JPH08301810A - 1,4-benzoquinone derivative, dibenzofuran-1,4-dione derivative and antitumor agent - Google Patents

Abstract

PURPOSE: To obtain a new 1,4-benzoquinone derivative which is represented by a specific formula, shows strong cytotoxicity and is useful as an antitumor agent. CONSTITUTION: The objective compound is represented by formula I (R<1> and R<2> are each a halogen selected from the group consisting of Cl, Br and I; R<3> is an alkyl, a cycloalkylmethyl; R<4> is H, methyl), preferably a compound of formula II (R<5> is H, an alkyl, a cycloalkylmehyl; R<6> and R<7> are each H, methyl), for example, 2,3-dichloro-5-methoxy-6-methyl-1,4-benzoquinone. This compound is prepared, for example, by halogenating 2-methoxy-3-methyl-1,4-benzoquinone of formula III with conc. hydrogen halide acid and aqueous hydrogen peroxide in the presence of magnesium halide at 0-30 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention shows a novel 1,4-benzoquinone derivative and dibenzofuran-1,4-dione derivative which exhibit strong cytotoxicity and are useful as an antitumor agent, and an antitumor containing them as an active ingredient. Regarding agents.

[0002]

2. Description of the Related Art There is a strong demand from society for the development of excellent antitumor agents, and the creation of novel compounds with strong cytotoxicity occupies a very important position in the development of excellent antitumor agents. ing. It is generally known that the antitumor activity and antitumor spectrum of a compound largely depend on its chemical structure, and a cytotoxic compound having a novel structure different from the known one is currently being put to practical use. The possibility of developing antitumor agents with superior characteristics is extremely large.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel compound that exhibits strong cytotoxicity and is useful as an antitumor agent, and further to provide a novel antitumor agent.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that dibenzofuran-
1,4-dione derivative and its intermediate 1,4
The inventors have found that the benzoquinone derivative exhibits strong cytotoxicity, and completed the present invention. The present invention has the following general formula (I)

[0005]

[Chemical 4]

(In the formula, R ¹ and R ² represent a halogen atom selected from the group consisting of chlorine atom, bromine atom and iodine atom, R ³ represents an alkyl group or a cycloalkylmethyl group, and R ⁴ represents a hydrogen atom. Or a 1,4-benzoquinone derivative represented by a methyl group.). This compound is also an intermediate for producing a 1,4-benzoquinone derivative represented by the following general formula (II). The present invention also provides
The following general formula (II)

[0007]

Embedded image

(Wherein R ² , R ³ and R ⁴ are the same as defined above, R ⁵ represents a hydrogen atom, an alkyl group or a cycloalkylmethyl group, and R ⁶ and R ⁷ represent a hydrogen atom or a methyl group. Represents a 1,4-benzoquinone derivative. It is also a production intermediate of this compound or a dibenzofuran-1,4-dione derivative represented by the following general formula (III).

The present invention also provides the following general formula (III)

[0010]

[Chemical 6]

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above), and dibenzofuran-1,4
-Dione derivatives.

The present invention also provides a 1,4-benzoquinone derivative represented by the above general formula (I) or (II), a dibenzofuran-1,4-dione derivative represented by the above general formula (III), or a pharmaceutical thereof. Relates to an antitumor agent containing a pharmaceutically acceptable salt as an active ingredient.

In the general formulas (I), (II) and (III),
The alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and is a methyl group, ethyl group, propyl group, butyl group, pentyl group, isopropyl group, isobutyl group, isoamyl group, hexyl group. Groups and the like.

The cycloalkylmethyl group means a methyl group substituted with a monocyclic or condensed bicyclic cycloalkyl group. A monocyclic cycloalkyl group has 3 carbon atoms.
To 7 saturated monocyclic cycloalkyl group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The condensed bicyclic cycloalkyl group means a saturated condensed 2 having 9 to 10 carbon atoms.
It means a cyclic cycloalkyl group, and examples thereof include a hexahydroindenyl group and a decahydronaphthyl group. Further, these monocyclic or fused bicyclic cycloalkyl groups are
It may be substituted with 1 to 4 methyl groups, and when these cycloalkyl groups have optical isomers, they mean any isomers.

Examples of the pharmaceutically acceptable salt of the 1,4-benzoquinone derivative or the dibenzofuran-1,4-dione derivative of the present invention include non-toxic salts conventionally used in medicine. These include, for example, inorganic or organic salts. Formed from a base. As the salt of such a base, an ammonium salt,
Alkali metal salts such as sodium and potassium salts,
There are alkaline earth metal salts such as calcium salts and magnesium salts. Such salts can be easily produced by means known per se. For example, in the case of a sodium salt, it is produced by dissolving a 1,4-benzoquinone derivative or a dibenzofuran-1,4-dione derivative having a free phenolic hydroxyl group in a necessary amount of sodium hydroxide aqueous solution.

<Production Method> The dibenzofuran-1,4-dione derivative represented by the general formula (III) is a 1,4-benzoquinone derivative represented by the general formula (II), which is a production intermediate. Further, the 1,4-benzoquinone derivative represented by the general formula (II) is a production intermediate,
It can be produced, for example, by the following synthesis steps 1 to 16 via the 1,4-benzoquinone derivative represented by the general formula (I).

[0017]

[Chemical 7]

[0018]

Embedded image

(In the formula, R ⁸ represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group.)

[0020]

[Chemical 9]

(In the formula, R ⁹ represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group.)

[0022]

[Chemical 10]

(In the formula, R ³ and R ⁵ have the same meanings as described above.)

[First Step] In this step, the 2-methoxy-3-methyl-1,4-benzoquinone represented by the above formula [IV] is reduced, and the hydroxyl group of the hydroquinone derivative produced is monomethylated, 3,4 represented by general formula [V]
-To produce dimethoxy-2-methylphenol.

The 2-methoxy-3-methyl-1,4-benzoquinone, which is the raw material in this step, is prepared by a known method [A. Rashid a
nd G. Read, J. Chem. Soc. (C), 1323 (1967)]. 2-methoxy-3-methyl-1,
Reduction of 4-benzoquinone to a hydroquinone derivative
It can be carried out by catalytic reduction using palladium-carbon or the like as a catalyst. The reaction is preferably carried out in a solvent, and as the solvent used, any solvent can be used as long as it does not participate in the reaction, but preferably, for example, N, N
An aprotic polar solvent such as dimethylformamide, acetone and acetonitrile, an ether solvent such as ether, tetrahydrofuran and dioxane, and an acetic acid ester solvent such as ethyl acetate can be used. The reaction proceeds smoothly at room temperature.

Subsequent monomethylation of the phenolic hydroxyl group is carried out in the presence of a base, using a methylating agent such as dimethylsulfate, methane iodide or methyl trifluoromethanesulfonate. As the base used, alkali metal hydrides such as sodium hydride and potassium hydride are used. This reaction can be carried out by a method of adding a methylating agent and a base to the reaction solution of the reduction reaction, and the reaction proceeds smoothly at 0 ° C to 30 ° C.

[Second Step] In this step, the 2-methoxy-3-methyl-1,4-benzoquinone represented by the above formula [IV] is halogenated to be represented by the above general formula [Ia], The compound of the present invention, 2,3-dihalo-5-methoxy-
It produces 6-methyl-1,4-benzoquinone.

The 2-methoxy-3-methyl-1,4-benzoquinone, which is the starting material for this step, is prepared by a known method [A. Rashid a
nd G. Read, J. Chem. Soc. (C), 1323 (1967)]. 2-methoxy-3-methyl-1,
The halogenation of 4-benzoquinone can be carried out with concentrated hydrohalic acid and an aqueous solution of hydrogen peroxide in the presence of magnesium halide. The reaction can be carried out using concentrated hydrohalic acid as a solvent, but it can also be carried out in another solvent, for example, an aprotic polar solvent such as acetone can be used. The reaction proceeds smoothly at 0 ° C to 30 ° C.

[Third Step] In this step, the phenolic hydroxyl group of the commercially available 3-methoxyphenol represented by the above formula [VI] is methoxymethylated to give 3-methoxy represented by the above general formula [VII]. -1-Methoxymethoxybenzene is produced.

