JP7121986B2 - Method for producing alkoxyflavone derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an alkoxyflavone derivative.

Hydroxyflavone derivatives having a flavone skeleton with hydroxy groups are widely distributed in plants and are known to exhibit various physiological activities. For example, quercetin (3,5,7,3',4'-pentahydroxyflavone), which is an example of a hydroxyflavone derivative, is known as a main component of onions.

On the other hand, alkoxyflavone derivatives obtained by alkoxylating the hydroxy groups of hydroxyflavone derivatives are also widely present in plants and are known to exhibit various physiological activities. For example, black turmeric contains 3,5,7,3′,4′-pentaalkoxyflavone in which all five hydroxyl groups in quercetin are alkoxylated, and this is considered to be one of the causes of aging. It is known to exhibit an anti-glycation effect on glycation.

By the way, attempts are currently being made to synthesize alkoxyflavone derivatives from hydroxyflavone derivatives, as described, for example, in Non-Patent Documents 1 and 2 below.

Shi, Z.; -H et al. , Eur. J. Med. Chem. , 2012, 54, 210-222. Kim, M.; et al. , J. Korean Soc. Appl. Biol. Chem. , 2015, 58, 343-248.

However, in Non-Patent Document 1, there is a problem that all the hydroxyl groups of the hydroxyflavone derivative cannot be alkoxylated, and a by-product in which some hydroxyl groups remain is produced.

On the other hand, Non-Patent Document 2 mentioned above reports that all the hydroxy groups of the hydroxyflavone derivative are alkoxylated, but there is a problem that the yield is low.

Therefore, in view of the above problems, an object of the present invention is to provide a method for producing an alkoxyflavone derivative by alkoxylating all the hydroxy groups in the hydroxyflavone derivative with high yield.

A method for producing an alkoxyflavone derivative according to one aspect of the present invention for solving the above problems comprises alkoxylating a hydroxyflavone derivative represented by the following formula in the presence of dimethylsulfoxide and an alkali hydroxide.

In the above formulas, R ₁₁ to R ₁₄ , R ₂₁ to R ₂₅ and R ₃ are each independently hydrogen, hydroxyl group, ester group, alkoxy group, alkylenedioxy group, sulfonyl group or alkyl group. be. However, at least two or more of R ₁₁ to R ₁₄ , R ₂₁ to R ₂₅ and R ₃ are hydroxyl groups.

As described above, the present invention can provide a method for producing an alkoxyflavone derivative in which all the hydroxy groups in the hydroxyflavone derivative are alkoxylated with high yield.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail. However, the present invention can be embodied in many different forms, and is not limited only to the specific exemplifications described in the embodiments and examples given below.

First, in the method for producing an alkoxyflavone derivative according to the present embodiment (hereinafter referred to as "the present production method"), a hydroxyflavone derivative represented by the following general formula is reacted with dialkoxysulfuric acid in the presence of dimethylsulfoxide and alkali hydroxide. The flavone derivative is alkoxylated by

In the above formulas, R ₁₁ to R ₁₄ , R ₂₁ to R ₂₅ and R ₃ are each independently hydrogen, hydroxyl group, ester group, alkoxy group, alkylenedioxy group, sulfonyl group or alkyl group. be. However, at least two or more of R ₁₁ to R ₁₄ , R ₂₁ to R ₂₅ and R ₃ are hydroxyl groups.

A hydroxyflavone derivative in the present production method means a compound having a flavone skeleton to which a hydroxy group is bonded, as described above. Many of these hydroxyflavone derivatives exist in plants, and many of them have characteristic physiological activities. The hydroxyflavone derivative used in this production method may be purified/extracted from plants, or may be artificially synthesized.

In the “hydroxyflavone derivative” used in this production method, if the substituents represented by R ₁₁ to R ₁₄ , R ₂₁ to R ₂₅ and R ₃ are alkoxy groups, the number of carbon atoms contained is 1 More than 5 groups are preferable, and examples thereof include methoxy group, ethoxy group, propoxy group, butoxy group, pentoxy group and benzyloxy group. Also, in the case of an alkyl group, the number of carbon atoms is preferably 1 or more and 5 or less, and a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or the like is preferable. Also in the case of a carboxy group, the number of carbon atoms contained is preferably 1 or more and 5 or less. In the case of an ester group and a sulfonyl group, the number of carbon atoms contained in the terminal functional group is preferably from 1 to 5, such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or A benzyl group and the like can be exemplified. In the case of an alkylenedioxy group, it is preferable that two of the above-mentioned adjacent functional groups are bonded to an oxygen atom and further have an alkylene group having 1 or more and 2 or less carbon atoms between them, such as a methylenedioxy group. , ethylenedioxy group, and the like.

In addition, although not limited as long as it has the above structure, hydroxyflavone derivatives include 3-hydroxyflavone, 5,7,4′-trihydroxyflavone (apigenin) 5,7,3′,4′ - tetrahydroxyflavone (luteolin), 3,5,7,4'-tetrahydroxyflavone (kaempferol), 3,5,7,3',4'-pentahydroxyflavone (quercetin), 3,5,7, 3′,4′,5′-Hexahydroxyflavone (myricetin) can be exemplified, but not limited thereto.

