JPH075556B2 - Method for producing pyridone-3-carboxamide compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a 1,4-dihydro-4-oxo-3-pyridinecarboxamide compound, a novel intermediate for producing the same, and a method for producing the same. is there. The compound obtained according to the present invention is useful as a medicine, an agricultural chemical, or a synthetic intermediate thereof.

(Prior Art) As a method for producing a 1,4-dihydro-4-oxo-3-pyridinecarboxamide compound according to the present invention,
The following are known: Kato, Tetsuzo, et al. Reported that N- (4-chlorophenyl) -1,1, by heating 3-aminocrotonanilides and diketene to 60 ° C or 90 ° C.
4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-4
-Oxo-N-phenyl-1- (phenylmethyl) -3
-Pyridinecarboxamide, N- (4-chlorophenyl) -1,4-dihydro-2,6-dimethyl-4-oxo-1
-(Phenylmethyl) -3-pyridinecarboxamide,
And 1,4-dihydro-N- (4-methoxyphenyl)
-2,6-Dimethyl-4-oxo-1- (phenylmethyl) -3-pyridinecarboxamide was obtained [see Pharmaceutical Journal, 101 , 40 (1981)], but the yield was low in all cases and industrially applied. It cannot be considered as a possible manufacturing method.

In Canadian Patent No. 1,115,278, N- (4-chlorophenyl) -3- (ethylamino) -2-butenamide and diketene are reacted in the presence of triethylamine under toluene reflux to give N- (4- Chlorophenyl) -1
-Ethyl-1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide was obtained, but the yield is not described. The same patent also discloses a method for producing 1,4-dihydro-4-oxo-3-pyridinecarboxamides by subjecting β-ketoamides to a double reaction involving dehydration in the presence of an acid catalyst. However, this method
Applicable only to the production of 1,4-dihydro-4-oxo-3-pyridinecarboxamide compounds in which the substituents at the 2- and 6-positions of the γ-pyridone ring and the substituents at the 1-position and the nitrogen atom of the amide are the same. Since it cannot be done, it is not a general manufacturing method.

In addition, Tetsuzo Kato [Chem.Pharm.Bull. 17 (9) 1889-18
95 (1969)] is a reaction of β-aminocrotonamide and diketene in chloroform, which is completely different from the object of the present invention, 3-acetimidoyl-4-hydroxy-.
6-Methyl-2 (1H) -pyridone has been obtained, and two intermediates are assumed on the mechanism of its formation, and a 3,5-dioxohexanamide derivative is mentioned as one of them.

However, these have been isolated and not confirmed. Therefore, the 3,5-dioxohexanamide derivative formed by the reaction of β-aminocrotonamides with diketene is believed to be a novel compound.

(Object of the Invention) The present invention provides a generally applicable method for producing a 1,4-dihydro-4-oxo-3-pyridinecarboxamide compound in a good yield, and a novel intermediate and a production method thereof. The purpose is to do.

(Structure of the Invention) According to the present invention, the general formula (I) or (I ′): [R ¹ is a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, a lower alkoxycarbonyl group, a cyano group, a nitro group or an aryl group which may be substituted with a trifluoromethyl group or a heterocyclic group; R ² the Aruru group or _{- (CH 2) n-R} 4 (n is an integer from 1 to 4; R ⁴ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group,
Cycloalkyl group, alkoxy group, alkylthio group, arylthio group, aryl group or heterocyclic group) or -O
-R ⁵ (R ⁵ represents an alkyl group or an aralkyl group), R ³ represents an alkyl group, an aralkyl group or an aryl group],
The same solvent or a different organic solvent as described above without treating the diketene with a solvent-free or inert organic solvent in the presence of a nitrogen-containing organic compound capable of activating the diketene, and then isolating the resulting intermediate. Alternatively, in water or a mixed solvent thereof, a strong inorganic or organic base, or an amine R ² —NH corresponding to the compound of the general formula (I) or (I ′)
Treated in the presence of ₂ (R ² is as defined above) to give a compound of general formula (II): (Wherein R ¹ , R ² and R ³ are the same as defined above) 1,
Provided is a method for producing a pyridone-3-carboxamide compound, which comprises obtaining a 4-dihydro-4-oxo-3-pyridinecarboxamide compound.

