtain the target product with a 74% isolated yield and single regioselectivity (Table 3, Entry 5). Therefore, Cu(CH3CN)4BF4 was selected as the catalyst and TEMPO as the co-oxidant.

[0083] Table 3 Screening of Oxidizing Agents

[0084]

[0085]

[0086] a Reaction conditions: Under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), CH3ONa (0.30 mmol), Oxident (0.18 mmol), Dioxane (1.5 mL),

[0087] Add alkali at 0°C and then raise the temperature to 50°C to react; b Separation yield c [Cu]=Cu(CH3CN)4BF4(7.0mol%), TEMPO(7.5mol%), O2balloon.

[0088] Example 5: Yield of P1 when screening different copper salts

[0089] Following the synthesis method described in Example 1, and after confirming that the addition of copper salts would increase the reaction yield, this invention further screened several common monovalent or divalent copper salts (Table 4). First, the effect of monovalent copper salts with different anions on the reaction was investigated. The results showed that the anionic portion of the copper salt had little effect on the reaction, and the yields of the investigated reactions were between 67% and 71% (Table 4, Entries 1-4). Finally, divalent copper was screened. Compared with monovalent copper, the yield of the reaction decreased and the reaction time increased when divalent copper was used as a catalyst (Table 4, Entry 5). Therefore, monovalent copper salts were selected as the co-catalyst for this reaction.

[0090] Table 4 Screening of copper salts

[0091]

[0092]

[0093] a Reaction conditions: under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), CH3ONa (0.30 mmol), TEMPo (7.5 mol%).

[0094] O2balloon; Dioxane (1.5 mL). Add alkali at 0°C and then raise the temperature to 50°C to react; b Separation yield

[0095] Example 6: Screening the yield of P1 with different TEMPO steric hindrance and electrical properties

[0096] Following the synthesis method of Example 1, the steric hindrance and electronic properties of TEMPO were modified to observe their effects on the reaction yield. Therefore, this invention further investigated several common TEMPO derivatives and the sterically less hindrance 9-azabicyclo[3.3.1]nonane-N-oxy radical (ABNO) (Table 5).

[0097] Table 5 Screening of TEMPO steric resistance and electrical properties

[0098]

[0099]

[0100] a Reaction conditions: under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), CH3ONa (0.30 mmol), Cu(CH3CN)4BF4 (7 mol%).

[0101] O2balloon; Dioxane (1.5 mL) was added to the base at 0 °C, and then the temperature was raised to 50 °C for reaction; b Separation yield.

[0102] Example 7: Screening the yield of P1 at different temperatures

[0103] Following the synthesis method of Example 1, the effect of temperature on the reaction was investigated (Table 6). Experimental results showed that appropriately lowering the temperature was beneficial to increasing the yield; therefore, the reaction conditions at 50℃, 40℃, and 20℃ were screened. At 40℃, the reaction time increased, but the reaction yield reached 81% (Table 6, Entry 2); when the temperature was further lowered to 20℃, the reaction time increased significantly due to the incomplete conversion of the intermediate, and the reaction yield was only 67% (Table 6, Entry 3). Therefore, 40℃ was determined to be the optimal reaction temperature.

[0104] Table 6 Reaction Temperature Screening

[0105]

[0106]

[0107] a Reaction conditions: Under argon protection, 1a (0.15 mmol), 2a (0.30 mmol), CH3ONa (0.30 mmol), Cu(CH3CN)4BF4 (7 mol%),

[0108] TEMPO (7.5 mol%), O2 balloon; Dioxane (1.5 mL), add base at 0 °C, then raise to the appropriate temperature for reaction; b Separation yield.

[0109] Using the synthetic method of Example 1, pyridine C2-position quaternary carbon substituted skeleton compounds P2-P35 were prepared, and their structures and characterizations are as follows:

[0110] P2: Product P2 (67%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-(naphth-2-yl)propionaldehyde.

[0111]

[0112] The obtained product P2 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0113] 1H NMR (400MHz, CDCl3) δ9.18 (d, J=2.2Hz, 1H), 8.20 (dd, J=8.3, 2.3Hz, 1H), 8.04 (d, J=2.0Hz, 1H), 7.90-7.8 4 (m, 1H), 7.82 (d, J=8.5Hz, 2H), 7.60-7.48 (m, 3H), 7.43 (dd, J=8.7, 2.0Hz, 1H), 2.63 (s, 3H), 2.30 (s, 3H). 13 C NMR (101MHz, CDCl3) δ196.00, 163.07, 149.67, 136.91, 136.69, 133.08, 132.75, 131.38, 129.16, 128.29 , 127.62, 126.92, 126.89, 125.31, 123.91, 122.41, 121.86, 49.09, 26.82, 26.54.ESI-HRMS (m / z): [M+Na] + calcd forC 20 H 16 N2ONa: 301.1160; found: 300.1154.

[0114] P3: Product P3 (99%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with indane-2-carboxaldehyde.

[0115]

[0116] The obtained product P3 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0117] 1 H NMR (400MHz, CDCl3) δ9.13 (d, J=2.3Hz, 1H), 8.26 (dd, J=8.3, 2.3Hz, 1H), 7.72 (d, J=8 .3Hz,1H),7.26(s,4H),3.84(d,J=15.9Hz,2H),3.73(d,J=15.9Hz,2H),2.64(s,3H). 13 C NMR(101MHz, CDCl3)δ196.00,162.00,149.81,138.93,136.99,131.58,127.74,124.51,123.52,120.92,49.94,45.88,26.84.ESI-HRMS(m / z):[M+H] + calcd for C 17 H 15N2O:263.1184; found:263.1176.

