JPH0768217B2 - Method for producing γ-pyridone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel method for producing a pyridone derivative. The compound obtained by this invention is useful as a medicine, an agricultural chemical, or a synthetic intermediate thereof.

(Prior Art) The following is known as a method for producing a pyridone derivative according to the present invention. Kato, Tetsuzo et al., Heated N- (4-chlorophenyl) -1,4-dividro-2,6-dimethyl-4-oxo- by heating 3-aminocrotonanilides and diketene to 60 ° C or 90 ° C. 3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide, N- (4-chlorophenyl)-
1,4-dividro-2,6-dimethyl-4-oxo-1- (phenylmethyl) -3-pyridinecarboxamide, 1,4-
Dihydro-N- (4methoxyphenyl) -2,6-dimethyl-4-oxo-1- (phenylmethyl) -3-pyridinecarboxide and 3- (1-benzyliminoethyl) -4-hydroxy-6-methyl -1-phenyl-2
(1H) -Pyridone is obtained [Pharmaceutical Journal 101 (1), 40
(1981)] has low yields in any case, and is not considered to be a production method industrially applicable.

In Canadian Patent No. 1,115,278, N- (4-chlorophenyl) -3- (ethylamino) -2-butenamide and diketene are reacted under the reflux of toluene in the presence of triethylamine to give N- (4-chlorophenyl)-. 1-Ethyl-1,4-dividro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide was obtained, but the yield is not described. Also, the same patent discloses that 1,4-dihydro-4 is prepared by dimerization reaction of β-ketoamides in the presence of an acid catalyst with dehydration.
Disclosed is a method of making -oxo-3-pyridinecarboxamides. However, this method is not applicable to 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 can be applied only to manufacturing, it cannot be said to be a general manufacturing method.

(Object of the Invention) An object of the present invention is to provide a method for producing a pyridone derivative shown in the scope of the present invention, which has not been known for a general production method, at low cost and in high yield. To provide.

(Structure of Invention) General formula (I): [R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heterocyclic group: R ² is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heterocyclic group , R ³ represents an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an aralkyl group, a halogenated lower alkyl group, a heterocyclic group or an aryl group] in a solvent , Treated with acid to give the general formula (II): A method for obtaining a pyridone derivative represented by [R ¹ , R ² , and R ³ are the same as those in the general formula (I)] is provided.

The compound of the general formula (I) used as a raw material in the method of the present invention is represented by the general formula (III): R ³ —COCH ₂ CONH-R ¹ (III) [wherein R ¹ and R ³ are the same as above]. A compound of the general formula (V) or (V ′) obtained by a method such as a dehydration condensation reaction between a compound and a compound of the general formula (IV): R ² —NH ₂ (IV) [wherein R ² is the same as above]: [Wherein R ¹ , R ² and R ³ are the same as above] and diketene in a solvent-free or inert organic solvent in the presence of a nitrogen-containing organic compound capable of activating diketene, preferably at 60 ° C. It is easily obtained by treating at the following temperature. Here, as the nitrogen-containing organic compound used, 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-methylpiperidine, N, N′-dimethylpiperazine, N-methylmorpholine, 1,4diazabicyclo [ 2.2.0] Octane, 1,5-diazabicyclo [5.4.0]
Aliphatic, aromatic or heterocyclic tertiary organic base such as undecene-5; tetramethylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, trioctylmethylammonium chloride, benzyltrimethylammonium chloride, benzyltributylammonium Quaternary ammonium salts such as chloride, N-laurylpyridinium chloride, N-benzylpicolinium chloride;
Amberlyst A-21, Amberlyst A-26 (Cl
^- form), Amberlyst A-27 (Cl ^- form), Diaion
Anion exchange resin whose exchange group such as WA30 is a tertiary amino group or a quaternary ammonium salt; imidazole, 1,3
-Thiazolidine-2-thione, 1,3-oxazoline-2
-One, 1,3-oxazolidin-2-one, N-hydroxysuccinimide, N-hydroxyphthalimide,
Examples thereof include active amides such as 2-pyridinethiol, active esters, and heterocyclic compounds capable of forming active thiol esters.

The compound of the general formula (I) thus obtained may have other isomer structural formulas based on tautomerism. Further, conformational isomers and geometrical isomers due to intramolecular hydrogen bonds may exist.

In the definition of R ¹ , the alkyl group is an alkyl group having 1 to 12 carbon atoms such as methyl, ethyl, propyl, tertiary butyl, pentyl, octyl and dodecyl; The cycloalkyl group is, for example, cyclopropyl or cyclohexyl. A cycloalkyl group having 3 to 7 carbon atoms; an aralkyl group substituted with an aryl group such as phenylmethyl group, 2-phenylethyl group, 1-phenylethyl group, 1-methyl-1-phenylethyl group; aryl; Chlorine as the base,
Halogen atom such as bromine, 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, nitro group, phenyl group or naphthyl group which may be optionally substituted with trifluoromethyl group; and as heterocyclic group, a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is 1 to 3 5-membered or 6-membered heterocyclic group contained therein is included. For example, furyl, tetrahydrofuryl, thienyl,
5-membered ring groups such as thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyrazolyl; and 6-membered rings such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and morpholino. 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,
And a quinoxalinyl group.

In the definition of R ² , the alkyl group is an alkyl group having 1 to 12 carbon atoms such as methyl, ethyl, propyl, tertiary butyl, pentyl, octyl and dodecyl; The cycloalkyl group is such as cyclopropyl and cyclohexyl. Cycloalkyl groups having 3 to 7 carbon atoms; aryl groups include halogen atoms such as chlorine, bromine and fluorine, methyl,
Lower alkoxy group such as ethyl or propyl; lower alkoxycarbonyl group such as phenoxy group, methoxycarbonyl or ethoxycarbonyl; phenyl group or naphthyl group optionally substituted with cyano group, nitro group, trifluoromethyl group; Examples of the aralkyl group include a lower alkyl group substituted with the above-mentioned aryl group. Also, as the heterocyclic group, a nitrogen atom,
1 to 3 heteroatoms selected from oxygen atom and sulfur atom
5-membered or 6-membered heterocyclic group contained therein is included. For example, furyl, tetrahydrofuryl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl,
5-membered ring groups such as isoxazolyl and pyrazolyl; and pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
Examples include 6-membered rings such as morpholino. These groups may be substituted with alkyl groups such as methyl or ethyl; alkoxy groups such as methoxy or ethoxy; halogen atoms or phenyl groups. 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 ³ , an alkyl group, a cycloalkyl group, an aralkyl group, a heterocyclic group or an aryl group includes the same ones as exemplified for R ² . Further, in the lower alkenyl group and lower alkynyl group,
Vinyl, allyl, isopropenyl, 2-butenyl, 1,3
-Butadier, 2-pentenyl, 1,4-pentadienyl, 1,6-heptadienyl, 1-hexenyl, ethynyl, 2-propynyl and the like. Lower alkoxyalkyl groups include methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl groups and the like. Halogenated lower alkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-bromoethyl,
4-chlorobutyl and the like are included.

When the compound of general formula (I) is obtained by the above method,
General formula (I ') or (I "): The compound represented by [wherein R ¹ , R ² and R ³ are the same as above] may be by-produced.

The production ratio of these compounds (I), (I ′) or (I ″) is determined by the type of the general formula (V) or (V ′) as the raw material, the type and amount of the solvent and the nitrogen-containing organic compound used, and the reaction temperature. ,
Depends on reaction time etc.

For example, when R ¹ in the general formula (V) or (V ′) is a phenyl group, R ³ is a lower alkyl group and R ² is a benzyl group, imidazole is used as the nitrogen-containing organic compound in the general formula (V).
Alternatively, when about 0.5 equivalent is used with respect to the compound of (V ′) and the reaction is carried out in toluene at 0 ° C. for several hours, the δ value in ¹ H-NMR is
The compounds of general formula (I) which give a relatively sharp singlet signal for one proton at 10-12 ppm are mainly obtained. However, when the above reaction is performed under the same conditions except that triethylamine is used as the nitrogen-containing organic compound, a general formula that gives two very broad signals (one proton) to a magnetic field lower than the δ value of 12 ppm in ¹ H-NMR. The compound of (I ′) or (I ″) is mainly obtained.

When R ¹ in the general formula (V) or (V ′) is a 2,6-diethylphenyl group, R ³ is a lower alkyl group, and R ² is an alkyl group or an aralkyl group, imidazole is used as the nitrogen-containing organic compound. using about 0.5 equivalents of the compound of general formula (V) or (V '), when reacted for several hours at 0 ℃ in toluene, even at in any case of using triethylamine in place of imidazole, ¹ H A compound of general formula (I) giving a relatively sharp singlet signal for one proton at a δ value of 10-12 ppm in NMR is mainly obtained. Pyridone derivatives can be obtained by treating any of the compounds obtained in the above examples with an acid. When the compound of the general formula (I) is used as a raw material, the γ-pyridone derivative is used as a raw material. When the compound of formula (I ′) or (I ″) is used, the α-pyridone derivative is selectively provided.