The compound of the general formula (I) or (I ′) used as a raw material in the method of the present invention has the general formula (IV): (Wherein R ¹ and R ³ are the same as those in the general formula (I) or (I ′)
R ¹ and R ³ ) and a compound represented by the general formula (V): R ² —NH ₂ (V) (wherein R ² is the same as R ² in the general formula (I) or (I ′)). It can be easily obtained by a method such as a dehydration condensation reaction with an amine represented by

In the definition of R ¹ , the aryl group is chlorine, bromine,
Halogen atom such as fluorine, lower alkyl group such as methyl, ethyl or propyl; lower alkoxy group such as methoxy, ethoxy or propoxy; lower alkoxycarbonyl group such as phenoxy group, methoxycarbonyl or ethoxycarbonyl; cyano group, A nitro group, a phenyl group or a naphthyl group which may be optionally substituted with a trifluoromethyl group; examples of the aralkyl group include a lower alkyl group substituted with the aryl group shown above and the like. Further, the heterocyclic group includes a 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. For example, furyl, tetrahydrofuryl, thienyl, thiazolyl,
Examples thereof include 5-membered ring groups such as thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyrazolyl; and 6-membered rings such as pyridyl, pyrimidyl, pyrazinyl and pyridazinyl. These groups may be substituted with an alkyl group such as methyl or ethyl; an alkoxy group such as methoxy or ethoxy; a halogen atom or a phenyl group. When substituted with a phenyl group, it may combine with two carbon atoms in the ring to form a fused ring. Examples of the case where a condensed ring is formed include benzothiazolyl, benzofuryl, quinazolinyl, quinoxalinyl groups and the like.

In the definition of R ² , the aryl group includes the same groups as those exemplified for R ¹ .

In the definition of R ⁴ , an alkenyl group or an alkynyl group is an alkenyl group or an alkynyl group having 2 to 7 carbon atoms; an alkoxy group or an alkylthio group is an alkoxy group or an alkylthio group having 1 to 5 carbon atoms; or an arylthio group is R ¹ Examples of the arylthio group including an aryl group: an alkyl group, a cycloalkyl group, an alur group or a heterocyclic group include the alkyl group, the cycloalkyl group, the aryl group or the heterocyclic group exemplified in R ¹ .

In the definition of R ⁵ , the alkyl group or aralkyl group includes the alkyl group or aralkyl group exemplified in R ¹ .

In the definition of R ³ , the alkyl group has 1 to 5 carbon atoms.
A lower alkyl group; and the aralkyl group includes a phenylmethyl group and a 2-phenylethyl group. The aryl group includes the same groups as those exemplified for R ¹ .

Examples of the nitrogen-containing organic compound used in the method of the present invention include triethylamine, tripropylamine, triisobutylamine, N, N-dimethylbenzylamine, N, N
-Dimethylcyclohexylamine, N, N, N ', N'-tetramethylethylenediamine, N, N, N', N'-tetramethyl-1,3-propanediamine, N, N-dimethylaniline,
N, N-diethylaniline, N, N-dimethyl-o-toluidine, pyridine, α-picoline, β-picoline, γ-picoline, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, N-methylpyrrolidine, N- Aliphatic such as methylpiperidine, N, N'-dimethylpiperazine, N-methylmorpholine, 1,4-diazabicyclo [2,2,0] octane, 1,5-diazabicyclo [5,4,0] undecene-5,
Aromatic or heterocyclic tertiary organic bases; tetramethylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide,
Trioctylmethylammonium chloride, benzyltrimethylammonium chloride, benzyl tributyl ammonium chloride, N- lauryl pyridinium chloride, N- benzyl picolinium chloride quaternary ammonium salts, such as chloride; Amberlyst A-21, Amberlyst A-26 (Cl ^- Shape), Amberlyst A-27 (C
anion exchange resin whose exchange group such as l ^- form) and diaion WA 30 is a tertiary amino group or a quaternary ammonium salt; imidazole, 1,3-thiazolidine-2-thione,
1,3-oxazolin-2-one, 1,3-oxazolidine-
Examples include active amides such as 2-one, N-hydroxysuccinimide, N-hydroxyphthalimide, and 2-pyridinethiol, active esters, or heterocyclic compounds capable of forming active thiol esters.

As the strong base used in the method of the present invention, hydroxides of alkali metals or alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide;
Alkoxides of alkali metals such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; carbonates of alkali metals such as sodium carbonate and potassium carbonate; tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, trioctylmethyl Quaternary alkylammonium hydroxides such as ammonium hydroxide and benzyltrimethylammonium hydroxide; Amberlyst A-26 (OH
^- form), Amberlyst A-27 (OH ^-, etc. form) anion exchange resin is the exchange groups such as quaternary ammonium hydroxide can be mentioned.

The method of this invention consists of two steps. In the first step, the reaction of the compound of general formula (I) or (I ') with diketene is carried out in the presence of a nitrogen-containing organic compound capable of activating diketene in a solvent-free or inert organic solvent.
The compound of the general formula (I) or (I ′) as a raw material does not necessarily have to be an isolated substance, and for example, a reaction mixture of the general formula (IV) and the general formula (V) is used as it is. Good. Examples of the inert organic solvent include hydrocarbons such as benzene, toluene, xylene and hexane; halides such as methylene chloride, chloroform and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane and anisole. The reaction temperature is preferably 60 ° C. or lower, but the reaction rate and yield,
From the viewpoint of operation, the range of -10 ° C to 40 ° C is particularly preferable.
When the reaction temperature exceeds 60 ° C., side reactions become significant, which is industrially disadvantageous. The amount of diketene used is preferably 1 to 1.5 equivalents relative to the compound of general formula (I) or (I '). Although it may be used in excess of 1.5 equivalents, it has no significant effect and is economically disadvantageous. The amount of the nitrogen-containing organic compound used is 0.01 with respect to the compound of the general formula (I) or (I ′), from the viewpoint of reaction rate and economy.
It is preferable to use ˜2 equivalents. However, this does not apply when an anion exchange resin is used. The reaction time varies depending on the kind of the compound of the general formula (I) as the raw material, the kind and amount of the nitrogen-containing organic compound, the reaction temperature, etc., but the reaction time is the compound of the general formula (I) or (I ′). When is disappeared, it is preferable to shift to the second step. According to the first step, the general formula (I) or (I ') reacts with diketene to form an intermediate.

In the second step, a strong inorganic or organic base or an amine R corresponding to the compound of the general formula (I) or (I ′) is used without isolation of the intermediate produced in the first step. ²
Performed in the presence of NH ₂ . When the intermediate is not isolated, the reaction mixture at the end of the first step may be used as it is, or may be subjected to physical operations such as concentration, solvent exchange, insoluble matter filtration, and the like. As the reaction solvent, in addition to the solvent exemplified in the first step, alcohol such as methanol, ethanol or isopropyl alcohol; water and the like can be used. The reaction temperature is preferably 60 ° C. or lower, but in the range of −10 ° C. to 40 ° C. is particularly preferable from the viewpoint of reaction rate, yield, and operation. The amount of the strong base used is 0.01 to 2 equivalents relative to the compound of the general formula (I) or (I ′) or the intermediate when it is isolated, from the viewpoint of reaction rate and economy. It is preferable to use.
However, this does not apply when an anion exchange resin is used as the strong base. The strong base may be present in advance from the first step as long as it does not adversely affect the reaction in the first step. For example, when using sodium hydroxide as a strong base, it is possible to allow sodium hydroxide powder to exist in the first step and add a solvent such as methanol or water at the end of the first step. In addition, the amine R ² -corresponding to the compound of the general formula (I) or (I ')
When NH ₂ is used, it is desirable to use 1 equivalent or more relative to the compound of the general formula (I) or (I ′) or the intermediate when it is isolated.

(Effect of the Invention) 1,4-Dihydro-4-oxo-3 is produced by the method of the present invention.
-The pyridinecarboxamide compound can be obtained in good yield by a simple operation using easily available raw materials.

Hereinafter, the present invention will be described more specifically with reference to Examples.

[Example 1] 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3-benzylaminocrotonanilide 1.33 g (5 mmol),
A mixture of 0.17 g (2.5 mmol) of imidazole and 7 ml of toluene, under ice cooling, 0.5 g (6 mmol) of diketene in toluene (3 m
l) The solution was added dropwise over 5 minutes, and the mixture was further stirred under ice cooling for 3 hours. The precipitated crystals are separated by filtration, washed and dried under reduced pressure to give 1,4,5,6-tetrahydro-6-hydroxy-2,6-dimethyl-4-oxo-N-phenyl-1-phenylmethyl-3-. Pyridinecarboxamide 1.09 g (62.4% yield)
was gotten.

Melting point: 82.0 to 83.0 ° C. IR (KBr disk): ν _{c = 0} 1630 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.38 (s, 3H), 2.40 (s, 3H), 2.79 (q, 2H), 4.69 ( q,
2H), 5.35 (br, 1H), 6.50-7.70 (m, 10H), 11.46
(S, 1H) Obtained 1,4,5,6-tetrahydro-6-hydroxy-2,6
-Dimethyl-4-oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide (0.70 g, 2 mmol) and toluene (5 ml) were added to a mixture of 1N sodium hydroxide methanol solution (0.2 ml) under ice cooling. Stir for 4 hours. The precipitated crystals were washed by filtration (water and ether), and dried under reduced pressure to give the title compound 0.61 g (yield 92.0%).

Melting point: 178 to 179 ° C. [Example 2] 1-butyl-N- (2,6-diethylphenyl) -1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide 2,6 -Diethylacetoacetanilide 2.33 g (10 mmol),
A drop of acetic acid was added to a mixture of 0.80 g (11 mmol) of butylamino and 27 ml of toluene, and the mixture was stirred at 50 ° C. for 1 hour and then heated under reflux for 1 hour, during which water and unreacted butylamine formed were distilled with about 10 ml of toluene. I left. To this reaction mixture, 0.07 g (1 mmol) of imidazole was added, and then a solution of 1.01 g (12 mmol) of diketene in toluene (5 ml) was added dropwise under ice cooling over 10 minutes, and the mixture was further stirred under ice cooling for 7 hours. After adding about 10 ml of ether, the precipitated substance was separated by filtration, washed and dried under reduced pressure to give 1-butyl-N- (2,6-diethylphenyl) -1,4,5,6-tetrahydro-6-hydroxy. −
2.46 g (yield 66.0%) of 2,6-dimethyl-4-oxo-3-pyridinecarboxamide was obtained.

Melting point: 121.5 to 123.0 ° C IR (KBr disk): ν _{c = o} 1625cm ^-1 NMR (CDCl ₃ ) δ value: 1.17 (t, 6H), 1.28 (s, 3H), 0.50 to 1.90 (m, 7H), 2.
52 (s, 3H), 2.00-3.00 (m, 6H), 3.00-3.70 (m, 2H), 5.67 (s, 1H), 7.02 (s, 3H), 1
0.85 (s, 1H) Obtained, 1-butyl-N- (2,6-diethylphenyl) -1,4,5,6-tetrahydro-6-hydroxy-2,6-
Dimethyl-4-oxo-3-pyridinecarboxamide 0.
To a mixture of 75 g (2 mmol) and 10 ml of toluene under ice cooling, 1N
0.2 ml of a sodium hydroxide solution in methanol was added, and the mixture was stirred under ice cooling for 4 hours and further at room temperature for 2.5 hours. The reaction mixture was transferred to a separatory funnel, washed with saturated brine, the organic layer was dried and concentrated by a conventional method, and the residue was crystallized from a mixture of toluene and hexane to give 0.65 g of the title compound (yield 91.
0%) was obtained.

Melting point: 120-121.5 ° C. [Example 3] N- (2,6-diethylphenyl) -1,4-dihydro-2,6
-Dimethyl-4-oxo-1- (2-phenylethyl)
-2-Pyridinecarboxamide 2,6-diethylacetoacetanilide 2.33 g (10 mmol),
β-phenethylamine 1.21 g (10 mmol) and toluene 1
One drop of acetic acid was added to the mixture of 7 ml, and the mixture was heated under reflux for 1 hour, and the water generated during that time was distilled off together with about 10 ml of toluene. To this reaction mixture was added 1.01 g (10 mmol) of triethylamine.
And 2 ml of methylene chloride are added, and to this, under ice-cooling,
A solution of 1.18 g (14 mmol) of toluene (3 ml) was added dropwise over 10 minutes, and the mixture was further stirred under ice cooling for 6 hours. After methylene chloride was distilled off under reduced pressure, about 10 ml of ether was added. The precipitated crystals were washed by filtration and dried under reduced pressure to give N- (2,
6-diethylphenyl) -1,4,5,6-tetrahydro-6-
Hydroxy-2,6-dimethyl-4-oxo-1- (2-
Phenylethyl) -3-pyridinecarboxamide 3.62 g
(Yield 86.1%) was obtained.

Melting point: 121.0 to 122.0 ° C. IR (KBr disk): ν _{c = o} 1620 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.15 (t, 6H), 1.27 (s, 3H), 2.57 (s, 3H), 2.10− 3.
30 (m, 8H), 3.30-4.00 (m, 2H), 4.30-5.70 (br, 1H), 6.85-7.60 (m, 8H), 10.84 (s,
1H) Obtained N- (2,6-diethylphenyl) -1,4,5,6-
Tetrahydro-6-hydroxy-2,6-dimethyl-4-
A mixture of 3.40 g (8.08 mmol) of oxo-1- (2-phenylethyl) -3-pyridinecarboxamide and 40 ml of toluene was added with 1N sodium hydroxide methanol solution under ice cooling.
1.6 ml was added, and the mixture was stirred under ice cooling for 4 hours and further at room temperature for 2.5 hours. The reaction mixture was transferred to a separatory funnel, washed with saturated brine, the organic layer was dried and concentrated by a conventional method, and the residue was crystallized from a mixture of ethyl acetate and hexane to give 2.95 g of the title compound (yield 90.6%). %)was gotten.

Melting point: 113 to 114.5 ° C IR (KBr disk): ν _{c = o} 1625,1657cm ^-1 NMR (CDCl ₃ ) δ value: 1.19 (t, 6H), 2.32 (s, 3H), 2.68 (q, 4H), 2.90 (s,
3H), 2.97 (t, 2H), 4.17 (t, 2H), 6.40 (s, 1H), 6.
80-7.50 (m, 8H), 11.58 (br, 1H) Example 4 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3- Benzylamino crotonanilide 2.66g (10mmo
l), 1.01 g (10 mmol) of triethylamine and toluene
A solution of 1.01 g (12 mmol) of diketene in toluene (5 ml) was added dropwise to 15 ml of the mixture over 10 minutes under ice cooling, and the mixture was further stirred under ice cooling for 3 hours. 4 ml of 1N sodium hydroxide methanol solution was added to this reaction mixture under ice cooling, and the mixture was further stirred for 4 hours. The solvent was evaporated from the reaction mixture in an amount of about 10 ml under reduced pressure, and the resulting crystals were washed by filtration (water and ether) and dried under reduced pressure to give the title compound (2.60 g, yield 78.3%).