[0118] P4: Product P4 (80%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 6-oxaspiro[4.5]decane-9-carboxaldehyde.

[0119]

[0120] The obtained product P4 was measured by NMR, and the resulting NMR data are as follows:

[0121] 1 H NMR (400MHz, CDCl3) δ9.1(s,0H),8.3(dt,J=8.3,1.6Hz,1H),7.7(d,J=8.2Hz,1H),4.0(t,J=12.5Hz,1H),3.9(dd,J=12.8,4.6Hz, 1H),2.6(s,3H),2.5–2.4(m,1H),2.4–2.3(m,2H),2.1–2.0(m,2H),1.8(dtt,J=20.6,9.7,4.3Hz,5H),1.6(td,J=9.6,5.1Hz,2H). 13 C NMR (101MHz, CDCl3) δ195.80,162.31,149.59,136.86,131.39,122.29,120.33,82.58, 58.81,42.90,42.60,42.19,34.49,32.59,26.62,24.59,22.13.ESI-HRMS(m / z):[M+H] + calcd for C 17 H 21 N2O2:285.1603; found:285.1600.

[0122] P5: Product P5 (28.8 mg, 76% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-(pyridin-2-yl)propionaldehyde.

[0123]

[0124] The obtained product P5 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0125] 1H NMR (400MHz, CDCl3) δ9.12(d,J=2.1Hz,1H),8.59(d,J=4.9Hz,1H),8.23(dd,J=8.3,2.3Hz,1H),7.73(td,J= 7.8,1.8Hz,1H),7.67(d,J=8.3Hz,1H),7.60(d,J=8.0Hz,1H),7.25–7.22(m,1H),2.61(s,3H),2.26(s,3H). 13 C NMR (101MHz, CDCl3) δ196.02,162.52,157.73,149.68,149.66,137.43,136.86,13 1.38,123.16,122.00,121.53,121.43,51.55,26.80,25.47.ESI-HRMS(m / z):[M+H] + calcd for C 15 H 14 N3O:252.1137; found:252.1129.

[0126] P6: Product P6 (28.6 mg, yield 84%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with cyclohexylformaldehyde.

[0127]

[0128] The obtained product P6 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0129] 1 H NMR (400MHz, CDCl3) δ9.13(d,J=2.3Hz,1H),8.26(dd,J=8.3,2.3Hz,1H),7.72(d,J=8.2Hz,1H),2.64(s,2H),2.15–1.99(m,5H),1.94–1.72(m,5H). 13 C NMR (101MHz, CDCl3) δ196.11,163.71,149.71,136.91,131.41,121.90,120.54,47.11,35.76,29.70,26.77,24.79,23.20.ESI-HRMS(m / z):[M+H] + calcd for C 14 H 17 N2O:229.1341; found:229.1336.

[0130] P7: Product P7 (37.2 mg, 75% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde.

[0131]

[0132] The obtained product P7 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0133] 1 H NMR (400MHz, CDCl3) δ9.13(d,J=2.2Hz,1H),8.28(dd,J=8.2,2.3Hz,1H),7.72(d,J=8.2Hz,1H),4. 29(s,2H),3.19(s,2H),2.64(s,3H),2.22(td,J=13.1,4.3Hz,2H),2.09–2.02(m,2H),1.47(s,9H). 13 C NMR (101MHz, CDCl3) δ195.97,161.89,154.37,149.87,137.12,131.73,120.63,80.22,45.55,34.72,28.41,26.83.ESI-HRMS(m / z):[M+Na] + calcdfor C 18 H 23 N3O3Na:352.1637; found:352.1636.

[0134] P8: Product P8 (27.8 mg, yield 86%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-methylpent-4-enal.

[0135]

[0136] The obtained product P8 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0137] 1 H NMR (400MHz, CDCl3) δ9.14(d,J=2.1Hz,1H),8.25(dd,J=8.3,2.0Hz,1H),7.69(d,J=8.2Hz,1H),5.69(ddt,J=15.4 ,10.2,7.4Hz,1H),5.17–5.08(m,2H),2.89–2.81(m,1H),2.69(dd,J=13.8,7.7Hz,1H),2.64(s,3H),1.76(s,3H).13 C NMR (101MHz, CDCl3) δ196.10,162.48,149.82,136.78,131.49,131.33,122.30,120.92,120.57,44.72,44.60,26.82,25.64.ESI-HRMS(m / z):[M+H] + calcd for C 13 H 15 N2O:215.1184; found:215.1172.

[0138] P9: The product P9 (35.5 mg, 72% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-(thiophen-2-yl)propionaldehyde.

[0139]

[0140] The obtained product P9 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0141] 1 H NMR (400MHz, CDCl3) δ9.16(d,J=2.3Hz,1H),8.25(dd,J=8.3,2.3Hz,1H),7.64(d,J=8.2Hz,1H),7.30(dd ,J=5.2,1.2Hz,1H),7.17(dd,J=3.6,1.3Hz,1H),6.98(dd,J=5.2,3.6Hz,1H),2.64(s,3H),2.26(s,3H). 13 CNMR (101MHz, CDCl3) δ195.90,162.58,149.75,142.89,137.13,131.60,126.9 8,126.64,126.18,121.50,120.73,46.02,28.30,26.83.ESI-HRMS(m / z):[M+H] + calcd for C 14 H 13 N2OS:257.0749; found:257.0737.

[0142] P10: The product P10 (28.6 mg, 90% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with cyclopent-3-ene-1-carboxaldehyde.

[0143]

[0144] The obtained product P10 was measured using a nuclear magnetic resonance spectrometer, and the resulting NMR data are as follows:

[0145] 1 H NMR (400MHz, CDCl3) δ9.14(d,J=2.4Hz,1H),8.26(dd,J=8.2,2.3Hz,1H),7.73(d,J=8.2Hz,1H),5.80(s,2H),3.33-3.13(m,4H),2.64(s,3H). 13 C NMR(101MHz, CDCl3)δ196.01,163.31,149.89,136.93,131.36,127.98,124.01,120.60,47.61,47.07,26.80.ESI-HRMS(m / z):[M+H] + calcd for C 13 H 13 N2O:213.1028; found:213.1026.

[0146] P11: The product P11 (28.1 mg, 84% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with tetrahydropyran-4-carboxaldehyde.

[0147]

[0148] The obtained product P11 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0149] 1 H NMR (400MHz, CDCl3) δ9.15(d,J=2.2Hz,1H),8.28(dd,J=8.3,2.3Hz,1H),7.70(d,J=8.2Hz,1H),4.09(dd,J=12.4, 4.5Hz,2H),3.88(td,J=12.3,1.8Hz,2H),2.64(s,3H),2.38(td,J=13.1,4.5Hz,2H),2.02(dd,J=13.6,2.1Hz,2H). 13 C NMR(101MHz, CDCl3)δ195.99,161.89,149.93,137.12,131.71,121.01,120.52,64.68,44.44,35.05,26.84.ESI-HRMS(m / z):[M+H] + calcd for C 13 H 15N2O2:231.1134; found:230.1135.

[0150] P12: The product P12 (39.6 mg, yield 69%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with cycloheptylformaldehyde.

[0151]

[0152] The obtained product P12 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0153] 1 H NMR (400MHz, CDCl3) δ9.11(d,J=2.2Hz,1H),8.24(dd,J=8.2,2.3Hz,1H),7.72(d,J =8.3Hz,1H),2.63(s,3H),2.29–2.09(m,4H),1.95–1.75(m,6H),1.72–1.59(m,2H). 13 CNMR(101MHz, CDCl3)δ196.13,165.10,149.67,136.89,131.19,122.91,120.14,49.89,39.14,29.70,27.49,26.79,24.08.ESI-HRMS(m / z):[M+H] + calcd for C 15 H 19 N2O:243.1497; found:243.1495.

[0154] P13: The product P13 (35.0 mg, 73% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 3-(4-tert-butylphenyl)-2-methylpropionaldehyde.

[0155]

[0156] The obtained product P13 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0157] 1H NMR (400MHz, CDCl3) δ9.20(d,J=2.3Hz,1H),8.16(dd,J=8.3,2.3Hz,1H),7.52(d,J=8.2Hz,1H),7.23(d,J=8.3Hz,2 H),6.97(d,J=8.3Hz,2H),3.35(d,J=13.5Hz,1H),3.19(d,J=13.4Hz,1H),2.66(s,3H),1.80(s,3H),1.27(s,10H). 13 C NMR (101MHz, CDCl3) δ196.16,162.58,150.34,149.72,136.60,131.93,131.32,129.81,1 25.22,122.47,121.36,46.27,45.92,34.46,31.30,26.82,25.65.ESI-HRMS(m / z):[M+H] + calcd for C 21 H 24 N2ONa:343.1786; found:343.1779.

[0158] P14: The product P14 (39.6 mg, 99%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 4,4-difluorocyclohexane-1-carboxaldehyde.

[0159]

[0160] The obtained product P14 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0161] 1 H NMR (400MHz, CDCl3) δ9.14 (d, J=1.4Hz, 1H), 8.29 (dd, J=8.3, 2.3Hz, 1H), 7.74 (d, J=8.3Hz,1H),2.65(s,3H),2.46(td,J=12.9,12.2,7.8Hz,2H),2.36–2.16(m,6H). 13 CNMR(101MHz,CDCl3)δ195.94,161.36,161.34,149.87,137.14,131.83,1 23.78,121.35,120.68,45.30,32.47,32.37,31.37,31.12,30.87,26.85. 19F NMR(376MHz, CDCl3)δ-93.3,-93.9,-102.2,-102.8.ESI-HRMS(m / z):[M+H] + calcd for C 14 H 15 F2N2O:265.1152; found:264.1142.

[0162] P15: The product P15 (27.5 mg, yield 59%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2,2-diphenylacetaldehyde.

[0163]

[0164] The obtained product P15 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0165] 1 H NMR (400MHz, Chloroform-d) δ9.20 (d, J = 2.2Hz, 1H), 8.24 (dd, J = 8.3, 2.3Hz, 1H), 7.42–7.33 (m, 7H), 7.29–7.20 (m, 4H), 2.64 (s, 3H). 13 C NMR(101MHz, CDCl3)δ195.94,163.02,149.93,138.81,136.67,131.33,128.93,128.73,128.58,123.17,121.94,60.06,26.84.ESI-HRMS(m / z):[M+H] + calcd for C 21 H 17 N2O:313.1431; found:313.1323.

[0166] P16: The product P16 (35.5 mg, 74% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-(4-bromophenyl)propionaldehyde.

[0167]

[0168] The obtained product P16 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0169] 1H NMR (400MHz, CDCl3) δ9.14 (d, J=2.0Hz, 1H), 8.22 (dd, J=8.2, 2.3Hz, 1H), 7.58 (dd, J=8.2,0.8Hz,1H),7.52–7.47(m,2H),7.37–7.32(m,2H),2.63(s,4H),2.18(s,4H). 13 CNMR(101MHz,CDCl3)δ195.89,162.46,149.76,138.59,137.06,132.22,131.4 8,128.10,122.61,121.96,121.45,48.53,26.82,26.63.ESI-HRMS(m / z):[M+H] + calcd forC 16 H 14 BrN2O:329.0290; found:329.0282(For 79 Br).

[0170] P17: The product P17 (30.2 mg, yield 67%) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-(4-bromophenyl)propionaldehyde.

[0171]

[0172] The obtained product P17 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0173] 1 H NMR(400MHz,Chloroform-d)δ9.17(d,J=2.2Hz,1H),8.94(d,J=4.1Hz,1H),8.28–8.13(m,2H) ,8.11–8.03(m,2H),7.70–7.60(m,2H),7.45(dd,J=8.4,4.2Hz,1H),2.63(s,3H),2.31(s,3H). 13 C NMR (101MHz, CDCl3) δ195.88,162.48,151.36,149.78,147.66,137.59,137.05,136.40,131.52,13 0.68,127.97,127.50,125.31,122.12,121.97,121.74,48.94,26.81,26.64.ESI-HRMS(m / z):[M+H] + calcd for C 19 H16 N3O:302.1293; found:302.1277.

[0174] P18: Product P18 (24.5 mg, 71%) was obtained by reacting 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate with 2-phenylpropanal.

[0175]

[0176] The obtained product P18 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0177] 1 H NMR(400MHz, CDCl3) δ9.21(d,J=2.2Hz,1H),8.27(dd,J=8.3,2.2Hz,1H),7.53(d,J=8.3Hz,1H), 7.47–7.42(m,2H),7.40–7.27(m,3H),4.41(q,J=7.1Hz,2H),2.20(s,3H),1.39(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ164.25,162.25,149.98,139.49,139.04,129.23,128.52,12 6.37,126.05,122.10,121.86,61.85,48.66,26.44,14.24.ESI-HRMS(m / z):[M+H] + calcd for C 17 H 17 N2O2:281.1290; found:281.1285.

[0178] P19: The product P19 (16.5 mg, yield 43%) was obtained by reacting 1-amino-3-carbamoylpyridine-1-onium 2,4,6-trimethylbenzenesulfonate with 2-phenylpropanal.

[0179]

[0180] The obtained product P19 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0181] 1H NMR (600MHz, CDCl3) δ9.0 (dd, J=2.3, 0.8Hz, 1H), 8.1 (dd, J=8.3, 2.3Hz, 1H), 7.5 (d d,J=8.3,0.8Hz,1H),7.4–7.4(m,2H),7.4–7.3(m,2H),7.3–7.3(m,1H),2.2(s,3H). 13 C NMR (151MHz, CDCl3) δ166.95,162.27,148.05,139.43,136.77,129.02,128.24,126.25,122.45,121.35,48.77,26.58.

[0182] P20: Product P20 (24.5 mg, 60%) was obtained by reacting 1-amino-3-carbamopyridine 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0183]

[0184] The obtained product P20 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0185] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=2.1Hz,1H),7.73(dd,J=8.1,2.2Hz,1H),7.66(d,J=8.0Hz,1H),3.56(q,J=7.3 Hz,2H),3.28(q,J=7.4Hz,2H),2.37(tt,J=7.7,4.7Hz,4H),2.06–1.93(m,4H),1.28–1.22(m,3H),1.17(m,3H). 13 C NMR(101MHz, CDCl3)δ168.21,159.23,147.16,135.33,131.97,123.96,120.73,49.90,40.09,24.94.ESI-HRMS(m / z):[M+H] + calcd for C 16 H 22 N3O:272.1757; found:272.1759.

[0186] P21: The product P21 (20.1 mg, 54% yield) was obtained by reacting 1'-amino-[2,3'-bipyridine]-1'-onium 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0187]

[0188] The obtained product P21 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0189] 1 H NMR(600MHz, CDCl3) δ9.1(d,J=2.3Hz,1H),8.7(dt,J=4.9,1.3Hz,1H),8.3(dd,J=8.2,2.4Hz,1H) ,7.8(td,J=7.7,1.8Hz,1H),7.7(dd,J=10.7,8.0Hz,2H),7.3–7.3(m,1H),2.4(m,4H),2.0(m,4H). 13 C NMR (151MHz, CDCl3) δ158.53,154.18,150.04,147.93,136.98,135.26,133.81 ,124.08,122.89,120.79,120.47,49.74,40.00,24.84.ESI-HRMS(m / z):[M+H] + calcd for C 16 H 16 N3:250.1344; found:250.1335.

[0190] P22: The product P22 (30.3 mg, 88%) was obtained by reacting 1-amino-4-(methoxycarbonyl)pyridine-1-onium 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0191]

[0192] The obtained product P22 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0193] 1 H NMR (400MHz, CDCl3) δ8.74(d,J=5.0,1H),8.13(s,1H),7.78(d,J=5.0Hz,1H),3.97(s,3H),2.56–2.23(m,4H),2.08–1.95(m,4H). 13 C NMR(101MHz, CDCl3)δ165.24,159.72,150.42,138.52,123.80,122.01,120.16,52.88,50.06,40.11,24.89.ESI-HRMS(m / z):[M+H] + calcd for C 13 H 15N2O2:231.1128; found:231.1123.

[0194] P23: Product P23 (28.3 mg, 51%) was obtained by reacting 1-amino-4-methoxy-3-nitropyridine-1-onium 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0195]

[0196] The obtained product P23 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0197] 1 H NMR (400MHz, CDCl3) δ8.97(s,1H),7.41(s,1H),4.10(s,3H),2.45–2.35(m,4H),2.06–2.00(m,4H). 13 C NMR (101MHz, CDCl3) δ168.80,165.43,159.65,147.20,123.63,106.03,56.93,40.51,31.52,29.72,25.32.ESI-HRMS(m / z):[M+H] + calcd for C 12 H 14 N3O3:248.1035; found:248.1034.

[0198] P24: The product P24 (24.5 mg, 72% yield) was obtained by reacting 1-amino-3-trifluoromethylpyridine 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0199]

[0200] The obtained product P24 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0201] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=2.3Hz,1H),7.96(dd,J=8.3,2.3Hz,1H),7.79(d,J=8.3Hz,1H),2.46-2.35(m,4H),2.07-1.97(m,4H). 13 C NMR(101MHz,CDCl3)δ162.40,146.66(q, 3 J (C,F) =4.0Hz), 134.30(q, 3 J(C,F) =4.0Hz), 125.89(q, 2 J (C,F) =33.3Hz), 124.67, 123.56(q, 1 J (C,F) =273.7Hz),120.86,50.03,40.34,29.72,25.09.ESI-HRMS(m / z):[M+H] + calcd for C 12 H 12 F3N2:241.0953; found:241.0947.

[0202] P25: The product P25 (28.3 mg, 77% yield) was obtained by reacting methyl 1-amino-2-methyl-3-carboxylate pyridine 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0203]

[0204] The obtained product P25 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0205] 1 H NMR (400MHz, CDCl3) δ8.19(d,J=8.1Hz,1H),7.52(d,J=8.1Hz,1H),3.92(s,3H),2.81(s,3H),2.42–2.32(m,4H),2.04–1.95(m,4H). 13 C NMR (101MHz, CDCl3) δ166.64,160.68,160.13,139.44,124.09,123.99,118.04,52.29,49.94,40.12,25.05.ESI-HRMS(m / z):[M+H] + calcd for C 14 H 16 N2O2:245.1285; found:245.1279.

[0206] P26: The product P26 (26.3 mg, 72% yield) was obtained by reacting 1-amino-3-methyl-5-nicotinic acid methyl pyridine 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0207]

[0208] The obtained product P26 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0209] 1 H NMR (400MHz, CDCl3) δ8.93(d,J=2.1Hz,1H),8.11(d,J=2.1Hz,1H),3.94(s,3H),2. 65(s,3H),2.51(ddd,J=8.1,5.4,2.9Hz,4H),2.04-1.90(m,2H),1.90-1.75(m,2H). 13 C NMR (101MHz, CDCl3) δ165.59,159.00,146.95,140.68,132.19,125.27,123.46,52.45,47.74,38.03,24.59,19.91.ESI-HRMS(m / z):[M+H] + calcd for C 14 H 17 N2O2:245.1285; found:245.1284.

[0210] P27: The product P27 (18.9 mg, yield 53%) was obtained by reacting 1-amino-quinoline 2,4,6-trimethylbenzenesulfonate with tetrahydropyran-4-carboxaldehyde.

[0211]

[0212] The obtained product P27 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0213] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=8.6Hz,1H),8.09(d,J=8.5Hz,1H),7.85(d,J=8.1Hz,1H),7.79–7.67(m,2H),7.58(t,J=7.5 Hz,1H),4.21–4.07(m,2H),3.95(td,J=12.3,1.9Hz,2H),2.53(td,J=13.1,12.7,4.5Hz,2H),2.16(dd,J=13.8,2.1Hz,2H). 13 CNMR(101MHz, CDCl3)δ157.47,148.36,137.72,130.11,129.58,127.55,127.12,120.68,118.24,64.87,35.19,29.72.ESI-HRMS(m / z):[M+H] + calcd for C 15 H 15N2O2:239.1179; found:239.1181.

[0214] P28: Product P28 (20.1 mg, yield 53%) was obtained by reacting 1-amino-isoquinoline 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0215]

[0216] The obtained product P28 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0217] 1 H NMR(600MHz,Chloroform-d)δ8.1–8.0(m,1H),7.9(d,J=9.2Hz,1H),7.7(d,J=8.5Hz,1H),7.4(dd, J=9.2,2.8Hz,1H),7.1(d,J=2.8Hz,1H),3.9(s,3H),2.6–2.5(m,2H),2.5(m,2H),2.1–2.0(m,4H). 13 C NMR(151MHz,CHLOROFORM-D)δ158.32,155.90,143.95,136.27,131.20,128.55,12 4.99,122.99,119.64,105.20,55.92,50.43,40.01,25.23.ESI-HRMS(m / z):[M+H] + calcd for C 16 H 17 N2O:253.1341; found:253.1333.

[0218] P29: Product P29 (26.3 mg, yield 72%) was obtained by reacting 1-amino-isoquinoline 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0219]

[0220] The obtained product P29 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0221] 1H NMR (400MHz, CDCl3) δ8.55(dd,J=7.8,1.8Hz,1H),8.44(d,J=5.6Hz,1H),7.88(dd,J=7.5,2.0Hz,1H),7.76–7.66(m ,2H),7.63(d,J=5.6Hz,1H),2.85–2.71(m,2H),2.72–2.58(m,2H),2.02(qt,J=7.9,3.7Hz,2H),1.95–1.80(m,2H). 13 C NMR(101MHz, CDCl3)δ155.92,140.74,137.23,130.03,128.00,127.46,125.93,125.65,125.01,121.53,47.43,38.95,24.74.ESI-HRMS(m / z):[M+H] + calcd for C 15 H 15 N2:223.1230; found:223.1231.

[0222] P30: The product P30 (24.4 mg, yield 52%) was obtained by reacting 1-amino-5-oxo-5H-cyclopentane[2,1-b:3,4-b']dipyridine 2,4,6-trimethylbenzenesulfonate with 2-phenylpropanal.

[0223]

[0224] The obtained product P30 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0225] 1 H NMR (600MHz, CDCl3) δ8.9 (dd, J=5.1, 1.6Hz, 1H), 8.0 (dd, J=7.5, 1.6Hz, 1H), 8.0 (d,J=7.8Hz,1H),7.6–7.5(m,3H),7.4–7.3(m,3H),7.3–7.3(m,1H),2.3(s,3H). 13 C NMR (151MHz, CDCl3) δ188.78,165.22,163.46,163.09,155.38,139.67,132.75,131.82,130.04 ,129.24,128.66,128.41,126.36,125.13,123.66,122.41,49.21,29.77.ESI-HRMS(m / z):[M+H] + calcd for C20 H 14 N3O:312.1137; found:312.1128.

[0226] P31: The product P31 (19.6 mg, yield 48%) was obtained by reacting 1-amino-1,10-phenanthroline 2,4,6-trimethylbenzenesulfonate with cyclopentylformaldehyde.

[0227]

[0228] The obtained product P31 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0229] 1 H NMR (600MHz, CDCl3) δ9.2(dd,J=4.4,1.8Hz,1H),8.3(d,J=8.3Hz,1H),8.3(dd,J=8.0,1.8Hz,1H),8.0 (d,J=8.2Hz,1H),7.8(s,2H),7.6(dd,J=8.0,4.3Hz,1H),2.8(m,2H),2.6–2.5(m,2H),2.2–2.1(m,4H). 13 C NMR (151MHz, CDCl3) δ158.24,150.69,146.10,145.61,137.42,136.36,129.29,127.97 ,127.02,126.34,124.54,123.15,121.45,51.24,39.95,24.68.ESI-HRMS(m / z):[M+H] + calcd for C 18 H 16 N3:274.1344; found:274.1337.

[0230] P32: The product P32 (20.3 mg, 35% yield) was obtained by reacting 1-amino-3-trifluoromethylpyridine 2,4,6-trimethylbenzenesulfonate with 2-[(1H-1,2,4-triazol-1-yl)methyl]hexanal.

[0231]

[0232] The obtained product P32 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0233] 1H NMR (600MHz, CDCl3) δ8.9 (d, J=2.2Hz, 1H), 7.9 (dd, J=8.3, 2.3Hz, 1H), 7.9 (s, 1H) ,7.8(s,1H),7.6(d,J=8.2Hz,1H),4.9(d,J=14.1Hz,1H),4.8(d,J=14.0Hz,1H),2 .3(td,J=12.9,4.5Hz,1H),2.0(td,J=12.9,4.3Hz,1H),1.5(dtt,J=12.9,9.7,4. 5Hz,1H),1.4–1.3(m,2H),1.0(tdd,J=12.9,9.1,4.7Hz,1H),0.9(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3) δ158.04,152.06,146.84,146.82,143.92,134.58,134.55,126.52,126.30,126.05,1 25.52,123.75,122.40,121.95,119.41,55.33,51.09,37.01,26.79,22.19,13.50.ESI-HRMS(m / z):[M+H] + calcd for C 15 H 17 N5F3:324.1436; found:324,1424.

[0234] P33: The product P33 (26.3 mg, 59% yield) was obtained by reacting 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate with 2-[(1H-1,2,4-triazol-1-yl)methyl]hexanal.

[0235]

[0236] The obtained product P33 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0237] 1H NMR (600MHz, CDCl3) δ9.2 (dd, J=2.3, 0.8Hz, 1H), 8.2 (dd, J=8.2, 2.2Hz, 1H), 7.9 ( s,1H),7.8(s,1H),7.6(dd,J=8.2,0.8Hz,1H),4.9(d,J=14.0Hz,1H),4.8(d,J=14 .0Hz,1H),2.6(s,3H),2.3–2.2(m,1H),2.1–2.0(m,1H),1.5(qdd,J=12.8,5.9,4. 5Hz,1H),1.4–1.2(m,2H),1.0(tdd,J=16.0,8.2,4.4Hz,1H),0.8(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3) δ195.87,158.53,152.30,150.17,137.17,131.93,122.78, 119.82,55.65,51.41,37.27,27.09,26.92,22.47,13.77.ESI-HRMS(m / z):[M+H] + calcd for C 16 H 20 N5O:298.1668; found:298.1657.

[0238] P34: The product P34 (25.2 mg, 52% yield) was obtained by reacting 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate with 2-[(1H-1,2,4-triazol-1-yl)methyl]hexanal.

[0239]

[0240] The obtained product P34 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0241] 1H NMR(600MHz, CDCl3)δ9.2(d,J=2.3Hz,1H),8.3(dt,J=8.1,1.9Hz,1H),7.8–7.8(m,2H),7.5( dd,J=8.1,2.9Hz,1H),4.9(dd,J=14.0,2.3Hz,1H),4.8(dd,J=14.1,2.0Hz,1H),4.5–4.4(m,2 H),2.2(td,J=12.8,4.4Hz,1H),2.0(td,J=12.9,4.3Hz,1H),1.5(tdd,J=16.0,10.5,6.0Hz,1 H),1.4–1.4(m,3H),1.3–1.2(m,2H),1.0(dtd,J=16.5,8.9,7.2,3.9Hz,1H),0.9–0.8(m,3H). 13 C NMR (151MHz, CDCl3) δ164.47,158.24,152.16,151.15,144.11,138.51,126.21,122.41, 119.82,61.81,55.58,51.26,37.18,27.00,22.39,14.31,13.71.ESI-HRMS(m / z):[M+H] + calcd for C 17 H 22 N5O2:328.1773; found:328.1763.

[0242] P35: The product P35 (24.3 mg, 45% yield) was obtained by reacting 1-amino-3-benzoylpyridine 2,4,6-trimethylbenzenesulfonate with 2-[(1H-1,2,4-triazol-1-yl)methyl]hexanal.

[0243]

[0244] The obtained product P35 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0245] 1H NMR (600MHz, CDCl3) δ9.1 (d, J=2.2Hz, 1H), 8.1 (dd, J=8.1, 2.2Hz, 1H), 7.9 (s, 1H), 7.9 (s,1H),7.8–7.8(m,2H),7.7–7.6(m,1H),7.6(d,J=8.1Hz,1H),7.5(t,J=7.8Hz,2H),5 .0(d,J=14.0Hz,1H),4.8(d,J=14.0Hz,1H),2.3(td,J=12.9,4.6Hz,1H),2.0(td,J=12 .9,4.4Hz,1H),1.6–1.4(m,1H),1.4–1.3(m,2H),1.1–1.0(m,1H),0.9(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3) δ193.98,157.78,152.21,151.18,144.21,144.20,138.74,136.44,133.60,132. 87,130.06,128.89,122.34,119.87,55.63,51.36,37.25,27.12,22.49,13.80.ESI-HRMS(m / z):[M+H] + calcd for C 21 H 22 N5O:360.1824; found:360.1814.

[0246] Example 8: Two-step one-pot synthesis of 2-(5-acetylpyridin-2-yl)-2-phenylpropionitrile

[0247] 3-Acetylpyridine (1.06 g, 8.8 mmol) was added to a dichloromethane solution (approximately 0.13 M) of O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine (MSH, 11 mmol). After the addition was complete, the mixture was stirred at 0 °C for 10 min. The resulting mixture was then heated to 50 °C under reflux. During the reaction, a solid precipitated, which was monitored by TLC. The reaction was completed in approximately 4 h. The solvent was removed by rotary evaporation, and the residue was rinsed three times with petroleum ether after stirring. The solid was filtered, collected, and vacuum dried to obtain the desired N-aminopyridinium salt. No further purification was required. The obtained N-aminopyridinium salt was added to a 50 mL round-bottom flask. Cu(CH3CN)4BF4 (193.8 mg, 0.62 mmol) and TEMPO (103.1 mg, 0.66 mmol) were added to 30 mL of dioxane, followed by 2-phenylpropanal (2.36 mL, 17.6 mmol). The reaction was placed in an ice-water bath. CH3ONa (950.8 mg, 17.2 mmol) was slowly added to the stirred suspension. After the addition was complete, an oxygen bulb was inserted, and the resulting mixture was heated to 40 °C and stirred. The reaction was monitored by TLC during the reaction. After 35 h of reaction, the mixture was directly concentrated under reduced pressure and purified by column chromatography (n-hexane / ethyl acetate = 15:1-4:1). Finally, 1.54 g of the product was obtained in 70% yield.

[0248] The reaction equation is:

[0249]

[0250] Example 9

[0251] Pyridine C2 quaternary carbon-substituted compounds P1 / P24 (0.2 mmol, 1.0 equiv.) and potassium carbonate (0.6 mmol, 3.0 equiv.) were added to a 10 mL reaction tube, followed by 2 mL of DMSO. The reaction mixture was stirred at 60 °C for 2.5 h. Subsequently, 30% H2O2 solution (0.7 mL, 10.0 equiv.) was slowly added dropwise, and the reaction was continued at the same temperature for 12 h. After the reaction was completed by TLC, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the target products P36 (45.6 mg, 85% yield) / P37 (41.3 mg, 80% yield).

[0252] The reaction equation is:

[0253]

[0254] The obtained product P36 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0255] 1 H NMR (400MHz, CDCl3) δ9.12(d,J=2.3Hz,1H),8.22(dd,J=8.4,2.3Hz,1H),7.51(d,J=8.3Hz,1H ),7.33–7.21(m,3H),7.16–7.09(m,2H),7.01(s,1H),6.04(s,1H),2.62(s,3H),2.00(s,3H). 13 C NMR (101MHz, CDCl3) δ196.28,175.85,167.74,148.86,144.78,136.47,130.55 ,128.64,127.55,127.21,122.66,58.89,26.78,26.00.ESI-HRMS(m / z):[M+Na] + calcd for C 16 H 16 N2O2Na:291.1109; found:291.1100.

[0256] The obtained product P37 was measured using an NMR spectrometer, and the resulting NMR data are as follows:

[0257] 1 H NMR (600MHz, CDCl3) δ8.8(d,J=2.3Hz,1H),7.9(dd,J=8.4,2.4Hz,1H),7.5(d,J=8.3Hz,1H),6.2(NH, s,1H),5.5(NH,s,1H),2.6–2.5(m,2H),2.3–2.2(m,2H),1.9–1.8(m,2H),1.7(tt,J=8.6,2.8Hz,2H). 13 C NMR (151MHz, CDCl3) δ176.31,167.00,145.99,145.97,145.94,145.91,134.06, 134.04,126.35,125.12,124.90,124.54,122.74,121.58,61.91,36.14,24.21.

[0258] Example 10 Activity Test

[0259] An in vitro gout inflammation model was established by stimulating mouse macrophages J774A.1 cells with a combination of lipopolysaccharide (LPS) and adenosine triphosphate (ATP). The release level of interleukin-1β (IL-1β) in the cell supernatant was detected using enzyme-linked immunosorbent assay (ELISA) at a concentration of 20 μM to evaluate the degree of inflammatory response. Due to space limitations, only a selection of compounds from each formula were used for activity testing. The main evaluation index was the release of the inflammatory factor IL-1β, and the inhibition rate is shown in Table 1 below. The results showed that compounds P2 and P3 had EC50... 50 like Figure 1 , Figure 2 As shown, the selected compounds P4, P5, P36, and P37 significantly inhibited the release of IL-1β at a concentration of 20 μM, indicating a certain therapeutic effect on inflammation caused by gout.