Introduction of a methoxymethyl group into 3-methoxyphenol is carried out using methoxymethyl chloride in the presence of a tertiary amine such as ethyldiisopropylamine, triethylamine, pyridine and 4- (N, N-dimethylamino) pyridine. be able to. The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably, for example, a halogenated hydrocarbon solvent such as dichloromethane or chloroform, an ether. Ether-based solvents such as, tetrahydrofuran and dioxane can be used. The reaction is-
It progresses smoothly at 50 ° C to 50 ° C.

[Fourth Step] In this step, 3-methoxy-1-methoxymethoxybenzene represented by the general formula [VII] obtained in the third step is hydroxyalkylated by utilizing an orthortiation reaction. And the general formula [VI
II] for producing 2-hydroxyalkyl-3-methoxy-1-methoxymethoxybenzene.

Lithiation of 3-methoxy-1-methoxymethoxybenzene at the 2-position can be carried out by using alkyllithium such as n-butyllithium, s-butyllithium and t-butyllithium.
The lithio compound thus prepared and R ⁸ —CHO (R ⁸
Is as defined above. ) Represented by acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, 2,2-dimethylpropanal, valeraldehyde, isovaleraldehyde, cyclopropanecarbaldehyde, cyclohexanecarbaldehyde,
Cis-decalin-1-carbaldehyde, trans-decalin-1-carbaldehyde, 8a-methyl-cis-
Hydroxyalkylation can be carried out by reacting with various aliphatic aldehydes such as decalin-1-carbaldehyde. The preparation of the lithio compound and the subsequent hydroxyalkylation are preferably carried out in a solvent. For example, a hydrocarbon solvent such as pentane, hexane, cyclohexane or the like, an ether solvent such as ether, tetrahydrofuran, dioxane or the like is used. You can Both reactions proceed smoothly at -78 ° C to 50 ° C.

[Fifth Step] In this step, the 2-hydroxyalkyl-3-methoxy-1-methoxymethoxybenzene represented by the general formula [VIII] obtained in the fourth step is added,
The compound is reductively dehydroxylated to produce 2-alkyl-3-methoxy-1-methoxymethoxybenzene represented by the above general formula [IX]. The reductive dehydroxylation in this step can be carried out by hydrogenolysis using palladium-carbon or the like as a catalyst. The reaction is preferably carried out in a solvent, for example, alcohol solvents such as methanol, ethanol, propanol, tetrahydrofuran,
An ether solvent such as dioxane can be used.
The reaction proceeds smoothly at room temperature.

[Sixth Step] In this step, the methoxymethyl group of the 2-alkyl-3-methoxy-1-methoxymethoxybenzene represented by the general formula [IX] obtained in the fifth step is removed, It is intended to produce a 2-alkyl-3-methoxyphenol represented by the general formula [X].

The removal of the methoxymethyl group in this step can be carried out using hydrochloric acid, acetic acid, sulfuric acid, perchloric acid, methanesulfonic acid, p-toluenesulfonic acid, dl-camphor-10-sulfonic acid or the like. It is desirable to carry out the reaction in a solvent, and for example, an alcohol solvent such as methanol, ethanol or propanol can be used. The reaction proceeds smoothly at -20 ° C to 50 ° C.

[Seventh Step] In this step, the 2-alkyl-3-methoxyphenol represented by the general formula [X] obtained in the sixth step is oxidized to a 1,4-benzoquinone derivative and further halogenated. By converting to the general formula [I
b], which is a compound of the present invention, 2,3-dihalo-5-methoxy-6-alkyl-1,4-benzoquinone.

Oxidation of 2-alkyl-3-methoxyphenol to a 1,4-benzoquinone derivative can be carried out using potassium nitrosodisulfonate (flemy salt), salcomine or the like. The reaction is preferably carried out in a solvent, and for example, a mixed solvent system of aprotic polar solvent such as acetone, N, N-dimethylformamide and water and water can be used. The reaction proceeds smoothly at 0 ° C to 30 ° C.

The subsequent halogenation can be carried out with pyridine and thionyl halide. The reaction is desirably performed in a solvent, and for example, a hydrocarbon solvent such as benzene or toluene can be used. It can also be carried out with concentrated hydrohalic acid and an aqueous solution of hydrogen peroxide in the presence of magnesium halide. The reaction can be carried out using concentrated hydrohalic acid as a solvent, but it can also be carried out in another solvent, for example, an aprotic polar solvent such as acetone can be used. Both reactions proceed smoothly at 0 ° C to 100 ° C.

[Eighth step] In this step, the phenolic hydroxyl group of the commercially available 3,4-dimethoxyphenol represented by the formula [XI] is methoxymethylated to obtain the compound represented by the general formula [XI].
I] to produce 3,4-dimethoxy-1-methoxymethoxybenzene. Introduction of a methoxymethyl group into 3,4-dimethoxyphenol is carried out by introducing ethyldiisopropylamine, triethylamine, pyridine, 4
It can be carried out using methoxymethyl chloride in the presence of a tertiary amine such as-(N, N-dimethylamino) pyridine.
The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably, for example, a halogenated hydrocarbon solvent such as dichloromethane or chloroform, an ether. ,
An ether solvent such as tetrahydrofuran or dioxane can be used. The reaction proceeds smoothly at -50 ° C to 50 ° C.

[Ninth Step] This step is 3,4-dimethoxy-type represented by the general formula [XII] obtained in the eighth step.
1-Methoxymethoxybenzene is hydroxyalkylated using an orthortiation reaction to give 2-hydroxyalkyl-3 represented by the general formula [XIII],
It is intended to produce 4-dimethoxy-1-methoxymethoxybenzene.

Lithiation of 3,4-dimethoxy-1-methoxymethoxybenzene at the 2-position can be carried out by using an alkyllithium such as n-butyllithium, s-butyllithium or t-butyllithium. it can. The thus prepared lithio compound and R ⁹ —CHO
(R ⁹ has the same meaning as above.), Acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, 2,2-dimethylpropanal,
Various types of valeraldehyde, isovaleraldehyde, cyclopropanecarbaldehyde, cyclohexanecarbaldehyde, cis-decalin-1-carbaldehyde, trans-decalin-1-carbaldehyde, 8a-methyl-cis-decalin-1-carbaldehyde, etc. Hydroxyalkylation can be carried out by reacting with aldehydes. The preparation of the lithio compound and the subsequent hydroxyalkylation are desirably carried out in a solvent, for example, hydrocarbon solvents such as pentane, hexane and cyclohexane, ether, tetrahydrofuran,
An ether solvent such as dioxane can be used.
Both reactions proceed smoothly at -78 ° C to 50 ° C.

[10th step] In this step, the 2-hydroxyalkyl-3,4-dimethoxy-1-methoxymethoxybenzene represented by the general formula [XIII] obtained in the 9th step is reductively removed. It is hydroxylated to give the compound of the general formula [XI
V] 2-alkyl-3,4-dimethoxy-1
-Methoxymethoxybenzene is produced.

The reductive dehydroxylation in this step can be carried out by hydrogenolysis using palladium-carbon or the like as a catalyst. It is desirable to carry out the reaction in a solvent, and for example, an alcohol solvent such as methanol, ethanol, propanol or the like, or an ether solvent such as tetrahydrofuran or dioxane can be used. The reaction proceeds smoothly at room temperature.

[11th Step] This step is a 2-alkyl-type represented by the general formula [XIV] obtained in the 10th step.
The methoxymethyl group of 3,4-dimethoxy-1-methoxymethoxybenzene is removed to produce a 2-alkyl-3,4-dimethoxyphenol represented by the above general formula [XV].

The removal of the methoxymethyl group in this step can be carried out using hydrochloric acid, acetic acid, sulfuric acid, perchloric acid, methanesulfonic acid, p-toluenesulfonic acid, dl-camphor-10-sulfonic acid or the like. It is desirable to carry out the reaction in a solvent, and for example, an alcohol solvent such as methanol, ethanol or propanol can be used. The reaction proceeds smoothly at -20 ° C to 50 ° C.

[Twelfth Step] In this step, the 3,4-dimethoxyphenol derivative represented by the general formula [V], [XI] or [XV] and the general formula [Ia] or [I] are used.
b] 2,3-dihalo-5-methoxy-1,4
2- (4,5-dimethoxy-2-hydroxyphenyl) -3-halo-5-methoxy-1, which is a compound of the present invention represented by the general formula [II] by condensing a benzoquinone derivative. , 4-benzoquinone derivative.

The condensation reaction in this step can be carried out using an alkali metal hydride such as sodium hydride. The reaction is preferably carried out in a solvent, and any solvent that does not participate in the reaction can be used, but preferably an ether solvent such as tetrahydrofuran can be used. Reaction is -50
The process proceeds smoothly at 30 ° C to 30 ° C.

[13th step] This step is the step of 2- (4,5-dimethoxy-2-hydroxyphenyl) -3-halo-5-methoxy represented by the general formula [II] obtained in the 12th step. By the cyclization reaction of the -1,4-benzoquinone derivative, 3,7,8-trimethoxydibenzofuran-1, which is the compound of the present invention represented by the general formula [IIIa],
It is intended to produce a 4-dione derivative.

The cyclization reaction in this step is carried out using sodium hydride,
It can be carried out using an alkali metal hydride such as potassium hydride or a strongly basic ion exchange resin such as Amberlite (registered trademark) IRA-900. The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably, for example, ether solvents such as tetrahydrofuran and dioxane, dichloromethane, chloroform and the like. An aprotic polar solvent such as the halogenated hydrocarbon-based solvent, N, N-dimethylformamide or the like can be used. The reaction proceeds smoothly at -50 ° C to 30 ° C.

[14th step] In this step, the demethylation of the methoxy group of the 3,7,8-trimethoxydibenzofuran-1,4-dione derivative represented by the general formula [IIIa] obtained in the 13th step is carried out. The compound of the present invention represented by the above general formula [IIIb] is 3,7-dihydroxy-
It is intended to produce an 8-methoxydibenzofuran-1,4-dione derivative.

The demethylation reaction in this step can be carried out using aluminum chloride. The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably a halogenated hydrocarbon solvent such as dichloromethane or chloroform is used. be able to. Reaction is 0 ℃
To 60 ℃, proceed smoothly.

[15th step] This step is the 8-position methoxy of the 3,7-dihydroxy-8-methoxydibenzofuran-1,4-dione derivative represented by the general formula [IIIb] obtained in the 14th step. By demethylating the group, a compound of the present invention represented by the above general formula [IIIc], 3,
It is intended to produce a 7,8-trihydroxydibenzofuran-1,4-dione derivative.

The demethylation reaction in this step can be carried out using boron tribromide. The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably,
For example, a halogenated hydrocarbon solvent such as dichloromethane or chloroform can be used. The reaction proceeds smoothly at 0 ° C to 60 ° C.

[16th step] This step is the demethylation of the methoxy group of the 3,7,8-trimethoxydibenzofuran-1,4-dione derivative represented by the general formula [IIIa] obtained in the 13th step. Is a compound of the present invention represented by the above general formula [IIIc], which is a 3,7,8-trihydroxydibenzofuran-1,4-dione derivative.

The demethylation reaction in this step can be carried out using boron tribromide. The reaction is preferably carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably,
For example, a halogenated hydrocarbon solvent such as dichloromethane or chloroform can be used. The reaction proceeds smoothly at 0 ° C to 60 ° C.

<< Application to Therapeutic Agent >> The 1,4-benzoquinone derivative of the present invention is useful as an antitumor agent. The animal to which the compound of the present invention is administered is not particularly limited, and not only humans but also various mammals such as mice, rats, dogs, cows, horses, goats, sheep, rabbits and pigs are targeted.

Administration to these animals and humans can be carried out by the usual administration routes, for example, oral, intramuscular, intravenous, subcutaneous, intraperitoneal, intranasal and intracerebral administration. The dose and frequency of administration vary depending on animal species, administration route, degree of symptoms, body weight, etc. and are not particularly limited, but in humans, about 1 μg to 1 g per adult is usually administered once a day or more times. To be done. As the dosage form,
Examples thereof include powders, fine granules, granules, tablets, capsules, suppositories, injections and nasal agents. When formulating,
It is produced by a conventional method using a usual pharmaceutical carrier. That is, in the case of preparing an oral preparation, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, etc. are added to the main drug, and then tablets, granules, powders, For example, capsules. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, a solubilizing agent, etc. are added if necessary, and the injection is prepared by a conventional method.

[0058]

The 1,4-benzoquinone derivative represented by the general formula (I) or (II) obtained above and the dibenzofuran-1,4-dione represented by the general formula (III) are obtained. The derivative was confirmed to have strong cytotoxicity by a malignant tumor cell growth inhibition test, and is useful as an antitumor agent. Further, the 1,4-benzoquinone derivative is also a production intermediate of the dibenzofuran-1,4-dione derivative.

[0059]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited thereto.

[Reference Example 1]

[0061]

[Chemical 11]

2-Methoxy-3-methyl-1,4-benzoquinone (101.5 mg, 0.67 mmol) was dissolved in anhydrous N, N-dimethylformamide (2 ml) and 10% palladium-carbon (100 mg) was added. 3 at room temperature under 1 atmosphere of hydrogen
Stir for hours. Dimethyl sulfate (0.028 ml,
0.30 mmol) and sodium hydride (32 mg, 1.33 mmo
l) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After adding 3% hydrochloric acid, the mixture was diluted with ethyl acetate, the organic layer was washed with saturated brine, and anhydrous magnesium sulfate was added to dry it. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (12 g), and crystals were obtained from a fraction of hexane-ethyl acetate (2: 1 v / v). This product was recrystallized from ether-hexane to give colorless plate crystals.
-Dimethoxy-2-methylphenol (26.4 mg, 23
%) Was obtained.

Mp 105-106 ° C. ¹ H-NMR (400 MHz, C ₆ D ₆ ) δ: 2.17 (3H, s), 3.38 (3H, s),
3.66 (3H, s), 4.03 (1H, s), 6.16 (1H, d, J = 8.7Hz), 6.41
(1H, d, J = 8.7Hz). IR (KBr, cm ^-1 ): 3430, 3180, 3020, 2970, 2850, 181
0, 1620, 1600, 1505, 1470, 1430, 1340, 1270, 1220,
1190, 1160, 1080, 1000, 955, 880, 800, 760,740, 6
90, 660, 615, 550, 480. MS m / z: 168 (M ⁺ ), 153 (M-CH ₃ ⁺ ). Elemental analysis: Calculated (C ₉ H ₁₂ O ₃ ): C, 64.27%; H , 7.19%.
Analytical value: C, 64.09%; H, 7.16%.

[Example 1]

[0065]

[Chemical 12]

2-Methoxy-3-methyl-1,4-benzoquinone (401.4 mg, 2.64 mmol) was suspended in concentrated hydrochloric acid (12 ml), and magnesium chloride (251 mg, 2.64 mmol) and aqueous hydrogen peroxide (30 ml) were added. wt.%, 0.54 ml, 5.3 mmol) was added and the mixture was stirred at 0 ° C. for 1 hour. It was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (30 g), and hexane-ethyl acetate (5: 1 v /
Crystals were obtained from the stream of v). This product was recrystallized from chloroform-hexane to give 2,3-dichloro-5-methoxy-6-methyl-1,4-benzoquinone (383.8 mg, 66%) as orange crystals.

Mp 107-111 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 2.04 (3H, s), 4.08 (3H, s). IR (KBr, cm ⁻¹ ): 3030, 2970, 2870 , 1680, 1660, 159
0, 1460, 1380, 1310, 1215, 1170, 1140, 1000, 910,
880, 825, 790, 730, 580. MS m / z: 220 (M ⁺ ), 222 (M + 2 ⁺ ), 224 (M + 4 ⁺ ). Elemental analysis: Calculated value (C ₈ H ₆ O ₃ Cl ₂ ): C, 43.47%; H, 2.73
%; Cl, 32.07%. Analytical value: C, 43.75%; H, 2.72%; Cl, 3
1.78%.

[Reference Example 2]

[0069]

[Chemical 13]

3-methoxyphenol (10.66 g, 85.8
mmol) was dissolved in methylene chloride (100 ml), ethyldiisopropylamine (23.9 ml, 137 mmol) and methoxymethyl chloride (9.78 ml, 129 mmol) were added at 0 ° C., and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate,
The organic layer was washed with a 1N sodium hydroxide aqueous solution and saturated saline, dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (70 g), and 1-methoxy was obtained as a colorless oily substance from the hexane-ethyl acetate (2: 1 v / v) stream. -3-Methoxymethoxybenzene (12.93 g, 90
%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.48 (3H,
s), 3.79 (3H, s), 5.16 (2H, s), 6.67-6.53 (3H, m), 7.18
(1H, t, J = 7.7Hz). IR (neat, cm ^-1 ): 3010, 2970, 2920, 2850, 1610, 150
0, 1470, 1410, 1290, 1270, 1220, 1200, 1150, 1080,
1050, 1020, 995, 930, 850, 770, 730, 695. MS m / z: 168 (M ⁺ ), 138 (M-CH ₂ O ⁺ ).