Mp: 178~179 ℃ (* Reference value 172-172.5 ° C.) * Pharmaceutical Journal, 101, 40 (1981) Example 5 1,4-dihydro-2,6-dimethyl-4-oxo -N- phenyl-1- (Phenylmethyl) -3-pyridinecarboxamide Using pyridine as the organic base, the reaction was carried out according to the same procedure as in Example 4 to obtain the title compound in a yield of 82.1%.

Melting point: 178 to 179 ° C Example 6 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide N-methylpiperidine was used as an organic base. Reaction was carried out according to the same procedure as in Example 4 to give 82.4% of the title compound.
Obtained in% yield.

Mp 178-179 ° C Example 7 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3-benzylaminocrotonanilide 2.66 g (10 mmo
l), trioctylmethylammonium chloride 0.16g
(0.4 mmol) and toluene 5 ml, diketene 0.
84 g (10 mmol) was added, and the mixture was stirred at 40 ° C for 1 hr. The reaction mixture was left standing at room temperature overnight, 0.20 g (1 mmol) of tetrapropylammonium hydroxide was added under ice cooling, and the mixture was stirred for 5 hours. The formed crystals are washed by filtration (water and ether) and dried under reduced pressure to give the title compound (1.71 g)
(Yield 51.5%) was obtained.

Melting point: 178-179 ° C Example 8 N- (2,6-diethylphenyl) -1,4-dihydro-2,6
-Dimethyl-4-oxo-1-phenylmethyl-3-pyridinecarboxamide 2,6-diethylacetoacetanilide 2.66 g (11.4 mmo
l), benzylamine 1.22 g (11.4 mmol) and toluene
One drop of acetic acid was added to 27 ml of the mixture, and the mixture was heated under reflux for 1 hour, during which water formed was distilled off together with about 10 ml of toluene. 1.15 g (11.4 mmol) of triethylamine was added to the reaction mixture.
In addition, a solution of 1.34 g (15.9 mmol) of diketene under ice-cooling in toluene (5 ml) was added dropwise over 10 minutes, and the mixture was further stirred under ice-cooling for 4 hours.
The mixture was added and stirred for 1 hour, and further stirred at room temperature for 3 hours.
Transfer the reaction mixture to a separatory funnel with about 30 ml of toluene,
The extract was washed with saturated brine, the organic layer was dried and concentrated by a conventional method, and the residue was crystallized from a mixture of toluene and ether to give the title compound (3.40 g, yield 76.7%).

Melting point: 140-143 ° C. IR (KBr disk): ν _{c = o} 1615 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.18 (t, 6H), 2.28 (s, 3H), 2.66 (q, 4H), 2.78 ( s,
3H), 5.20 (s, 2H), 6.48 (s, 1H), 6.75-7.60 (m, 8
H), 11.64 (br, 1H) Example 9 1,4-Dihydro-2,6-dimethyl-1- (4-methylphenylmethyl) -4-oxo-N-phenyl-3-pyridinecarboxamide acetoacetanilide 1.77 1 drop of acetic acid was added to a mixture of g (10 mmol), p-methylbenzylamine 1.21 g (10 mmol) and toluene 27 ml, and the mixture was heated under reflux for 1 hour, and then the produced water and toluene were distilled off under reduced pressure. Methylene chloride (15 ml) and triethylamine (1.01 g (10 mmol)) were added to the residue, and a solution of diketene (1.01 g, 12 mmol) in methylene chloride (5 ml) was added dropwise over 10 minutes under ice cooling, and the mixture was further stirred under ice cooling for 4 hours. 3m of 1N sodium hydroxide methanol solution
Then, the mixture was stirred for 4.5 hours. The reaction mixture was transferred to a separatory funnel together with about 30 ml of methylene chloride, washed with a saturated saline solution, and the organic layer was dried according to a conventional method and then concentrated to about 10 ml. After drying, the title compound (2.57 g, yield 74.2%) was obtained.

Melting point: 202 to 202.5 ° C. IR (KBr disk): ν _{c = o} 1627,1665 cm ⁻¹ NMR (CDCl ₃ ) δ value: 2.27 (s, 3H), 2.33 (s, 3H), 2.83 (s, 3H), 5.17 (s,
2H), 6.44 (s, 1H), 6.60-8.00 (m, 9H), 12.69 (br,
1H) Example 10 1- (4-Chlorophenylmethyl) -1,4-dihydro-
2,6-Dimethyl-N- (2-methylphenyl) -4-oxo-3-pyridinecarboxamide o-methylacetoacetanilide 1.91 g (10 mmol), p
-A drop of acetic acid was added to a mixture of 1.42 g (10 mmol) of chlorobenzylamine and 27 ml of toluene, and the mixture was heated under reflux for 1 hour,
The water formed during that time was distilled off together with about 10 ml of toluene.
1.01 g (10 mmol) of triethylamine was added to the reaction mixture.
Was added, and a solution of 1.18 g (14 mmol) of diketene in toluene (5 ml) was added dropwise under ice cooling over 10 minutes.
After stirring for 1 hour, add 1N sodium hydroxide methanol solution.
5 ml was added, the mixture was stirred for 3.5 hours, and left at room temperature overnight.
The solvent was distilled off from the reaction mixture under reduced pressure, the residue was transferred to a separating funnel together with about 50 ml of methylene chloride, washed with a saturated saline solution, and the organic layer was dried and concentrated according to a conventional method, and the residue was diluted with toluene and ether. Crystallization from the mixture of the title compound 2.
46 g (yield 64.7%) was obtained.

Melting point: 152.5-155.5 ° C. IR (KBr disk): ν _{c = o} 1623,1657 cm ⁻¹ NMR (CDCl ₃ ) δ value: 2.21 (s, 3H), 2.42 (s, 3H), 2.78 (s, 3H), 5.11 (s,
2H), 6.39 (s, 1H), 6.55-8.30 (m, 8H), 12.42 (br,
1H) Example 11 1-Butyl-N- (2,6-diethylphenyl) -1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide 2,6-diethylacetoacetanilide 2.33 g (10 mmol),
1 drop of acetic acid was added to a mixture of 0.80 g (11 mmol) of butylamine and 27 ml of toluene, and the mixture was stirred at 50 ° C. for 1 hour and then heated under reflux for 1 hour, while water formed and unreacted butylamine were distilled with about 10 ml of toluene. I left. To this reaction mixture, 1.01 g (10 mmol) of triethylamine was added, and while cooling with ice, a solution of 1.01 g (12 mmol) of diketene in toluene (5 ml) was added.
After dripping over a minute, and further stirring under ice cooling for 7 hours,
3 ml of a 1N sodium hydroxide methanol solution was added, and the mixture was stirred for 1 hour, and further left at room temperature overnight. The reaction mixture was transferred to a separating funnel together with about 30 ml of toluene, washed with saturated saline, and the organic layer was dried and concentrated according to a conventional method, and the residue was crystallized from a mixture of toluene and hexane to give the title compound.
2.53 g (71.4% yield) was obtained.

Melting point: 120 to 121.5 ° C IR (KBr disk): ν _{c = o} 1623,1655cm ^-1 NMR (CDCl ₃ ) δ value: 1.18 (t, 6H), 0.70-2.20 (m, 7H), 2.38 (s, 3H) ), 2.
65 (q, 4H), 2.88 (s, 3H), 3.65-4.15 (m, 2H), 6.40
(S, 1H), 7.05 (s, 3H), 11.66 (br, 1H) Example 12 1-Butyl-N- (2,6-diethylphenyl) -1,4-dihydro-2,6-dimethyl- 4-oxo-3-pyridinecarboxamide 2,6-diethylacetoacetanilide 2.23 g (10 mmol),
1 drop of acetic acid was added to a mixture of 0.80 g (11 mmol) of butylamine and 27 ml of toluene, and the mixture was stirred at 50 ° C. for 1 hour and then heated under reflux for 1 hour, while water formed and unreacted butylamine were distilled with about 10 ml of toluene. I left. To this reaction mixture was added 0.10 g (1 mmol) of triethylamine, a solution of 1.01 g (12 mmol) of diketene in toluene (5 ml) was added dropwise at 20 ° C. over 10 minutes, and the mixture was further stirred at this temperature for 5 hours, then 1N.
5 ml of a potassium hydroxide methanol solution was added, and the mixture was stirred for 1 hour, and left at room temperature overnight. The reaction mixture was transferred to a separating funnel together with about 30 ml of toluene, washed with saturated saline,
The organic layer was dried and concentrated according to a conventional method, and the residue was crystallized from a mixture of toluene and hexane to give the title compound 1.76.
g (yield 49.5%) was obtained.

Melting point: 120-121.5 ° C Example 13 N- (2-chlorophenyl) -1,4-dihydro-2,6-dimethyl-4-oxo-1- (2-pyridylmethyl) -3
-Pyridinecarboxamide Using o-chloroacetoacetanilide and 2-pyridylmethylamine as starting materials, the reaction was performed according to the same procedure as in Example 10 to obtain the title compound in a yield of 78.0%.

Melting point: 181-183 ° C IR (KBr disk): ν _{c = o} 1630,1670 cm ^-1 NMR (CDCl ₃ ) δ value: 2.28 (s, 3H), 2.80 (s, 3H), 5.27 (s, 2H), 6.43 (s,
1H), 6.70-8.70 (m, 8H), 13.06 (br, 1H) Example 14 N- (tert-butyl) -1,4-dihydro-2,6-dimethyl-4-oxo-1-phenylmethyl-3 -Pyridinecarboxamide Using N- (tert-butyl) -acetoacetamide and benzylamide as starting materials, the reaction was performed according to the same procedure as in Example 8 to obtain the title compound in a yield of 76.9%.

Melting point: 166-168 ° C. IR (KBr disk): ν _{c = o} 1625,1650 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.43 (s, 9H), 2.24 (s, 3H), 2.68 (s, 3H), 5.17 (s,
2H), 6.30 (s, 1H), 6.60-7.60 (m, 5H), 9.48 (br, 1)
H) Example 15 1,4-Dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3-benzylaminocrotonanilide 2.66 g (10 mmo
l), triethylamine 1.01 g (10 mmol) and benzene
A solution of 0.92 g (11 mmol) of diketene in benzene (5 ml) was added dropwise to 5 ml of the mixture over 10 minutes under ice cooling.
Stir for 0 minutes. After distilling off the solvent from this reaction mixture under reduced pressure, ethanol 60 ml, water 12 ml, benzylamine 1
0.7 g (100 mmol) was added, and the mixture was stirred at room temperature for 1 day. The solvent and benzylamine were evaporated from the reaction mixture under reduced pressure, and the residue was crystallized from a mixture of toluene and ether to give the title compound (1.96 g, yield 59.0%).

Melting point: 178-179 ° C Example 16 2-Butyl-1,4-dihydro-6-methyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3-oxo-N-phenyl- Heptanoic acid amide 1.10 g (5
mmol), benzylamine 530 mg (5 mmol) and toluene
One drop of acetic acid was added to 15 ml of the mixture and the mixture was heated to reflux for 1 hour, during which water formed was distilled off together with about 10 ml of toluene. 10 ml of toluene and 0.7 ml of triethylamine were added to the reaction mixture.
Then, 0.51 g (6 mmol) of diketene was added dropwise thereto under ice cooling over 2 minutes, and the mixture was further stirred under ice cooling for 23.5 hours. The precipitated crystals were washed by filtration and dried under reduced pressure to give 5,6-dihydro-4,6-dihydroxy-6-methyl-1-phenyl-
3- (1-phenylmethyliminopentyl) -2 (1H)
865 mg (44% yield) of pyridone was obtained.

IR (KBr disk): ν _{c = o} 1600 cm ^-1 NMR (CDCl ₃ ) δ value: 0.60-2.05 (m, 7H), 2.34 (s, 3H), 2.80-4.10 (m, 3)
H), 2.91 (d, 2H), 4.53 (d, 2H), 6.90-7.60 (m, 10H), 1
2.50-16.50 (br, 1H) Obtained, 5,6-dihydro-4,6-dihydroxy-6-methyl-1-phenyl-3- (1-phenylmethyliminopentyl) -2 (1H) -pyridone 800 mg To a mixture of (2.04 mmol) and methylene chloride (7 ml) was added 1N sodium hydroxide methanol solution (0.6 ml) under ice cooling, and the mixture was left overnight under ice cooling. The reaction mixture was transferred to a separatory funnel, washed with saturated brine, the organic layer was dried and concentrated by a conventional method, and the residue was crystallized from a mixture of ethyl acetate and hexane to give the title compound.
526 mg (69% yield) was obtained.

Melting point: 133 to 134.5 ° C IR (KBr disc): ν _{c = o} 1630,1675cm ^-1 NMR (CDCl ₃ ) δ value: 0.89 (t, 3H), 1.00-2.00 (m, 4H), 2.25 (s, 3H ), 3.
22 (t, 2H), 5.19 (s, 2H), 6.41 (s, 1H), 6.70−7.70
(M, 10H), 12.70 (br, 1H) Example 17 2-Butyl-1,4-dihydro-6-methyl-4-oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide 3-oxo- 2.19 g of N-phenyl-heptanoic acid amide (1
0 mmol), benzylamine 1.07 g (10 mmol) and 20 ml of toluene, 1 drop of acetic acid was added, and the mixture was heated under reflux for 1 hour,
The water formed during that time was distilled off together with toluene. 15 ml of methylene chloride and 1.01 of triethylamine were added to the obtained residue.
g (10 mmol) was added, and 0.93 ml (12 mmo of diketene under ice cooling
l) methylene chloride (5 ml) solution was added dropwise over 10 minutes,
The mixture was further stirred under ice cooling for 6.5 hours. 0.53 g of benzylamine and 5 ml of 1N sodium hydroxide methanol solution were added to this reaction mixture under ice cooling, and the mixture was stirred for 22 hours. The reaction mixture was transferred to a separatory funnel, washed with saturated brine, the organic layer was dried and concentrated according to a conventional method, and the residue was crystallized from a mixture of ethyl acetate and hexane to give the title compound (2.43 g)
(Yield 65%) was obtained.

Melting point: 133-134.5 ° C Example 18 1,4-Dihydro-6-methyl-4-oxo-N-phenyl-1-phenylmethyl-2-propyl-3-pyridinecarboxamide 3-oxo-N-phenyl-hexanoic acid Using amide and benzylamine as starting materials, the reaction was carried out according to the same procedure as in Example 17 to obtain the title compound in 71% yield.

Melting point: 150 to 152 ° C. IR (KBr disc): ν _{c = o} 1627,1667 cm ⁻¹ NMR (CDCl ₃ ) δ value: 0.98 (t, 3H), 1.80 (six, 2H) 2.24 (s, 3H), 3.18 (T,
2H), 5.16 (s, 2H), 6.40 (s, 1H), 6.70-7.70 (m, 10
H), 12.75 (br, 1H) Example 19 1,4-Dihydro-6-methyl-4-oxo-2-pentyl-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide 3-oxo-N-phenyl Using octanoic acid amide and benzylamine as starting materials, the reaction was performed according to the same procedure as in Example 17 to obtain the title compound in 65% yield.

Melting point: 114 to 115.5 ° C. IR (KBr disc): ν _{c = o} 1627,1670 cm ⁻¹ NMR (CDCl ₃ ) δ value: 0.87 (t, 3H), 1.00−2.10 (m, 6H), 2.22 (s, 3H) ), 3.
23 (t, 2H), 5.16 (s, 2H), 6.40 (s, 1H), 6.70−7.70
(M, 10H), 12.63 (br, 1H) Example 20 1-Butyl-N- (2,6-diethylphenyl) -1,4-dihydro-6-methyl-4-oxo-2-phenyl-3-
Pyridinecarboxamide N- (2,6-diethylphenyl) -3-oxo-3-phenyl-propionic acid amide and butylamine were used as starting materials, and the reaction was carried out in the same manner as in Example 17,
The title compound was obtained in 55% yield.

Melting point: 152-153 ° C IR (KBr disc): ν _{c = o} 1620,1667cm ^-1 NMR (CDCl ₃ ) δ value: 0.59 (t, 3H), 1.10 (t, 6H), 0.50-1.80 (m, 4H ), 2.
43 (s, 3H), 2.50 (q, 4H), 3.62 (t, 2H), 6.53 (s, 1
H), 7.00-7.50 (m, 8H), 11.06 (br, 1H)

Claims (10)

[Claims] 1. General formula (I) or (I '): [R ¹ is; a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, a lower alkoxycarbonyl group,
An aryl group which may be substituted with a cyano group, a nitro group or a trifluoromethyl group; or a heterocyclic group: R ² is an aryl group or — (CH ₂ ) nR ⁴ (n is an integer of 1 to 4: R ⁴ is a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, alkylthio group, arylthio group, aryl group or heterocyclic group) or —O—R ⁵ (R ⁵ is an alkyl group or aralkyl Basis):
R ³ represents an alkyl group, an aralkyl group or an aryl group] and diketene in a solvent-free or inert organic solvent in the presence of a nitrogen-containing organic compound capable of activating diketene, and then produced. Corresponding to a strong inorganic or organic base, or a compound of the general formula (I) or (I ′) in the same solvent as described above or a different organic solvent or water or a mixed solvent thereof without isolation of the intermediate. In the presence of an amine R ² —NH ₂ (R ² is as defined above) to give a compound of general formula (II): (Wherein R ¹ , R ² and R ³ are the same as defined above) 1,
A method for producing a pyridone-3-carboxamide compound, which comprises obtaining a 4-dihydro-4-oxo-3-pyridinecarboxamide compound. 2. The method according to claim 1, wherein the intermediate is isolated. 3. A nitrogen-containing organic compound is an aliphatic, aromatic or heterocyclic tertiary organic base, or a heterocyclic compound capable of forming an active amide, active ester or active thiol ester. The method according to item 1. 4. The method according to claim 3, wherein the tertiary organic base is triethylamine, pyridine or N-methylpiperidine, and the heterocyclic compound is imidazole. 5. The method according to claim 1, wherein the strong base is an alkali metal or alkaline earth metal hydroxide or alkoxide, or a quaternary alkylammonium hydroxide. 6. The method according to claim 5, wherein the strong base is sodium hydroxide, potassium hydroxide or tetrapropylammonium hydroxide. 7. The method according to claim 1, wherein a nitrogen-containing organic compound and a strong base are used in catalytic amounts. 8. The method according to claim 1, wherein the treatment of the compound of general formula (I) or (I ') with diketene is carried out under mild temperature conditions. 9. The method according to claim 1, wherein the mild temperature condition is -10 ° C to 40 ° C. 10. The process according to claim 1, wherein the reaction product of the compound of the general formula (I) or (I ') and diketene is treated at -10 ° C to 40 ° C.