JPH0717607B2 - Process for producing α-pyridone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel method for producing an α-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-pyridinecarboxamide and 3- (1-benzyliminoethyl) -4-hydroxy-6-methyl- 1-phenyl-2
(1H) -Pyridone has been obtained [Pharmaceutical Journal 101 (1) 40 (1
981)] has low yields in any case, and is not considered to be a production method that can be industrially applied.

(Object of the Invention) The present invention shows a production method of an α-pyridone derivative shown in the claims of the present invention, which has been heretofore unknown in general production method, at a low cost and in a high yield.

(Structure of Invention) General formula (I): [R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, a heterocyclic group: R ² and R ² ′ are a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, an alkoxy group. , An alkenyloxy 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. Represent. ] The compound represented by the general formula (II) is treated with an acid in a suitable solvent. A method for obtaining an α-pyridone derivative represented by [R ¹ , R ² , 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 has 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): R ² R ² ′ NH (IV) [wherein R ² and R ² ′ are the same as those defined above] obtained by a dehydration condensation reaction method or the like: [Wherein R ¹ , R ² , R ² ′ and R ³ are the same as above], or when at least one of R ² and R ² ′ is a hydrogen atom, its tautomer and diketene It is a diketene adduct which is easily obtained by treating and in a solvent-free or inert organic solvent in the presence of a nitrogen-containing organic compound capable of activating diketene, preferably at a temperature of 60 ° C. or lower. 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), Amba - List 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.

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 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; and as the heterocyclic group, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The 5- 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 and R ² ′, an alkyl group having 1 to 12 carbon atoms such as methyl, ethyl, propyl, tertiary butyl, pentyl, octyl and dodecyl; a cycloalkyl group having cyclopropyl, C3-C7 cycloalkyl groups such as cyclohexyl; alkoxy groups such as methoxy, ethoxy and propoxy groups; alkenyloxy groups such as allyloxy and vinyloxy; aryl groups such as chlorine, bromine and fluorine atoms such as fluorine. , A lower alkoxy group such as methyl, ethyl or propyl; a lower alkoxycarbonyl group such as a phenoxy group, methoxycarbonyl or ethoxycarbonyl; a phenyl group which may be optionally substituted with a cyano group, a nitro group or a trifluoromethyl group or Naphthyl group;
Examples of the aralkyl group include a lower alkyl group substituted with the above-mentioned aryl group. 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,
5-membered ring groups such as thienyl, 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 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, quinoxalicyl groups and the like.

Further, when both R ² and R ² ′ are alkyl groups, they may form a heterocyclic group together with the nitrogen atom of the amino group to which they are bonded and optionally other heteroatoms. Specific examples of such a heterocyclic group include a pyrrolidine ring, a piperidine ring, a piperazine ring, and a morpholine ring.

In the definition of R ³ , an alkyl group, a cycloalkyl group,
As the aralkyl group, heterocyclic group or aryl group, the same groups as those exemplified for R ² are included. Further, the lower alkenyl group and lower alkynyl group include vinyl, allyl, isopropenyl, 2-butenyl, 1,3-butadiene, 2-pentenyl, 1,4-pentadienyl, 1,6-heptadienyl,
1-hexenyl, ethynyl, 2-propynyl and the like are included. Lower alkoxyalkyl groups include methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl groups and the like. The halogenated lower alkyl group includes
Included are trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-promoethyl, 4-chlorobutyl and the like.

The compound of general formula (I) obtained by the above method is
It can have tautomers. For example, when R ² ′ is a hydrogen atom, general formula (I ′) (I ″): A structural formula represented by [R ¹ , R ² and R ³ are the same as in the general formula (I)] can be adopted.

Further, when the compound of the general formula (I) is obtained by the above method, when R ² ′ is a hydrogen atom, the compound of the general formula (VI): A compound represented by the formula [R ¹ , R ² and R ³ are the same as those in formula (I)] may be by-produced. The production ratio of these compounds (I) or (VI) depends on 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, the reaction temperature, the reaction time, etc. different.

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

Further, in the general formula (V) or (V ′), when R ¹ is a 2,6-diethylphenyl group, R ³ is a lower alkyl group, R ² is an alkyl group or an aralkyl group, and R ² ′ is a hydrogen atom, As the nitrogen-containing organic compound, imidazole is represented by the general formula (V) or (V ′)
About 0.5 equivalent to the compound of Example ^{1 and} reacted in toluene at 0 ° C. for several hours, and when triethylamine was used instead of imidazole, δ value in ¹ H-NMR was 10 to 12 ppm. A compound of the general formula (VI) which gives a relatively sharp singlet signal for one proton 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 (VI) is used as a raw material, the γ-pyridone derivative is used as a raw material. When a compound of formula (I) or (I ') or (I ") is used, the α-pyridone derivative is selectively provided, respectively.

The compound of the general formula (I) or (I ′) or (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 It is also possible to use the reaction mixture which has been subjected to treatments such as concentration, solvent exchange, filtration, neutralization, etc. Treatment with the compound of the general formula (I) or (I ') or (I ") according to the present invention. Examples of the acid include organic acids such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, oxalic acid, acetic acid, and formic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and a heteropoly acid, and a positive acid. Examples thereof include ion exchange resins and solid acids. The amount of acid used is 1 mol of the compound represented by the general formula (I) or (I ') or (I ").
It may be 10 ⁻⁵ to 1 mol, and even if it is used in excess of 1 mol, there is no significant effect. As a solvent used in the reaction, carbon tetrachloride,
Chlorine-containing solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, and methanol, ethanol, isopropyl alcohol, etc. Alcohol solvents, ketone solvents such as acetone and methyl ethyl ketone, and dimethyl sulfoxide, N, N
-Dimethylformamide and water, or a mixture thereof and the like. 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.

Compounds of general formula as an objective compound in the method (II) of the present invention, when at least one of hydrogen atoms of R ² or R ² ', may take tautomers. For example, when R ² ′ is a hydrogen atom, general formula (II ′): The structural formula and the like represented by [R ¹ , R ² and R ³ are the same as those in the general formula (I)] can be adopted.

(Effect of the Invention) According to the present invention, it is possible to obtain a pyridone derivative represented by the scope of the claims 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.

Example 1. 1,2,3,4-Tetrahydro-6-methyl-1-phenyl-
3- (1-phenylmethylaminoethylidene) -2,4-
Synthesis of pyridinedione 3-benzylaminocrotonanilide 26.6g (100mmo
l), triethylamine 10.1 g (100 mmol) and toluene 5
A solution of 8.5 ml (110 mmol) of diketene in toluene (20 ml) was added dropwise to 0 ml of the mixture over 30 minutes under ice cooling, and the mixture was further stirred under ice cooling for 3 hours. The precipitated crystals were separated by filtration, washed and dried under reduced pressure to give the corresponding adduct (yield 65%).

Melting point: 146.5-149 ° C IR (CHCl ₃ ): ν _{c =} 1633 cm ^-1 NMR (CDCl ₃ ) δ value: 1.23 (s, 3H), 2.58 (s, 3H), 2.82 (d, 1H), 3.04 ( d,
1H), 3.78 (s) and 4.30 (s) (total 1H), 4.49 (s)
And 4.57 (s) (total 2H), 7.10 to 7.50 (m, 10H), 12.74
(Br) and 13.42 (br) (total 1H) 3.5 g (10 mmol) of this compound and p-toluenesulfonic acid
0.035 g (0.2 mmol) was dissolved in 20 ml of methylene chloride and reacted at room temperature for 4.5 hours. The reaction solution was transferred to a separating funnel, washed with saturated aqueous sodium hydrogen carbonate and water, and the organic layer was dried and desolvated by a conventional method, and the obtained crystalline residue was recrystallized from ethyl acetate to give 2.99 g of the title compound ( Yield 90%) Melting point: 148-149 ° C IR (KBr disk): ν _{c =} 1655cm ^-1 NMR (CDCl ₃ ) δ value: 1.80 (s, 3H), 2.68 (s, 3H), 4.65 (D, 2H), 5.75 (s,
1H), 7.05 to 7.80 (m, 10H), 15.20 to 15.80 (br., 1H) Example 2. 1- (4-chlorophenyl) -1,2,3,4-tetrahydro-6-methyl-3- ( 1-Phenylmethylaminoethylidene) -2,4-pyridindione 3.85 g (10 mmol) of a diketene adduct of N- (4-chlorophenyl) -3-phenylmethylamino-2-butenamide obtained by the same method as in Example 1. Was dissolved in 20 ml of methylene chloride, 0.05 ml of sulfuric acid was added, and the mixture was reacted at room temperature for 5 hours. The reaction mixture was transferred to a separatory funnel, washed with cold water, 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. To 3.
Obtained in 4 g (93% yield).

