JP2010150152A - Method for producing lyoniresinol or analogue thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method, by which lyoniresinol useful as an ingredient for antimicrobial agents, bleaching agents and the like and having a naturally existing specific three-dimensional configuration can simply be obtained in a large amount. <P>SOLUTION: This method for producing the lyoniresinol comprises: (a) a process for reducing a compound of formula III into a compound of formula II preferably in the presence of palladium hydroxide/carbon catalyst; (b) a process for closing a ring from the compound of formula II to a compound of formula I; and, if necessary, (c) a process for reducing a compound of formula IV to compounds of formula II and/or formula III in the presence of potassium ferricyanide. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a process for producing rioniresinol or an analogue thereof having a specific configuration identical to that derived from nature.

Lyoniresinol, a kind of lignans, is known to be contained in many plants such as beech family Quercus genus plants, plum wine, plum vinegar, etc., and has an antibacterial action, an antioxidant action, an aroma enhancing action, etc. (Patent Document 1). There are three asymmetric centers in rioniresinol, and in addition to (+) and (−)-rioniresinol, there are six stereoisomers with the same planar structure. Patent Document 2 describes that (+) and (−)-Lionilesinol having a specific configuration derived from a natural product have high melanin production inhibitory activity and tyrosinase inhibitory activity, respectively. Further, as a method for synthesizing rioniresinol, methods disclosed in Non-Patent Documents 1 and 2 are known, and a method for producing related intermediates is described in Non-Patent Document 3.
JP 2003-128568 A WO2006 / 068254 Indian J. Chem. , 14B, 127-128 (1976) Chem. Ber. , 94, 2522-2533 (1961) Chem. Ber. 91,581-590 (1958)

  Regarding the synthesis method of rioniresinol, Non-Patent Document 1 describes only the essence of the method, and further, a method in which (+) and (−)-lioniresinol having a specific configuration existing in nature are not selectively obtained. The present inventors have confirmed that this is the case. In addition, according to the method described in Non-Patent Document 2, as shown in FIG. 1, although ryoniresinol having a natural configuration is obtained from syringaresinol through a reduction step and a ring closure step, its yield, particularly The inventors have also confirmed that the yield in the reduction step is low. Furthermore, as shown in FIG. 1, Non-Patent Document 3 describes a method for obtaining syringalesinol from sinapyr alcohol. In this method, in order to disperse sinapyr alcohol which is hardly soluble in water. As a result of using THF for the solvent, the amount of solvent becomes very large relative to the reaction substrate, and a long period of oxygen bubbling is necessary for the progress of the reaction (contact between oxygen and combustible solvent is dangerous) There is a big problem.

  In view of the above circumstances, an object of the present invention is to provide a production method for easily and easily obtaining lionilesinol having a natural configuration, which is useful as a component such as an antibacterial agent and a whitening agent.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found a method for synthesizing rioniresinol including a step of efficiently reducing syringaresinol. Furthermore, it has also been found that lyoniresinol can be synthesized by reusing the intermediate by-product generated in the reduction, thereby making it possible to improve the yield of the entire production method. Moreover, the synthetic | combination method which can achieve the safe and high yield of syringaresinol was also discovered. These findings can be applied not only to the production of rioniresinol but also to the production of analogs in which the methoxy group on the phenyl group of rioniresinol is replaced with another alkoxy group.

That is, the present invention
1. c) Compounds of formula IV:

(Wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group) potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-peroxide In the presence of at least one oxidant selected from the group consisting of hydrogen oxide,
Compound of formula III:

(Wherein R ¹ and R ² are as defined above). A process for the preparation of a compound of formula III comprising an oxidation step.
2. The process according to 1, wherein step c) is carried out in the presence of potassium ferricyanide.
3. Step c) according to 1 or 2; and a) a compound of formula II of a compound of formula III:

(Wherein R ¹ and R ² are as defined above), a process for producing a compound of formula (II) comprising a reduction step.
Step c) according to 4.1 or 2; and Step a) according to 3; and b) Formula Ia to Formula Id of a compound of formula II:

(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound.
5). c ′) Compounds of formula IV:

(Wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group) potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-peroxide A compound of formula II in the presence of at least one oxidant selected from the group consisting of hydrogen oxide:

(Wherein R ¹ and R ² are as defined above). A process for the preparation of a compound of formula II comprising an oxidation step.
6). 6. The method according to 5, wherein step c ′) is performed in the presence of potassium ferricyanide.
Step c ′) according to 7.5 or 6; and b) a compound of formula II, of formula Ia to formula Id:

(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound.
8). a ′) Compounds of formula III:

At least selected from palladium hydroxide / carbon, palladium oxide, palladium black, palladium / carbon, wherein R ¹ and R ² are the same or different and are C _1-6 alkyl groups. Compound of formula II in the presence of one catalyst:

A process for preparing a compound of formula II comprising a catalytic reduction step to (wherein R ¹ and R ² are as defined above).
9. Process according to 8, wherein step a ′) is carried out in THF in the presence of palladium hydroxide / carbon.
Step a ′) according to 10.8 or 9; and b) Formula Ia to Id of a compound of formula II:

(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound.
11. e) Compound of formula V:

A compound of formula III wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group:

(Wherein R ¹ and R ² are as defined above) selected from the group consisting of potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-hydrogen peroxide. An oxidation step in the presence of at least one oxidizing agent or by Pt electrode oxidation;
A process for the preparation of a compound of formula III comprising
12 12. The method according to 11, wherein step e) is performed in the presence of potassium ferricyanide.
Step e) according to 13.11 or 12; and a) a compound of formula II of a compound of formula III:

A process for the preparation of a compound of formula II comprising a reduction step to (wherein R ¹ and R ² are as defined above).
14 d) Compounds of formula VI:

A compound of formula V wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group:

A reduction step to (wherein R ¹ and R ² are as defined above);
Step e) according to 11 or 12;
Steps a); and b) of the compound of formula II according to formula Ia to formula Id:

(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound.
15. The method according to any one of 1 to 14, wherein R ¹ and R ² are both methyl.
16. A whitening agent comprising lionilesinol produced by the method according to any one of 16.1 to 15, and having a tyrosinase inhibitory action or a melanin production inhibitory action.
17. The whitening agent according to 16, which is a food, drink, cosmetic or pharmaceutical product.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to easily and in large quantities provide rioniresinol having a specific configuration that has been obtained mainly by extraction from natural products. In particular, since rioniresinol extracted from natural products was a mixture with other various stereoisomers, a purification separation step using a chiral column or the like was required to obtain linolesinol having a specific configuration. According to the manufacturing method of the invention, such a step is hardly necessary.

  As shown in FIG. 2, the present invention provides compounds of formulas Ia to Id:

(Wherein R ¹ and R ² are the same or different and are C _1-6 alkyl groups)
Provides an excellent method for the preparation of

The term “C _1-6 alkyl group” used in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, and n-propyl group. Group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, 3-methylbutyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethyl A propyl group, an n-hexyl group, and the like are included.

Below, each process in the manufacturing method of this invention is demonstrated in detail (refer FIG. 2).
Step a)
The production method of the present invention includes a step of reducing a compound of formula III to a compound of formula II.

  Compound III used in step a) can be produced by steps d) and e) described later, or can be produced by a known method as described in Non-Patent Document 3.

  The reduction step a) can be performed using a method known to those skilled in the art, such as the method described in Non-Patent Document 2, and the conditions found by the present inventor as in step a ′) described below. Can also be used. Specifically, for example, using a catalytic reduction catalyst such as palladium, palladium / carbon, palladium hydroxide / carbon, palladium black, palladium oxide in a solvent such as ethyl acetate, acetic acid, THF, methanol, ethanol, etc., 20-50. Catalytic reduction is carried out at 0 ° C. with introduction of hydrogen gas. The reaction time is not particularly limited, but is typically about 2 hours.

  In the above reduction step, not only the compound of formula II, which is the target intermediate, but also the compound of formula IV, in which the reduction further proceeds, is obtained as a byproduct from the compound of formula III. For example, as in Non-Patent Document 2, the inventor of the present application corresponds to the case where the reduction step of syringaresinol, which is one of the compounds of formula III, is carried out using palladium in ethyl acetate and introducing hydrogen gas. The yields of the compound of formula II and the compound of formula IV were confirmed to be 29% and 46.2%, respectively.

Step a ′)
In order to increase the selectivity and yield of the compound of formula II, the above reduction step preferably involves introducing hydrogen gas using palladium hydroxide / carbon, palladium oxide, palladium black or palladium / carbon as a catalyst. Do it below. A particularly preferred catalyst is palladium hydroxide / carbon (more preferably 20% palladium hydroxide / carbon). Preferably, THF is used as a solvent, and the reaction temperature is preferably 35 to 37 ° C. This condition in step a ′) may of course be used in step a).

  The mixture (unreacted compound III + compound II + compound IV) obtained in steps a) and a ′) can be separated using techniques known to those skilled in the art, for example, by silica gel chromatography. be able to. The solvent system used for chromatography is not particularly limited as long as these compounds can be separated. For example, a dichloromethane / tetrahydrofuran / methanol system or an ethyl acetate / hexane system can be used. Among them, the dichloromethane / tetrahydrofuran / methanol system has high solubility of the compounds II to IV and is effective for large-scale treatment.

  The reaction of steps a) and a ') can also be used to obtain compounds of formula IV. In this case, conditions that can improve the yield of the compound of formula IV are preferred. The resulting compound of formula IV can be subjected to step c) or c ').

Step b)
The compounds of formulas Ia to Id, which are the final products in the production method of the present invention, are obtained by ring-closing the compound of formula II using a method known to those skilled in the art as described in Non-Patent Document 2. be able to. Specifically, for example, the solution is heated and refluxed in an appropriate solvent such as an aqueous solution of organic acid such as formic acid, acetic acid and citric acid (about 1 to 2%) or an inorganic acid aqueous solution such as phosphoric acid, hydrochloric acid and sulfuric acid. A thermal ring closure reaction can be performed. The reaction time is not particularly limited as long as the compounds of formulas Ia to Id are obtained, but is typically 1.5 hours.

  By performing step b) as described above, at least one compound of the formulas Ia to Id is obtained. For example, dimethoxylariciresinol is used as the compound of formula II and ring closure in 2% acetic acid can give lioniniresinol. The lyoniresinol thus obtained had a natural configuration (mixture of (+) and (−)-ryoniresinol).

Steps c) and c ′)
By subjecting the compound of formula IV, which is a by-product obtained when the compound of formula III is reduced in the above step a) (or step a ′)), to an oxidative ring closure reaction, a compound of formula III or II is obtained. be able to. The yield of the compound of formula I can then be increased by reusing the resulting compounds of formula III and II in steps a) or a ′) and b), respectively.

  Examples of the oxidizing agent used in the oxidative ring closing step c) or c ′) include ferric chloride, potassium ferricyanide, ferrous sulfate-hydrogen peroxide useful for the oxidative coupling reaction of phenolic compounds. Peroxidase-hydrogen peroxide is preferred, and potassium ferricyanide is particularly preferred. In this step, the oxidizing agent can be used, for example, in a molar ratio of 2.0 to 3.0 times, particularly 2.0 to 2.1 times the amount of the compound of formula IV.

When potassium ferricyanide is used in the oxidation reaction in this step, as shown in the following formula, 1 equivalent of alkali is required for potassium ferricyanide.
2K ₃ Fe (CN) ₆ + 2KOH = 2K ₄ Fe (CN) ₆ + H ₂ O + O
Examples of the alkali used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. In this step, potassium hydroxide is particularly preferable.

  The solvent that can be used in this step is not particularly limited as long as it is an inert solvent for the reaction. For example, it can be mixed with water such as acetonitrile, methanol, tetrahydrofuran, dioxane, dimethylformamide and the like in any ratio. A solvent is preferable, and this can be used by mixing with water. In particular, it is preferable to use a mixed solvent (1: 1) of acetonitrile and water. The reaction temperature in this step is, for example, 0 ° C. to 25 ° C., and particularly 5 ° C. to 22 ° C. The reaction time is not particularly limited, but is typically about 1 to 2 hours.

  As an example of the reaction of step c), the reaction carried out using dimethoxysecoisolariciresinol, which is one of the compounds of formula IV, is shown below. Dimethoxyisolariciresinol corresponding to Formula II and syringaresinol corresponding to Formula III were obtained in 51.5% and 37% yields, respectively.

The compound of formula II obtained by oxidation of the compound of formula IV can then be subjected to step b) to give the compound of formula I. Also, the compound of formula III obtained in this oxidative cyclization step can be subjected again to the reduction step of step a). Since the yield of the oxidation reaction from the compound of formula IV in step c ′) to the compound of formula II is high, the compound of formula IV is preferentially produced in step a) and then step c ′) is performed. It is also possible to obtain the compound of formula II efficiently.

Step d)
The compound of formula III is obtained by subjecting the compound of formula V obtained by step d) of reducing the compound of formula VI to step e) of further oxidation.

  As the reducing agent that can be used in step d) of reducing the compound of formula VI to obtain the compound of formula V, a reducing agent commonly used in the art to reduce a carboxylic acid ester can be used. For example, metal hydrides such as DIBAL (diisobutylaluminum hydride) and lithium aluminum hydride can be used. Particularly in this step, reduction with DIBAL is preferred. In this step, the reducing agent can be used in an amount of, for example, 2 to 3 times, particularly 2.1 to 2.3 times in molar ratio to the compound of formula VI.

  The solvent that can be used in this step is not particularly limited as long as it is an inert solvent for the reaction. For example, hexane, toluene, dichloromethane, tetrahydrofuran, t-butyl methyl ether, dichloroethane alone or these can be used. Can be mixed and used. In particular, it is preferable to use dichloromethane. The reaction temperature in this step is preferably, for example, −60 ° C. to −30 ° C., and particularly preferably −56 ° C. to −40 ° C. The reaction time is not particularly limited, but is typically about 1 hour.

  After performing the above reduction reaction, post-treatment is performed. Specifically, excess metal hydride is decomposed using methanol or the like as necessary, and an acid is added to the reaction solution to produce an alcohol form of formula V. Next, the alcohol of formula V is separated by an operation such as extraction with an organic solvent. As the acid, organic acids such as acetic acid and citric acid or inorganic acids such as dilute sulfuric acid and dilute hydrochloric acid can be used. Preferably citric acid is used. Hydrochloric acid is not always preferred (data not shown but confirmed by NMR) because it can be added to the double bond of a compound of formula VI, such as sinapyr alcohol, but may be used in some cases.

The compound of formula VI used in step d) can be obtained using techniques known to those skilled in the art. For example, when the compound of formula VI is methyl sinapic acid, commercially available sinapic acid can be obtained by methyl esterification using techniques known to those skilled in the art. Specifically, for example, as shown in Example 1, acetone is used as a solvent, and sinapinic acid is heated to reflux at 65 ° C. together with potassium hydrogen carbonate (KHCO ₃ ) and dimethyl sulfate (Me ₂ SO ₄ ). In addition to being able to obtain methyl sinapic acid, it can also be obtained by an esterification method in which it is heated to reflux in methanol under a concentrated sulfuric acid catalyst.

Step e)
By oxidizing the compound of formula V obtained using the procedure described above, a compound of formula III can be obtained, which can be subjected to step a). The oxidation step e) of the compound of formula V to the compound of formula III comprises an oxidative coupling reaction of a phenolic compound such as ferric chloride, potassium ferricyanide, ferrous sulfate-hydrogen peroxide, peroxidase-hydrogen peroxide. It can be carried out using an oxidizing agent known to be useful for Pt or by Pt electrode oxidation. In this step, it is preferable to use 2 equivalents of the oxidizing agent relative to the compound of formula V.

  For example, when potassium ferricyanide, an allyloxy radical generator that induces oxidative phenol coupling, is used as the oxidizing agent, step e can be carried out by using 2 equivalents of potassium ferricyanide of the compound of formula V. .

  The solvent that can be used in this step is not particularly limited as long as it is an inert solvent for the reaction. For example, dichloromethane, hexane, ethyl acetate, tetrahydrofuran, t-butyl methyl ether, dichloroethane, or a mixed solvent thereof. In particular, a mixed solvent of dichloromethane, hexane, and ethyl acetate can be used. Further water may be added. The reaction temperature in this step is, for example, 0 ° C. to 25 ° C., and particularly 5 ° C. to 22 ° C.

The reaction time of step e) of the present invention is very short, typically around 10 minutes.
As mentioned above, the oxidation step e) of the compound of formula V in the present method gives the compound of formula III in a short time and in high yield.

  Non-Patent Document 3 describes a method for obtaining a compound of formula III by using an oxidative reaction with oxygen in an aqueous solution containing copper sulfate using sinapyl alcohol corresponding to the compound of formula V. Since pill alcohol is sparingly soluble in water, 1/3 volume of THF is required as a dispersant, and as a result, the amount of solvent is large relative to the reaction substrate (about 140 times). In addition, in the method described in Non-Patent Document 3, it is necessary to use oxygen. However, in the shielding system, oxygen gas absorption does not proceed at all, and oxygen bubbling needs to be performed for a long time (7 hours). ) The reaction would not proceed unless it was done. Such a condition is not preferred because contact between oxygen and the flammable solvent is dangerous. On the other hand, these problems are solved in step e) of the present invention. For example, the reaction time is short and there is no need for oxygen bubbling.

Step d) and step e)
The alcohol compound V obtained in step d) and then used in step e) is likely to be oxidized to the corresponding aldehyde, and it is considered that an electrophilic addition reaction to the double bond portion and a polymerization reaction of the portion are likely to occur. It is done. In view of this, the compound of formula V obtained in step d) is preferably derived into a compound of formula III by use in step e) without being isolated and purified after being produced by post-treatment.

  Therefore, preferably, the reaction solution after the post-treatment with the acid obtained in step d) is extracted with an organic solvent (for example, ethyl acetate), and the resulting extract (for example, extraction with ethyl acetate containing dichloromethane and hexane) is performed. The compound of formula III can be obtained in good yield by a simple method of adding an oxidizing agent (potassium ferricyanide aqueous solution) to the liquid and adding 1 equivalent of potassium bicarbonate while keeping the pH at 5. In Example 2 according to this method, compound III was obtained in high yield.

The structure and purity of the compound obtained in each step (for example, rioniresinol) can be confirmed by ¹ H-NMR, ¹³ C-NMR, HPLC, TLC and the like.
Rioniresinol, which is one of the compounds obtained by the production method of the present invention, can be used for various uses known to those skilled in the art. For example, natural configuration (+)-Lionilesinol and (−)-Lionilesinol have a melanogenesis inhibitory activity and a tyrosinase inhibitory activity, respectively, and can be used as an active ingredient of a whitening agent. The whitening agent may be either oral or parenteral, and can be in the form of various foods, cosmetics, pharmaceuticals, etc. using techniques known to those skilled in the art. The amount of rioniresinol to be added to the whitening agent varies depending on the form and use, but can be generally added in an amount of 0.0001 to 10% by weight, preferably about 0.05 to 5% by weight. Can be blended.

  The present invention is described in more detail in the following examples, but the present invention is not limited thereto. Various changes and modifications can be made by those skilled in the art, and these changes and modifications are also included in the present invention.

Example 1 Synthesis of methyl sinapic acid (Compound VI) Sinapic acid (common name: sinapineic acid or sinapic acid, chemical name: 3,5-Dimethoxy-4-hydroxy-trans-cinnamic acid) (2000 g, 8.92 mol, Lancaster) (Compound VII), potassium hydrogen carbonate (KHCO ₃ ) (982.4 g, 1.1 eq.), Acetone (18 L) in a suspension solution of dimethyl sulfate (Me ₂ SO ₄ ) (1237.6 g, 1.1 eq) .) Was added, and the mixture was heated to reflux for 13 hours in an oil bath at 65 ° C. The reaction solution was filtered and the back solution was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1976 g of crude crystals of methyl sinapinate (Compound VI) (93% yield).
¹ H-NMR (300 MHz, DMSO-d6) δ _H (ppm): 3.86 (3H, s), 3.90 (6H, s), 6.30 (1H, d, J = 18.3 Hz), 7.63 (1H, d, J = 18.3 Hz).

Example 2 Synthesis of syringaresinol (Compound III) Under a stream of argon, methyl sinapicate (Compound VI) (1265 g, 5.31 mol) was dissolved in dehydrated dichloromethane (CH ₂ Cl ₂ ) (12.7 L) and dried. It cooled to -56 degreeC (internal temperature) with ice / acetone. While stirring, 19 mol of hexane solution of diisobutylaluminum hydride (0.95M DIBAL / Hex soln. (20 L, 1.15 eq.)) Was added dropwise over 1 hour and a half (internal temperature -41 ° C.), and the resulting slurry was the same. Stir at temperature for an additional hour. Thereafter, while paying attention to foaming, methanol (5.3 L) was added dropwise over 45 minutes (internal temperature 0 ° C.). Further, 20% aqueous citric acid solution (40 L) was added over 45 minutes (internal temperature of 10 ° C. or lower), and then sodium chloride (10.6 kg) and ethyl acetate (AcOEt) (10.6 L) were added. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (AcOEt) (4.8 L). This process was repeated four times (in this step, synapyl alcohol was extracted). The organic layers were combined and ion exchanged water (16 L) and potassium ferricyanide (K ₃ Fe (CN) ₆ ) (2 kg, 1.14 eq.) Were added. Subsequently, potassium hydrogen carbonate (KHCO ₃ ) (900 g) was added in 4 portions over 1 hour so that the pH was 5 with vigorous stirring. The organic layer was separated and the aqueous layer was further extracted twice with ethyl acetate (AcOEt) (10 L). The organic layers were combined, washed with saturated brine (8 L), and dried over anhydrous magnesium sulfate (2 kg). Concentration under reduced pressure and the resulting crude crystals were recrystallized from dichloromethane / methanol to give Syringaresinol (Compound III) (980 g, 88%) as white crystals.

Sinapyr alcohol (compound V) [3,5-Dimethoxy-4-hydroxycinnyl alcohol]
¹ H-NMR (300 MHz, DMSO-d6) δ _H (ppm): 3.91 (6H, s), 4.32 (2H, m), 5.52 (1H, s), 6.24 (1H, m), 6.55 (1H, d, J = 15.6 Hz), 6.63 (2H, s).
Syringaresinol (Compound III)
¹ H-NMR (300 MHz, DMSO-d6) δ _H (ppm): 3.10 (2H, m), 3.85 (12H, s), 3.85 (2H, m), 4.30 (2H, m), 4.70 (2H, m), 5.50 (2H, s), 6.58 (4H, s).
¹³ C-NMR (300 MHz, DMSO-d6) δ _C (ppm): 54.1 (CH), 56.2 (OMe), 71.6 (CH ₂ ), 85.8 (CH), 102.6 ( C), 131.9 (C), 134.2 (C), 147.0 (C).
mp: 169-170 ° C.

Example 3 Synthesis of Dimethoxylariciresinol (Compound II) Syringaresinol (Compound III) (748 g) was suspended in tetrahydrofuran (THF) (7.5 L) and heated to 37 ° C. to obtain a homogeneous solution. After that, 20% palladium hydroxide / carbon (Pd (OH) ₂ / C) (50% water content, 187 g, Kawaken Fine Chemical) was added. Hydrogen gas (H ₂ ) was introduced for 4 hours while maintaining the internal temperature at 35 ° C. to 37 ° C. with stirring. The reaction solution was filtered, the catalyst was washed with tetrahydrofuran (THF), and the filtrate was concentrated under reduced pressure. The concentrate was divided into two equal parts, subjected to flash column chromatography on silica gel (9 L), developed with dichloromethane / tetrahydrofuran / methanol (100: 10: 1) to recover unreacted raw materials, and further dichloromethane / tetrahydrofuran. Development with / methanol (170: 30: 20) yielded dimethoxylaricilesinol (compound II) and dimethoxysecoisolariciresinol (compound IV). In the same manner, after recovering the unreacted raw material, syringaresinol (compound III) (328 g, 43.9%) and the desired dimethoxylariciresinol (compound II) (256 g, 34. %) And dimethoxy secoisolariciresinol (Compound IV) (106 g, to obtain a 14.2%).

Dimethoxylariciresinol (Compound II)
¹ H-NMR (300 MHz, DMSO-d6) δ _H (ppm): 2.43 (1H, m), 2.54 (1H, m), 2.73 (1H, m), 2.93 (1H, dd, J = 13.3, 4.9 Hz), 3.72-3.86 (3H, m), 4.05 (1 H, m), 4.79 (1 H, d, J = 6.3 Hz), 5.39 (1H, s), 5.46 (1H, s), 6.41 (2H, s), 6.57 (2H, s).
Dimethoxysecoisolariciresinol (Compound IV)
¹ H-NMR (300 MHz, DMSO-d6) δ _H (ppm): 1.83 (2H, br.s), 2.48-2.79 (4H, m), 3.54 (2H, m), 3.83 (2H, m), 6.23 (2H, s), 6.35 (4H, s).
Example 4 Synthesis of rioniresinol (Compound I) Dimethoxylariciresinol (Compound II) (256 g) was suspended in acetic acid (1 L) and ion-exchanged water (49 L), and heated under reflux for 2 hours with stirring. Immediately after that, it was filtered under normal pressure and allowed to cool. After concentration under reduced pressure (to about 1 L), the precipitated crystals were filtered, washed with ethanol and then ethyl acetate. Drying under reduced pressure (50 ° C.) overnight gave (+) and (−)-Lioniresinol (compound I) (220 g, 86%).

Although various instrumental analyzes were performed about the obtained rioniresinol, all data corresponded well with the thing of the natural origin obtained in the reference example 1 mentioned later.
¹ H-NMR spectrum and ¹³ C-NMR spectrum were measured by using DMX-750 (1H-NMR) and DMX-500 (13C-NMR) manufactured by Bruker Biospin (resonance frequencies: 750.13 MHz and 500.13, respectively). MHz). The measurement solvents were DMSO-d6 and acetone-d6, respectively. ^{The 1} H-NMR spectrum is shown in FIG. 3, and the ¹³ C-NMR spectrum is shown in FIG.

Mass spectra were measured using H2O: MeOH: HCOOH (50: 50: 0.1) as a solvent and Micromass Q-TOF as a measuring device. The measured mass spectrum is shown in FIG.
Reversed phase HPLC analysis of rioniresinol was also performed. Specifically, using an Inertsil ODS-2 column (250 × 4.6 mm ID; GL Sciences Inc.) and CH ₃ CN: H ₂ O (40:60) as an eluent, a flow rate of 0.6 ml / min. Then, measurement was performed at 40 ° C. for about 12 minutes. The measurement wavelength was 254 nm. The obtained HPLC chart is shown in FIG. The main peak around 5 minutes is (±) -Lionilesinol.

  In addition, HPLC analysis of rioniresinol using an optical column was also performed. Specifically, using a CHIRALCEL OD-H column (250 × 4.6 mm ID; Daicel Chemical Industries, Ltd.) and using IPA: Hex: TFA (500: 500: 1) as an eluent, a flow rate of 0.7 ml / The measurement was performed at 35 ° C. for about 24 minutes. The measurement wavelength was 254 nm. The obtained HPLC chart is shown in FIG. The main peak near 8 minutes is (+)-Lionilesinol, and the main peak near 12 minutes is (-)-Lionilesinol.

Example 5 Synthesis of dimethoxy secarisoresinol (compound II) and syringaresinol (compound III) from dimethoxy secoisolariciresinol (compound IV) Dimethoxy secicoisolariciresinol (compound IV) (422 mg, 1 mmol) Was dissolved in a mixed solvent (22 ml) of acetonitrile: water (1: 1), and potassium ferricyanide (758 mg, 2.3 mmol) was added under ice cooling. After becoming a pale yellow uniform solution, 1N potassium hydroxide aqueous solution (2.3 ml, 2.3 mmol) was added at an internal temperature of 5 ° C., and the temperature was gradually returned to room temperature (22 ° C.). After evaporating the solvent under reduced pressure, the residue was saturated with sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.41 g of a light brown foam. Silica gel (30 ml) was charged with hexane and the concentrate was charged with a small amount of dichloromethane. After developing with ethyl acetate: hexane (4: 1) and elution of syringaresinol (Compound III), then development with only ethyl acetate was performed to elute dimethoxylariciresinol (Compound II). Finally, development was performed with ethyl acetate: methanol (5: 1), and unreacted raw material dimethoxysecoisolariciresinol (compound IV) was recovered. The yield and yield of each are as follows.
Syringaresinol (compound III) 140 mg (37%), dimethoxylariciresinol (compound II) 197 mg (51.8%), dimethoxysecoisolariciresinol (compound IV) 40 mg (9.5%).

Reference Example 1 Isolation and Purification of Naturally-Derived Lionylesinol According to the method described in WO2006 / 068254 A1, (+) and (−)-ryoniresinol derived from the beech family Quercus were obtained. Briefly, Fagaceae Quercus plants are extracted with an aqueous solution of lower alcohols having 1 to 4 carbon atoms and purified by column chromatography using a resin such as Sephadex manufactured by Pharmacia, and further a chiral column. Was isolated and purified by high performance liquid chromatography (HPLC).

FIG. 1 is a diagram showing a synthesis route described in Non-Patent Documents 2 and 3. FIG. 2 is a diagram showing a synthesis route in the production method of the present invention. FIG. 3 is a ¹ H-NMR spectrum of rioniresinol synthesized in Example 4. FIG. 4 is a ¹³ C-NMR spectrum of rioniresinol synthesized in Example 4. FIG. 5 is a mass spectrum of rioniresinol synthesized in Example 4. FIG. 6 is a chart of HPLC analysis using the lionilesinol Inertsil ODS-2 column synthesized in Example 4. FIG. 7 is a chart of HPLC analysis using the CHIRALCEL OD-H column of rioniresinol synthesized in Example 4.

Claims (15)

c) Compounds of formula IV:
(Wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group) potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-peroxide In the presence of at least one oxidant selected from the group consisting of hydrogen oxide,
Compound of formula III:
(Wherein R ¹ and R ² are as defined above). A process for the preparation of a compound of formula III comprising an oxidation step.   The process according to claim 1, wherein step c) is carried out in the presence of potassium ferricyanide. Step c) according to claim 1 or 2; and a) a compound of formula III of a compound of formula III:
Wherein R ¹ and R ² are as defined above; and b) a compound of formula II, formula Ia to formula Id:
(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound. c ′) Compounds of formula IV:
(Wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group) potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-peroxide A compound of formula II in the presence of at least one oxidant selected from the group consisting of hydrogen oxide:
(Wherein R ¹ and R ² are as defined above). A process for the preparation of a compound of formula II comprising an oxidation step.   The process according to claim 4, wherein step c ') is carried out in the presence of potassium ferricyanide. Step c ′) according to claim 4 or 5; and b) a compound of formula II, of formula Ia to formula Id:
(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound. a ′) Compounds of formula III:
At least selected from palladium hydroxide / carbon, palladium oxide, palladium black, palladium / carbon, wherein R ¹ and R ² are the same or different and are C _1-6 alkyl groups. Compound of formula II in the presence of one catalyst:
A process for preparing a compound of formula II comprising a catalytic reduction step to (wherein R ¹ and R ² are as defined above).   The process according to claim 7, wherein step a ') is carried out in THF in the presence of palladium hydroxide / carbon. Step a ′) according to claim 7 or 8; and b) a compound of formula II, of formula Ia to formula Id:
(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound. e) Compound of formula V:
A compound of formula III wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group:
(Wherein R ¹ and R ² are as defined above) selected from the group consisting of potassium ferricyanide, ferric chloride, ferrous sulfate-hydrogen peroxide, peroxidase-hydrogen peroxide. An oxidation step in the presence of at least one oxidizing agent or by Pt electrode oxidation.   The process according to claim 10, wherein step e) is carried out in the presence of potassium ferricyanide. d) Compounds of formula VI:
A compound of formula V wherein R ¹ and R ² are the same or different and are a C _1-6 alkyl group:
A reduction step to (wherein R ¹ and R ² are as defined above);
Step e) according to claim 10 or 11;
a) a compound of formula II of a compound of formula III:
Wherein R ¹ and R ² are as defined above; and b) a compound of formula II, formula Ia to formula Id:
(Wherein R ¹ and R ² are as defined above), a method for producing a compound of any one of formulas Ia to Id, comprising a ring closure step to at least one compound. The method according to any one of claims 1 to 12, wherein R ¹ and R ² are both methyl.   A whitening agent comprising lionilesinol produced by the method according to any one of claims 1 to 13 and having a tyrosinase inhibitory action or a melanin production inhibitory action.   The whitening agent of Claim 14 which is food-drinks, cosmetics, or a pharmaceutical.