JPH0710847B2 - Process for producing pyridone-3-carboxamide compound - Google Patents

Description

TECHNICAL FIELD The present invention also relates to a method for producing 1,4-dihydro-4-oxo-3-pyridinecarboxamides, and a compound obtained by the present invention is It is useful as a medicine, a pesticide, or an intermediate thereof.

(Prior Art) Conventionally, among 1,4-dihydro-4-oxo-3-pyridinecarboxamides, 1,4-dihydro-2,6-dimethyl-
It has been known that a compound belonging to the 4-oxo-3-pyridinecarboxamide derivative is produced by reacting a suitable 3-aminocrotonamide derivative with diketene in the absence of a solvent. In other words, Kato et al. (Pharmaceutical magazine, 10
1 , 40-47 (1981)), three 3-benzylaminocrotonanilide compounds (in formula (I), R ¹ = phenyl group, 4-methoxyphenyl group or 4
-Chlorophenyl group; R ² = phenyl group; R ³ = methyl group and corresponds to the case of n = 1) without using a solvent, and the reaction mixture obtained by reacting diketene under heating at 60 to 90 ° C. From 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide and its derivatives (formula (III ), R ¹ = phenyl group, 4-methoxyphenyl group or 4
-Chlorophenyl group; R ² = phenyl group; R ³ = methyl group and corresponding respectively when n = 1) are obtained in a yield of 2 to 9%. This method uses diketene that is industrially easily available and has a simple operation in which the reaction is simply performed under heating. However, in all cases reported, the yield is low and the method is industrially applied. It cannot be considered as a possible manufacturing method. The main product of the reaction by the method of Kato et al. Is rather 4-hydroxy-6-methyl-1-phenyl-3- [1- (phenylmethylimino) ethyl] -2 (1H) -pyridinone or its derivative.

Further, according to Canadian Patent No. 1,115,278, N- (4-chlorophenyl) -3- (ethylamino) -2-butenamide (in the formula (I), R ¹ = 4-chlorophenyl group,
To a toluene solution of (CH ₂ ) nR ² = ethyl group and R ³ = methyl group) was added triethylamine and diketene (50% acetone solution), and the mixture was heated under reflux for 4 hours, and after cooling, the reaction mixture was added. An oily substance separates when 10% hydrochloric acid is added. From this oil, firstly the hydrochloride salt of 1-ethyl-1,4-dihydro-2,6-dimethyl-4-oxo-N- (4-chlorophenyl) -3-pyridinecarboxamide was obtained, and further the free carboxamide was obtained. (Refer to Example 14 of the above-mentioned patent). This method is different from the method of Kato et al. Described above in using a solvent for the reaction, reacting diketene in the presence of triethylamine, and insolubilizing the reaction product as a hydrochloride,
The yield of the product is not described, and its usefulness as a production method is unknown.

Zankowska-Jasinska et al. (Bull.Acad.Pol.Sci., Ser.Sc
i.Chim.1975, 23 (11) 901) 1,4-dihydro- by the self-organization reaction of enamine with benzoylacetanilide derivative and aniline derivative with hydrochloric acid or phosgene.
Although a 4-oxo-3-pyridinecarboxamide derivative has been synthesized, this method can only synthesize the 2- and 6-positions. Also they (Zes
z.Nauk.Uniw.Jagellonian., Pr.Chem.1976,21,141)
Various 1,4-dihydro-4-oxo-3-pyridinecarboxamide derivatives have been synthesized by a self-condensation reaction of benzoylacetanilide derivative, acetoacetanilide derivative and shiff bases thereof with succinic acid chloride as a catalyst. Also in this method, it is possible to synthesize only those having the same 2-position and 6-position.

(Object of the Invention) As is apparent from the above-mentioned prior art, a method for obtaining 1,4-dihydro-4-oxo-3-pyridinecarboxamides in a high yield has not been heretofore known. This is because the conditions for selectively providing the desired product have not been found. The present inventors have earnestly studied for a simple and high-yield synthetic method of a 1,4-dihydro-4-oxo-3-pyridinecarboxamide compound, and as a result, have shown that an enamine (I) derived from β-ketoamide and a primary amine.
The present invention has been completed in which a 1,4-dihydro-4-oxo-3-pyridinecarboxamide compound is advantageously produced by an adduct (II) of diketene and ketone.

(Structure of the Invention) This invention has the formula (I): (In the formula, R ¹ is a C _1-3 alkyl group, a halogen atom or C _1-3.
Represents an aryl group which may be substituted with an alkoxy group, R ² is a hydrogen atom; a C _1-3 alkyl group, a halogen atom or an aryl group which may be substituted with a C _1-3 alkoxy group; or C _1- C ₁₁ represents a linear or branched alkyl group, and R ³ represents a C ₂ -C ₁₁ linear or branched alkyl group. n represents an integer of 1 to 4. ) And a compound of formula (II): (In the formula, R ⁴ and R ⁵ are C ₁ -C ₄ alkyl groups.) The compound represented by the formula (III): (Wherein R ¹ , R ² , R ³ and n are the same as those in formula (I)), 1,4-dihydro-6-methyl-4-oxo is obtained. A method for producing a -3-pyridinecarboxamide compound.

One of the raw materials used in the method of the present invention is a compound represented by the formula (I), generally a ketoamide compound represented by the following formula (IV): It is a substance obtained as a product of a dehydration condensation reaction with a primary amine H ₂ N (CH ₂ ) nR ² (V) represented by the formula (V).
When the compound represented by the formula (I) is used for the purpose of the present invention, it is not necessary to use a purified substance, and the crude reaction mixture of the above dehydration condensation reaction can be used as it is. Therefore, when the dehydration condensation reaction of the compounds represented by the formulas (IV) and (V) is carried out in a solvent, the formula (I) and the formula (I
The process can be simplified by choosing the same insoluble solvent used in the reaction with I).

In the compound represented by the formula (I), R ¹ is an aryl group such as a phenyl group or a naphthyl group, more specifically an unsubstituted phenyl group, and an alkyl group having 1 to 3 carbon atoms, It includes an alkoxy group, a halogen atom such as fluorine, chlorine and bromine, a phenyl group substituted with 1 to 5 substituents selected from an acetylamino group, and a 1-naphthyl group.

R ² in the formula (I) is a hydrogen atom; a C _1-3 alkyl group, a halogen atom or an aryl group which may be substituted with a C _1-3 alkoxy group; or a C ₁ -C ₁₁ linear or branched group. Represents an alkyl group represented by the formula: and n represents an integer of 1 to 4. Therefore, as the group of (CH ₂ ) nR ² , specifically, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, hexyl, octyl, 2-ethylhexyl,
Examples thereof include an alkyl group such as dodecyl; a phenylmethyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group and an aralkyl group having a substituent on these phenyl groups.

R ³ represents a C ₂ -C ₁₁ linear or branched alkyl group. Therefore, the R ³ group specifically represents an alkyl group such as ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, hexyl, octyl, 2-ethylhexyl, dodecyl and the like.

Another raw material used in the method of the present invention is a 4H-1,3-dioxin-4-one compound represented by the formula (II). F. Method reported by MFCaroll et al. [Journal of the American
Chemical Sosaetei (J.Amer.Chem.Soc.), 75, 5400
(1953)], it can be prepared from diketene and the corresponding ketone. In the case of diketene and acetone, a small amount of paratoluenesulfonic acid is added to the mixture and kept under reflux for 3 hours. When the odor of diketene disappears, excess acetone is distilled off, and the product is put under reduced pressure (2 Torr). There is a description that a yield of 91% based on diketene is obtained by distillation. According to the study by the present inventors, it is clear that the distillation of the above product needs to be carried out by using a thin film evaporation type apparatus, and that the desired result cannot be obtained by the batch distillation. It was In order to avoid this drawback and simplify the process, it was studied to use a crude reaction product of diketene and acetone as it is as a raw material of the method of the present invention without a purification step. It was confirmed that the same reaction results as those obtained by using the standard product purified by the method described in (1) were obtained. Among the compounds represented by the formula (II), those suitable for the purpose of the present invention are those obtained by an addition reaction of diketene and a lower alkyl ketone, for example, addition of diketene with acetone, methyl ethyl ketone or methyl isobutyl ketone. Among them, those which can be used particularly advantageously in practical use are the adducts of diketene and acetone.

Now, among the reaction conditions of the compound represented by the formula (I) and the compound represented by the formula (II), the reaction temperature, the selection of the inert solvent to be used, etc. are particularly important to consider.
For the reaction temperature, see G. G. Jger et al. [Lieb Hiss Annalen del Himmy (Lieb
igs Ann. Chem., 1976, pp. 1689-1712] provides a guide. That is, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, which is an adduct of diketene and acetone, decomposes into acetone and acetylketene when heated to a temperature of 120 ° C or higher. Therefore, other 4H-
In the case of the 1,3-dioxin-4-one derivative as well, the reaction temperature is set with the temperature of thermal decomposition as a guide. Practically the reaction temperature is between about 110 ° C and about 140 ° C.

The amount of the compound represented by formula (II) used is
The amount is preferably 1.5 to 3 times the molar amount of the compound represented by.

Next, the inert solvent to be used in the reaction is selected in consideration of the chemical reaction activity, the boiling point, the ease with which the anhydrous solvent is prepared, the solubility of the product of interest of the present invention at room temperature, and the like.
Specifically, aromatic hydrocarbon solvents are suitable, and it is desirable to use benzene, toluene, xylene, or a mixture thereof. The use of these solvents also provides ketones represented by the following formula (VI), which are produced as the reaction proceeds, (In the formula, R ⁴ and R ⁵ are C ₁ -C ₄ alkyl groups, and are represented by the formula (I
Same as the definition of R ⁴ and R ^{5 in} I)) Since it does not form an azeotrope with, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc., the distillation separation operation is facilitated, which is advantageous for recovery and reuse of the above ketone. . By recovering the ketone produced in the reaction and reacting it with diketene, 4H-1,3-represented by the above formula (II) is obtained.
Since a dioxin-4-one compound can be obtained,
The method of the present invention, which consumes substantially only diketene,
It enables the preparation of 4-dihydro-6-methyl-4-oxo-3-pyridinecarboxamide compounds.

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

Reference Example 1. Diketene (327 g, 3.89 mol), acetone (240 g, 4.13 mol) and paratoluenesulfonic acid monohydrate (1.0 g) were weighed into a 1-liter three-necked flask, and a stirrer and a reflux condenser were used. And a thermometer attached and heated in an oil bath with stirring. The temperature of the reaction mixture is from 24 ℃ to 75 ℃ after 1 hour.
Then, after 2 hours, the temperature rose to 90 ° C. Thereafter, heating was further continued, the temperature of the reaction mixture was kept at 97 to 100 ° C., the oil bath was removed 5 hours after the start of heating, and the dark brown reaction mixture was allowed to cool at room temperature. The crude reaction product weighed 564 g. If the reaction yield is 100%, 1.00 g of this crude reaction product
Is 2,2,6-trimethyl-4H-1,3-dioxin-4-one
It will contain 6.9 mmol.

Reference Example 2. Diketene (110 g, 1.31 mol), methyl isobutyl ketone (145 g, 1.48 mol) and paratoluene sulfonic acid monohydrate (0.5 g) were weighed into a 500-milliliter three-necked flask, and stirred and refluxed. A condenser and thermometer were attached and heated to 95-98 ° C in an oil bath for 10 hours with stirring. 21 g of this reaction crude liquid was collected and subjected to Kugelrohr distillation to obtain 13.9 g of a main distillate (0.2 Torr, 106 ° C.). The preparation contained dehydroacetic acid, and its purity was estimated to be 91% from the signal integral value of the nuclear magnetic resonance absorption spectrum.

NMR signal (CDCl ₃ ): δ (ppm) 0.97 (6H, d., J = 6Hz), 1.62 (3H, s.), 1.93 (3H, s.), 5.13 (1H, s.).

Example 1. Synthesis of 2-butyl-1,4-dihydro-6-methyl-4-oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide 3.93 g (13.4 mmol) of 3-oxoheptanoic acid anilide, A mixture of 1.43 g (13.4 mmol) of benzylamine, 2 drops of acetic acid and 20 ml of toluene was kept at reflux temperature for 1.5 hours with stirring, and water generated during the reaction was distilled out of the system together with about 12 ml of toluene. While keeping the reaction mixture under reflux,
2,2,6-Trimethyl-4H-1,3-dioxin-4-one 4.
A solution of 74 g (33.4 mmol) in toluene (12 ml) was added dropwise over 30 minutes, followed by heating for another 1.5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, and the obtained yellow oil was separated by column chromatography to give the title compound as 1.
78 g (yield 35.6%) was obtained.

Melting point 132-134 ° C. Example 2. 2-Butyl-N- (2-chlorophenyl) -1,4-dihydro-6-methyl-4-oxo-1-phenylmethyl-
Synthesis of 3-pyridinecarboxamide N- (2-chlorophenyl) -3-oxoheptanoic acid amide 3.10 g (12.2 mmol), benzylamine 1.31 g (12.2 mm
ol), 2 drops of acetic acid and 20 ml of toluene with stirring at the reflux temperature for 1.5 hours, and about 1 hour of water formed during that time.
It was distilled off together with 2 ml of toluene. While maintaining the reaction mixture at reflux temperature, 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one 4.78 g (30.61 mmol)
Was added dropwise over 30 minutes, and heating was continued for another 1.5 hours. The reaction liquid was cooled to room temperature and then concentrated under reduced pressure, and the obtained yellow oily substance was purified by column chromatography to obtain 1.55 g (yield 31%) of the title compound.

Melting point 121-123 ° C. Example 3. Synthesis of 2-butyl-N- (2,6-diethylphenyl) -1,4-dihydro-1,6-dimethyl-4-oxo-3-pyridinecarboxamide N- (2 , 6-Diethylphenyl) -3-oxo-heptanoic acid amide 5.86 g (21.3 mmol) was dissolved in 25 ml of toluene, 3.31 g (42.6 mmol) of methylamine 40% aqueous solution and 2 drops of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. did.

The reaction mixture was then heated to reflux temperature and water was distilled out of the system with about 15 ml of toluene. While continuing the reflux, 2,
2,6-trimethyl-4H-1,3-dioxin-4-one 2.
26.7 ml of 0M toluene solution was added dropwise over 30 minutes, and heating was continued for another 45 minutes. During this period, 20 ml of distillate was removed out of the system. The reaction mixture was separated by silica gel chromatography to give the title compound (3.44 g, yield 45.6%).

Melting point 95.5-96.0 ° C. Example 4. Synthesis of 1-butyl-1,4-dihydro-6-methyl-4-oxo-N-phenyl-2-bromopyr-3-pyridinecarboxamide 3-oxo-hexanoic acid anilide 4.16 g (20.3mmol),
To a mixture of 2.08 g (28.4 mmol) of butylamine and 25 ml of toluene was added 3 ml of acetic acid, and the mixture was stirred at room temperature and then slowly heated to the reflux temperature.

Water and excess amine formed during the 1.5 hour reflux were distilled out of the system along with about 12 ml of toluene. 2,2,6-
A solution of trimethyl-4H-1,3-dioxin-4-one (7.2 g) in toluene (20 ml) was added dropwise over 30 minutes, and while heating and refluxing was continued for 45 minutes while distilling off the low boiling point produced, the reaction solution was It was left at room temperature. Thereafter, in the same manner as in the above Example, 1.39 g (yield 21.0%) of the title compound was obtained as a yellow oil.

Melting point 116-117 ° C. Examples 5-11. The corresponding β-ketoamides and primary amines were reacted according to the method of Example 1 to obtain the following compounds.

1,4-Dihydro-6-methyl-4-oxo-N-phenyl-1,2-bis- (phenylmethyl) -3-pyridinecarboxamide (Example 5) Yield 36.4% Melting point 190.5-193 ° C 2-Ethyl -1,4-Dihydro-6-methyl-4-oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide (Example 6) Yield 35.4% Melting point 155-157 ° C 1,4-Dihydro-6- Methyl-1- (4-methylphenylmethyl) -4-oxo-2-pentyl-N-phenyl-3-pyridinecarboxamide (Example 7) Yield 20.0% Melting point 151-152.5 ° C 1,4-dihydro-6- Methyl-4-oxo-2-pentyl-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide (Example 8) Yield 40.0% Melting point 114-115.5 ° C 1- (4-chlorophenylmethyl) -1,4- Dihydro-
6-Methyl-N- (2-methylphenyl) -4-oxo-2-pentyl-3-pyridinecarboxamide (Example 9) Yield 30.6% Melting point 155-156.5 ° C N- (2-chlorophenyl) -2-ethyl -1,4-dihydro-6-methyl-4-oxo-1-phenylmethyl-
3-Pyridinecarboxamide (Example 10) Yield 42.0% Melting point 174.5-177 ° C 2- (2-furyl) -1,4-dihydro-6-methyl-4
-Oxo-N-phenyl-1-phenylmethyl-3-pyridinecarboxamide (Example 11) Yield 25% (oil) Molecular formula and infrared absorption spectrum (IR) of the compound obtained by the synthesis described in the above Examples, The proton nuclear magnetic resonance spectrum (IH-NMR) data is shown in Table I. The solvent for NMR was CDCl ₃ , and the IR was measured by the KBr method.

Claims (13)

[Claims] 1. Formula (I): (In the formula, R ¹ is a C _1-3 alkyl group, a halogen atom or C _1-3.
Represents an aryl group which may be substituted with an alkoxy group, R ² is a hydrogen atom; a C _1-3 alkyl group, a halogen atom or an aryl group which may be substituted with a C _1-3 alkoxy group; or C _1- C ₁₁ represents a linear or branched alkyl group, and R ² represents a C ₂ -C ₁₁ linear or branched alkyl group. n represents an integer of 1 to 4. ) And a compound of formula (II): (In the formula, R ⁴ and R ⁵ are C ₁ -C ₄ alkyl groups.) The compound represented by the formula (III): (Wherein R ¹ , R ² , R ³ and n are the same as those in formula (I)), 1,4-dihydro-6-methyl-4-oxo is obtained. -3-A method for producing a 3-pyridinecarboxamide compound. 2. R ⁴ and R ⁵ in formula (II) are methyl groups,
The production method according to claim 1, which is a compound having an ethyl group or an isobutyl group. 3. The method according to claim 1, wherein R ⁴ and R ⁵ in the formula (II) are both methyl groups. 4. The process according to claim 1, wherein the compound of formula (II) comprises a crude reaction liquid obtained by reacting a mixture of diketene and acetone at a temperature of about 100 ° C. or lower. 5. A compound of formula (I) is of formula (IV) The compound of the formula _{(V) H 2 N (CH} 2) nR 2 (V) ( formula (IV) in the R ¹ and R ^3, R ² in the formula (V) is defined in each formula (I) The same production method as described in claim 1), which comprises a crude reaction solution obtained by dehydration-condensation of the above compound) in an inert solvent. 6. The production method according to any one of claims 1 to 4, wherein the inert solvent is toluene, xylene or mesitylene. 7. The production method according to claim 5, wherein the inert solvent is toluene, xylene, or mesitylene. 8. The production method according to claim 5, wherein the inert solvent is toluene. 9. The production method according to any one of claims 1 to 5, wherein the same inert solvent is toluene. 10. The production method according to claim 1, wherein the ketone produced during the reaction is recovered and reused. 11. The production method according to claim ^1, wherein R ¹ and R ² of the formula (I) are compounds having a phenyl group or a substituted phenyl group. 12. The process according to claim 1, wherein the reaction temperature between the compound of formula (I) and the compound of formula (II) is 110 ° C. to 140 ° C. 13. The method according to claim 1 or 12, wherein the compound of the formula (II) is used in a molar amount of 1.5 to 3 times that of the compound of the formula (I).