Moreover, dimethyl sulfoxide (C ₂ H ₆ SO, DMSO) used in this production method functions as a solvent capable of dissolving the hydroxyflavone derivative and the dialkyl sulfate.

In addition, the amount of DMSO used in the present production method is not limited as long as it has the above function. is 750 mL or more and 3500 mL or less, more preferably 1200 mL or more and 2400 mL or less.

In addition, the dialkyl sulfuric acid used in this production method is used as a supply source of alkyl groups in this production method. Here, the alkyl group of "dialkylsulfuric acid" is not limited, but is preferably any of methyl, ethyl, propyl, butyl, or pentyl, specifically dimethylsulfuric acid, diethylsulfuric acid, dipropyl Any one of sulfuric acid, dibutylsulfuric acid, and dipentylsulfuric acid is preferred.

In the present production method, the amount of dialkylsulfuric acid used is not limited as long as it contains an amount that allows the hydroxy group in the hydroxyflavone derivative to be substituted with an alkyl group, and can be adjusted as appropriate. For example, when the hydroxyl group of the hydroxyflavone derivative to be used is 1 mol, it preferably contains 1 mol or more, more preferably 1 mol or more and 3 mol or less, and still more preferably 1.5 mol or more and 2 mol or less.

Further, the alkali hydroxide used in the present production method acts as a base, and is not limited as long as it has this function. Examples include lithium hydroxide, sodium hydroxide and potassium hydroxide. At least one of can be exemplified, but is not limited to this.

Moreover, the amount of alkali hydroxide used in the present production method is not limited as long as the reaction can be sufficiently advanced. For example, when the hydroxy group of the hydroxyflavone derivative is 1 mol, it is preferably 1 mol or more, more preferably 1 mol or more and 3 mol or less, and still more preferably 1.5 mol or more and 2 mol or less. .

Moreover, in this production method, the temperature during the reaction is not particularly limited, and for example, it is preferably 10° C. or higher and 50° C. or lower, and more preferably 20° C. or higher and 40° C. or lower.

Moreover, in the present production method, the reaction time is not limited as long as the hydroxyl group can be substituted with the methoxy group, and is preferably 1 hour or more and 6 hours or less. By setting the time to 2 hours or more, the hydroxy group can be sufficiently substituted with the alkoxy group, while by setting the time to 3 hours or less, it is unnecessary to secure unnecessary time.

In addition, in the present production method, it is also preferable to perform a separation/purification treatment after the above reaction. As the separation and purification treatment, for example, filtration, distribution using water or an organic solvent, or the like can be used, but is not limited thereto.

In addition, the alkoxyflavone derivative produced by the present production method is a compound in which all the hydroxy groups in the hydroxyflavone derivative are alkoxylated, and in the case of methylation, a methoxy group (--OMe). It is represented by a general formula. In the general formula below, the number of methoxy groups (--OMe) is not limited to two, because the hydroxyl group in the alkoxyflavone derivative has changed.

Further, specific compounds of the alkoxyflavone derivative in the present production method include, for example, 3-alkoxyflavone, 5,7,4′-trialkoxyflavone, 5,7,3′,4′-tetraalkoxyflavone, 3 , 5,7,4′-tetraalkoxyflavone, 3,5,7,3′,4′-pentaalkoxyflavone, 3,5,7,3′,4′,5′-hexaalkoxyflavone, etc. can be, but is not limited to.

As described above, according to the present production method, it is possible to provide a method for producing an alkoxyflavone derivative in which all the hydroxy groups in the hydroxyflavone derivative are alkoxylated with a high yield. Furthermore, in this production method, the reaction time can be significantly reduced as compared with the conventional technology, and the amount of alkali hydroxide and solvent to be used can also be reduced. These confirmations will become clear from the examples described later.

In the following, the effect of the above manufacturing method was actually confirmed. This confirmation will be specifically described.

(Example 1)
Dimethyl sulfoxide (DMSO) (8 mL) was added to powdered granular potassium hydroxide (1.66 g, 29.7 mmol) and stirred at room temperature. After sequentially adding quercetin (1 g, 3.3 mmol) and dimethyl sulfate (2.5 mL, 26.4 mmol) to the suspension at 10° C. or lower, the mixture was stirred at room temperature for 2 hours. As the reaction proceeded, the dark brown solution turned into a light brown suspension.

After completion of the reaction, water (80 mL) was added and extracted three times with ethyl acetate (50 mL/20 mL/20 mL each). The ethyl acetate extract was washed with 5% sodium hydroxide solution (10 mL x 4), water (10 mL x 3), and saturated brine (10 mL x 1), dried over sodium sulfate, and the solvent was removed under reduced pressure. Removal gave a light brown solid (1.05 g). This solid showed a single spot on thin-layer chromatography, and showed colorless prism crystals when recrystallized with methanol. This product has a melting point (147-149°C) that agrees with the literature value (136-137°C: 0005 Non-Patent Document 1 in this specification). I have confirmed that it is set.

¹ H-NMR δ 3.88 (3H, s, OMe), 3.90 (3H, s, OMe), 3.95 (9H, s, OMe x 3), 6.34 (1H, d, J = 2.2 Hz, 6- or 8-H), 6.49 (1H, d, J = 2.2 Hz, 6- or 8-H), 6.97 (1H, d, J = 8.4 Hz ¹³ C -NMR δ 55.9, 56.1, 56.3, 56.6, 60.1, 92.7, 96.0, 109.8, 111.2, 111.8, 121.8, 123.8 , 141.4, 149.0, 151.2, 152.6, 159.0, 161.3, 164.1, 174.1.

As a result of this reaction, it was confirmed that the yield was 85%, confirming the effectiveness of this method.

(Example 2)
Dimethyl sulfoxide (DMSO) (1 mL) was added to powdered granular sodium hydroxide (0.221 g, 5.5 mmol) and stirred at room temperature. After sequentially adding quercetin (0.203 g, 0.67 mmol) and dimethyl sulfate (0.6 mL, 6.3 mmol) to the suspension at room temperature, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (10 mL) was added, and after stirring for 1 hour, insoluble matter was filtered to obtain a solid (0.166 g, 66%). This was consistent with the product obtained in Example 1.

(Comparative example 1)
With reference to Non-Patent Documents 1 and 2, quercetin (0.498 g, 1.7 mmol) was dissolved in DMF (3.3 mL), and potassium carbonate (3.4 g, 24.6 mmol) and dimethyl sulfate (3.4 g, 24.6 mmol) were dissolved at room temperature. 0.9 mL, 7.8 mmol) were added sequentially. The suspension was warmed to 70° C. and stirred for 5 hours. After that, water was added to stop the reaction, and the reaction solution was acidified with 20% sulfuric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the resulting residue (0.590 g) was purified by preparative chromatography to give a pentamethoxy compound (0.30 g, 49%) and a tetramethoxy compound. (0.10 g, 18%) and trimethoxy (0.05 g, 12%). As a result, the reaction was insufficient under these conditions, and a sufficient yield could not be obtained.

(Comparative example 2)
Also, in the same manner as in Comparative Example 1 above, quercetin (0.202 g, 0.7 mmol) was dissolved in DMSO (1.6 mL), and potassium carbonate (0.808 g, 5.8 mmol) and dimethyl sulfate (0 .55 mL, 5.8 mmol) were added sequentially. The suspension was stirred at room temperature for 24 hours. Thereafter, water was added to stop the reaction, the reaction solution was acidified with 20% sulfuric acid, and insoluble matter was filtered to obtain a residue (0.191 g). This product showed three or more spots containing tetramethoxy and trimethoxy compounds in thin-layer chromatography and no pentamethoxy compound was observed, so further purification was discontinued. As a result, the reaction was insufficient even under these conditions.

(Comparative Example 3)
Dimethyl sulfoxide (DMSO) (4 mL) was added to powdered granular potassium hydroxide (0.83 g, 14.8 mmol) and stirred at room temperature. After sequentially adding quercetin (0.51 g, 1.67 mmol) and methyl iodide (0.9 mL, 14.5 mmol) to the suspension at 10° C. or below, the mixture was stirred at room temperature for 1.5 hours. After that, water was added to stop the reaction, and the reaction solution was acidified with 20% sulfuric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off. The obtained residue (0.492 g) was washed with acetone to give a pentamethoxy derivative (0.394 g). The acetone washings were distilled off under reduced pressure, and the obtained residue was purified by preparative chromatography to obtain 0.02 g of the pentamethoxy derivative (total 0.418 g, 67%). A 6-methylpentamethoxy compound (0.007 g, 1%) was obtained as a by-product from this preparative chromatography. This complicates the reaction with methyl iodide.

(Comparative Example 4)
Dimethylformamide (DMF) (0.8 mL) was added to powdered granular potassium hydroxide (0.34 g, 5.5 mmol) and stirred at room temperature. After sequentially adding quercetin (0.203 g, 0.67 mmol) and dimethyl sulfate (0.5 mL, 5.3 mmol) to the suspension at room temperature, the mixture was stirred at room temperature for 24 hours. After that, water was added to stop the reaction, and after acidifying the reaction solution with 20% sulfuric acid, insoluble matter was filtered and washed repeatedly with water. The resulting solid (0.181 g) was purified by preparative chromatography to yield pentamethoxy (0.022 g, 8.9%), tetramethoxy (0.071 g, 29%), and trimethoxy (0.071 g, 29%). 0.056 g, 25%). As a result, when this solvent was used, the reaction was insufficient and a sufficient yield could not be obtained.

INDUSTRIAL APPLICABILITY The present invention has industrial applicability as a method for producing an alkoxyflavone derivative.

Claims (2)

3,5,7,3',4'-pentyl sulfate is obtained by reacting quercetin with at least one of dimethylsulfate, diethylsulfate, dipropylsulfate, dibutylsulfate and dipentylsulfate in the presence of dimethylsulfoxide and an alkali hydroxide. A method for producing alkoxyflavone . 2. The method for producing 3,5,7,3′,4′-pentaalkoxyflavone according to claim 1, wherein said alkali hydroxide contains at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide.