JPH0613497B2 - Process for producing pyrone-3-carboxamide derivative - 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, several methods have been conventionally reported.

Among them, diketene is reacted with an isocyanate, a primary amine, an acetoacetyl derivative thereof, or a β-aminocrotonic acid amide derivative to give 4-oxo-4.
As a reported example of obtaining an H-pyran-3-carboxamide compound, Japanese Examined Patent Publication No. 45-31663; Pharmaceutical Journal, 87 , 1212 (196
7); Chem. Pharm. Bull., 19 , 1477 (1971); Chem. Pharm. Bull., 20 , 133 (1972); Chem. Pharm. Bull., 28 , 2129 (1980); Pharmaceutical Journal, 101 , 40 (198
1) etc. However, these methods are limited to compounds in which the resulting 4-oxo-4H-pyran-3-carboxamide compound has a methyl group at both the 2- and 6-positions of the pyran ring and a hydrogen atom at the 5-position. Therefore, the compound of the present invention cannot be produced.

A method for obtaining a 4-oxo-4H-pyran-3-carboxamide compound by dimerizing a β-ketoamide derivative is also known (J. Org. Chem., 29 , 3548 and 3555 (1964); Zesz. . Nauk. Uniw. Jagiellon., Pr.
Chem. 1976, 21, 141 ,; Zesz. Nauk. Uniw. Jagiello
n .; Pr. Chem. 1980,25,7.) The compounds obtained by these methods are not common because the substituents at the 2- and 6-positions of the pyran ring are both the same. As described above, 4-oxo-4H- which has been conventionally included in the present invention
A general method for producing a pyran-3-carboxamide compound is not known.

(Structure of the Invention) This invention has the general formula (I) or (I) ′. [In the formulas (I) and (I) ′, R ₁ is an aryl group or heterocyclic group which may have a substituent, and R ₂ is C ₁
To C ₁₁ alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group,
An optionally substituted aryl group, an optionally substituted aralkyl group, a halogenated alkyl group or a 5- or 6-membered heterocyclic group, R ₃ is a dialkylamino group, and n
Represents an integer of 0 to 6] and a compound represented by the general formula (II): (In the formula, R ₄ and R ₅ may be a hydrogen atom, an alkyl group or an aryl group, or may form a cycloalkyl group when R ₄ and R ₅ are both alkyl groups. R ₆ is a hydrogen atom or C _{1 to} C ₁₁ Is an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, or a halogenated alkyl group, and R ₆ is In the case of a hydrogen atom, R ₇ is a hydrogen atom, C ₂ to C.
_{11 represents} an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or a halogenated alkyl group, R
_{When 6} is a substituent other than a hydrogen atom, R ₇ is a hydrogen atom,
C ₁ -C ₁₁ alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, optionally substituted aryl group, optionally substituted aralkyl group or halogenated alkyl group Or R ₆ and R ₇ together are — (CH ₂ ) m
-(M represents 3 or 4)] or a compound represented by the general formula (III): [R ₁ and R ₂ are the same as defined in formulas (I) and (I) ′, R ₈
Represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group or a heterocyclic group] and a compound of the general formula (II) in the presence of a tertiary organic base, Formula (IV): (Wherein R ₁ , R ₂ , R ₆ , and R ₇ are the same as above), a process for producing a 4-oxo-4H-pyran-3-carboxamide compound is summarized.

The compounds represented by the general formulas (I) and (I) ′ to (III) include a β-ketoamide derivative represented by the following formula (V) and R ₂ —COCH ₂ CONHR ₁ (V) [in the formula, R ₁ , R ₂ has the same definition as in formulas (I), (I) ′ and (III)] dehydration condensation reaction with a primary amine represented by formula (VI) or (VII) H ₂ N (CH ₂ ) nR ₃ (VI) H ₂ NR ₈ (VII) means a product obtained by R ₃ , R ₈ and n are as defined in formulas (I), (I) ′ and (III). Cage, general formula (I)
The expressions (1) to (I) 'mean isomers which can be mutually converted by prototropy of one compound,
The abundance ratio differs depending on n and R ₁ in the formula.

R in the general formulas (I), (I) ′, (III) and (IV)
₁ 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, particularly furyl and tetrahydro. 5-membered ring groups such as furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl,
Examples include 6-membered ring groups such as 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.

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 in the formulas (I), (I) ′, (III) and (IV) is C
_{1 to} C ₁₁ alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, optionally substituted aryl group, optionally substituted aralkyl group, halogenated alkyl group, 5 or 6-membered Represents a heterocyclic group.

In the present invention, the term "lower" used in a lower alkyl group, a lower alkoxy group and the like means a group containing a C _{1 to} C ₅ carbon atom. Specifically, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl; lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy; methoxycarbonyl, ethoxycarbonyl, Lower alkoxycarbonyl groups such as propoxycarbonyl, butoxycarbonyl; methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Lower alkylthio groups such as pentylthio,
Those having C _{1 to} C ₄ are preferable.

The lower alkenyl group and lower alkynyl group include vinyl,
Allyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 1,4-pentadienyl,
1,6-heptadienyl, 1-hexenyl, ethynyl,
2-propynyl is included.

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

Halogenated alkyl groups include trifluoromethyl, chloromethyl 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, preferably fluorine, chlorine or bromine atom, particularly preferably 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,
A 4-phenylbutyl group and the like are included.

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

The optionally substituted aryl or aralkyl group means an unsubstituted aryl or aralkyl group such as phenyl group, naphthyl group, benzyl, 3-phenylpropyl, etc., and a nucleus of these groups is a halogen atom, a lower alkyl group or a lower alkyl group. Those substituted with 1 to 3 alkoxy groups and cyano groups are included. Generally, the number of substituted aryl groups in R ₁ is preferably 1 to 3. The substituent of the aryl group or aralkyl group in R ₂ and R ₇ is generally 1 to
Three is preferable. Further, the substituted amount of the aryl group or aralkyl group in R ₆ is also preferably 1 to 3 in general.

R ₃ represents a dialkylamino group. The alkyl group is
It means an alkyl group such as methyl, ethyl, propyl, isopropyl and butyl. Two alkyl groups may be joined together to form a cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl. The two alkyl groups may also form a heterocyclic group with the nitrogen atom of the amino group to which they are attached 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.

N in the general formula (I) or (I) ′ represents an integer of 0 to 6, and when 0, forms a hydrazino bond in the molecule of the compound of (I) or (I) ′.

Examples of the primary amine raw material of the formula (VI) used for forming the compound of the general formula (I) or (I) ′ include N, N-dimethylhydrazine, N, N-diethylhydrazine, N-aminopyrrolidine, N-aminopiperidine, N-aminomorpholine, 1-amino-4-methylpiperazine, N, N
-Dimethylethylenediamine, N, N-diethylethylenediamine, N- (2-aminoethyl) pyrrolidine, N
-(2-Aminoethyl) piperidine, N- (2-aminoethyl) morpholine, N- (3-aminopropyl) morpholine, N- (6-aminohexyl) morpholine and the like can be mentioned.

The 1,3-dioxin-4-one compound represented by the general formula (II) can be produced by a conventionally known method [C
hem.Pharm.Bull., 31 , 1896 (1983); JP-A-54-106478
No .; see JP-A-61-22077].

R ₄ and R ₅ in the general formula (II) mean a hydrogen atom, an alkyl group or an aryl group, or when both R ₄ and R ₅ are alkyl groups, they may be bonded to each other to form a cycloalkyl group. Good. These R ₄ and R ₅ are groups that are not introduced into the desired product, and it is desirable to select and use easily available and inexpensive ones. As R ₄ and R ₅ , a methyl group or an ethyl group is preferable.

R ₆ in the general formula (II) is a hydrogen atom or a C _{1 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, or a substituted group. Optionally represents an aralkyl group or a halogenated alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, a halogenated alkyl group, an optionally substituted aryl group or a substituted The aralkyl groups which may be mentioned include the same ones as exemplified for R ₂ .

When R ₆ is a hydrogen atom, R ₇ in the general formula (II) is a hydrogen atom, a C _{2 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, a substituent. An optionally substituted aryl group,
Represents an optionally substituted aralkyl group or a halogenated alkyl group, and when R ₆ is a substituent other than a hydrogen atom, a hydrogen atom, a C _{1 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, Represents a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or a halogenated alkyl group, or R ₆ and R ₇ together represent-(CH ₂ ) m Represents-(m is 3 or 4). The lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, aralkyl group, halosaponified alkyl group, optionally substituted aryl group or optionally substituted aralkyl group are the same as those exemplified for R ₂ . Is included.

The alkyl group of R ₈ in the general formula (III) is an alkyl group having 1 to 11 carbon atoms, the aralkyl group is benzyl group, 2-phenylethyl group, etc., and the cycloalkyl group is cycloalkyl having 3 to 7 carbon atoms. The alkyl group is included, and the substituted aryl or heterocyclic group is the same as those exemplified for R ₁ .

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,
Examples of aromatic tertiary amines such as N, N, N ', N'-tetramethyl-1,3-propanediamine include N, N-
Dimethylaniline, N, N-diethylaniline, N, N
Examples of the nitrogen-containing heterocyclic base such as -dimethyl-o-toluidine include N-methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N-methylmorpholine and 1,4-diazabicyclo [2.2.2. ] Examples include octane.

Reaction of a compound represented by the general formula (I) or (I) ′ with a compound represented by the general formula (II)
The reaction between the compound represented by (III) and the compound represented by the general formula (II) can be carried out without a solvent or in an inert solvent. Examples of preferable inert solvents include benzene, toluene, xylene, mesitylene, tetralin, decalin, diphenyl ether and the like. As the reaction temperature, a temperature of about 100 ° C. to 200 ° C. is used with the thermal decomposition temperature of the compound represented by the general formula (II) as a guide.

The amount of the compound represented by the general formula (II) to be used is 1 equivalent or more with respect to the compound represented by the general formula (I), (I) 'or (III), but it is preferably 1.2. Good results are obtained in the range of up to 3.0 equivalents.

In this invention, a carbonyl compound represented by the formula (VIII) is generated as a thermal decomposition product in the reaction system. If the boiling point of this compound is lower than the set reaction temperature, During the reaction, it is advantageous to carry out the reaction by distilling it out of the system together with a part of the solvent used if necessary.

In the reaction of the compound represented by the general formula (III) with the compound represented by the general formula (II), the amount of the tertiary organic base used is 0.5 equivalent to the compound of the general formula (III). that's all,
Preferably, good results are obtained when 1 equivalent or more is used.
Even if 10 equivalents or more are used, a larger effect cannot be obtained.

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

Example 1. N- (2,6-diethylphenyl) -5,6-dimethyl-4-oxo-2-propyl-4H-pyran-3-carboxamide N- (2,6-diethylphenyl) -3-oxo-hexanoic acid amide A mixture of 5.22 g (20 mmol), 2.40 g (40 mmol) of N, N-dimethylhydrazine and 40 ml of toluene was added at 60 ° C.
After heating for 6 hours under stirring at room temperature, the reaction mixture is heated to distill off unreacted N, N-dimethylhydrazine and the produced water together with about 12 ml of toluene under atmospheric pressure, and further under reduced pressure. The solvent was removed to dryness using a rotary evaporator. 2,2,5,6-tetramethyl-4H-1,3-dioxin-4-one 6.87 g (44 mm
ol) and 20 ml of mesitylene were added, and the resulting acetone was gently heated to reflux for 1.5 hours while removing the generated acetone outside the system. The solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was treated by column chromatography using silica gel, and further crystallized from hexane to obtain 5.39 g (yield 78.9%) of the title compound. .

Melting point: 59.5-61 ° C IR (KBr disc): 1650, 1680 cm ^-1 , NMR (CDCl ₃ ) δ value: 0.98 (t, 3H), 1.16 (t, 6H), 1.75 (six, 2H), 2.00 (s , 3H), 2.32 (s, 3H), 2.62 (q, 4H), 3.20 (t, 2H), 7.04 (s, 3H), 11.10 (br, 1H).

Example 2. 2-Butyl-N- (2,6-diethylphenyl) -5,
6-Dimethyl-4-oxo-4H-pyran-3-carboxamide As a starting material, N- (2,6-diethylphenyl)-
Example 1 except using 3-oxo-heptanoic acid amide
The reaction was performed in the same manner as in, and then the product was purified by silica gel column chromatography to obtain the title mixture in a yield of 77.1%.

IR (neat): 1655, 1680 cm ^-1 , NMR (CDCl ₃ ) δ value: 0.80-2.00 (m, 7H), 1.17 (t, 6H), 2.00 (s, 3H), 2.32 (s, 3H), 2.61 (Q, 4H), 3.20 (t, 2H), 7.04 (s, 3H), 11.13 (br, 1H) Example 3. 5-ethyl-N- (2,6-diethylphenyl) -6-
Methyl-4-oxo-2-propyl-4H-pyran-3
-Carboxamide 1,3-dioxin-4-one Reaction as in Example 1 except that 5-ethyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one was used as the compound. After that, the title compound was obtained in a yield of 75.1% by purification by silica gel column chromatography.

IR (neat): 1650, 1680 cm ^-1 NMR (CDCl ₃ ) δ value: 0.96 (t, 3H), 1.09 (t, 3H), 1.16 (t, 6H), 1.73 (six, 2H), 2.31 (s, 3H), 2.49 (q, 2H), 2.61 (q, 4H), 3.17 (t, 2H), 7.04 (s, 3H), 11.14 (br, 1H).

Example 4. 2-Butyl-5,6-dimethyl-N- (2,3-dimethylphenyl) -4-oxo-4H-pyran-3-carboxamide N- (2,3-dimethylphenyl) -3-oxo-heptanoic acid amide After adding 1 drop of acetic acid to a mixture of 2.47 g (10 mmol), 1- (2-aminoethyl) pyrrolidine 1.14 g (10 mmol) and toluene 20 ml, the mixture was heated and stirred at 80 ° C. for 1 hour,
Keep under reflux for 1 hour, and water generated during
It was distilled off together with 12 ml, and the solvent was removed to dryness under reduced pressure using a rotary evaporator. To the obtained residue, 2,2,5,6-tetramethyl-4H-1,3-dioxin-4-one (3.44 g, 22 mmol) and mesitylene (10 m) were added.
Add l to remove generated acetone out of the system, and
Gently heated to reflux for a period of time. The solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was transferred to a separating funnel together with ether, washed with 1N hydrochloric acid, and then washed with water, and the organic layer was dried and concentrated according to a conventional method to obtain a product. The crystalline residue,
Recrystallization from a mixture of ether and hexane gave 2.42 g (yield 74.0%) of the title compound.

Melting point: 98-99.5 ° C IR (KBr disc): 1605, 1645, 1693 cm ^-1 NMR (CDCl ₃ ) δ value: 0.65 to 2.00 (m, 7H), 1.98 (s, 3H), 2.26 (s, 9H), 3.27 (t, 2H), 6.70 to 7.80 (m, 3H), 11.80 (br, 1H).

Example 5. 2- (3-chlorophenyl) -5,6-dimethyl-4-
Oxo-N-phenyl-4H-pyran-3-carboxamide As starting materials, 3- (3-chlorophenyl) -3-oxo-N-phenyl-propionic acid amide and N, N
Example 3 except that dimethylethylenediamine was used
After carrying out the same reaction as above, the solvent was distilled off under reduced pressure, the obtained residue was transferred to a separating funnel together with methylene chloride, and 1N
The organic layer was washed with hydrochloric acid and then washed with water, the organic layer was dried and concentrated according to a conventional method, and the obtained crystalline residue was recrystallized from ethyl acetate to obtain the title compound in a yield of 65.3%.

Melting point: 173.5-175 ° C IR (KBr disc): 1645, 1695 cm ^-1 NMR (CDCl ₃ ) δ value: 2.06 (s, 3H), 2.39 (s, 3H), 7.00 to 7.10 (m, 9H), 11.40 ( br, 1H).

Example 6. N- (4-chlorophenyl) -2-methyl-4-oxo-6-phenyl-4H-pyran-3-carboxamide p-chloroacetoacetanilide 2.12 g (10 mmol), benzylamine 1.07 g (10 mmol) and a mixture of toluene 20 ml. Was kept under reflux for 1 hour, the water formed during that time was distilled off together with about 12 ml of toluene, and the solvent was removed to dryness using a rotary evaporator under reduced pressure. 2,2-Dimethyl-6-phenyl-4H-1,3 was added to the obtained residue.
-Dioxin-4-one 4.49 g (22 mmol), N, N,
N ', N'-tetramethylethylenediamine 4.65g (40mm
ol) and 20 ml of xylene were added, and the resulting acetone was gently heated to reflux for 1.5 hours while removing the resulting acetone from the system.
The reaction mixture was allowed to cool, the precipitated crystals were filtered and dried,
2.63 g (yield 77.5%) of the title compound was obtained.

Melting point: 220-224 ° C IR (KBr disc): 1638, 1685 cm ^-1 NMR (CDCl ₃ ) δ value: 2.97 (s, 3H), 6.83 (s, 1H), 7.10 to 7.83 (m, 9H), 12.10 ( br, 1H).

Example 7. N- (2,6-diethylphenyl) -5,6,7,8-
Tetrahydro-2-methyl-4-oxo-4H-chromene-3-carboxamide N- (2,6-diethylphenyl) -3-oxo-butyric acid amide 2.33 g (10 mmol), 40% methylamine aqueous solution 1.56 g (2
(0 mmol) and 20 ml of toluene, add 1 drop of acetic acid,
After stirring at room temperature for 8 hours, the reaction mixture was heated to distill off unreacted methylamine and water together with about 12 ml of toluene, and then the solvent was removed to dryness using a rotary evaporator under reduced pressure. 2,2-Dimethyl-5,6,7,8-tetrahydro-4H-1,3- was added to the obtained residue.
Benzdioxin-4-one 4.01 g (22 mmol), N, N,
N ', N'-tetramethyl-1,3-propanediamine
5.21 g (40 mmol) and 20 ml of mesitylene were added, and the mixture was gently heated to reflux for 1.5 hours while removing the produced acetone from the system. From the reaction mixture, the solvent was distilled off under reduced pressure,
The obtained residue was treated by column chromatography using silica gel, and then crystallized from hexane to obtain 2.16 g (yield 63.5%) of the title compound.

Melting point: 115-117 ° C IR (KBr disc): 1655, 1677 cm ^-1 NMR (CDCl ₃ ) δ value: 1.16 (t, 6H), 1.40 to 2.85 (m, 8H), 2.59 (q, 4H), 2.76 ( s, 3H), 7.01 (s, 3H), 11.23 (br, 1H).

Example 8. N- (2,6-diethylphenyl) -2,6-dimethyl-4-oxo-5-phenylmethyl-4H-pyran-3
-Carboxamide N- (2,6-diethylphenyl) -3-oxo-butyric acid amide 2.33 g (10 mmol), butylamine 0.73 g (10 mmol) and 1 ml of acetic acid was added to a mixture of 20 ml of toluene, and the mixture was heated with stirring at 80 ° C for 1 hour. After that, the mixture was kept under reflux for 1 hour, water generated during that time was distilled off together with about 12 ml of toluene, and further under reduced pressure,
The solvent was removed to dryness using a rotary evaporator. The resulting residue obtained is 2,2,6-trimethyl-
5-phenylmethyl-4H-1,3-dioxin-4-
5.11 g (22 mmol) of ON, 5.21 g (40 mmol) of N, N, N ', N'-tetramethyl-1,3-propanediamine and 20 ml of mesitylene were added, and the generated acetone was removed from the system for 1.5 hours. Gently heated to reflux. The solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was treated by column chromatography using silica gel, and further crystallized from hexane to give the title compound 2.
57 g (yield 66.0%) was obtained.

Melting point: 95-96 ° C. IR (KBr disc): 1640,1717 cm ⁻¹ NMR (CDCl ₃ ) δ value: 1.13 (t, 6H), 2.25 (s, 3H), 2.60 (q, 4H), 2.73 (s, 3H), 3.81 (s, 2H), 7.05 (s, 3H), 7.15 (s, 5H), 11.25 (br, 1H) (Effect of the invention) By the method of the present invention, a wide variety of substituents can be substituted at arbitrary positions. It has become possible to obtain the 4-oxo-4H-pyran-3-carboxamide compound of 1) in good yield by a simple operation using readily available raw materials.

Claims (8)

[Claims] 1. A formula (I) or (I) ' [In the formulas (I) and (I) ′, R ₁ is an aryl group or heterocyclic group which may have a substituent, and R ₂ is C ₁
To C ₁₁ alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group,
An optionally substituted aryl group, an optionally substituted aralkyl group, a halogenated alkyl group or a 5- or 6-membered heterocyclic group, R ₃ is a dialkylamino group, and n
Represents an integer of 0 to 6] and a compound represented by the general formula (II): [Wherein R ₄ and R ₅ are a hydrogen atom, an alkyl group or an aryl group, or when R ₄ and R ₅ are both alkyl groups, a cycloalkyl group may be formed. R ₆ is a hydrogen atom or a C _{1 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, Or a halogenated alkyl group, when R ₆ is a hydrogen atom, R ₇ is a hydrogen atom, C ₂ -C
_{11 represents} an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or a halogenated alkyl group, R
_{When 6} is a substituent other than a hydrogen atom, R ₇ is a hydrogen atom,
C ₁ -C ₁₁ alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, optionally substituted aryl group, optionally substituted aralkyl group or halogenated alkyl group Or R ₆ and R ₇ together are — (CH ₂ ) m
-(M is 3 or 4)] is reacted with a compound represented by the general formula (IV): [Wherein R ₁ , R ₂ , R ₆ , and R ₇ are the same as above], a process for producing a 4-oxa-4H-pyran-3-carboxamide compound. 2. R ₃ (CH ₂ ) of formula (I) or (I) ′.
The production method according to claim 1, wherein n is a dimethylamino group. 3. R ₃ (C in formula (I) or (I) ′.
The method according to claim 1, wherein H ₂ ) n is a 2- (N, N-dimethylaminoethyl) group or a 2- (1-pyrrolidinylethyl) group. 4. The method according to claim 1, wherein R ₄ and R _{5 in} the formula (II) are a methyl group or an ethyl group. 5. General formula (III): (In the formula, R ₁ is an aryl group which may have a substituent or a heterocyclic group, R ₂ is a C ₁ -C ₁₁ alkyl group,
A lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, a halogenated alkyl group, or a 5- or 6-membered heterocyclic group , R
₈ represents an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group or a heterocyclic group), and a compound represented by the general formula (II): (In the formula, R ₄ and R ₅ may be a hydrogen atom, an alkyl group or an aryl group, or may form a cycloalkyl group when R ₄ and R ₅ are both alkyl groups. R ₆ is a hydrogen atom or C _{1 to} C ₁₁ Alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, optionally substituted aryl group, optionally substituted aralkyl group, halogenated alkyl group or 5
Or, when it is a 6-membered heterocyclic group and R ₆ is a hydrogen atom, R ₇ is a hydrogen atom, a C _{2 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, It represents an optionally substituted aryl group, an optionally substituted aralkyl group or a halogenated alkyl group, and when R ₆ is a substituent other than a hydrogen atom, R ₇ is a hydrogen atom, C _{1 to} C ₁₁ Represents an alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or a halogenated alkyl group; or R ₆ and R ₇ together - (CH 2) _{m- (m} is 3 or 4) presence reaction of tertiary organic base and a compound represented by representing the] Let general formula (IV): [Wherein R ₁ , R ₂ , R ₆ , and R ₇ are the same as above], a process for producing a 4-oxa-4H-pyran-3-carboxamide compound. 6. The production method according to claim ₅ , wherein R ₄ and R ₅ of the formula (II) are a methyl group or an ethyl group. 7. A tertiary organic base is triethylamine,
N, N, N ', N'-tetramethylethylenediamine,
The method according to any one of claims 5 to 6, which is N, N, N ', N'-tetramethyl-1,3-propanediamine. 8. The method according to claim 5, wherein the tertiary organic base is used in an amount of 0.5 equivalent or more based on the compound of the general formula (III).
7. The manufacturing method according to any one of item 7.