The compound of the general formula (I) may be isolated and used, but it may be used as a reaction mixture of the compound of the general formula (V) or (V ′) and diketene, or the reaction mixture may be concentrated, solvent exchanged, filtered, It is also possible to use those that have been subjected to treatment such as neutralization. Examples of the acid to be treated with the compound of the general formula (I) in the present invention include organic acids such as trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid, benzoic acid, oxalic acid, acetic acid and formic acid, hydrochloric acid, sulfuric acid, Examples thereof include inorganic acids such as nitric acid and phosphoric acid, heteropoly acids, cation exchange resins, and solid acids. The amount of the acid used may be 10 ⁻⁵ to 1 mol per 1 mol of the compound represented by the general formula (I), and use of more than 1 mol has no significant effect. Examples of the solvent used in the reaction include chlorine-containing solvents such as carbon tetrachloride, methylene chloride and chloroform, aromatic hydrocarbon solvents such as benzene, toluene and xylene, and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Examples thereof include system solvents, alcohol solvents such as methanol, ethanol and isopropyl alcohol, ketone solvents such as acetone and methyl ethyl ketone, and dimethyl sulfoxide, N, N-dimethylformamide and water. Particularly good results are obtained when using methylene chloride, chloroform, toluene or benzene.
If the acid used is a liquid, the acid can be used as a solvent. The reaction temperature may be in the range of -20 ° C to the boiling point of the solvent used, but it is particularly preferably in the range of 0 ° C to 40 ° C.

(Effects of the Invention) According to the present invention, it is possible to obtain the pyridone derivative shown in the scope of the present invention, which has heretofore been impossible to selectively synthesize, in a high yield by a simple operation using easily available raw materials. became. The present invention will be described in more detail with reference to the following examples.

Examples Example 1. 1,4-Dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide 3-benzylaminocrotonanilide 1.33 g (5 mmol) ,
To 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 washed by filtration and dried under reduced pressure.
1.09 g of 1,4,5,6-tetrahydro-6-hydroxy-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide (yield 62.4
%)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 in a mixture of 0.70 g and methylene chloride 5 ml, p-toluenesulfonic acid 0.0
7 g was added and stirred at room temperature for 2 hours. The reaction mixture was transferred to a separatory funnel, washed with saturated aqueous sodium hydrogen carbonate and water, and the organic layer was dried and desolvated according to a conventional method, and the obtained crystalline residue was recrystallized from ethyl acetate to give the title compound (0.63). g (95% yield) was obtained.

Melting point: 178-179 ° C. Example 2 1-Butyl-N- (2,6-diethylphenyl) -1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide 2,6-diethylacetate 2.33 g (10 mmol) of acetanilide,
A 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. To this reaction mixture, 0.07 g (1 mmol) of imidazole was added, and then 1.01 g (12 mmol) of diketene in toluene (5 ml) was added dropwise over 10 minutes under ice cooling, and the mixture was further stirred under ice cooling for 7 hours. Ether about 10ml
After the addition, the precipitated crystals were washed by filtration and dried under reduced pressure to give 1-butyl-N- (2,6-diethylphenyl) -1,
2.46 g (yield 66.0%) of 4,5,6-tetrahydro-6-hydroxy-2,6-dimethyl-4-oxo-3-pyridinecarboxamide was obtained.

Melting point: 121.5 to 123.0 ° C IR (KBr disk): ν _{C =} 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 to 3.00 (m, 6H), 3.00 to 3.37 (m, 2
H), 5.67 (s, 1H), 7.02 (s, 3H), 10.85 (s, 1H) Obtained 1-butyl-N- (2,6-diethylphenyl)
-1,4,5,6-Tetrahydro-6-hydroxy-2,6-dimethyl-4-oxo-3-pyridinecarboxamide 0.75 g
0.07 g of p-toluenesulfonic acid was added to a mixture of (2 mmol) and 5 ml of methylene chloride, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was transferred to a separating funnel, washed with saturated aqueous sodium hydrogen carbonate, 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 (0.66 g, yield 93%). was gotten.

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 17 m
One drop of acetic acid was added to the mixture of 1 and the mixture was heated under reflux for 1 hour, and the water formed during that time was distilled off together with about 10 ml of toluene. To this reaction mixture, 1.01 g (10 mmol) of triethylamine and 2 ml of methylene chloride were added, and a solution of 1.18 g (14 mmol) of diketene in toluene (3 ml) was added dropwise over 10 minutes under ice cooling, 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 separated by filtration, washed 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)-
3.62 g (yield 86.1%) of 3-pyridinecarboxamide was obtained.

