JP2013124230A - Method for producing alkyl derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing an alkyl derivative of a polyphenol.SOLUTION: The method for producing an alkyl derivative of a polyphenol includes a step of reacting an acetic acid salt and an alkylating agent with the polyphenol.

Description

  The present invention relates to a method for producing an alkyl derivative of polyphenol.

Polyphenols are compounds that are abundant in nature and are known to have various physiological activities. For example, tea catechin has an effect of suppressing blood pressure elevation, blood cholesterol regulation, body fat accumulation, blood glucose It has stronger physiological activity because it has an anti-rise job, antioxidant action, anti-aging action, anti-cancer action, antibacterial action, anti-viral action, anti-cavity action, anti-allergic action, and deodorant action. In search of compounds, derivatives of polyphenols have been vigorously synthesized.
One of the derivatives of polyphenols is an alkyl derivative. However, when an attempt is made to produce a polyphenol that is abundant in nature by alkylating it, the presence of oxygen (for example, non-patented) References 1 and 2), heating at a high temperature (for example, refer to Non-patent document 3), or alkaline conditions (for example, refer to Non-patent document 4) are not used for purposes such as oxidation, polymerization, and epimerization. There was a difficulty that the reaction proceeded mainly. For this reason, almost no method for producing an alkyl derivative by directly alkylating a polyphenol has been reported so far. As a few examples, tea catechin is allowed to act by reacting lithium carbonate and an alkyl halide. Although a method for methylating catechins has been reported, in order to suppress unintended reactions, the reaction is carried out in a reaction vessel filled with an inert gas over a long period of 20 hours or more at a low temperature of room temperature. There was a need (see Patent Document 1).

JP 2001-253879 A

Kinetic analysis and mechanistic aspects of autoxdation of catechins, Biochicica et Biophysica Acta 1569 (2002) 35-44. A thermal treatment to increase the antioxidant capacity of natural phenols: catechin, resveratrol and grape extract cases, Eur Food Res Technol (2005) 221: 284-290. Preparation of Epimers of Tea Catechins by Heat TreatmentBioSci.Biotechnol.Biochem., 61 (9), 1434-1439, 1997. Epimerizaiton of Tea Catechins under Weakly Acidic and Alkaline Conditions, BioSci. Biotechnol. Biochem., 74 (4), 875-877, 2010.

  An object of this invention is to provide the novel manufacturing method of the alkyl derivative of polyphenol.

The method for producing an alkyl derivative of polyphenol according to the present invention includes a step of allowing an acetate and an alkylating agent to act on polyphenol.
_{^{Acetates, CR 1 R 2 R 3 CO}} 2 - in ^{M + (wherein,} R 1 ^{R 2} and ^{R 3} are each independently, H, is selected from F or Cl, and, ^{M +} is a monovalent It is preferably a compound represented by (a metal cation). Here, M ⁺ is more preferably Na ⁺ , K ⁺ , or Li ⁺ , and R ¹ , R ^2, and R ³ are more preferably H.
The alkylating agent is preferably an alkyl halide. The alkyl halide can be, for example, a halogenated C _1-20 alkyl.

The polyphenol may have a flavan skeleton, a trans-stilbene skeleton, or a cis-stilbene skeleton. For example, it is preferable that the polyphenol has any structural formula described below.

More preferably, the polyphenol has any structural formula described below.

  According to the present invention, it is possible to provide a novel method for producing an alkyl derivative of polyphenol.

  Hereinafter, embodiments of the present invention completed based on the above knowledge will be described in detail with reference to examples. The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. it can. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustration or explanation, and the present invention is not limited to them. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.

  The method for producing an alkyl derivative of polyphenol according to the present invention includes a step of allowing an acetate and an alkylating agent to act on polyphenol. By using such a production method, it is possible to produce an alkyl derivative from polyphenol directly in a very short time while suppressing side reactions such as oxidation, polymerization and epimerization even in the presence of oxygen. it can.

  The position at which the polyphenol is alkylated is not particularly limited. For example, a hydroxyl group (—OH) is alkylated to produce an alkyl derivative (—OA, where A is an alkyl group). Preferably, it is more preferable to produce an alkyl derivative by alkylating a hydroxyl group bonded to a carbon atom on the benzene ring, a so-called phenolic hydroxyl group. Moreover, the location to be alkylated may be one location or two or more locations.

The structure of the polyphenol is not particularly limited. For example, it may be a polyphenol having a flavan skeleton, a trans-stilbene skeleton, or a cis-stilbene skeleton represented by the following structural formula.

Examples of the polyphenol having a flavan skeleton include flavonols (such as quercetin and rutin), flavones (such as apigenin and luteolin), isoflavones (such as daidzein and genistein), flavanones (such as naringenin and naringin), flavanols (such as catechin, EC and EGCg), And flavonoids such as anthocyanidins (cyanidine and the like), and optical isomers and glycosides thereof. Examples of the polyphenol having a stilbene skeleton include resveratrol and stilbenes such as piceatannol, and cis-trans isomers thereof. Among these, it is preferable that the polyphenol has any structural formula described below.

EGCg ((−)-epigallocatechin-3-O-gallate), GCg ((−)-gallocatechin-3-O-gallate), naringenin, trans-resveratrol represented by the following structural formula Or trans-piceatannol is more preferable.

  When an alkyl derivative is produced using a polyphenol having a flavan skeleton, the corresponding alkyl derivative can be produced while maintaining the optical activity on the flavan skeleton, that is, while suppressing side reactions such as epimerization. . When a polyphenol having a stilbene skeleton is used, a corresponding alkyl derivative can be produced while suppressing side reactions such as cis-trans isomerization.

Type of acid salt is not particularly _{^{limited, CR 1 R 2 R 3 CO}} 2 - in ^{M + (wherein,} R 1, ^{R 2} and ^{R 3} are each independently, H, F, or, is selected from Cl And M ⁺ is a monovalent metal cation). Here, M ⁺ is preferably Na ⁺ , K ⁺ , or Li ⁺ , or R ¹ , R ^2, and R ³ are more preferably H, and CR ¹ R ² R ³ CO ₂ ⁻ More preferably, M ⁺ is CH ₃ CO ₂ Na (AcONa, sodium acetate), CH ₃ CO ₂ K (AcOK, potassium acetate), or CH ₃ CO ₂ Li (AcOLi, lithium acetate).
The amount of acetate to be used is not particularly limited, but may be 0.01 to 20 equivalents or 0.1 to 12 equivalents with respect to polyphenol, for example, from the viewpoint of reaction time and economy. Preferably, it is 1-8 equivalents, more preferably 2-4 equivalents.

The type of alkylating agent is not particularly limited, but is preferably an alkyl halide. The halogen contained in the alkyl halide may be any of F, Cl, Br, or I, but from the viewpoint of reactivity, Cl, Br, or I is preferable, and Br, or I is more preferable, and I is more preferable. The alkyl group contained in the halogenated alkyl is not particularly limited, but is preferably a C _1-20 alkyl group and more preferably a C _1-10 alkyl group from the viewpoint of availability and reactivity. preferable.

The alkyl group contained in the alkylating agent and the alkyl derivative of polyphenol may be a saturated alkyl group or an unsaturated alkyl group, and may be linear, branched or cyclic. The saturated alkyl group is preferable.
Examples of saturated C _1-10 alkyl groups include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n -Pentyl group, i-pentyl group, neopentyl group, 1-methylbutyl group, n-hexyl group, methylpentyl group (the bonding position of the methyl group is not particularly limited, the same applies hereinafter), n-heptyl group, methyl Examples include, but are not limited to, a hexyl group, an n-octyl group, a methylheptyl group, an n-nonanyl group, a methyloctyl group, an n-decyl group, and a methylnonanyl group.
The amount of the alkylating agent to be used is not particularly limited, but from the viewpoint of reaction time and economy, for example, it may be 1 to 50 equivalents, preferably 1 to 25 equivalents with respect to polyphenol, preferably 2 More preferably, it is ˜16 equivalents.

The method of allowing acetate and an alkylating agent to act on polyphenol is not particularly limited, but dissolving or suspending polyphenol, acetate and alkylating agent in a solvent, and stirring the resulting solution or suspension It is preferable to carry out by. Although the kind of solvent to be used is not specifically limited, For example, it is preferable that they are aprotic polar solvents, such as DMF, DMSO, acetonitrile, and acetone, and it is more preferable that it is DMF.
The temperature at which the acetate and the alkylating agent are allowed to act on the polyphenol is not particularly limited, and can be appropriately set by those skilled in the art in consideration of the type of solvent used. Considering suppression of reaction and shortening of reaction time, for example, it may be −78 ° C. to 300 ° C., preferably 0 ° C. to 200 ° C., and about 20 ° C. to 160 ° C. Is more preferable, it is more preferable that it is 50 to 120 degreeC, and it is still more preferable that it is 70 to 120 degreeC. As described above, the step of allowing the acetate and the alkylating agent to act on the polyphenol can be performed at a very wide temperature range. That is, the target polyphenol alkyl derivative can be produced even at a low temperature, and even at a high temperature, oxidation and polymerization, epimerization of polyphenol as a raw material and polyphenol alkyl derivative as a product can be produced. An alkyl derivative of polyphenol can be produced while suppressing side reactions such as conversion.
A person skilled in the art can appropriately adjust the time for which the acetate and the alkylating agent are allowed to act on the polyphenol while appropriately monitoring the reaction by TLC, HPLC, or ¹ H-NMR.

The step of allowing acetate and an alkylating agent to act on polyphenol can be performed in the presence of oxygen such as in the air or in the absence of oxygen substituted with an inert gas. Even in this case, the target polyphenol alkyl derivative can be produced while suppressing side reactions.
Further, in the step of allowing acetate and alkylating agent to act on polyphenol, a base other than acetate, such as lithium carbonate, may coexist. An alkyl derivative of polyphenol can be produced.

  The method for recovering the produced alkyl derivative of polyphenol is not particularly limited, and examples thereof include a method of purifying using a suitable chromatography after the solvent is distilled off from the reaction mixture under reduced pressure.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.

[Example 1] Comparison of bases After theavigo ^TM (EGCg ≧ 94%, 137.5 mg, 0.3 mmol) was dissolved in DMF (1.0 mL), each base (4.0 equivalents) shown in Table 1 and iodine Methyl chloride (144.8 μL, 2.4 mmol, 8.0 eq) was added and stirred at 100 ° C. or room temperature for 5 to 600 minutes in an air atmosphere. Then, ODS-HPLC [column: Lighttysil RP-18GP 20 × 250 mm (particle size: 5 μm), manufactured by Kanto Chemical Co., Ltd., developing solvent: acetonitrile: water: acetic acid (2: 18: 1), flow rate: 5.0 mL / min, detection Separation and purification at a wavelength of 210 nm], an unreacted EGCg was obtained at a retention time of 27.7 minutes, and 4 "Me-EGCg ((-)-epigallo represented by the following structural formula at a retention time of 44.9 minutes. Catechin-3- (4-O-methyl) gallate) was obtained.

The obtained 4 ″ Me-EGCg was identified as a target substance by measurement of optical rotation, ¹ H-NMR and ¹³ C-NMR, and mass spectrometry.
4 ”Me-EGCg
[α] _D ²⁰ -157.1 ° (c = 1.0, acetone)
¹ H-NMR (500 MHz, CD ₃ OD): 2.84 (1H, dd, J = 17.4, 2.5), 2.98 (1H, dd, J = 17.4, 4.4), 3.81 (3H, s), 4.97 (1H, bs), 5.53 (1H, m), 5.95 (2H, bs), 6.49 (2H, bs), 6.91 (2H, bs)
¹³ C-NMR (125 MHz, CD ₃ OD): 26.8, 60.7, 70.3, 78.5, 95.9, 96.5, 99.3, 106.8, 110.3, 126.6, 130.7, 133.8, 141.2, 146.7, 151.5, 157.2, 157.8, 157.9, 167.1
MS (ESI) m / z: 471.1 (M -)

  Table 1 shows the type of base used, reaction temperature and reaction time, and the yield of the target product and the raw material recovery rate.

No. in Table 1 In 1-7, it reacted by changing only the kind of base on the fixed conditions of reaction temperature 100 degreeC and reaction time 5 minutes. No. As shown in 1-3, when metal acetate is used, 4 "Me-EGCg, which is the target product, is obtained in a very high yield of 33% to 47% regardless of the type of metal. Furthermore, EGCg which is an unreacted raw material can also be recovered at a high recovery rate of 47% to 55%, and the total of the yield of the target product and the raw material recovery rate is 88% to 95%. On the other hand, side reactions such as oxidation and polymerization hardly occurred in No. 4 using ammonium salt of acetic acid, whereas the reaction itself hardly progressed and the raw material recovery rate was 96%. It was.
No. As shown in FIG. 5, even when lithium carbonate was allowed to coexist in the reaction system in addition to the acetic acid metal salt, no. As in 1-3, the target product was produced in a high yield, and the raw materials could be recovered at a high recovery rate.

No. In Nos. 6 and 7, a base other than acetate was used. In No. 6, reactions other than the purpose such as oxidation and polymerization proceeded, and it was not possible to recover the raw material or obtain the desired product.
No. using lithium carbonate In No. 7, the target product was produced and unreacted raw materials could be recovered, but the yield of the target product was No. 1 using a metal acetate salt. It became a low value compared with 1-4. When lithium carbonate was used as the base and the reaction temperature was kept at 100 ° C. and the reaction time was extended to 120 minutes to 480 minutes, No. As shown by 8 to 10, reactions other than the purpose such as oxidation and polymerization mainly proceed with the passage of time, and the sum of the yield of the target product and the raw material recovery rate is the case where the reaction time is 120 minutes. 43%, 35% at 240 minutes, and 26% at 480 minutes. In addition, when the reaction is performed at a temperature as low as room temperature in order to suppress the progress of reactions other than these purposes, No. As shown in FIG. 11, the target methylation reaction hardly proceeded.

  As shown by the above results, even if oxygen is present in the reaction system by allowing acetate and an alkylating agent to act on polyphenol, even if the reaction temperature is as high as 100 ° C., While suppressing side reactions such as oxidation, polymerization, and epimerization, it is possible to produce a corresponding polyphenol alkyl derivative from polyphenol in a very short time.

[Example 2] Comparison of reaction time Except that sodium acetate (98.4 mg, 1.2 mmol, 4.0 equivalents) was used as a base, the reaction temperature was 100 ° C, and the reaction time was 2 to 600 minutes. According to the method described in Example 1, 4 ″ Me-EGCg was produced from EGCg.
The results are shown in Table 2.

No. in Table 2 1 and no. As shown in Fig. 2, 35% of the target 4 "Me-EGCg was already produced immediately after the start of the reaction, and 47% was produced 5 minutes after the start of the reaction. By reacting an acetate and an alkylating agent, the corresponding alkyl derivative of polyphenol can be produced from polyphenol in a very short time.
No. As shown in Nos. 1 to 7, oxygen is present in the reaction system, and side reactions such as oxidation and polymerization hardly occur even at a high temperature of 100 ° C., and the reaction time is 600 minutes. Even in the case of 7, the total of the yield of the target product and the raw material recovery rate was a very high value of 71%.

Example 3 Comparison of Reaction Temperatures Sodium acetate (98.4 mg, 1.2 mmol, 4.0 equivalents) was used as the base, the reaction time was 5 minutes, and the reaction temperature was room temperature to 120 ° C. According to the method described in Example 1, 4 ″ Me-EGCg was produced from EGCg.
The results are shown in Table 3.

No. in Table 3 As shown in FIG. 1, even at a low reaction temperature of room temperature, the target product, 4 ″ Me-EGCg, was produced only 5 minutes after the start of the reaction. Even at such a very high reaction temperature, the total of the raw material recovery rate and the yield of the target product was as high as 90%, and side reactions such as oxidation and polymerization hardly occurred.
As these results show, by reacting polyphenols with acetate and alkylating agents, side reactions such as oxidation, polymerization, epimerization, etc., even at low and high reaction temperatures. Thus, the corresponding alkyl derivative of polyphenol can be produced from polyphenol in a very short time. In particular, in the range of 50 ° C. to 120 ° C., an alkyl derivative of polyphenol is produced in a high yield of 23% or more from polyphenol in a very short time while suppressing side reactions such as oxidation, polymerization and epimerization. Furthermore, in the range of 70 ° C. to 120 ° C., while suppressing these side reactions, the polyphenol alkyl derivative from polyphenol can be obtained in an extremely high yield of about 35% or more in a very short time. Can be manufactured.

[Example 4] Comparison of reaction temperature The reaction temperature was kept at 100 ° C, the reaction time was kept constant at 5 minutes, sodium acetate (2.0 eq to 8.0 eq) was added to the base, and methyl iodide (4.0 4 ″ Me-EGCg was prepared from EGCg according to the method described in Example 1 except that equivalent to 16.0 equivalents) was used.
The results are shown in Table 4.

No. As shown in FIG. 1, even when the amount of sodium acetate is 2.0 equivalents and the amount of methyl iodide is 4.0 equivalents, even when a small excess is used relative to the raw material EGCg, After 5 minutes from the start, 4 ″ Me-EGCg, which was the target product, was produced in a yield of 30%.
No. 2-No. As shown in FIG. 4, when the amount of sodium acetate is 4.0 equivalents or more and the amount of methyl iodide is 8.0 equivalents or more, in each case, the yield is about 45% or more. I was able to get the target.

Example 5 Alkylation of various polyphenols (a) GCg
After GCg (56.4 mg, 0.12 mmol) was dissolved in DMF (0.41 mL), sodium acetate (40.4 mg, 0.49 mmol, 4.0 eq) and methyl iodide (59.4 μL, 0.98 mmol) 8.0 equivalents) and stirred at 100 ° C. for 5 minutes. Thereafter, separation and purification were performed by ODS-HPLC to obtain 23.4 mg of unreacted GCg (recovery rate: 41.5%) at a retention time of 33.4 minutes, and represented by the following structural formula at a retention time of 58.8 minutes. 4 ″ Me-GCg 24.8 mg (yield: 42.6%) was obtained.

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained 4 ″ Me-GCg was identified as a target product by ¹ H-NMR and ¹³ C-NMR measurements and mass spectrometry.
4 ”Me-GCg
¹ H-NMR (700 MHz, acetone-d ₆ ): 2.77 (1H, dd, J = 16.6, 5.3), 2.82 (1H, dd, J = 16.6, 4.8), 3.83 (3H, s), 5.13 (1H , d, J = 5.3), 5.40 (1H, m), 5.97 (1H, d, J = 2.2), 6.05 (1H, d, J = 2.2), 6.47 (2H, bs), 7.01 (2H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 23.6, 60.6, 70.6, 78.5, 95.4, 96.3, 98.9, 106.1, 109.8, 126.3, 130.7, 133.3, 140.5, 146.5, 151.1, 156.1, 157.2, 158.0 165.8
MS (ESI) m / z: 471.1 (M -)

(B) Naringenin Naringenin (81.7 mg, 0.30 mmol) was dissolved in DMF (1.0 mL), and then sodium acetate (98.4 mg, 1.20 mmol, 4.0 equivalents) and methyl iodide (144.8 μL) 2.40 mmol, 8.0 equivalents) was added and stirred at 100 ° C. for 5 minutes. Thereafter, separation and purification were performed by ODS-HPLC to obtain 34.6 mg of unreacted naringenin (recovery rate: 42.4%) at a retention time of 25.1 minutes, and represented by the following structural formula at a retention time of 46.6 minutes. 27.3 mg (yield: 31.8%) of 7Me-naringenin was obtained.

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained 7Me-naringenin was identified as the target product by ¹ H-NMR and ¹³ C-NMR measurements and mass spectrometry.
7Me--naringenin
¹ H-NMR (700 MHz, DMSO-d ₆ ): 3.77 (3H, s), 2.71 (1H, dd, J = 17.3, 2.8), 3.29 (1H, dd, J = 17.3, 13.1), 5.46 (1H , dd, J = 13.1, 2.8), 6.07 (1H, d, J = 2.2), 6.09 (1H, d, J = 2.2), 6.79 (2H, d, J = 8.4), 7.31 (2H, d, J = 8.4), 12.1 (1H, bs)
¹³ C-NMR (175 MHz, DMSO-d ₆ ): 42.3, 56.1, 78.9, 94.0, 94.9, 102.8, 115.4, 115.4, 128.6, 128.6, 128.9, 158.0, 163.1, 163.4, 167.6, 172.3, 197.2
MS (ESI) m / z: 285.3 (M -)

(C) trans-resveratrol
After trans-resveratrol (162.1 mg, 0.71 mmol) was dissolved in DMF (2.4 mL), sodium acetate (233.0 mg, 2.84 mmol, 4.0 eq) and methyl iodide (342.7 μL) 5.68 mmol, 8.0 equivalents) was added and stirred at 100 ° C. for 5 minutes. Thereafter, separation and purification were performed by ODS-HPLC, and unreacted trans-resveratrol 134.2 mg (recovery rate: 82.8%) was obtained at a retention time of 23.4 minutes. 3.8 mg (yield: 2.2%) of trans-3Me-resveratrol represented by the structural formula on the left side was obtained, and trans- 5.3 mg (yield: 3.1%) of 4′Me-resveratrol was obtained.

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained trans-3Me-resveratrol and trans-4'Me-resveratrol were identified as the target substances by measurement of ¹ H-NMR and ¹³ C-NMR and mass spectrometry, respectively. did.
trans-4'Me-resveratrol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.80 (3H, s), 6.27 (1H, dd, J = 1.8, 1.8), 6.54 (2H, d, J = 1.8), 6.91 (2H, d , J = 8.4), 6.92 (1H, d, J = 16.4), 7.03 (1H, d, J = 16.4), 7.49 (2H, d, J = 8.4), 8.24 (2H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.5, 102.7, 105.7, 105.7, 114.9, 114.9, 127.5, 128.6, 128.6, 128.7, 130.9, 140.7, 159.5, 159.5, 160.3
MS (ESI) m / z: 241.3 (M -)
trans-3Me-resveratrol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.76 (3H, s), 6.30 (1H, bs), 6.62 (2H, bs), 6.83 (2H, d, J = 8.0), 6.92 (1H, d, J = 16.0), 7.08 (1H, d, J = 16.0), 7.42 (2H, d, J = 8.0)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.4, 101.3, 103.9, 106.6, 116.4, 116.4, 126.6, 128.7, 128.7, 129.4, 129.8, 140.8, 158.2, 159.5, 162.0
MS (ESI) m / z: 241.3 (M -)

(D) trans-piceatannol
After trans-piceatannol (131.9 mg, 0.54 mmol) was dissolved in DMF (1.8 mL), sodium acetate (177.2 mg, 2.16 mmol, 4.0 eq) and methyl iodide (260.6 μL) 4.32 mmol, 8.0 equivalents) was added and stirred at 100 ° C. for 5 minutes. Thereafter, separation and purification were performed by ODS-HPLC to obtain 85.5 mg of unreacted trans-piceatannol (recovery: 64.8%) at a retention time of 24.7 minutes, and at a retention time of 42.9 minutes the following. 11.3 mg (yield: 8.1%) of trans-3Me-piceatannol represented by the structural formula in the upper left was obtained, and trans-4Me- represented by the structural formula in the upper right below was obtained at a retention time of 45.1 minutes. 18.0 mg (yield: 12.9%) of piceatannol was obtained, and 2.0 mg (yield: trans-3′Me-piceatannol represented by the following left lower structural formula) at a retention time of 51.7 minutes. 1.4%), and 1.5 mg (yield: 1.0%) of trans-3,4diMe-piceatannol represented by the following right lower structural formula was obtained at a retention time of 54.6 minutes. .

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained trans-3Me-piceatannol, trans-4Me-piceatannol, trans-3′Me-piceatannol, and trans-3,4diMe-piceatannol are respectively represented by ¹ H-NMR and ¹³ It was identified as the target product by C-NMR measurement and mass spectrometry.
trans-3Me-piceatannol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.88 (3H, s), 6.26 (1H, dd, J = 2.2, 2.2), 6.53 (2H, d, J = 2.2), 6.80 (1H, d , J = 7.9), 6.91 (1H, d, J = 16.4), 7.00 (1H, d, J = 16.4), 7.01 (1H, dd, J = 7.9, 1.9), 7.21 (1H, d, J = 1.9 ), 7.73 (1H, bs), 8.23 (2H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.4, 101.8, 104.8, 104.8, 109.2, 115.1, 120.4, 126.2, 128.6, 129.6, 140.0, 146.7, 147.7, 158.7, 158.7
MS (ESI) m / z: 257.2 (M -)
trans-4Me-piceatannol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.83 (3H, s), 6.27 (1H, dd, J = 2.2, 2.2), 6.55 (2H, d, J = 2.2), 6.88 (1H, d , J = 16.1), 6.91 (1H, d, J = 8.5), 6.97 (1H, dd, J = 8.5, 1.9), 6.98 (1H, d, J = 16.1), 7.09 (1H, d, J = 1.9 ), 7.63 (1H, bs), 8.25 (2H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.4, 101.9, 104.9, 104.9, 111.5, 112.4, 118.9, 126.8, 128.2, 130.9, 139.9, 146.7, 147.5, 158.7, 158.7
MS (ESI) m / z: 257.1 (M -)
trans-3'Me-piceatannol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.76 (3H, s), 6.29 (1H, dd, J = 1.8, 2.2), 6.61 (2H, bs), 6.80 (1H, d, J = 8.4 ), 6.86 (1H, d, J = 16.4), 6.90 (1H, dd, J = 8.4, 1.8), 7.01 (1H, d, J = 16.4), 7.08 (1H, d, J = 1.8), 8.18 ( 3H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.6, 100.4, 103.1, 105.8, 113.0, 115.4, 119.2, 125.9, 128.9, 129.8, 140.0 145.3, 145.3, 158.7, 161.3
MS (ESI) m / z: 257.2 (M -)
trans-3,4diMe-piceatannol
¹ H-NMR (700 MHz, acetone-d ₆ ): 3.81 (3H, s), 3.85 (3H, s), 6.27 (1H, dd, J = 2.2, 2.2), 6.54 (2H, d, J = 2.2 ), 6.92 (1H, d, J = 8.4), 6.95 (1H, d, J = 16.4), 7.02 (1H, dd, J = 16.4), 7.06 (1H, dd, J = 8.4, 1.8), 7.22 ( 1H, bd, J = 1.8), 8.22 (2H, bs)
¹³ C-NMR (175 MHz, acetone-d ₆ ): 55.2, 55.2, 101.9, 104.9, 104.9, 109.4, 111.8, 120.0, 126.8, 128.3, 130.6, 139.9, 149.5, 149.7, 158.8, 158.8
MS (ESI) m / z: 271.1 (M -)

  As the above results show, by having acetic acid salt and alkylating agent act on polyphenol, it has various structures in a very short time while suppressing side reactions such as oxidation, polymerization and epimerization. It is possible to produce alkyl derivatives of the corresponding polyphenols from polyphenols.

Example 6 Various alkylations of polyphenols (a) Ethylation Theavigo ^™ (EGCg ≧ 94%, 137.5 mg, 0.3 mmol) was dissolved in DMF (1.0 mL) followed by sodium acetate (98.4 mg). 1.2 mmol, 4.0 equivalents) and ethyl iodide (193.0 μL, 2.4 mmol, 8.0 equivalents) were added and stirred at 100 ° C. for 5 minutes. Thereafter, separation and purification were performed by ODS-HPLC to obtain 66.8 mg of unreacted EGCg (recovery rate: 48.6%) at a retention time of 28.5 minutes, and 4 "Et- at a retention time of 49.2 minutes. 60.2 mg (yield: 41.3%) of EGCg ((−)-epigallocatechin-3- (4-O-ethyl) gallate) was obtained.

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained 4 ″ Et-EGCg was identified as the target product by ¹ H-NMR and ¹³ C-NMR measurements and mass spectrometry.
4 ”Et-EGCg
¹ H-NMR (500 MHz, CD ₃ OD): 1.30 (3H, t, J = 7.0), 2.84 (1H, dd, J = 17.5, 2.5), 2.98 (1H, dd, J = 17.5, 5.0), 4.09 (2H, q, J = 7.0), 4.97 (1H, bs), 5.53 (1H, m), 5.95 (2H, bs), 6.49 (2H, bs), 6.91 (2H, bs)
¹³ C-NMR (125 MHz, CD ₃ OD): 15.6, 26.8, 69.3, 70.3, 78.5, 95.9, 96.5, 99.3, 106.8, 110.2, 126.4, 130.7, 133.8, 139.8, 146.7, 151.7, 157.2, 157.8, 157.9 , 167.2
MS (ESI) m / z: 485.1 (M -)

(B) Pentylated Theavigo ^™ (EGCg ≧ 94%, 137.5 mg, 0.3 mmol) was dissolved in DMF (1.0 mL) and sodium acetate (98.4 mg, 1.2 mmol, 4.0 equivalents) and 1 -Pentyl iodide (312.7 μL, 2.4 mmol, 4.0 equivalents) was added and stirred at 85 ° C. for 120 minutes. Then, it isolate | separates and refine | purifies by ODS-HPLC, 46.3-pentyl-EGCg ((-)-epigallocatechin-3- (4-On-pentyl) gallate) 26.3 mg (retention time 48.2 minutes) Yield: 16.6%).

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained 4 ″ pentyl-EGCg was identified as a target product by measurement of ¹ H-NMR and ¹³ C-NMR and mass spectrometry.
4 ”pentyl-EGCg
¹ H-NMR (500 MHz, CD ₃ OD): 0.90 (3H, dd, J = 7.3, 7.0), 1.31-1.40 (4H, overlapping), 1.72 (2H, m), 2.84 (1H, dd, J = 17.4, 2.3), 2.98 (1H, dd, J = 17.4, 4.8), 4.01 (2H, t, J = 7.2), 4.97 (1H, bs), 5.53 (1H, m), 5.95 (2H, bs), 6.49 (2H, bs), 6.92 (2H, bs)
¹³ C-NMR (125 MHz, CD ₃ OD): 14.4, 23.5, 26.9, 29.0, 30.6, 70.2, 73.9, 78.5, 95.9, 96.5, 99.3, 106.8, 110.3, 126.2, 130.7, 133.8, 140.2, 146.7, 151.6 , 157.2, 157.8, 157.9, 167.2
MS (ESI) m / z: 527.1 (M -)

(C) Decylation Theavigo ^™ (EGCg ≧ 94%, 137.5 mg, 0.3 mmol) was dissolved in DMF (1.0 mL) and then sodium acetate (98.4 mg, 1.2 mmol, 4.0 equivalents) and 1-decyl iodide (510.8 μL, 2.4 mmol, 8.0 eq) was added and stirred at 85 ° C. for 120 minutes. Thereafter, separation and purification were performed by ODS-HPLC, and 40.9 decyl-EGCg ((−)-epigallocatechin-3- (4-On-decyl) gallate) 30.9 mg (retention time 60.4 minutes) Yield: 17.2%).

<< Conditions for Separation / Purification by ODS-HPLC >>
Column: Mightysil RP-18GP 20 × 250 mm (particle diameter: 5 μm) Detection wavelength: 210 nm, manufactured by Kanto Chemical Co., Inc.
Flow rate: 5.0 mL / min
Developing solvent: H ₂ O + 5% AcOH / MeCN + 5% AcOH

The obtained 4 ″ decyl-EGCg was identified as the target product by ¹ H-NMR and ¹³ C-NMR measurements and mass spectrometry.
4 ”decyl-EGCg
¹ H-NMR (500 MHz, CD ₃ OD): 0.87 (3H, dd, J = 7.0, 6.9), 1.22-1.32 (12H, overlapping), 1.39 (2H, m), 1.71 (2H, m), 2.85 (1H, dd, J = 17.3, 2.2), 2.98 (1H, dd, J = 17.3, 4.7), 4.01 (2H, t, J = 7.0), 4.97 (1H, bs), 5.53 (1H, m), 5.95 (2H, bs), 6.50 (2H, bs), 6.92 (2H, bs)
¹³ C-NMR (125 MHz, CD ₃ OD): 14.4, 23.7, 26.8, 26.8, 30.4, 30.5, 30.7, 30.7, 30.9, 33.0, 70.2, 73.9, 78.5, 95.9, 96.5, 99.3, 106.8, 110.3, 126.2 , 130.7, 133.7, 140.2, 146.7, 151.6, 157.2, 157.8, 157.9, 167.2
MS (ESI) m / z: 597.2 (M -)

  As the above results show, by reacting polyphenols with acetate and alkylating agent, the side reactions such as oxidation, polymerization, epimerization, etc. are suppressed, and in a very short time, corresponding to polyphenols. Various alkyl derivatives of polyphenols can be produced.

Claims (9)

A method for producing an alkyl derivative of polyphenol, comprising:
A method for producing an alkyl derivative, comprising a step of allowing an acetate and an alkylating agent to act on the polyphenol. The _{^{acetates, CR 1 R 2 R 3 CO}} 2 - in ^{M + (wherein,} R 1, ^{R 2} and ^{R 3} are each independently, H, F, or, is selected from Cl, and, ^{M +} is The method for producing an alkyl derivative according to claim 1, wherein the compound is a monovalent metal cation. The method for producing an alkyl derivative according to claim 2, wherein M ⁺ is Na ⁺ , K ⁺ , or Li ⁺ . The method for producing an alkyl derivative according to claim ² , wherein R ¹ , R ² and R ³ are H.   The method for producing an alkyl derivative according to any one of claims 1 to 4, wherein the alkylating agent is an alkyl halide. The method for producing an alkyl derivative according to claim 5, wherein the halogenated alkyl is a halogenated _C1-20 alkyl.   The method for producing an alkyl derivative according to any one of claims 1 to 6, wherein the polyphenol has a flavan skeleton, a trans-stilbene skeleton, or a cis-stilbene skeleton. The method for producing an alkyl derivative according to any one of claims 1 to 7, wherein the polyphenol has any one of the following structural formulas.
The method for producing an alkyl derivative according to any one of claims 1 to 8, wherein the polyphenol has the structural formula described below.