[Reference Example 3]

[0073]

Embedded image

1-Methoxy-3-methoxymethoxybenzene (3.09 g, 18.4 mmol) was dissolved in anhydrous hexane (60 ml) and t-butyllithium (1.57 mol / l pentane solution, 15.2 ml, 23.9 mmol) was added at 0 ° C. ) Was added dropwise, and the mixture was stirred for 1 hour. Butyraldehyde (2.15 ml,
23.9 mmol) was added and stirring was continued overnight. After water was added to stop the reaction, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, and anhydrous magnesium sulfate was added to dry it.
After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (70 g), and as a colorless oily substance from a hexane-ethyl acetate (5: 1 v / v) fraction, 2-
(1-Hydroxybutyl) -1-methoxy-3-methoxymethoxybenzene (2.73 g, 62%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.93 (3H, t,
J = 7.1Hz), 2.0-1.2 (4H, m), 3.48 (3H, s), 3.65 (1H, d, J = 1
1.6Hz), 3.84 (3H, s), 5.20 (2H, s), 5.25-5.10 (1H, m),
6.59 (1H, d, J = 7.9Hz), 6.76 (1H, d, J = 8.1Hz), 7.14 (1H, t,
J = 8.3Hz). IR (neat, cm ^-1 ): 3580, 3460, 2970, 2950, 2880, 160
0, 1480, 1445, 1415, 1385, 1330, 1275, 1235, 1185,
1160, 1115, 1075, 1015, 965, 930, 790, 735,660, 5
80, 545, 510.MS m / z: 240 (M ⁺ ), 197 (M-CH ₂ CH ₂ CH ₃ ⁺ ) .HRMS (m / z): M ⁺ (C ₁₃ H ₂₀ O ₄ ) calculated 240.1360 Analysis value
240.1382.

[Reference Example 4]

[0077]

[Chemical 15]

1-Methoxy-3-methoxymethoxybenzene (3.14 g, 18.7 mmol) was dissolved in anhydrous hexane (60 ml) and t-butyllithium (1.57 mol / l pentane solution, 15.4 ml, 24.2 mmol) was added at 0 ° C. ) Was added dropwise, and the mixture was stirred for 1 hour. Cyclohexanecarbaldehyde (2.94 ml, 24.2 mmol) was added to the reaction suspension, and stirring was continued overnight. After the reaction was stopped by adding 1N hydrochloric acid (10 ml), the mixture was extracted with ethyl acetate, the organic layer was washed with 1N hydrochloric acid and saturated saline, and anhydrous magnesium sulfate was added to dry the organic layer. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (75 g), and a colorless oily matter was obtained from a fraction of hexane-ethyl acetate (5: 1 v / v) as 2- ( 1
-Hydroxycyclohexylmethyl) -1-methoxy-
3-Methoxymethoxybenzene (4.57 g, 87%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35-0.95
(6H, m), 1.9-1.55 (4H, m), 2.3-2.15 (1H, m), 3.48 (3H,
s), 3.52 (1H, d, J = 11.9Hz), 3.83 (3H, s), 4.82 (1H, dd, J =
11.6, 9.0Hz), 5.17 (1H, d, J = 8.0), 5.20 (1H, d, J = 8.1H
z), 6.59 (1H, d, J = 8.3Hz), 6.75 (1H, d, J = 8.3Hz), 7.14 (1
H, t, J = 8.4Hz). IR (neat, cm ^-1 ): 3575, 3005, 2940, 2870, 1600, 148
0, 1410, 1355, 1330, 1270, 1235, 1205, 1190, 1160,
1130, 1100, 1070, 1010, 960, 930, 910, 895,850, 8
20, 785, 760, 740, 670, 585.MS m / z: 280 (M ⁺ ), 197 (MC ₆ H ₁₁ ⁺ ), 137 (MC ₆ H ₁₁ -OCHOC
H ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₆ H ₂₄ O ₄ ) calculated 280.1673; analytical
280.1693.

[Reference Example 5]

[0081]

Embedded image

(8aR) -3,4,8,8a-tetrahydro-8a-methyl-1,6 (2H, 7H) -naphthalenedione (Vieland-Mischerketone) (4.5 g,
25 mmol) is dissolved in benzene (120 ml), ethylene glycol (16 ml, 290 mmol) and p-toluenesulfonic acid (45
(mg, 0.24 mmol) was added and the mixture was heated under reflux for 1 hour for azeotropic dehydration. Sodium hydrogen carbonate (40 mg, 0.48 mmol) was added, the mixture was allowed to cool, and water was added. After extraction with ether, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (75 g), and crystals were obtained from a fraction of hexane-ethyl acetate (3: 1 v / v). This product was recrystallized from diisopropyl ether to give (8aR) -1,1 as white crystals.
-Ethylenedioxy-1,2,3,4,8,8a-hexahydro-8a-methyl-6 (7H) -naphthalenone (4.4 g, 77%) was obtained.

Mp: 57.0-58.5 ° C. [α] _D ²⁰ = −119 ° (c = 1.10, benzene). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.36 (3H, s), 1.53-1.92
(5H, m), 2.24-2.46 (5H, m), 3.91-4.03 (4H, m), 5.82 (1
H, d, J = 1.8Hz). IR (KBr, cm ^-1 ): 3040, 2990, 2975, 2950, 2910, 288
0, 2840, 1665, 1620, 1485, 1455, 1430, 1380, 1345,
1335, 1290, 1280, 1240, 1220, 1190, 1160, 1145, 1
120, 1100, 1080, 1060, 1035, 980, 955, 940, 920, 8
80, 850, 780, 750, 680, 580, 515, 495, 475, 425. MS m / z: 222 (M ⁺ ). Elemental analysis: Calculated (C ₁₃ H ₁₈ O ₃ ): C, 70.24%; H, 8.16
Analysis value: C, 70.16%; H, 8.27%.

[Reference Example 6]

[0085]

[Chemical 17]

(8aR) -1,1-ethylenedioxy-
1,2,3,4,8,8a-Hexahydro-8a-methyl-6 (7H) -naphthalenone (3.3 g, 15 mmol) was dissolved in ethanol (26 ml), and 10% palladium-carbon (0.25
g) was added, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 2.5 hours. After the catalyst was filtered off, it was washed with chloroform, and the filter wash solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to column chromatography using silica gel (50 g), and hexane-ethyl acetate (3:
The ketone was obtained as a cis-trans mixture from the 1 v / v) fraction. Recrystallized from diisopropyl ether, (4
aS, 8aR) -1,1-ethylenedioxy-1,2,
There was obtained 3,4,4a, 5,8,8a-octahydro-8a-methyl-6 (7H) -naphthalenone (2.1 g, 33%).

[Α] _D ²⁰ = -44.2 ° (c = 1.24, benzene). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, s), 1.22-1.30
(1H, m), 1.46-1.69 (5H, m), 1.77 (1H, dddd, J = 13.3,
7.0, 3.0, 1.7Hz), 2.06-2.20 (3H, m), 2.29-2.36 (1H,
m), 2.44 (1H, dddd, J = 15.2, 12.5, 7.1, 0.8Hz), 2.63
(1H, dd, J = 14.7,5.7Hz), 3.95-4.00 (4H, m). IR (neat, cm ^-1 ): 2940, 2875, 1710, 1470, 1460, 142
0, 1370, 1340, 1330, 1320, 1285, 1260, 1225, 1185,
1150, 1110, 1085, 1050, 1030, 990, 945, 905, 880,
820, 735.MS m / z: 224 (M ⁺ ), 209 (M-CH ₃ ⁺ ), 181 (M-OCH = CH ₂ ⁺ ). HRMS (m / z): M ⁺ (C ₁₃ H ₂₀ O ₃ ) Calculated 224.1410; Analytical
224.1391.

