JPH08818B2 - 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 reported so far.

Of these, diketene is the isocyanate or the first
4-oxo- by reacting with a primary amine or its acetoacetyl derivative or a β-aminocrotonamide derivative
As a reported example of obtaining a 4H-pyran-3-carboxamide compound, JP-B-45-31663; Pharmaceutical Journal, 87 , 1212 (19
67): Chemical Pharmaceutical-Bulletin (Chem.Pharm.Bull.) 19 , 1477 (1971); The same magazine 20 , 133 (1)
972); ibid 28 , 2129 (1980); pharmacy journal, 101, 40 (198
1) etc. However, in these methods, the resulting 4-oxo-4H-pyran-3-carboxamide compound has a methyl group at both the 2-position and the 6-position of the pyran ring,
In addition, the compound of the present invention cannot be produced because it is limited to the compound in which the 5-position is a hydrogen atom.

Further, by dimerization of the β-ketoamide derivative, 4-
A method for obtaining an oxo-4H-pyran-3-carboxamide compound is also known (J. Org. Chem., 29 , 3548 and 3555 (1964) Chemical Abstracts 88 , 225655 g and ibid. 94). , 191177m).
The compounds obtained by these methods are limited to those in which the substituents at the 2- and 6-positions of the pyran ring are both the same, and are limited to those having a hydrogen atom at the 5-position. It is not possible.

As described above, conventionally, a general method for producing a 4-oxo-4H-pyran-3-carboxamide compound included in the present invention has not been known.

(Structure of the Invention) The present invention provides the following formula (IV) R ₂ —COCH ₂ CONHR ₁ (IV) [wherein, R ₁ is an aryl group or heterocyclic group which may have a substituent, R ₂ is a 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 A group or a 5- or 6-membered heterocyclic group]
And a compound represented by the following formula (V) R ₃ R _{3 ′} NH (V) [wherein R ₃ and R _{3 ′} are a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group or a heterocyclic ring] And R ₃ and R _{3 ′} may form a heterocyclic group together with the nitrogen atom to which they are attached], which is formed by a reaction with a compound represented by the following general formula (I): [Wherein R ₁ , R ₂ , R ₃ and R _{3 ′} are the same as those defined above] and the compound represented by the general formula (II): [In the formula, R ₄ and R ₅ represent a hydrogen atom, an alkyl group or an aryl group, and when both R ₄ and R ₅ are alkyl groups, a cycloalkyl group may be formed. R ₆ is 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, a halogenated alkyl group or a 5- or 6-membered heterocyclic group R ₇ is a hydrogen atom, 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 A group or a halogenated alkyl group, R ₆ and R ₇ together are-(CH
₂ ) _m- (m may be 3 or 4) may be formed] to react with a compound represented by the general formula (III): [In the formula, R ₁ , R ₂ , R ₆ and R ₇ are the same as above] 4-oxo-4H-pyran-3-
A method for producing a carboxamide compound is summarized.

R ₁ in the general formulas (I), (III) and (IV) represents an aryl group which may have a substituent or a heterocyclic group. The aryl group includes a phenyl group or a naphthyl group. The heterocyclic group includes a nitrogen atom, a sulfur atom,
It includes a 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen atoms, particularly furyl, tetrahydrofuryl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isooxolyl, pyrazolyl. And a 6-membered ring group 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.

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

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 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.

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

The 5- or 6-membered 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, thienyl, thiazolyl,
5-membered ring groups such as isothiazolyl, oxazolyl, isoxazolyl, and pyrazolyl; pyridyl, pyrimidinyl,
Examples thereof include 6-membered ring groups such as 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.

The optionally substituted aryl or aralkyl group is an unsubstituted aryl or aralkyl group such as a phenyl group, a naphthyl group, benzyl, 3-phenylpropyl, and a halogen atom in the aryl portion of these groups,
Those substituted with 1 to 3 groups inert to this reaction such as a lower alkyl group, a lower alkoxy group and a cyano group are included.