[0260] Table 1 shows the inhibition rates of some compounds on gout inflammatory factors.

[0261] Compound VX765 P4 P5 P36 P37 Cell inhibition rate / % 87 62 63 55 40

[0262] Subsequently, using the broad-spectrum fungicide Myclobutanil as a positive control, the inhibitory activity of this type of compound against rice sheath blight and wheat scab was evaluated at a concentration of 50 ppm. The results are shown in Tables 2 and 2.

[0263] Table 2 shows the inhibition rates of some compounds against rice sheath blight.

[0264] Compound VX765 P32 P34 P35 Cell inhibition rate / % 96 61 54 51

[0265] Table 3 shows the inhibition rates of some compounds against wheat scab.

[0266] Compound VX765 P32 P33 P34 P35 Cell inhibition rate / % 100 49 26 56 48

[0267] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for regioselectively constructing a C2 all-carbon quaternary carbon center in nitrogen aromatic compounds, characterized in that: By reacting the N-amino salt of an electron-deficient nitrogen-containing aromatic compound with an α-substituted aldehyde in the presence of a base, oxidant, and organic solvent at a temperature of -78°C to 150°C, a pyridine C2-quaternary carbon-substituted skeleton compound can be synthesized.

2. The method for regioselectively constructing a C2 all-carbon quaternary carbon center of a nitrogen aromatic compound according to claim 1, characterized in that: Electron-deficient nitrogen-containing aromatic compounds are reacted with electrophilic amination reagents to synthesize N-amino salts of electron-deficient nitrogen-containing aromatic compounds in situ. Then, in the presence of alkali, oxidant, and organic solvent, they are reacted with α-substituted aldehydes at -78°C to 150°C for 0.5 h to 80 h to synthesize pyridine C2-position quaternary carbon-substituted skeleton compounds.

3. A method for regioselectively constructing a C2 all-carbon quaternary carbon center of a nitrogen-aromatic compound according to claim 1 or 2, characterized in that: The base is one of the following: triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-5-nonene, tetramethylguanidine, Cs2CO3, K2CO3, Na2CO3, Li2CO3, K3PO4, K2HPO3, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, and potassium hexamethyldisilamide. The oxidant is one of peroxide, high-valent iodine reagent, organic nitrogen oxide, or a composite oxidant formed by organic nitrogen oxide and copper / iron salt; The organic solvent is one of toluene, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether. The amount of the base used is 0.1 to 5 equivalents, the amount of the oxidant used is 0.01 to 2 equivalents, and the reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M.

4. The method for regioselectively constructing a C2 all-carbon quaternary carbon center of a nitrogen aromatic compound according to claim 3, characterized in that: The peroxide is one of tert-butanol peroxide and hydrogen peroxide; the high-valent iodine reagent is one of 2-iodobenzoic acid, Dys-Martin oxidant, iodobenzene diacetate, and iodobenzene di(trifluoroacetic acid); the organic nitrogen oxide is tetramethylpiperidine oxide, 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide, 4-amino-2,2,6,6-tetramethylpiperidine oxide, and 9-azabicyclo[3.3.1]nonane-N-oxy radical. One of the following: the copper salt / iron salt is one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, Fe(NO3)3·9H2O, FeCl2, and FeCl3, and the amount of the copper salt / iron salt used is from 0.01 equivalents to 2 equivalents.

5. The method for regioselectively constructing a C2 all-carbon quaternary carbon center of a nitrogen aromatic compound according to claim 2, characterized in that: The electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrophenylhydroxylamine and its substitutes; The substitute for O-benzenesulfonyl hydroxylamine is one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine. The alternative to the O-alkylsulfonyl hydroxylamine is one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine; The alternative to the O-benzoyl hydroxylamine is one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine. The alternative to O-nitrophenylhydroxylamine is one of O-2-nitrophenylhydroxylamine, O-4-nitrophenylhydroxylamine, O-o-nitrophenylhydroxylamine, O-m-nitrophenylhydroxylamine, O-p-nitrophenylhydroxylamine, and O-2,4-dinitrophenylhydroxylamine.

6. A method for regioselectively constructing a C2 all-carbon quaternary carbon center of a nitrogen-aromatic compound according to claim 1 or 2, characterized in that: The electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, and substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkylsulfonate, arylsulfonate, benzoic acid and its derivatives, phenol and its derivatives, halide, sulfate, and phosphate.

7. A pyridine C2-position quaternary carbon-substituted skeleton compound constructed by the method for regioselectively constructing a nitrogen aromatic compound with a C2 all-carbon quaternary carbon center according to any one of claims 1-6, characterized in that: The general structural formula of the pyridine C2-position quaternary carbon-substituted skeleton compound is any one of the following: Among them, R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

8. A pyridine C2-position quaternary carbon-substituted skeleton compound according to claim 7, characterized in that: When R 1 R 2 When each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; And / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; R X It is any one of hydrogen atom, alkyl, fluoroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide; Or, when R 1 R 2 Each is an independent aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7 Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 These atoms can form rings through carbon chains and heteroatoms.

9. A pharmaceutical composition, characterized in that: This includes pyridine C2-quaternary carbon-substituted skeleton compounds as described in claim 7 or 8, or their stereoisomers, tautomers, or salts thereof, or their prodrug molecules and medically or pesticide-acceptable carriers.

10. The use of a pyridine C2-position quaternary carbon-substituted skeleton compound of claim 7 or 8, or the pharmaceutical composition of claim 9, in the preparation of a drug for treating gouty arthritis, preventing rice sheath blight, or preventing wheat scab.

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