JPH08819B2 - Method for producing 4-oxo-4H-pyran-3-carboxamide compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a 4-oxo-4H-pyran-3-carboxamide compound. The compound obtained by this invention is useful as a medicine, an agricultural chemical, or a synthetic intermediate thereof.

(Prior Art) As a method for producing a 4-oxo-4H-pyran-3-carboxamide compound according to the present invention, several methods have been reported. A. Some of the acetoacetanilide derivatives, such as A. Mallams, give the corresponding 2,6-dimethyl-4-oxo-4H-pyran-3-carboxamide compounds upon treatment with polyacid under heat. Have found that [Journal, of,
Olga Nick, chemistry (J.Org.Chem.), 29, 3548
And 3555 (1964)]. R. Garner (R. Garn
[J. Chem. Soc. (C), 186 (1966)] reported by Malams et al. characterized acetoacetanilide derivatives having electron-withdrawing substituents. Support that it is a recoil. However, according to this method, if acetoacetanilide itself is used, it gives a 2-hydroxyquinoline derivative, and even a pyrone compound is not recognized.

Japanese Examined Patent Publication No. 45-31663 is characterized by reacting an isocyanate with a diketene in the presence of an acidic catalyst.
3,4-dihydro-2,4-dioxo-6-methyl-2H-1,
Preparation of 3-oxazines and / or 2,6-dimethyl-4-oxo-4H-pyran-3-carboxamitos (referred to as 3-carbamyl-2,6-dimethyl-4-pyrones in the above publication) In this concurrent reaction, ortho-substituted products such as O-chlorophenyl isocyanate and o-nitrophenyl isocyanate and meta-substituted products such as m-nitrophenyl isocyanate are described in the latter 2,6-dimethyl-4. The reaction to -oxo-4H-pyran-3-carboxamides is observed to be predominant. Although this method is effective when the starting isocyanate is easily available, it is said that the method is generally applicable because the structure of the isocyanate has a significant influence on the reaction selectivity. hard.

In addition, it is known that a 2,6-dimethyl-4-oxo-4H-pyran-3-carboxamide compound can be obtained as a reaction product of a diketene and a primary arylamine. Details of the reaction have been reported for derivatives, aminotropones, and aminopyridines.

Hitoshi Kato [Pharmaceutical Journal, 87.1212 (1967) Reference will consider the reaction of the diketene with aniline derivative in the presence of a basic catalyst have reported that pyridone-type closed-ring form is obtained, with the exception, It has been shown that p-nitroaniline gives 2,6-dimethyl-N- (4-nitrophenyl) -4-oxo-4H-pyran-3-carboxamide.

H. H.Toda, etc. [Chemical, And, Pharmaceutical, Bulletin (Chem.Pharm.Bull) 1
9 , 1477 (1971)] reported the reaction of aminotropones with diketene, but when 4-aminotropone and 2-aminotropone were used, 4-pyrone compounds were obtained, and 5-aminotropolone was used. If it is, a closed pyridone is obtained. Results of studies of reactions of aminopyridines [T. T. Kato, etc. [Chemical, And, Pharmaceutical, Bulletin (Chem.Pham.
Bull.), 20, 133 (1972)], 2-amino and 4
It was revealed that the -aminopyridine derivative mainly produces a 4-pyrone body, and the 3-aminopyridine derivative mainly produces a pyridone type ring-closed body. In addition, the findings on the reactivity of heterocyclic amines have been reported by RF Lauer, et al. [Journal, Of, Heterocycle, Chemistry (J. Hetrocyclic Chem.) 13 , 291].
(1976)], and 2-amino-1,3,4-thiadiazole gives the 4-pyrone form although the yield is unknown. As is clear from the above, in the reaction of diketene with primary arylamines, the structure of arylamine has an important influence on the selectivity of the reaction, and as long as primary arylamines are used as a raw material, It has hitherto been impossible to change this selectivity so as to favor the production of 4-pyrone form.

Similarly, when an acetoacetyl derivative of an arylamine, which is considered to be a reaction intermediate, is treated with diketene by the above method, a pyridone ring-closed product or a 4-pyrone product may be obtained depending on the structure of the arylamine. It has been reported. Of particular note is the fact that in the case of N-methylaniline, which is a secondary arylamine in which the pyridone ring-closing compound cannot be formed, the 4-pyrone compound can be obtained almost quantitatively using quaternary ammonium chloride as a catalyst. There [A. Fau. EV Dehmlow, Ah. Elle. ARShamout, Liebigs, Annalen, Dare, Hiemie (Liebigs Ann.Che
m.), 2062 (1982)].

Further, a reaction for obtaining a 4-pyrone form using 2,2,6-trimethyl-1,3-dioxin-4-one is known. T. Kato, etc. [Chemical, And, Pharmaceutical, Bulletin (Chem.Pharm.Bull.) 30 , 1315 (198
2), sees the reaction of amides and their acetoacetyl compounds with 2,2,6-trimethyl-1,3-dioxin-4-one, in which N-formylacetoacetamide is Reacts with 2,2,6-trimethyl-1,3-dioxin-4-one in the presence of N, N-dimethylaniline to give pyridone-type ring-closure as the main product and 4-pyrone as the by-product. Have reported that.

The conventional method for producing a 4-oxo-4H-pyran-3-carboxamide compound in the above-mentioned range has a common feature in that the selectivity is influenced by the structure of the starting material, and can be generally applied. Not the way. Methods for avoiding this difficulty have been known in the past, including Kato et al. [Pharmaceutical Journal, 10
1 , 40 (1981)], it has been reported that when a 3-morpholino crotonanilide derivative and diketene are heated and reacted, a corresponding 4-pyrone compound is obtained, but the yield is low,
For example, 2,6-dimethyl-4-oxo-4H-pyran 3-, obtained from 3-morpholino crotonanilide and diketene.
The carboxamide yield is 19%.

(Structure of the Invention) This invention has the general formula (I); [In the formula (I), R ₁ is an aryl group or heterocyclic group which may have a substituent, and R ₂ and R ₃ are the same or different and are a lower alkyl group, a cycloalkyl group, a substituent Is an aryl group or heterocyclic group which may have, and R ₂ and R ₃ may form a ring. R ₄ is a C ₁ -C ₂ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an aryl group which may have a substituent, an aryl moiety is a halogen atom, a lower alkyl group. And an aralkyl group which may be substituted with one or two lower alkoxy groups, a halogenated alkyl group or a 5- or 6-membered heterocyclic group. ] In the presence of a tertiary amine, a diketene or a compound represented by the general formula (II); [In the formula, R ₅ and R ₆ represent a hydrogen atom, an alkyl group or a phenyl group, and when both R ₅ and R ₆ are alkyl groups, a cycloalkyl group may be formed. ] The compound represented by the general formula (III); A method for producing a 4-oxo-4H-pyran-3-carboxamide compound, which comprises obtaining a compound represented by the formula: wherein R ₁ and R ₄ are the same as above.

The compound represented by the general formula (I) includes a β-ketoamide derivative represented by the following formula (IV) and R ₄ —COCOCH ₂ CONHR ₁ (IV) [wherein R ₁ and R ₄ are represented by the formula (I), Same definition as in (III)] Dehydration condensation reaction with primary amine represented by formula (V) [Wherein R ₂ and R ₃ are the same as defined in formula (I)].

R ₁ in the general formulas (I) and (III) represents an aryl group or a heterocyclic group which may have a substituent. The aryl group includes a phenyl group or a naphthyl group. The heterocyclic group includes a 5-membered or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and particularly furyl and tetrahydro. Examples thereof include 5-membered ring groups such as furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyrazolyl, and 6-membered ring groups such as pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

The substituent is not particularly limited as long as it is a group inert to the reaction of the present invention. Specific examples of the substituent include halogen atom such as chlorine atom, bromine atom and fluorine atom; alkyl group such as methyl, ethyl, propyl, isopropyl and butyl; alkoxy group such as methoxy, ethoxy and propoxy; methoxycarbonyl. , An alkoxycarbonyl group such as ethoxycarbonyl; a cyano group, a nitro group, a trifluoromethyl group and the like. The above aryl group or heterocyclic group may be substituted with 1 to 3, preferably 1 or 2 of these substituents.

Although the present invention is characterized by the reaction itself as described above, R ₁ is selected from the viewpoint of being useful as a final target product (for example, a pesticide showing a plant growth inhibitory action, or a drug showing an anti-inflammatory action). It is desirable to do.

R ₂ and R ₃ are the same or different lower alkyl groups, cycloalkyl groups, aryl groups, or heterocyclic groups, and R ₂
It is also good to form a ring with and R ₃ .

Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and impentyl groups.

Cycloalkyl groups include cyclopropyl, cyclopentyl or cyclohexyl groups and the like. Further, in the two alkyl groups, a heterocyclic group may be formed together with the nitrogen atom of the amino group to which they are bound 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. The aryl group includes a phenyl group or a naphthyl group. The heterocyclic group includes a 5-membered or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, particularly furyl and tetrahydro. Examples thereof include 6-membered ring groups such as furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, and pyridazinyl.

The substituent is not particularly limited as long as it is a group inert to the reaction of the present invention. Specific examples of the substituent include halogen atom such as chlorine atom, bromine atom and fluorine atom: alkyl group such as methyl, ethyl, propyl, isopropyl and butyl; alkoxy group such as methoxy, ethoxy and propoxy; methoxycarbonyl. , Alkoxycarbonyl such as ethoxycarbonyl; cyano group, nitro group, trifluoromethyl group and the like. The above aryl group or heterocyclic group may be substituted with 1 to 3, preferably 1 or 2 of these substituents.

R _{4 in the} formulas (I) and (III) is a C ₁ -C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group,
A lower alkoxyalkyl group, an aryl group which may have a substituent, an aralkyl group which may have an aryl moiety substituted with 1 to 2 of a halogen atom, a lower alkyl and a lower alkoxy group, a halogenated alkyl group, a 5-membered Or 6
Represents a heterocyclic group of a member.

The lower alkenyl group and lower alkynyl group include vinyl, allyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 1,4-pentadienyl,
1,6-butadienyl, 1-hexenyl, ethynyl, 2-
Includes propynyl and the like.

Cycloalkyl groups include cyclopropyl, cyclopentyl or cyclohexyl groups and the like.

Halogenated alkyl groups include trifluoromethyl, chloromethyl groups and the like.

Lower alkoxyalkyl groups include methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl groups and the like.

The halogen atom includes chlorine, bromine, iodine or fluorine atom.

Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl groups.

Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy groups.

Aralkyl groups include benzyl, 3-phenylpropyl, 4-phenylbutyl groups and the like.

The 5-membered or 6-membered heterocyclic group includes a 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples thereof include 5-membered ring groups such as furyl, tetrahydrofuryl, thienyl, thiazolyl, isociazolyl, oxazolyl, isoxazolyl and pyrazolyl; and 6-membered ring groups such as pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. These groups may be substituted with alkyl groups such as methyl or ethyl, 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.

On the other hand, the reaction partner of the compound represented by the general formula (I) is diketene or 6 represented by the general formula (II).
-Methyl-4H-1,3-dioxin-4-one compound, the latter being an adduct of diketene and a ketone or an aldehyde, which can be prepared by a conventionally known method [M.
F. Carroll, MF. R. Batter (ARBader), Journal of American Chemical Society (J.Amer.Chem.Soc.) 74, 6305
(1952); ibid. 75, 5400 (1953); Fau. EV Dehmlow, Ah. Elle. Shemout (A.
R. Shamout) [See Liebigs Ann. Chem.) 1753 (1982).

R ₅ and R ₆ in the general formula (II) mean a hydrogen atom, an alkyl group or a phenyl group, or when both R ₅ and R ₆ are alkyl groups, they may be bonded to each other to form a cycloalkyl group. Good. These R ₅ and R ₆ are groups that are not introduced into the target product, and it is desirable to select and use those that are easily available and inexpensive. Preferred compounds of general formula (II) include 2,
2,6-trimethyl-4H-1,3-dioxin-4-one may be mentioned.

Tertiary organic bases include aliphatic or aromatic tertiary amines and nitrogen-containing heterocyclic bases. Examples of the aliphatic tertiary amine include triethylamine, tripropylamine, triisobutylamine, N, N-dimethylbenzylamine, N, N-dimethylcyclohexylamine, N, N,
N ', N'-tetramethylethylenediamine, N, N, N', N '
-Tetramethyl-1,3-propanediamine, etc., as aromatic tertiary amines, N, N-dimethylaniline, N, N-
Examples of nitrogen-containing chlorine ring bases such as diethylaniline and N, N-dimethyl-o-toluidine include N-methylpyrrolidine, N-methylmorpholine and 1,4-diazacyclo (2.2.
2) Octane and the like.

In the case of using the compound represented by the general formula (II) in the present invention, it is possible to carry out the reaction in the absence of a solvent, but more preferably in an aromatic hydrocarbon solvent such as benzene, toluene or xylene. It is recommended to carry out the reaction as a homogeneous system. Also, the setting of reaction temperature is
The thermal decomposition temperature of the compound represented by the general formula (II) is used as a guide, and the temperature is in the range of about 100 ° C to 150 ° C. From the viewpoint of reaction rate, this temperature is particularly preferably in the range of 110 ° C to 140 ° C.

The amount of the compound represented by the general formula (II) used is, of course, 1 equivalent or more with respect to the compound represented by the general formula (I), but preferably in the range of 1.5 to 3.0 equivalents, good results are obtained. can get. When the compound represented by the general formula (II) is used, a carbonyl compound represented by the formula (VI) is generated in the reaction system as a thermal decomposition product.

If the melting point of this compound is lower than the reaction set temperature,
It is advantageous to carry out the reaction while distilling it out of the system along with a part of the solution used during the reaction. Therefore, it can be said that it is generally preferable to carry out the reaction at the reflux temperature for use and dissolution.

On the other hand, in the case of reacting with diketene in the present invention, it is preferable to carry out the reaction as a homogeneous system in an aromatic carbon solvent such as benzene, toluene, xylene, etc., and the reaction temperature is about -20 ° C to 130 ° C. Can be performed in the range of. The upper limit temperature of this reaction is limited by the melting point of diketene, and is not limited to this when the reaction is carried out under pressure. Further, good results are obtained when diketene is used in an amount of 1 equivalent or more, preferably 1.5 to 3.0 equivalents, relative to the compound represented by the general formula (I).

Third used in the reaction between the compound represented by the general formula (I) and diketene or the compound represented by the general formula (II)
Good results are obtained when the amount of the primary organic base used is 0.5 equivalent or more, preferably 1 or more equivalents to the compound of the general formula (I). Even if 10 equivalents or more are used, a larger effect cannot be obtained. The tertiary organic base may be appropriately selected and used from those exemplified above, but triethylamine, N, N,
It is preferable to use N ', N'-tetramethylethylenediamine, N, N-dimethianiline, N-methylpiperidine and the like.

(Effects of the Invention) According to the method of the present invention, a 4-oxo-4H-pyran-3-carboxamide compound, which has heretofore been impossible to selectively synthesize, is obtained by a simple operation using an easily available raw material. You can get it efficiently.

(Examples) The present invention will be described in more detail with reference to the following examples.

Example 1 Synthesis of 2,6-dimethyl-4-oxo-N-phenyl-4H-pyran-3carboxamide A mixture of β-morpholino crotonanilide 2.4 g (10 mmol), triethylamine 6.06 g (60 mmol) and toluene 12 ml is heated under reflux. Do not let diketene 2.1 g (25 mmol) in toluene (8 ml) heat while refluxing diketene 2.1.
A solution of g (25 mmol) in toluene (8 ml) was heated under reflux for an additional 2.5 hours under an appropriate temperature over 12 minutes. After distilling off the solvent, the residue was transferred to a separating funnel together with methylene chloride and water and extracted, and the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then with water, and dried over magnesium sulfate.
After treating by a conventional method, the obtained crystalline residue was recrystallized from ethyl acetate to obtain 1.3 g of the title compound (yield 53%).

Melting point: 148-149 ° C IR (KBr disk): 1652, 1682 cm ^-1 NMR (CDCl ₃ ) δ value: 2.24 (s, 3H), 2.82 (s, 3H), 6.20
(S, 1H), 6.80 to 7.80 (m, 5H), 11.97 (br., 1H). Example 2. Following the procedure of Example 1, but using β- (N, N-dimethylamine) crotonanilide as the starting material, 2,6
-Dimethyl-4-oxo-N-phenyl-4H-pyran-
3-carboxamide was obtained in a yield of 50%.

Example 3. 2-Ethyl-6-methyl-4-oxo-6-phenyl-
4H-pyran-3-carboxamide β-morpholino-2-pentenoic acid anilide 2.6 g (10 mm
ol), 0.88 g of N, N-dimethylethylenediamine (10 mmo
l) and a mixture of toluene (25 ml) with heating under reflux, a solution of 2,5,6-trimethyl-4H-1,3-dioxin-4-one 3.55 g (25 mmol) in toluene (12 ml) was added over 30 minutes. Then, the mixture was heated under reflux for 2.5 hours. After the solvent was distilled off, the residue was transferred to a separating funnel together with methylene chloride and water for extraction, the organic layer was washed with 1N hydrochloric acid saturated aqueous sodium hydrogen carbonate solution and water, and then dried over magnesium sulfate. After treating by a conventional method, the obtained crystalline residue was recrystallized from a mixed solution of ethyl acetate and hexane to give 1.
1 g (yield 42.8%) was obtained.

Melting point: 154.5-156 ° C IR (KBr disk): 1650, 1670 cm ^-1 NMR (CDCl ₃ ) δ value: 1.31 (t, 3H), 2.27 (s, 3H), 3.28
(Q, 4H), 6.18 (s, 1H), 6.90−7.70 (m, 5H), 11.90 (b
r., 1H). Examples 4 to 5 According to the method of Example 1, enamine which can be obtained from the corresponding β-ketoamide derivative and N, N-dimethylamine was used as a starting material to obtain the following compounds.

6-Methyl-N- (2,3-dimethyphenyl) -4-oxo-2-phenyl-4H-pyran-3-carboxamide (Example 4) Yield 45% Melting point: 164-166 ° C IR (KBr disk) : 1655, 1697 cm ^-1 NMR (CDCl ₃ ) δ value: 2.24 (s, 6H), 2.31 (s, 3H), 6.23
(S, 1H), 6.70 to 7.65 (m, 8H), 10.47 (br., 1H). N- (2-chlorophenyl) -6-methyl-4-oxo-2-phenyl-4H-pyran-3-carboxamide (Example 5) Yield: 55% Melting point: 168-170 ° C IR (KBr disk): 1655 , 1700 cm ^-1 NMR (CDCl ₃ ) δ value: 2.34 (s, 3H), 6.31 (s, 3H), 6.80
~ 8.32 (m, 9H), 10.23 (br., 1H). Examples 6-7 According to the method of Example 1, the following compounds were obtained using the corresponding β-ketoamide derivative and enamine synthesized from morpholine as a starting material.

N- (4-chlorophenyl) -6-methyl-4-oxo-2-phenyl-4H-pyran-3-carboxamide (Example 6) Yield: 60% Melting point: 194-197 ° C IR (KBr disk): 1650 , 1688 cm ^-1 NMR (CDCl3) δ value: 2.27 (s, 3H), 2.81 (s, 3H), 6.20
(S, 1H), 7.00 to 7.80 (m, 4H), 12.05 (br., 1H). 6-Methyl-N- (2-methylphenyl) -4-oxo-2-propyl-4H-pyran-3-carboxamide (Example 7) Yield: 48% Melting point: 118.5-120.5 ° C IR (KBr disk): 1620, 1657, 1697 cm ^-1 NMR (CDCl3) δ value: 1.00 (t, 3H), 1.75 (six, 2H), 2.2
8 (s, 3H), 2.36 (s, 3H), 3.23 (t, 2H), 6.16 (s, 1
H) 6.80-8.10 (m, 4H), 11.76 (br., 1H). Example 8 N- (2,6-diethylphenyl) -6-methyl-4-oxo-2-phenyl-4H-pyran-3-carboxamide N- (2,6-diethylphenyl) -3-morpholinocrotonamide The title compound was obtained according to the method of Example 1 except that the starting material was isolated by column chromatography.

Yield 42% Melting point 68-69 ° C IR (KBr disk): 1627, 1640, 1670cm ^-1 NMR (CDCl3) δ value: 0.98 (t, 3H), 1.17 (t, 6H), 1.75
(Six, 2H) 2.28 (s, 3H), 2.63 (g, 4H), 3.24 (t, 2
H), 6.24 (s, 1H) 7.06 (s, 3H), 10.98 (br.1H).

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [In the formula (1), R ₁ is an aryl group or a heterocyclic group which may have a substituent, and R ₂ and R ₃ are the same or different and are a lower alkyl group, a cycloalkyl group or a substituent. Is an aryl group or heterocyclic group which may have, and R ₂ and R ₃ may form a ring. R ₄ is a C _{1 to} C ₁₂ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group,
An alkoxy group which is lower, an aryl group which may have a substituent, an aralkyl group which may be substituted on the aryl moiety with one or two of a halogen atom, a lower alkyl group and a lower alkoxy group, a halogenated alkyl group Or 5
Alternatively, it is a 6-membered heterocyclic group. ] In the presence of a tertiary amine, a diketene or a compound represented by the general formula (I
I); [In the formula, R ₅ and R ₆ represent a hydrogen atom, an alkyl group or a phenyl group, and when both R ₅ and R ₆ are alkyl groups, a cycloalkyl group may be formed. ] The compound represented by the general formula (III); A method for producing a 4-oxo-4H-pyran-3-carboxamide compound, which comprises obtaining a compound represented by the formula: wherein R ₁ and R ₄ are the same as above.