Melting point: 121.0 to 122.0 ° C IR (KBr disk): ν _{C =} 1620 cm ^-1 NMR (CDCl ₃ ) δ value: 1.15 (t, 6H), 1.27 (s, 3H), 2.57 (s, 3H), 2.10 to 3.
30 (m, 8H), 3.30 to 4.00 (m, 2H), 4.30 to 5.70 (br., 1
H), 6.85 to 7.60 (m, 8H), 10.84 (s, 1H) Obtained N- (2,6-diethylphenyl) -1,4,5,6-tetrahydro-6-hydroxy-2,6- To a mixture of 3,40 g (8.80 mmol) of dimethyl-4-oxo-1- (2-phenylethyl) -3-pyridinecarboxamide and 40 ml of methylene chloride, 0.17 g of p-toluenesulfonic acid was added, and the mixture was allowed to stand at room temperature for 2 hours.
Stir for hours. The reaction mixture was transferred to a separatory funnel, washed with saturated aqueous sodium hydrogen carbonate, 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 3.00 g of the title compound (yield 92 %)was gotten.

Melting point: 113 to 114.5 ° C IR (KBr disk): ν _{C =} 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 2-Butyl-1,4-dihydro-6-methyl-4-oxo-N-phenyl-1- (phenylmethyl) -3- Pyridinecarboxamide 3-benzylamino-N-phenyl-2-heptenoic acid amide was used as the starting material according to the method of Example 1 to obtain 2-butyl-1,4,5,6-tetrahydro-6-hydroxy-6-methyl-4. -Oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide was obtained. This was treated with p-toluenesulfonic acid according to the method of Example 1 to obtain the title compound with a yield of 91%.

Melting point: 133 to 134.5 ° C IR (KBr disc): 1630, 1675 cm ^-1 NMR (CDCl ₃ ) δ value: 0.89 (t, 3H), 1.00 to 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 5 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1- (phenylmethyl) -3-pyridinecarboxamide p-toluene The reaction was performed in the same manner as in Example 1 except that concentrated sulfuric acid (0.04 ml) was used instead of sulfonic acid, and the title compound was obtained in a yield of 94%.

Melting point: 178-179 ° C Example 6 N- (2,6-diethylphenyl) -1,4-dihydro-1,6
-Dimethyl-4-oxo-2-propyl-3-pyridinecarboxamide N- (2,6-diethylphenyl-3-methylamino-2
-Using hexenoic acid amide as a starting material, N- (2,6-diethylphenyl)-was prepared according to the procedure of Example 1.
1,4,5,6-Tetrahydro-6-hydroxy-1,6-dimethyl-4-oxo-2-propyl-3-pyridinecarboxamide was obtained. This was treated with p-toluenesulfonic acid according to the method of Example 1 to obtain the title compound with a yield of 92%.

Melting point: 99.5-100.5 ° C IR (KBr disk): 1633, 1673 cm ^-1 NMR (CDCl ₃ ) δ value: 1.03 (t, 3H), 1.19 (t, 6H), 1.67 (six 2H), 2.30
(S, 3H), 2.66 (q, 4H), 3.30 (t, 2H), 2.49 (s, 3
H), 6.33 (s, 1H), 7.05 (s, 3H), 11.90 (br., 1H) Example 7 N, 1-dibutyl-1,4-dihydro-2,6-dimethyl-4-
Oxo-3-pyridinecarboxamide N-butyl-3-oxobutanamide as a starting material,
The title compound was obtained in the yield by the operation according to the method of Example 2.
Obtained at 75% Melting point: 107-108 ° C IR (KBr disk): 1642, 1655 cm ^-1 NMR (CDCl ₃ ) δ value: 0.70-2.00 (m, 14H), 2.35 (s, 3H), 2.83 (s, 3H),
3.15 ~ 3.60 (m, 2H), 3.91 (t, 2H), 6.30 (s, 1H), 9.
85 (br., 1H)

Claims (1)

[Claims] 1. General formula (I): [R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heterocyclic group; R ² is a hydrogen atom,
An alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heterocyclic group; R ³ is an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an aralkyl group, a halogenated lower alkyl group, A heterocyclic group or an aryl group] is treated with an acid in a solvent to give a compound of the general formula (II): [R ¹ , R ² and R ³ are the same as those in the general formula (I)] A method for producing a γ-pyridone derivative, which comprises: