JP2000247966A - Production of 2,6-dialkyl-gamma-pyrone derivative and intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an intermediate for producing compounds having anti-carcinogenesis promoter activity and cerebral nerve cell death inhibitory action and the like. SOLUTION: This new compound is a compound shown by formura I [R1, R3 and R4 are each a lower alkyl; R2 is a lower alkyl, aralkyl or (substituted) aryl], e.g. 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-pentylperhydro-3H-pyran-3- one. The compound of formula I is obtained by reacting a compound of formula II (e.g. 6-methoxy-6-methyl-2-pentyl-2,6-dihydro-3H-pyran-3-one) with a compound of the formura: R4OH (e.g. methanol) and a nitrous acid compound such as sodium nitrite in a solvent such as hydrochloric acid-methanol solution, pref. at -20 to 50 deg.C for 1-10 h. This compound is useful as an intermediate for producing 2,6-dialkyl-y-pyrone derivatives.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound represented by the following general formula (2) having antitumor promoter activity, brain nerve cell death inhibitory activity and the like.

[0002]

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[Wherein R¹And R^FourAre the same or different
Represents an optionally substituted lower alkyl group; ^TwoIs lower alkyl
Aryl, which may have a group, an aralkyl group or a substituent
2,6-dialkyl-γ-pyro represented by
Novel production method of the derivative of
It relates to a method for synthesizing this production intermediate.

[0004]

BACKGROUND OF THE INVENTION A series of 2,6-dialkyl-γ-pyrone derivatives, including 3-hydroxy-6-methyl-5-methoxy-2-pentyl-4H-pyran-4-one, are known to inhibit cancer promoters. It is known to have an action (JP-A-2-311462), an action of inhibiting cell death of brain nerve cells and an action of promoting neurite branching (WO 97/2822), and is useful as an anticancer agent and an agent for improving brain disease. It is said that there is. 3-hydroxy-6-methyl-5-methoxy-
2-Pentyl-4H-pyran-4-one is an extract from a plant belonging to the genus Allium and has been chemically identified as D-
Synthesis method using (α) -mannose as a starting material (Hirokazu
Arimoto et.al, Tetrahedron Letters, Vol. 38, No. 44, p
p.7761-7762, 1997) and a synthesis method using a selenium oxidation from a furan derivative via a β-pyrone derivative (Yoshih
iro Matsumura et.al, Tetrahedron Letters, Vol. 39, No.
16, pp. 2339-2340, 1998).
However, these synthetic methods are not yet practically sufficient because of low yields and the use of harmful reagents.

[0005]

Accordingly, an object of the present invention is to provide 3-hydroxy-6-methyl-5-methoxy-2-.
Pentyl-4H-pyran-4-one and other 2,
An object of the present invention is to provide a method capable of easily and safely producing a 6-dialkyl-γ-pyrone derivative.

[0006]

In view of such circumstances, the present inventors have conducted various studies in order to obtain a simple method for chemically synthesizing a 2,6-dialkyl-γ-pyrone derivative.
Novel 4- (Oxidized) β-pyrone derivative
The present inventors have found that a 2,6-dialkyl-γ-pyrone derivative can be efficiently and safely produced in three steps by using a hydroxyiminotetrahydro-β-pyrone derivative as a synthetic intermediate, and have completed the present invention. The method for producing the 2,6-dialkyl-γ-pyrone derivative of the present invention is represented by the following reaction formula 1.

[0007]

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[Wherein R ¹ , R ³ and R ⁴ represent lower alkyl groups which may be the same or different, and R ² represents a lower alkyl group, an aralkyl group or an aryl group which may have a substituent. Show)

That is, the β-pyrone derivative represented by the general formula (3) is reacted with an alcohol represented by R ⁴ OH and a nitrite compound to produce a 4-hydroxyiminotetrahydro compound represented by the general formula (1). -Β-pyrone derivative (step-
1) Further, by subjecting this to an acidic hydrolysis reaction (Step-2), a 2,6-dialkyl-γ-pyrone derivative represented by the general formula (2) can be produced.

Here, the present invention provides a 4-hydroxyiminotetrahydro-β-pyrone derivative represented by the general formula (1).

Further, the present invention provides a compound represented by the general formula (2) wherein the 4-hydroxyiminotetrahydro-β-pyrone derivative represented by the general formula (1) is subjected to an acidic hydrolysis reaction. And a method for producing a 6,6-dialkyl-γ-pyrone derivative.

Further, the present invention relates to a compound represented by the general formula (1) wherein a β-pyrone derivative represented by the general formula (3) is reacted with an alcohol represented by R ⁴ OH and a nitrite compound. Represented 4-hydroxyiminotetrahydro-
It is intended to provide a method for producing a β-pyrone derivative.

Further, the present invention provides a β-pyrone derivative represented by the general formula (3) which is reacted with an alcohol represented by R ⁴ OH and a nitrite compound to obtain a compound represented by the general formula (1). A process for producing a 2,6-dialkyl-γ-pyrone derivative represented by the general formula (2), characterized in that the derivative is subjected to an acidic hydrolysis reaction, which is a -hydroxyiminotetrahydro-β-pyrone derivative. It is.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, general formulas (1) to (1)
In the formula of (3), R¹~ R^FourAnd a lower alkyl group represented by
Is a linear or branched alkyl group having 1 to 7 carbon atoms,
Specifically, a methyl group, an ethyl group, an n-propyl group, i
-Propyl group, n-butyl group, i-butyl group, sec-
Butyl group, tert-butyl group, n-pentyl group, i-
Pentyl group, n-hexyl group, i-hexyl group, n-hexyl
A butyl group, an i-heptyl group and the like. this house,
Those having 1 to 5 carbon atoms are preferred.¹As
And R is preferably^TwoIs an n-butyl group or n-pe
An alkyl group is preferred, and R ^ThreeIs preferably a methyl group
K, R^FourIs preferably a methyl group or an ethyl group.

The aralkyl group represented by R ² is an aralkyl group having an alkyl moiety having 1 to 3 carbon atoms, specifically, benzyl, 1-phenylethyl, 1-phenylpropyl, and 2-phenylpropyl. And the like, and among them, a benzyl group is particularly preferred.

Examples of the aryl group which may have a substituent represented by R ² include a phenyl group, a naphthyl group, a phenyl group substituted by a lower alkyl group or a halogen atom, a naphthyl group, and the like. , Preferably a phenyl group. The lower alkyl group in this case includes the above-mentioned R
Examples of the lower alkyl group represented by ^{1 to} R ⁴ include the same as those exemplified above, but a methyl group is particularly preferable.
As the halogen atom, a fluorine atom is particularly preferred.

Hereinafter, each step of the production method of the present invention will be described in detail.

[Step-1] β- represented by the general formula (3)
The 4-hydroxyiminotetrahydro-β-pyrone derivative (1) can be produced by reacting a pyrone derivative with an alcohol represented by the general formula R ⁴ OH and a nitrite compound.

The nitrite compound used herein refers to an alkaline earth metal nitrite or nitrite, and examples of the alkaline earth metal nitrite include sodium nitrite,
Potassium nitrite and the like, and as the nitrite, for example, methyl nitrite, ethyl nitrite and the like,
Among them, sodium nitrite is particularly preferred.

As R ⁴ OH, a group to be introduced —OR ⁴
Alcohols corresponding to the above, ie, methanol, ethanol, isopropanol and the like.

Any solvent may be used as long as it dissolves the starting compound and does not inhibit the production of the target compound.
For example, methanol, ethanol, isopropanol,
t-butanol, octanol, cyclohexanol,
Alcohols such as methyl cellosolve, diethylene glycol and glycerin; hexane, heptane, ligroin,
Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, dioxane Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; esters such as ethyl formate, ethyl acetate, butyl acetate and diethyl carbonate; nitro compounds such as nitroethane and nitrobenzene; acetonitrile and isobutyi Nitriles such as lonitrile; acid amides such as formamide, N, N-dimethylformamide and acetamide; sulfur compounds such as dimethylsulfoxide and sulfolane; Solvents are preferred, especially hydrochloric acid alcohol.

The amounts of R ⁴ OH and nitrite used are preferably 1 to 10 equivalents to the β-pyrone derivative (3), and the reaction is carried out at -20 ° C. to 50 ° C. for 1 hour to 10 hours. It is particularly preferable to perform the reaction at 0 ° C. to room temperature.

[Step-2] The 2,6-dialkyl-γ-pyrone derivative (2) is obtained by acidic hydrolysis of the 4-hydroxyiminotetrahydro-β-pyrone derivative (1).
Can be obtained.

This reaction is carried out in a solvent in the presence of a conventional acid used as a hydrolysis catalyst. Examples of the acid include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid;
Organic acids such as acetic acid, propionic acid and aromatic sulfonic acid can be used, but hydrochloric acid is particularly preferred. In this reaction, the target compound can be efficiently obtained by coexisting a carbonyl compound such as acetone, formaldehyde and acetylacetone for the purpose of collecting the hydroxylamine by-product generated.

As the reaction solvent, for example, water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and diethylene glycol, acetic acid and the like can be used. The reaction is usually performed at a temperature of room temperature to about 150 ° C, preferably about 20 to 100 ° C. This reaction can also be carried out by heating and refluxing for 1 hour to 50 hours in a mixed solvent of aqueous sodium sulfite water / methanol (for example, 1: 1).

The desired product can be isolated from the reaction mixture by a conventional method, for example, washing, recrystallization, column chromatography and the like.

In the method for producing a 2,6-dialkyl-γ-pyrone derivative of the present invention, the β-pyrone derivative (3) as a starting compound can be produced by a known method, for example, by the following reaction formula 2.

[0028]

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Wherein R ^{1 to} R ⁴ are the same as described above. ]

[0030]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of 2- (1-hydroxyhexyl) -5-methylfuran: 3.4 g (140 m) of magnesium in a three-necked flask.
mol), catalytic amount of iodine, anhydrous diethyl ether 20
0 ml was added, and the inside of the system was replaced with nitrogen. 15.8 g (105 mmol) of 1-pentyl bromide was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. To this solution, a solution of 7.7 g (70 mmol) of 5-methylfuraldehyde in 20 ml of anhydrous diethyl ether was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. 200 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 200 g,
Purification with hexane: ethyl acetate = 4: 1) afforded 11.0 g (86%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.89 (t, J = 5.6 Hz, 3H), 1.
20-1.56 (m, 6H), 1.73-1.90 (m, 2H), 2.27 (s, 3H), 4.58 (t, J =
6.9Hz, 1H), 5.89 (d, J = 2.6Hz, 1H), 6.09 (d, J = 2.6Hz, 1H)

Reference Example 2 Synthesis of 2- (1-hydroxypentyl) -5-methylfuran: 2.2 g (90 mm) of magnesium was placed in a three-necked flask.
ol), a catalytic amount of iodine, anhydrous diethyl ether 180
Then, the system was replaced with nitrogen. 1-butyl bromide 1
0.7 g (78 mmol) was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. 5-methylfuraldehyde6.
6 g (60 mmol) of anhydrous diethyl ether 20 ml
The solution was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. 200 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 200 g, hexane: ethyl acetate = 4: 1) to obtain 9.0 g (89%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.91 (t, J = 6.9 Hz, 3H), 1.
25-1.46 (m, 4H), 1.81-1.87 (m, 2H), 2.28 (s, 3H), 4.60 (t, J
= 6.9Hz, 1H), 5.9 (d, J = 2.8Hz, 1H), 6.1 (d, J = 2.8Hz, 1H)

Reference Example 3 Synthesis of 2- (1-hydroxyisobutyl) -5-methylfuran: 2.2 g (90 m) of magnesium was placed in a three-necked flask.
mol), catalytic amount of iodine, anhydrous diethyl ether 18
0 ml was added, and the inside of the system was replaced with nitrogen. 9.6 g (78 mmol) of isopropyl bromide was slowly added dropwise at room temperature,
The mixture was stirred for 2 hours. To this solution was slowly added dropwise a solution of 6.6 g (60 mmol) of 5-methylfuraldehyde in 20 ml of anhydrous diethyl ether at room temperature.
Stirred for hours. Saturated aqueous ammonium chloride solution 2
00 ml was added and stirred for 30 minutes. The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 150 g, hexane: ethyl acetate = 4: 1) to obtain 6.4 g (69%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.86 (d, J = 6.9 Hz, 3H), 1.
03 (d, J = 6.4Hz, 3H), 2.04-2.11 (m, 1H), 2.27 (d, J = 0.9Hz, 3
H), 4.28 (d, J = 7.3Hz, 1H), 5.89 (d, J = 2.7Hz, 1H), 6.09 (d, J =
(2.7Hz, 1H)

Reference Example 4 Synthesis of 2- (1-hydroxybutyl) -5-methylfuran: 3.9 g of magnesium (160 mm) was placed in a three-necked flask.
ol), a catalytic amount of iodine, anhydrous diethyl ether 200
Then, the system was replaced with nitrogen. 16.8 g (136 mmol) of 1-propyl bromide was slowly added dropwise at room temperature, and the mixture was stirred overnight. To this solution, 8.9 g (81 mmol) of 5-methylfuraldehyde was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 15
0 g, hexane: ethyl acetate = 8: 1) to give 11.3 g (69%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.95 (t, J = 7.4 Hz, 3H), 1.
25-1.55 (m, 2H), 1.74-1.88 (m, 3H), 2.28 (d, J = 0.3Hz, 3H),
4.61 (t, J = 6.9Hz, 1H), 5.86-5.93 (m, 1H), 6.10 (d, J = 3.0Hz,
1H)

Reference Example 5 Synthesis of 2- (1-hydroxybenzyl) -5-methylfuran: 2.2 g (94 mm) of magnesium was placed in a three-necked flask.
ol), a catalytic amount of iodine, anhydrous diethyl ether 200
Then, the system was replaced with nitrogen. 9.7 g (61 mmol) of bromobenzene was slowly added dropwise at room temperature, and the mixture was stirred overnight. 5.5 g (50 mmol) of 5-methylfuraldehyde was slowly added dropwise to this solution at room temperature, and the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 150 g,
Purification with hexane: ethyl acetate = 4: 1) gave 7.8 g (82%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 2.27 (d, J = 0.9 Hz, 3H), 2.
42 (d, J = 4.5Hz, 1H), 5.76 (d, J = 4.5Hz, 1H), 5.86-5.89 (m, 1
H), 5.93 (d, J = 3.3Hz, 1H), 7.24-7.46 (m, 5H)

Reference Example 6 Synthesis of 6-methoxy-6-methyl-2-pentyl-2,6-dihydro-3H-pyran-3-one: 4.5 g of 2- (1-hydroxyhexyl) -5-methylfuran (25
mmol), 1.3 g (13 mmol) of sodium bromide
Was added to 100 ml of methanol, and an electrode (platinum anode 12 ×
5797, stainless steel cathode 12 × 5 cm), electric quantity 4797C (2 F / mol, 2.7 hours), electric current 500
The current was passed at mA, a voltage of 4 V, and -30 ° C. After completion of the reaction, 473 mg of p-toluenesulfonic acid monohydrate was added to the reaction solution.
(2.5 mmol) was added and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 10).
0 g, hexane: ethyl acetate = 8: 1).
3.2 g (61%) of the title compound were obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.90 (t, J = 6.6 Hz, 3H), 1.
21-1.49 (m, 6H), 1.52 (s, 3H), 1.57-1.73 (m, 1H), 1.88-2.06
(m, 1H), 3.35 (s, 3H), 4.27 (dd, J = 8.3,3.5Hz, 1H), 6.00 (d, J
= 10.1Hz, 1H), 6.75 (d, J = 10.1Hz, 1H)

Reference Example 7 Synthesis of 6-methoxy-6-methyl-2-butyl-2,6-dihydro-3H-pyran-3-one: 4.0 g of 2- (1-hydroxypentyl) -5-methylfuran (24m
mol) and 1.2 g (12 mmol) of sodium bromide in 100 ml of methanol, and an electrode (platinum anode 12 × 5
cm, stainless steel cathode 12 × 5cm), and electric quantity 4
589C (2F / mol, 2.5 hours), current 500m
A, a voltage of 4.5 V was applied at −30 ° C. After the reaction,
452 mg of p-toluenesulfonic acid monohydrate was added to the reaction solution.
(2.4 mmol), and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 80).
g, hexane: ethyl acetate = 8: 1) to give 4.0 g (85%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.92 (t, J = 6.9 Hz, 3H), 1.
28-1.48 (m, 4H), 1.52 (s, 3H), 1.58-1.69 (m, 1H), 1.89-2.0
4 (m, 1H), 3.35 (s, 3H), 4.27 (dd, J = 8.7,3.7Hz, 1H), 6.00 (d,
J = 10.1,1H), 6.75 (d, J = 10.1Hz, 1H)

Reference Example 8: 6-methoxy-6-methyl-2-isopropyl-2,6
Synthesis of -dihydro-3H-pyran-3-one: 2- (1
-Hydroxyisobutyl) -5-methylfuran 3 g (2
0 mmol), 1.0 g of sodium bromide (10 mmol
l) was added to 100 ml of methanol, and an electrode (platinum anode 1) was added.
2 × 5 cm, stainless steel cathode 12 × 5 cm), electric quantity 3764 C (2 F / mol, 2.1 hours), current 5
The current was supplied at 00 mA, a voltage of 5 V, and -30 ° C. After completion of the reaction, p-toluenesulfonic acid monohydrate (370 m) was added to the reaction mixture.
g (2 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure,
The residue was subjected to column chromatography (silica gel 60 g,
Separation and purification with hexane: ethyl acetate = 8: 1) gave 2.7 g (73%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.87 (d, J = 6.9 Hz, 3H), 1.
07 (d, J = 7.2Hz, 3H), 1.53 (s, 3H), 2.50-2.67 (m, 1H), 3.34
(s, 3H), 4.13 (d, J = 2.7Hz, 1H), 6.00 (d, J = 10.2Hz, 1H), 6.76
(d, J = 10.2Hz, 1H)

Reference Example 9 Synthesis of 6-methoxy-6-methyl-2-propyl-2,6-dihydro-3H-pyran-3-one: 9.4 g of 2- (1-hydroxybutyl) -5-methylfuran (61m
mol) and 6.5 g (62 mmol) of sodium bromide in 100 ml of methanol.
cm, platinum cathode 2 × 2 cm) and the amount of electricity
C (2 F / mol, 16.3 hours), current 200 mA,
Electric current was applied at a voltage of 4 V and -10 ° C. After completion of the reaction, 1.9 g (10 mmol) of p-toluenesulfonic acid monohydrate was added to the reaction solution.
l) was added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (180 g of silica gel, hexane: ethyl acetate = 8: 1) to obtain 7.0 g of the title compound as an oil (63 g).
%)Obtained.

¹ H-NMR (CDCl ₃ ) δ; 0.92 (t, J = 7.1 Hz, 3H), 1.
20-1.72 (m, 4H), 1.53 (s, 3H), 3.35 (s, 3H), 4.26 (dd, J = 8.4,
3.6Hz, 1H), 6.00 (d, J = 9.9Hz, 1H), 6.76 (s, J = 9.9Hz, 1H)

Reference Example 10 Synthesis of 6-methoxy-6-methyl-2-phenyl-2,6-dihydro-3H-pyran-3-one: 7.5 g of 2- (1-hydroxybenzyl) -5-methylfuran (40
mmol), 1.6 g (15 mmol) of sodium bromide
Was added to 100 ml of methanol, and an electrode (platinum anode 12 ×
5 cm, platinum cathode 2 × 2 cm) and an electric quantity of 7691
C (2 F / mol, 10.7 hours), current 200 mA,
Electric current was applied at a voltage of 4 V and -10 ° C. After completion of the reaction, 2.1 g (11 mmol) of p-toluenesulfonic acid monohydrate was added to the reaction solution.
l) was added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 150 g, hexane: ethyl acetate = 8: 1), and 2.7 g of the title compound as an oil (73 g).
%)Obtained.

[0050] _{^{1 H-NMR (CDCl 3)}} δ; 1.63 (s, 3H), 3.40 (s, 3
H), 5.31 (s, 1H), 6.12 (d, J = 10.2Hz, 1H), 6.88 (s, J = 10.2Hz,
1H), 7.31-7.43 (m, 5H)

Example 1 (Step-1) Synthesis of 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-pentylperhydro-3H-pyran-3-one: 6-methoxy-6-methyl- 2-
Pentyl-2,6-dihydro-3H-pyran-3-one 2.5 g (12 mmol), sodium nitrite 3.3 g
(47 mmol) was added to 15 ml of methanol, and 34.4 g (94 mm) of a 10% hydrochloric acid-methanol solution was added under ice-cooling.
ol) was added dropwise, and the mixture was stirred under water cooling for 3 hours. The reaction temperature was returned to ice again, and 3.3 g of sodium nitrite (47 m
mol) and 34.4 g of a 10% hydrochloric acid-methanol solution.
(94 mmol) was added dropwise, and the mixture was stirred under water cooling for 3 hours.
Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with water. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 3: 1). 2.0 g of the title compound as an oil (61 g)
%)Obtained.

¹ H-NMR (CDCl ₃ ) δ; 0.88 (t, J = 6.3 Hz, 3H), 1.
18-1.38 (m, 4H), 1.38-1.56 (m, 2H), 1.52 (s, 3H), 1.58-1.95
(m, 2H), 3.29 (s, 3H), 3.47 (s, 3H), 4.04 (dd, J = 8.0,4.4Hz, 1
H), 4.54 (s, 1H)

Example 2 Synthesis of 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-butylperhydro-3H-pyran-3-one: 6-methoxy-6-methyl-2-butyl-2 , 6
-Dihydro-3H-pyran-3-one 3.4 g (17 m
mol), 4.7 g (69 mmol) of sodium nitrite
Was added to 20 ml of methanol, 50 g (137 mmol) of a 10% hydrochloric acid-methanol solution was added dropwise under ice cooling, and the mixture was stirred under water cooling for 3 hours. The reaction temperature was returned to ice again, 2.4 g (34 mmol) of sodium nitrite was added, and 10%
25 g (69 mmol) of a hydrochloric acid-methanol solution was added dropwise, and the mixture was stirred under water cooling for 3 hours. Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with water. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 70 g, hexane: ethyl acetate = 3: 1). 2.4 g (53%) of the title compound were obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.90 (t, J = 7.3 Hz, 3H), 1.
21-1.50 (m, 4H), 1.53 (s, 3H), 1.73-1.95 (m, 2H), 3.31 (s, 3
H), 3.47 (s, 3H), 4.04 (dd, J = 8.3,4.1Hz, 1H), 4.53 (s, 1H)

Example 3 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-isopropylperhydro-3H-pyran-3-
Synthesis of ON: 6-methoxy-6-methyl-2-isopropyl-2,6-dihydro-3H-pyran-3-one
5 g (13 mmol), 3.7 g of sodium nitrite (5
3 mmol) was added to 15 ml of methanol.
39 g (106 mmol) of a 0% hydrochloric acid-methanol solution was added dropwise, and the mixture was stirred under water cooling for 3 hours. The reaction temperature was returned to ice again, and 3.7 g (53 mmol) of sodium nitrite was obtained.
And a 39% hydrochloric acid-methanol solution 39 g (106 mm
ol) was added dropwise, and the mixture was stirred under water cooling for 3 hours. Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with water. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 50).
g, hexane: ethyl acetate = 3: 1).
2.2 g (69%) of the title compound were obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ; 0.97 (d, J = 6.9 Hz, 3H), 1.
04 (d, J = 6.9Hz, 3H), 1.52 (s, 3H), 2.29-2.42 (m, 1H), 3.28
(s, 3H), 3.47 (s, 3H), 3.89 (d, J = 3.4Hz, 1H), 4.48 (s, 1H)

Example 4 Synthesis of 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-propylperhydro-3H-pyran-3-one: 6-methoxy-6-methyl-2-propyl-
4.2 g of 2,6-dihydro-3H-pyran-3-one
(20 mmol), 8.6 g of sodium nitrite (125
mmol) in 100 ml of methanol, and the mixture was cooled with ice.
120 ml of a 1.38 M hydrochloric acid-methanol solution was added dropwise,
The mixture was stirred for 3 hours under water cooling. Saturated sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used for the next reaction as it was

¹ H-NMR (CDCl ₃ ) δ; 0.93 (t, J = 7.2 Hz, 3H), 1.
16-1.60 (m, 2H), 1.53 (s, 3H), 1.65-1.98 (m, 2H), 3.30 (s, 3
H), 3.47 (s, 1H), 4.05 (dd, J = 7.7,4.4Hz, 1H), 4.53 (s, 1H)

Example 5 Synthesis of 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-phenylperhydro-3H-pyran-3-one: 6-methoxy-6-methyl-2-phenyl-
4.4 g of 2,6-dihydro-3H-pyran-3-one
(20 mmol), 2.2 g of sodium nitrite (30 m
mol) was added to 20 ml of methanol, 60 ml of a 1M hydrochloric acid-methanol solution was added dropwise under ice cooling, and the mixture was stirred for 3 hours under water cooling. Saturated sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica gel 80 g, hexane: ethyl acetate = 3: 1). This gave 1.4 g (24%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ; 1.61 (s, 3H), 3.39 (s, 3
H), 3.54 (s, 3H), 4.58 (s, 1H), 5.09 (s, 1H), 7.24-7.43 (m, 3
H), 7.44-7.63 (m, 2H)

Example 6 (Step-2) Synthesis of 3-hydroxy-5-methoxy-6-methyl-2-pentyl-4H-pyran-3-one: 4
-Hydroxyimino-5,6-dimethoxy-6-methyl-2-pentylperhydro-3H-pyran-3-one 2.3 g (8 mmol) in 37% formaldehyde 6
6.8 g (823 mmol), 10 g hydrochloric acid 60 g (16
5 mmol) and heated under reflux for 1 hour. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was extracted and washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 3: 1). 680 mg of the title compound as a colorless powder
(37%).

¹ H-NMR (CDCl ₃ ) δ; 0.90 (t, J = 6.8 Hz, 3H), 1.
18-1.41 (m, 4H), 1.58-1.74 (m, 2H), 2.34 (s, 3H), 2.67 (t, J =
7.5Hz, 2H), 3.89 (s, 3H) Melting point: 75-76 ℃

Example 7 Synthesis of 3-hydroxy-5-methoxy-6-methyl-2-butyl-4H-pyran-3-one: 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-butyl 2.4 g of perhydro-3H-pyran-3-one (9 mmol
l) was converted to 74.2 g (914 mm) of 37% formaldehyde.
ol), 10% hydrochloric acid (67 g, 183 mmol) and 1
Heated to reflux for an hour. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was extracted and washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 3: 1). 1.1 g (55%) of the title compound was obtained as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ; 0.95 (t, J = 7.3 Hz, 3H), 1.
32-1.46 (m, 2H), 1.53-1.71 (m, 2H), 2.33 (s, 3H), 2.68 (t, J =
7.9Hz, 2H), 3.89 (s, 3H) Melting point: 66-69 ℃

Example 8 Synthesis of 3-hydroxy-5-methoxy-6-methyl-2-isopropyl-4H-pyran-3-one: 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-isopropyl Perhydro-3H-pyran-3-one 2.2
g (9 mmol) in 75.2 g of 37% formaldehyde
(927 mmol), 68 g of 10% hydrochloric acid (185 mmol)
In addition to l), the mixture was heated under reflux for 1 hour. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was extracted and washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 5).
0 g, hexane: ethyl acetate = 3: 1). 830 mg (45%) of the title compound as a colorless powder
Obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.25 (d, J = 7.0 Hz, 6H), 2.
34 (s, 3H), 3.22-3.32 (m, 1H), 3.89 (s, 3H) Melting point: 96-105 ℃

Example 9 Synthesis of 3-hydroxy-5-methoxy-6-methyl-2-propyl-4H-pyran-3-one: 4-hydroxyimino-5,6-dimethoxy- obtained in Example 4. 6-
Methyl-2-propylperhydro-3H-pyran-3-
ON was added to 100 ml of 37% formaldehyde and 20 ml of 10% hydrochloric acid, and the mixture was heated under reflux for 15 minutes. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, hexane: ethyl acetate = 3: 1). 421 mg of the title compound was obtained as a colorless powder.

[0068] _{^{1 H-NMR (CDCl 3)}} δ; 0.98 (t, J = 5.0Hz, 3H), 1.
69 (m., 2H), 2.34 (s, 3H), 2.66 (t, J = 5.0Hz, 2H), 3.89 (s, 3H
H), 6.20-6.80 (brs, 1H) Melting point: 74-75 ℃

Example 10 Synthesis of 3-hydroxy-5-methoxy-6-methyl-2-phenyl-4H-pyran-3-one: 4-hydroxyimino-5,6-dimethoxy-6-methyl-2-phenyl 388 mg of perhydro-3H-pyran-3-one (1
(mmol) was added to 8 ml of 37% formaldehyde and 3 ml of 10% hydrochloric acid, and the mixture was heated under reflux for 15 minutes. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel 8 g, hexane: ethyl acetate = 3: 1). 123 mg (53%) of the title compound were obtained as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ; 1.56 (brs, 1H), 2.47 (s, 3H), 3.95 (s, 3H), 7.40-7.49 (m, 3
H), 8.03-8.08 (m, 2H) Melting point: 197.8-198.6 ℃

[0071]

According to the method of the present invention using the novel intermediate of the present invention, 2,6-dialkyl-γ having an antitumor promoter activity and an inhibitory effect on cell death of brain nerve cells.
-The pyrone derivative (2) can be efficiently and safely produced without using harmful reagents.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 309/38 C07D 309/38 (72) Inventor Jiro Yoshida 1624 Shimodate, Koda-cho, Takada-gun, Hiroshima Yukinaga Pharmaceutical F term in reference (reference) 4C062 CC01 DD13 4C086 AA04 BA07 ZA15 ZB26

Claims (4)

[Claims] 1. The following general formula (1): [Wherein, R ¹ , R ³ and R ⁴ represent a lower alkyl group which may be the same or different, and R ² represents a lower alkyl group, an aralkyl group or an aryl group which may have a substituent] 4-hydroxyiminotetrahydro- represented by
β-pyrone derivative. 2. The following general formula (1): [Wherein, R ¹ , R ³ and R ⁴ represent a lower alkyl group which may be the same or different, and R ² represents a lower alkyl group, an aralkyl group or an aryl group which may have a substituent] 4-hydroxyiminotetrahydro- represented by
The following general formula (2), wherein the β-pyrone derivative is subjected to an acidic hydrolysis reaction. [Wherein R ¹ , R ² and R ⁴ are the same as defined above. ] A method for producing a 2,6-dialkyl-γ-pyrone derivative represented by the formula: 3. The following general formula (3):[Wherein, R¹And R^ThreeMay be the same or different
Represents a lower alkyl group; ^TwoIs lower alkyl group, aralkyl
Represents an aryl group or an aryl group which may have a substituent]
The β-pyrone derivative represented by the following general formula R^FourOH [wherein, R^FourRepresents a lower alkyl group).
Characterized by reacting with coal and nitrite compounds
The following general formula (1)[Wherein, R¹~ R^FourIndicates the same as above. ]
4-hydroxyiminotetrahydro-β-pyrone induction
Manufacturing method of conductor. 4. The following general formula (3):[Wherein, R¹And R^ThreeMay be the same or different
Represents a lower alkyl group; ^TwoIs lower alkyl group, aralkyl
Represents an aryl group or an aryl group which may have a substituent]
The β-pyrone derivative represented by the following general formula R^FourOH [wherein, R^FourRepresents a lower alkyl group).
The following general formula (1) is reacted with coal and a nitrous acid compound.[Wherein, R¹~ R^FourIndicates the same as above. ]
4-hydroxyiminotetrahydro-β-pyrone induction
A conductor, which is subjected to an acidic hydrolysis reaction.
The following general formula (2)[Wherein, R¹, R^TwoAnd R^FourIndicates the same as above
You. 2,6-dialkyl-γ-pyrone derivative represented by the formula:
How to make the body.