Melting point: 190 to 192 ° C IR (KBr disc): ν _{c = 0} 1645cm ^-1 NMR (CDCl ₃ ) δ value: 1.85 (s, 3H), 2.73 (s, 3H), 4.76 (d, 2H), 5.90
(S, 1H), 7.17 to 7.82 (m, 9H), 15.40 to 15.80 (br., 1
H) Example 3-7 The corresponding diketene adduct obtained by the same method as in Example 1 was used as a starting material and reacted according to the method of Example 1 to obtain the following compound. 1,2,3,4-tetrahydro-1- (4
-Methoxyphenyl) -6-methyl-3-phenylmethylaminoethylidene-2,4-pyridinedione (Example 3) Yield: 85% Melting point: 171-174 ° C [The above literature values are Kato et al., Pharmaceutical Journal 101. (1) 40 (198
According to 1). ] IR (Kbr disc): ν _{c = 0} 1620, 1640 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.83 (s, 3H), 2.70 (s, 3H), 3.85 (s, 3H), 4.72 (d,
2H), 5.80 (d, 1H), 7.41 (s, 5H), 7.72 (m, 4H), 1
5.40-15.80 (br., 1H) 3- {1- (2,6-dichlorophenylmethylamino) ethylidene} -1,2,3,4-tetrahydro-6-methyl-1
- (2-methylphenyl) -2,4-pyridine-dione (Example 4) Yield: 91% _{mp: 246~248 ℃ NMR (CDCl 3)} δ value: 1.73 (s, 3H), 2.09 (s, 3H ), 2.85 (s, 3H), 4.93 (d,
2H), 5.72 (s, 1H), 6.90 ~ 7.50 (m, 7H), 15.35 ~ 15.
80 (br., 1H) 3- (1-cyclohexylaminoethylidene) -1,2,3,
4-Tetrahydro-6-methyl-1-phenyl-2,4-pyridindione (Example 5) Yield: 75% NMR (CDCl ₃ ) δ value: 0.70 to 2.10 (m, 11H), 1.80 (s, 3H ), 2.64 (s, 3H),
3.29 (t, 2H), 5.72 (s, 1H), 7.00 to 7.60 (m, 5H), 1
4.80 to 15.50 (br., 1H) 3- (1-butylaminoethylidene) -1- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-6-methyl-2,4-pyridinedione ( example 6) yield: 88% _{mp: 194~194.5 ℃ NMR (CDCl 3)} δ value: 0.70~2.10 (m, 7H) 1.82 (s, 3H), 2.62 (s, 3H), 3.43 (q, 2H ), 5.69 (s,
1H), 6.87 to 7.60 (m, 3H), 14.70 to 15.40 (br., 1H) 3- (1-butylaminoethylidene) -1,2,3,4-tetrahydro-6-methyl-1- (2- Pyridyl) -2,4-
Pyridinedione (Example 7) Yield: 94% Melting point: 106.5-108.5 ° C NMR (CDCl ₃ ) δ value: 0.70-2.10 (m, 7H), 1.81 (s, 3H), 2.66 (s, 3H), 3 .
45 (q, 2H), 5.73 (s, 1H), 7.15 to 8.70 (m, 4H), 14.7
0 ~ 15.50 (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, a heterocyclic group: R ² and R ² ′ are a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, an alkoxy group. , An alkenyloxy 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. Represent. ] The compound represented by the general formula (II) is treated with an acid in a suitable solvent. A method for producing an α-pyridone derivative, characterized by obtaining a compound represented by the formula [R ¹ , R ² , R ² ′ and R ³ are the same as those in the general formula (I)]