The alkyl group represented by R ₃ or R ₃ ′ in the general formulas (I) and (V) is an alkyl group having 1 to 11 carbon atoms, the aralkyl group is a benzyl group, a 2-phenylethyl group, and the like.
The cycloalkyl group includes a cycloalkyl group having 3 to 7 carbon atoms, and the aryl group or the heterocyclic group includes the same groups as those exemplified for R ₁ . When R ₃ and R ₃ ′ are both alkyl groups, they may form a heterocyclic group together with the nitrogen atom of the amino group to which they are bonded and optionally with another heteroatom. Specific examples of such a heterocyclic group include:
Examples thereof include a pyrrolidine ring, a piperidine ring, a piperazine ring and a morpholine ring.

The 1,3-dioxin-4-one compound represented by the general formula (II) can be produced by a conventionally known method [Chemical Pharmaceutical Buretin (Che
m, Pharm.Bull.) 31, 1896 (1983)].

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 intended 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 formulas (II) and (III) represents 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, or an optionally substituted aryl. Group, an optionally substituted aralkyl group, or a halogenated alkyl group, and a lower alkenyl group, lower alkynyl group, cycloalkyl group, lower alkoxyalkyl group, halogenated alkyl group, optionally substituted aryl group or substituted The aralkyl groups which may be included include the same groups as those exemplified for R ₂ .

R ₇ in the general formulas (II) and (III) represents a hydrogen atom, a C _{1 to} C ₁₁ alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, or an optionally substituted aryl. Represents a group, an optionally substituted aralkyl group or a halogenated alkyl group. R ₆ and R ₇ together form-(CH ₂ ) _m- (m is 3
Or 4) may be formed. Lower alkenyl group,
A lower alkynyl group, a cycloalkyl group, a lower alkoxyalkyl group, an aralkyl group, a halogenated alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group include the same as those exemplified for R ₂ . .

The reaction between the compound represented by the general formula (I) and the compound represented by the general formula (II) can be carried out without a solvent or in an inert solvent without using a tertiary organic base. 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), but preferably in the range of 1.2 to 3.0 equivalents. can get.

In this invention, a carbonyl compound represented by the formula (VI) is generated in the reaction system as a thermal decomposition product. 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.

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

Example 1 N- (4-bromo-2,6-diethylphenyl) -2,5,6-
Trimethyl-4-oxo-4H-pyran-3-carboxamide N- (4-bromo-2,6-diethylphenyl) -3-
Oxobutyric acid amide 3,12 g (10 mmol), butylamine 0.73 g
To the mixture of (10 mmol) and 20 ml of toluene, 1 drop of acetic acid was added, and the mixture was stirred with heating at 90 ° C for 1 hour, and after 1 hour, the mixture was kept under reflux, and the water formed 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. 2,2,5,6-tetramethyl-4H-1,3-dioxin-4-one 3.44 g (22 mm
ol) and 10 ml of methylene were added, and the mixture was gently heated to reflux for 1.5 hours while removing the produced acetone out of 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 ethyl acetate to obtain 2.22 g (yield 57%) of the title compound. .

Melting point: 137-139.5 ° C IR (KBr disk): 1657,1680 cm ^-1 NMR (CDCl ₃ ) δ value: 1.16 (t, 6H), 1.99 (s, 3H), 2.33 (s, 3H), 2.57 (q, Four
H), 2.78 (s, 3H), 7.18 (s, 2H), 11.25 (br, 1H) Example 2 5-Ethyl-N- (2,6-diethylphenyl) -6-
Methyl-4-oxo-2-propyl-4H-pyran-3-
Carboxamide N- (2,6-diethylphenyl) -3 as a starting material
-Oxo-hexanoic acid amide, 1,3-dioxin-4
After the reaction was performed in the same manner as in Example except that 5-ethyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one was used as the -one compound, a column using silica gel was used. Purification by chromatography gave the title compound in 65% yield.

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, 2
H) 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 3 2-Butyl-5,6-dimethyl-N- (2,3-dimethylphenyl) -4-oxo-4H-pyran-carboxamide N -(2,3-Dimethylphenyl) -3-oxo-heptanoic acid amide 2.47 g (10 mmol), benzylamine 1.07 g
A mixture of (10 mmol) and 20 ml of toluene was kept under reflux for 1 hour, water generated during that time was distilled off together with about 12 ml of toluene, and the solvent was removed to dryness under reduced pressure using a rotary evaporator. The residue obtained is 2,2,5,6
-Tetramethyl-4H-1,3-dioxin-4-one 3.44 g
(22 mmol) and 10 ml of mesitylene were added, and the mixture was gently heated to reflux for 1.5 hours while removing the produced acetone outside the system. The solvent was distilled off from the reaction mixture under reduced pressure, the resulting residue was treated by column chromatography using silica gel, and the obtained crystalline residue was recrystallized from a mixture of ether and hexane to give 2.09 g of the title compound ( Yield 64
%) Was obtained.

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 4 2- (3-chlorophenyl) -5,6-dimethyl-4-
Oxo-N-phenyl-4H-pyran-3-carboxamide Reaction and column chromatography were performed in the same manner as in Example 3 except that 3- (3-chlorophenyl) -3-oxo-N-phenylpropionic acid amide was used as a starting material. The mixture was treated and the obtained crystalline residue was recrystallized from ethyl acetate to give the title compound in a yield of 53%.

Melting point: 173.5-175 ° C IR (KBr disk): 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 5 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
To the mixture of (22 mmol) and 20 ml of toluene, 1 drop of acetic acid was added, and after stirring at room temperature for 8 hours, the reaction mixture was heated,
Unreacted methylamine and water were distilled off together with about 12 ml of toluene, and the solvent was removed to dryness using a rotary evaporator under reduced pressure. To the obtained residue, 2,2-dimethyl-5,6,7,8-tetrahydro-4H-1,3-benzodioxin-4-one 4.01 g (22 mmol) and mesitylene 20 m
Add l to remove generated acetone out of the system, and
Gently heated to dryness for an hour. From the reaction mixture, the solvent was evaporated under reduced pressure, the obtained residue was treated by column chromatography using silica gel, and further crystallized from hexane to give 2.07 g of the title compound (yield 6
1%).

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 6 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)
1 drop of acetic acid was added to the mixture of 20 ml of toluene and toluene, and the mixture was heated with stirring at 80 ° C. for 1 hour and then kept under reflux for 1 hour, while water formed was distilled off together with about 12 ml of toluene, and the mixture was further rotary evaporated under reduced pressure. The solvent was removed to dryness using. 5.12 g of 2,2,6-trimethyl-5-phenylmethyl-4H-1,3-dioxin-4-one was added to the obtained residue.
(22 mmol) and mesitylene (20 ml) were added, and the resulting acetone was gently heated to reflux for 1.5 hours while removing the resulting acetone from 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 2.34 g of the title compound (yield 60%). It was

Melting point 95-96 ° C IR (KBr disk): 1640,1717cm ^-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) Example 7 N- (2,6-diethylphenyl) -2,6-dimethyl-4
-Oxo-5-phenylmethyl-4H-pyran-3-carboxamido The reaction and purification were conducted in the same manner as in Example 6 except that pyrrolidine was used instead of butylamine to give the title compound in a yield of 55%.

Melting point 95-96 ° C

Claims (2)

[Claims] 1. A compound represented by the following formula (IV) R ₂ —COCH ₂ CONHR ₁ (IV) [wherein 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, optionally substituted aryl group, optionally substituted aralkyl group, halogenated alkyl group, or 5 Or a 6-membered heterocyclic group]
And a compound represented by the following formula (V) R ₃ R _{3 ′} NH (V) [wherein R ₃ and R _{3 ′} are a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group or a heterocyclic ring] And R ₃ and R _{3 ′} may form a heterocyclic group together with the nitrogen atom to which they are attached], which is formed by a reaction with a compound represented by the following general formula (I): [Wherein R ₁ , R ₂ , R ₃ and R _{3 ′} are the same as those defined above] and the compound represented by the general formula (II): [In the formula, R ₄ and R ₅ represent a hydrogen atom, an alkyl group or an aryl group, and when both R ₄ and R ₅ are alkyl groups, a cycloalkyl group may be formed. R ₆ is 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, a halogenated alkyl group or a 5- or 6-membered heterocyclic group R ₇ is a hydrogen atom, 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 A group or a halogenated alkyl group, R ₆ and R ₇ together are-(CH
₂ ) _m- (m may be 3 or 4) may be formed] to react with a compound represented by the general formula (III): [In the formula, R ₁ , R ₂ , R ₆ and R ₇ are the same as above] 4-oxo-4H-pyran-3-
Process for producing carboxamide compound. 2. The production method according to claim 1, wherein R ₄ and R _{5 in} the formula (II) are a methyl group or an ethyl group.