[Reference Example 7]

[0089]

Embedded image

(4aS, 8aR) -1,1-ethylenedioxy-1,2,3,4,4a, 5,8,8a-octahydro-8a-methyl-6 (7H) -naphthalenone (1.
Dissolve 6 g, 7.1 mmol) in diethylene glycol (15 ml) and add potassium hydroxide (1.6 g, 29 mmol) and hydrazine 1
The hydrate (1.3 ml, 21 mmol) was added. After heating under reflux for 2 hours, the cooling tube was removed and the mixture was further stirred at 200 ° C. for 4 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was silica gel (30 g).
Column chromatography using hexane-
From the flow of ethyl acetate (9: 1 v / v) (4aR, 8aR)
-1,1-ethylenedioxy-1,2,3,4,4a,
5,6,7,8,8a-decahydro-8a-methylnaphthalene (1.3 g, 87%) was obtained.

[Α] _D ²⁰ = -16.1 ° (c = 1.02, benzene). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.99 (3H, s), 1.26-1.78
(15H, m), 3.88-3.98 (4H, m). IR (neat, cm ^-1 ): 2970, 2925, 2850, 1465, 1440, 137
0, 1340, 1330, 1300, 1280, 1250, 1220, 1190, 1160,
1130, 1120, 1090, 1080, 1040, 1000, 970, 945, 89
0, 855, 830, 805, 730. MS m / z: 210 (M ⁺ ), 167 (M-OCH = CH ₂ ⁺ ). HRMS (m / z): M ⁺ (C ₁₃ H ₂₂ O ₂ ) calculation Value 210.1618; Analytical value
210.1641.

[Reference Example 8]

[0093]

[Chemical 19]

(4aR, 8aR) -1,1-ethylenedioxy-1,2,3,4,4a, 5,6,7,8,8a
-Decahydro-8a-methylnaphthalene (2.6 g, 12mmo
l) was dissolved in ethanol (40 ml), 4N hydrochloric acid (20 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (50 g),
Hexane-ethyl acetate (20: 1 v / v) stream (4a
R, 8aR) -3,4,4a, 5,6,7,8,8a-
Octahydro-8a-methyl-1 (2H) -naphthalenone (1.9 g, 92%) was obtained.

[Α] _D ²⁰ = + 42.4 ° (c = 0.81, benzene). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.92 (1H, ddd, J = 13.4, 1
0.7, 4.3Hz), 1.21 (3H, s), 1.26-1.86 (9H, m), 1.89-2.
17 (3H, m), 2.25-2.32 (1H, m), 2.50 (1H, ddd, J = 15.0,
10.9, 6.7Hz). IR (neat, cm ^-1 ): 2920, 2850, 1700, 1460, 1440, 142
0, 1375, 1340, 1310, 1270, 1255, 1230, 1145, 1100,
1035, 1015, 990, 940, 920, 880, 850, 820, 690, 63
5, 590, 530, 490, 440.MS m / z: 166 (M ⁺ ), 151 (M-CH ₃ ⁺ ), 124 (M-CH ₂ CH ₂ CH ₂ ⁺ ). HRMS (m / z): M ⁺ (C ₁₁ H ₁₈ O) Calculated 166.1356; Analytical
166.1360.

[Reference Example 9]

[0097]

Embedded image

Methylene bromide (1 ml, 14 mmol) was added to a suspension of zinc (2.9 g, 44 mmol) in tetrahydrofuran (20 ml), the mixture was cooled to 0 ° C., and then titanium tetrachloride (1 mol / l methylene chloride solution, 11 ml, 11 mmol). ) Was added. After stirring for 15 minutes,
(4aR, 8aR) -3,4,4a, 5,6,7,8,
A solution of 8a-octahydro-8a-methyl-1 (2H) -naphthalenone (0.16 g, 1.0 mmol) in methylene chloride (2 ml) was added dropwise, and the mixture was further stirred at the same temperature for 3 hours. After diluting with ether, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered and washed with ether. The organic layer of the filter wash solution was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and from the hexane stream, (4aR, 8aR) -3,4,4a, 5,6,7,
8,8a-Octahydro-8a-methyl-1 (2H)-
Methylenenaphthalene (0.11 g, 69%) was obtained.

[Α] _D ²⁰ = + 14.1 ° (c = 1.02, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.05-1.12 (1H, m), 1.14
(3H, s), 1.23-1.33 (5H, m), 1.36-1.49 (6H, m), 1.51-
1.67 (3H, m), 1.80 (1H, br t), 1.96-2.02 (1H, m), 2.1
4-2.20 (1H, m), 2.26-2.33 (1H, m), 4.67 (1H, t, J = 1.4
Hz), 4.77 (1H, s). IR (neat, cm ^-1 ): 3100, 3000, 2950, 2880, 1645, 147
0, 1455, 1380, 1030, 900, 875.MS m / z: 164 (M ⁺ ), 149 (M-CH ₃ ⁺ ), 135 (M-CH ₂ -CH ₃ ⁺ ). HRMS (m / z) : M ⁺ (C ₁₂ H ₂₀ ) calculated 164.1563; analytical 1
64.1559.

[Reference Example 10]

[0101]

[Chemical 21]

(4aR, 8aR) -3, 4, 4a, 5,
6,7,8,8a-octahydro-8a-methyl-1
(2H) -Methylenenaphthalene (49 mg, 0.30 mmol) was dissolved in tetrahydrofuran (6 ml), and borane-tetrahydrofuran complex (1 mol / l tetrahydrofuran solution, 0.6
0 ml, 0.60 mmol) was added at 0 ° C. After stirring for 1 hour, 0 ℃
Then, water (1 ml), 3N sodium hydroxide (1 ml), and 30% aqueous hydrogen peroxide (1 ml) were sequentially added, and the mixture was stirred at room temperature for 15 hours. After diluting with water, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and from the fraction of hexane-ethyl acetate (5: 1 v / v) (4aR, 8aR)-
1,2,3,4,4a, 5,6,7,8,8a-decahydro-1-hydroxymethyl-8a-methylnaphthalene (54 mg, 100%) as a mixture of diastereomers at position 1 7: 3. Was obtained at a production ratio of.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.87 (0.9H,
s), 0.90-1.91 (1H, m), 1.12 (2.1H, s), 1.15-1.32 (6H,
m), 1.36-1.97 (9H, m), 3.27-3.34 (1H, m), 3.80 (0.3
H, dd, J = 10.2, 3.8Hz), 3.86 (0.7H, dd, J = 10.3, 2.2H
z). IR (neat, cm ^-1 ): 3360, 2940, 2880, 1475, 1455, 138
5, 1075, 1050, 1035, 1005, 865. MS m / z: 182 (M ⁺ ), 164 (MH ₂ O ⁺ ), 149 (M-CH ₃ -H ₂ O ⁺ ). HRMS (m / z) : M ⁺ (C ₁₂ H ₂₂ O) calculated 182.1669; analytical
182.1671.

[Reference Example 11]

[0105]

[Chemical formula 22]

(4aR, 8aR) -1,2,3,4,4
a, 5,6,7,8,8a-decahydro-1-hydroxymethyl-8a-methylnaphthalene (2.7 g, 15 mmol)
Was dissolved in methylene chloride (75 ml), Dess-Martin reagent (6.9 g, 16 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ether, washed successively with saturated aqueous sodium hydrogen carbonate solution, 20% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (50 g), and from the fraction of hexane-ethyl acetate (40: 1 v / v), (4aR, 8aR) -1-
Formyl-1,2,3,4,4a, 5,6,7,8,8
a-decahydro-8a-methylnaphthalene (2.3 g, 87
%) Was obtained as a mixture of diastereomers with respect to the 1-position with a production ratio of 7: 3.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95-1.96 (1
5H, m), 1.07 (0.9H, s), 1.29 (2.1H, s), 2.03-2.07
(0.7H, m), 2.68-2.72 (0.3H, m), 9.78 (0.3H, d, J = 3.0
Hz), 9.84 (0.7H, d, J = 2.7Hz). IR (neat, cm ^-1 ): 2950, 2880, 1725, 1475, 1455, 139
0.MS m / z: 180 (M ⁺ ), 162 (MH ₂ O ⁺ ), 147 (M-CH ₃ -H ₂ O ⁺ ). HRMS (m / z): M ⁺ (C ₁₂ H ₂₀ O) Calculated 180.1514; Analytical
180.1525.

[Reference Example 12]

[0109]

[Chemical formula 23]

1-Methoxy-3-methoxymethoxybenzene (1.9 g, 11 mmol) was dissolved in anhydrous hexane (50 ml), and t-butyllithium (1.57 mol / l pentane solution, 7.0 ml, 11 mmol) was added dropwise at 0 ° C. And stirred for 30 minutes. (4aR, 8aR) -1-formyl-1,2,3,4,4a, 5,6,7,8,8a-decahydro-8a-methylnaphthalene (1.8 g, 10 mmol) was added to the reaction suspension at the same temperature. ) Was added and stirred for 2 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, anhydrous magnesium sulfate was added and dried, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (50 g) and a 7: 3 mixture of epimers related to position 1 (2.74 g, 78) from a hexane-ethyl acetate (9: 1 v / v) stream fraction.
%). This product was again subjected to column chromatography using silica gel (150 g), and from the fraction of hexane-ethyl acetate (9: 1 v / v) (1S, 4aR, 8aR)-
1,2,3,4,4a, 5,6,7,8,8a-decahydro-1- (α-hydroxy-2-methoxy-6-methoxymethoxybenzyl) -8a-methylnaphthalene was obtained.

Main product Colorless oily substance [α] _D ²⁰ = + 10.8 ° (c = 1.10, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.33 (5H, m), 1.25
(3H, s), 1.36-1.96 (11H, m), 3.48 (3H, s), 3.82 (3H,
s), 4.40 (1H, d, J = 10.9Hz), 5.19 (1H, d, J = 6.8Hz),
5.20 (1H, d, J = 6.8Hz), 5.54 (1H, dd, J = 10.9, 1.5Hz),
6.59 (1H, dd, J = 8.3, 0.7Hz), 6.77 (1H, dd, J = 8.4,
0.7Hz), 7.14 (1H, dd, J = 8.4, 8.3Hz). IR (neat, cm ^-1 ): 3570, 2940, 2870, 1600, 1480, 144
0, 1430, 1410, 1365, 1320, 1270, 1240, 1210, 1180,
1160, 1100, 1070, 1010, 960, 930, 910, 870,850, 8
40, 820, 800, 780, 740, 680, 660, 630. Elemental analysis: Calculated (C ₂₁ H ₃₂ O ₄ ): C, 72.38%; H, 9.26
Analytical value: C, 72.11%; H, 9.29%. Secondary product colorless oil [α] _D ²⁰ = + 1.7 ° (c = 0.95, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ : 0.87-1.91 (14H, m), 1.1
6 (3H, s), 1.96-2.10 (2H, m), 3.48 (3H, s), 3.83 (3H,
s), 4.12 (1H, d, J = 11.3Hz), 5.19 (1H, d, J = 6.9Hz),
5.21 (1H, d, J = 6.9Hz), 5.43 (1H, dd, J = 11.3, 2.7Hz),
6.60 (1H, dd, J = 8.3, 0.6Hz), 6.79 (1H, dd, J = 8.5,
0.6Hz), 7.15 (1H, dd, J = 8.5, 8.3Hz). IR (neat, cm ^-1 ): 3570, 2940, 2870, 1600, 1480, 145
0, 1430, 1410, 1390, 1360, 1320, 1270, 1240, 1190,
1160, 1110, 1080, 1020, 960, 930, 910, 880,840, 8
30, 790, 780, 740, 690. Elemental analysis: Calculated (C ₂₁ H ₃₂ O ₄ ): C, 72.38%; H, 9.26
Analytical values: C, 72.09%; H, 9.30%.

[Reference Example 13]

[0113]

[Chemical formula 24]

2- (1-hydroxybutyl) -1-methoxy-3-methoxymethoxybenzene (1.76 g, 7.32 m)
mol) in methanol (50 ml), 10% palladium-carbon (87.8 mg) was added, and the mixture was mixed with hydrogen at 1 atm under 5 atmosphere.
Stir for hours. After separating the catalyst by filtration, washing with chloroform,
The filter wash solution was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (50 g), and was obtained as a colorless oily substance from a stream of hexane-ethyl acetate (3: 1 v / v).
-Butyl-1-methoxy-3-methoxymethoxybenzene (1.50 g, 92%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t,
J = 7.0Hz), 1.55-1.25 (4H, m), 2.66 (2H, t, J = 7.7Hz), 3.4
8 (3H, s), 3.81 (3H, s), 5.18 (2H, s), 6.56 (1H, d, J = 8.2H
z), 6.71 (1H, d, J = 8.1Hz), 7.08 (1H, t, J = 8.3Hz). IR (neat, cm ^-1 ): 2970, 2940, 2870, 2850, 1600, 147
5, 1445, 1410, 1380, 1330, 1275, 1260, 1210, 1160,
1130, 1070, 1020, 930, 780, 730, 650.MS m / z: 224 (M ⁺ ), 181 (M-CH ₂ CH ₂ CH ₃ ⁺ ), 151 (M-CH ₂ CH ₂ C
H ₃ -CH ₂ O ⁺ ) .HRMS (m / z): M ⁺ (C ₁₃ H ₂₀ O ₃ ) calculated 224.1411; analyzed
224.1401.

[Reference Example 14]

[0117]

[Chemical 25]

2- (1-Hydroxycyclohexylmethyl) -1-methoxy-3-methoxymethoxybenzene (89.5 mg, 0.32 mmol) was dissolved in methanol (4 ml) and 10% palladium-carbon (14.6 mg) was added. The mixture was stirred under a hydrogen atmosphere at 1 atm for 6 hours. After separating the catalyst by filtration, the catalyst was washed with chloroform, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and 2-cyclohexylmethyl-1-methoxy-3-methoxy was obtained as a colorless oily substance from a stream of hexane-ethyl acetate (1: 1 v / v). Methoxybenzene (76.5 mg, 91
%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.3-0.9 (5
H, m), 1.75-1.45 (6H, m), 2.55 (2H, d, J = 6.8Hz), 3.48 (3
H, s), 3.79 (3H, s), 5.17 (2H, s), 6.56 (1H, d, J = 8.3Hz),
6.72 (1H, d, J = 8.2Hz), 7.09 (1H, t, J = 8.3Hz). IR (neat, cm ^-1 ): 3010, 2930, 2860, 1600, 1475, 145
0, 1410, 1340, 1320, 1275, 1255, 1200, 1180, 1160,
1140, 1100, 1075, 1025, 950, 930, 770, 730, 655.MS m / z: 264 (M ⁺ ), 181 (MC ₆ H ₁₁ ⁺ ), 151 (MC ₆ H ₁₁ -CH
₂ O ⁺ ), 137 (MC ₆ H ₁₁ -CHOCH ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₆ H ₂₄ O ₃ ) calculated 264.1723; analyzed
264.1722.

[Reference Example 15]

[0121]

[Chemical formula 26]

(1S, 4aR, 8aR) -1, 2, 3,
4,4a, 5,6,7,8,8a-decahydro-1-
(Α-Hydroxy-2-methoxy-6-methoxymethoxybenzyl) -8a-methylnaphthalene (32.3 mg, 0.09
3 mmol) was dissolved in methanol (1.5 ml), 10% palladium-carbon (30 mg) was added, and the mixture was stirred at room temperature for 1 hr under a hydrogen atmosphere of 1 atm. After the catalyst was filtered off, it was washed with methanol, and the filter wash solution was concentrated under reduced pressure. Preparative thin layer chromatography of the residue (hexane-ethyl acetate = 4: 1 v / v)
Attached to (1R, 4aR, 8aR) -1, 2, 3, 4,
4a, 5,6,7,8,8a-decahydro-1- (2-
Methoxy-6-methoxymethoxybenzyl) -8a-methylnaphthalene (24.9 mg, 81%) was obtained as a colorless oil.

[Α] _D ²⁰ = + 21.5 ° (c = 1.07, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.96-1.75 (15H, m), 1.24
(3H, s), 1.87-2.00 (1H, m), 2.43 (1H, dd, J = 12.4, 10.
9Hz), 2.71 (1H, dd, J = 12.4, 2.2Hz), 3.48 (3H, s), 3.7
9 (3H, s), 5.15 (1H, d, J = 6.7Hz), 5.16 (1H, d, J = 6.7H
z), 6.55 (1H, dd, J = 8.3, 0.7Hz), 6.71 (1H, dd, J = 8.
3, 0.7Hz), 7.08 (1H, t, J = 8.3Hz). IR (neat, cm ^-1 ): 2950, 2880, 1600, 1480, 1450, 141
0, 1390, 1360, 1340, 1280, 1260, 1240, 1200, 1180,
1160, 1140, 1100, 1080, 1030, 930, 780, 740, 660,
560, 520.MS m / z: 332 (M ⁺ ), 182. HRMS (m / z): M ⁺ (C ₂₁ H ₃₂ O ₃ ) calculated value 332.2350; analytical value
332.2356.

[Reference Example 16]

[0125]

[Chemical 27]

2-Butyl-1-methoxy-3-methoxymethoxybenzene (1.50 g, 6.68 mmol) was dissolved in methanol (150 ml), concentrated hydrochloric acid (7.5 ml) was added, and the mixture was stirred at room temperature overnight. After the solvent was concentrated, the mixture was extracted with ethyl acetate, the organic layer was washed with 1N hydrochloric acid and saturated saline, and anhydrous magnesium sulfate was added to dry it. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (25 g), and a colorless oily matter was obtained from the fraction of hexane-ethyl acetate (2: 1 v / v) as 2-butyl. -3-Methoxyphenol (1.20 g, 100%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.93 (3H, t,
J = 7.2Hz), 1.6-1.25 (4H, m), 2.62 (2H, t, 7.8Hz), 3.80 (3
H, s), 4.65 (1H, s), 6.43 (1H, d, J = 7.6Hz), 6.47 (1H, d, J =
7.6Hz), 7.02 (1H, t, J = 8.1Hz). IR (neat, cm ^-1 ): 3450, 2970, 2940, 2875, 2850, 160
0, 1505, 1475, 1445, 1380, 1340, 1280, 1245, 1210,
1175, 1115, 1120, 1070, 960, 910, 780, 730,700, 5
80, 540, 510.MS m / z: 180 (M ⁺ ), 137 (M-CH ₂ CH ₂ CH ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₁ H ₁₆ O ₂ ) calculated 180.1149 Analysis value
180.1134.

[Reference Example 17]

[0129]

[Chemical 28]

2-Cyclohexylmethyl-1-methoxy-3-methoxymethoxybenzene (2.55 g, 9.64 mmo
l) dissolved in methanol (150 ml) and concentrated hydrochloric acid (7.5 m
l) was added and the mixture was stirred overnight at room temperature. After the solvent was concentrated, the mixture was extracted with ethyl acetate, the organic layer was washed with 1N hydrochloric acid and saturated saline, and anhydrous magnesium sulfate was added to dry it. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (75 g), and 2-cyclohexyl was obtained as a colorless oily substance from the hexane-ethyl acetate (5: 1 v / v) stream. Methyl-3-methoxyphenol (1.95 g, 92
%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.3-0.9 (5
H, m), 1.75-1.4 (6H, m), 2.50 (2H, d, J = 7.0Hz), 3.79 (3H,
s), 4.64 (1H, s), 6.45 (1H, d, J = 8.1Hz), 6.47 (1H, d, J = 8.
2Hz), 7.03 (1H, t, J = 8.2Hz). IR (neat, cm ^-1 ): 3450, 2930, 2870, 1600, 1505, 147
5, 1455, 1380, 1345, 1285, 1270, 1260, 1210, 1180,
1140, 1090, 1070, 1055, 965, 930, 905, 830,800, 7
75, 735, 710, 540, 505.MS m / z: 220 (M ⁺ ), 137 (MC ₆ H ₁₁ ⁺ ), 107 (MC ₆ H ₁₁ -CH
₂ O ⁺ ). HRMS (m / z): M ⁺ (C ₁₄ H ₂₀ O ₂ ) calculated 220.1462; analyzed
220.1477.

[Reference Example 18]

[0133]

[Chemical 29]

(1R, 4aR, 8aR) -1, 2, 3,
4,4a, 5,6,7,8,8a-decahydro-1-
(2-Methoxy-6-methoxymethoxybenzyl) -8
A methanol solution (3 ml) of a-methylnaphthalene (20 mg, 0.060 mmol) was cooled to 0 ° C., and concentrated hydrochloric acid (0.1 ml) was added. After stirring at room temperature for 3.5 hours, dilute with 1N hydrochloric acid,
Extracted 3 times with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and hexane-ethyl acetate (15: 1
v / v) flow fraction (1R, 4aR, 8aR) -1, 2,
3,4,4a, 5,6,7,8,8a-decahydro-1
-(2-Hydroxy-6-methoxybenzyl) -8a-
Methylnaphthalene (16 mg, 93%) was obtained as a colorless oil.

[Α] _D ²⁰ = + 18.8 ° (c = 1.44, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.02-1.36 (8H, m), 1.25
(3H, s), 1.40-1.76 (7H, m), 1.87-1.96 (1H, m), 2.31 (1
H, dd, J = 13.3, 10.8Hz), 2.73 (1H, dd, J = 13.3, 2.1H
z), 3.78 (3H, s), 4.69 (1H, s), 6.45 (1H, dd, J = 8.1,
0.9Hz), 6.46 (1H, d, J = 8.2Hz), 7.02 (1H, dd, J = 8.2,
8.1Hz). IR (neat, cm ^-1 ): 3600, 3540, 3460, 3430, 2940, 287
0, 1600, 1500, 1475, 1445, 1390, 1340, 1280, 1240,
1200, 1180, 1155, 1135, 1095, 1080, 1050, 980, 95
5, 930, 885, 860, 845, 780, 765, 740, 710, 630, 58
0, 540, 505.MS m / z: 288 (M ⁺ ), 151. HRMS (m / z): M ⁺ (C ₂₁ H ₃₂ O ₃ ) Calculated value 288.2087; Analytical value
288.2072.

[Example 2]

[0137]

Embedded image

2-butyl-3-methoxyphenol (6
4.4 mg, 0.36 mmol) was added to N, N-dimethylformamide (10
, potassium nitrosodisulfonate (Flemy's salt) (383 mg, 1.43 mmol) in an aqueous solution (14 ml) of potassium dihydrogen phosphate (194 mg, 1.43 mmol), and then the N, N- It was added to the dimethylformamide solution.
After stirring at room temperature for 14 hours, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. After the solvent was distilled off under reduced pressure, the obtained crude 2-butyl-3
-Methoxy-1,4-benzoquinone in acetone (5 ml)
, Magnesium chloride (68 mg, 0.72 mmol) and concentrated hydrochloric acid (5 ml) were added, and an aqueous hydrogen peroxide solution (30% wt, 0.146 ml) was added dropwise at 0 ° C. After stirring at room temperature for 3 hours, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (25 g), and 2-butyl as a pale yellow oil was obtained from the hexane-chloroform (1: 1 v / v) fraction. -5,6-dichloro-
3-Methoxy-1,4-benzoquinone (15.1 mg, 16%)
I got

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t,
J = 7.1Hz), 1.5-1.3 (4H, m), 2.50 (2H, t, J = 7.4Hz), 4.06
(3H, s). IR (neat, cm ^-1 ): 2975, 2950, 2880, 1690, 1670, 163
0, 1585, 1460, 1385, 1340, 1310, 1210, 1175, 1145,
1080, 1060, 1030, 955, 910, 885, 830, 740.MS m / z: 262 (M ⁺ ), 264 (M + 2 ⁺ ), 266 (M + 4 ⁺ ), 220 (M-CH ₂ =
CHCH ₃ ⁺ ), 222 (M-CH ₂ = CHCH ₃ +2 ⁺ ). HRMS (m / z): M ⁺ (C ₁₁ H ₁₂ O ₃ Cl ₂ ) calculated 262.0162; analytic 262.0147.

[Example 3]

[0141]

[Chemical 31]

2-Cyclohexylmethyl-3-methoxyphenol (599.0 mg, 2.72 mmol) was dissolved in N, N-dimethylformamide (90 ml) and potassium nitrosodisulfonate (Fremy salt) (2.92 g, 10.9 mmol) was added. An aqueous solution of potassium dihydrogen phosphate (1.48 g, 10.9 mmol) (135
ml) and then added to the N, N-dimethylformamide solution. After stirring at room temperature for 14 hours, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. After evaporating the solvent under reduced pressure, the obtained crude 2-cyclohexylmethyl-3-methoxy-1,4-benzoquinone was dissolved in acetone (45 ml), and magnesium chloride (518 mg, 5.4 mmol) and concentrated hydrochloric acid (45 ml), and at 0 ℃, hydrogen peroxide solution (30% wt, 1.11 m
l) was added dropwise. After stirring at room temperature for 4 hours, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (35 g), and as a pale yellow oily substance from a fraction of hexane-chloroform (1: 1 v / v),
2,3-Dichloro-5-cyclohexylmethyl-6-methoxy-1,4-benzoquinone (164.4 mg, 20%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.8-0.9 (11
H, m), 2.41 (2H, d, J = 7.0Hz), 4.05 (3H, s). IR (neat, cm ^-1 ): 2930, 2860, 1680, 1670, 1630, 158
0, 1450, 1310, 1210, 1170, 1150, 1100, 1020, 960,
930, 910, 885, 850, 825, 805, 740, 630, 590, 510.MS m / z: 302 (M ⁺ ), 304 (M + 2 ⁺ ), 220 (MC ₆ H ₁₀ ⁺ ), 222 (M-
C ₆ H ₁₀ +2 ⁺ ). HRMS (m / z): M ⁺ (C ₁₄ H ₁₆ O ₃ Cl ₂ ) calcd 302.0476; calc 302.0482.

[Example 4]

[0145]

Embedded image

(1R, 4aR, 8aR) -1, 2, 3,
4,4a, 5,6,7,8,8a-decahydro-1-
A solution of (2-hydroxy-6-methoxybenzyl) -8a-methylnaphthalene (10 mg, 0.036 mmol) in N, N-dimethylformamide (1 ml) was supplemented with salcomine (12 mg, 0.036 mmo).
l) was added, and the mixture was stirred under an oxygen atmosphere at room temperature for 2.5 hours. The mixture was filtered and washed with ethyl acetate, and then the filter wash solution was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and from the flow of hexane-ethyl acetate (20: 1 v / v) (1R, 4
aR, 8aR) -1,2,3,4,4a, 5,6,7,
8,8a-decahydro-1- [2- (3-methoxy-
1,4-benzoquinonyl) methyl] -8a-methylnaphthalene (8 mg, 73%) was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.95-1.73
(15H, m), 1.21 (3H, s), 1.85-1.94 (1H, m), 2.23 (1H,
dd, J = 12.1, 10.5Hz), 2.51 (1H, dd, J = 12.1, 2.3Hz),
4.00 (3H, s), 6.59 (1H, d, J = 10.0Hz), 6.66 (1H, d, J =
10.0Hz). IR (neat, cm ^-1 ): 3470, 2940, 2870, 1675, 1655, 160
0, 1475, 1450, 1380, 1320, 1245, 1220, 1160, 1070,
1050, 850.MS m / z: 302 (M ⁺ ), 152. HRMS (m / z): M ⁺ (C ₁₉ H ₂₆ O ₃ ) calculated 302.1880; analyzed
302.1867.

[Embodiment 5]

[0149]

[Chemical 33]

(1R, 4aR, 8aR) -1, 2, 3,
4,4a, 5,6,7,8,8a-decahydro-1-
Pyridine (1.6 ml, 19.8 mmo) was added to a chloroform solution (20 ml) of [2- (3-methoxy-1,4-benzoquinonyl) methyl] -8a-methylnaphthalene (71 mg, 0.24 mmol).
l) and thionyl chloride (0.6 ml, 8.2 mmol) were added sequentially, and 2.5
Heated to reflux for hours. After cooling to 0 ° C., water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and from the fraction of hexane-ethyl acetate (30: 1 v / v), (1R, 4aR, 8aR) -1. , 2, 3, 4, 4
a, 5,6,7,8,8a-decahydro-1- [6-
(2,3-Dichloro-5-methoxy-1,4-benzoquinonyl) methyl] -8a-methylnaphthalene (54 mg, 62
%) As a yellow oil.

[Α] _D ²⁰ = + 30.3 ° (c = 0.033, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.05-1.79 (15H, m), 1.21
(3H, s), 1.85-1.94 (1H, m), 2.29 (1H, dd, J = 12.1, 10.
4Hz), 2.58 (1H, dd, J = 12.1, 1.9Hz), 4.05 (3H, s). IR (neat, cm ^-1 ): 3500, 3350, 2940, 2870, 1680, 166
5, 1625, 1580, 1470, 1450, 1385, 1320, 1300, 1240,
1210, 1170, 1100, 1080, 1050, 1020, 1000, 950, 90
0, 880, 860, 830, 800, 790, 740, 700, 650, 580, 51
0, 430.MS m / z: 370 (M ⁺ ). HRMS (m / z): M ⁺ (C ₁₉ H ₂₄ O ₃ Cl ₂ ) calculated 370.1100; analytic 370.1076.

[Reference Example 19]

[0153]

Embedded image

3,4-dimethoxyphenol (11.54 g,
74.9 mmol) was dissolved in methylene chloride (100 ml) and the temperature was 0 ° C.
And ethyldiisopropylamine (20.9 ml, 120 mmol)
And methoxymethyl chloride (8.53 ml, 112 mmol) were added, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide aqueous solution and saturated saline, and anhydrous magnesium sulfate was added to dry the organic layer. After evaporating the solvent under reduced pressure, the residue was washed with silica gel (70
g) was subjected to column chromatography, and 1,2-dimethoxy-4-methoxymethoxybenzene (12.26 g, 83% was obtained as a colorless oily substance from the hexane-ethyl acetate (2: 1 v / v) stream. ) Got.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.49 (3H,
s), 3.84 (3H, s), 3.86 (3H, s), 5.12 (2H, s), 6.59 (1H, d
d, J = 8.5, 2.7Hz), 6.64 (1H, d, J = 2.6Hz), 6.78 (1H, d, J =
8.5Hz). IR (neat, cm ^-1 ): 3010, 2960, 2840, 1600, 1515, 147
0, 1460, 1450, 1420, 1410, 1270, 1235, 1195, 1160,
1080, 1030, 930, 840, 800, 770, 710, 660, 555. MS m / z: 198 (M +), 168 (M-CH 2 O +), 153 (M-CH 2 OCH 3 +). HRMS (m / z): M ⁺ (C ₁₀ H ₁₄ O ₄ ) calculated 198.0890; analytical
198.0874.

[Reference Example 20]

[0157]

Embedded image

1,2-Dimethoxy-4-methoxymethoxybenzene (0.74 g, 3.72 mmol) was added to anhydrous hexane (15
ml) and t-butyllithium (1.57 mol / l
Pentane solution, 3.08 ml, 4.84 mmol) was added dropwise and stirred for 1 hour. The reaction suspension was charged with butyraldehyde (0.
44 ml, 4.9 mmol) was added and stirring was continued overnight. After water was added to stop the reaction, extraction was performed with ethyl acetate, the organic layer was washed with water, and anhydrous sodium sulfate was added to dry the organic layer. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (50 g), and a colorless oily substance was obtained from the hexane-ethyl acetate (5: 1 v / v) stream as a 2- ( 1-
Hydroxybutyl) -3,4-dimethoxy-1-methoxymethoxybenzene (0.31 g, 31%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94 (3H, t,
J = 7.1Hz), 2.0-1.2 (4H, m), 3.48 (3H, s), 3.62 (1H, d, J = 1
1.5Hz), 3.82 (3H, s), 3.89 (3H, s), 5.15-5.0 (1H, m), 5.
14 (1H, d, J = 6.9Hz), 5.18 (1H, d, J = 6.9Hz), 6.73 (1H, d, J =
9.0Hz), 6.82 (1H, d, J = 9.0Hz). IR (neat, cm ^-1 ): 3560, 2970, 2950, 2880, 2850, 160
0, 1490, 1470, 1425, 1410, 1295, 1260, 1240, 1160,
1120, 1080, 1050, 1010, 980, 940, 930, 850,805, 7
60, 740, 680, 650.MS m / z: 270 (M ⁺ ), 208 (M-OCH ₃ -OCH ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₄ H ₂₂ O ₅ ) Calculated value 270.1465; Analytical value
270.1457.

[Reference Example 21]

[0161]

Embedded image

1,2-Dimethoxy-4-methoxymethoxybenzene (1.17 g, 5.91 mmol) was added to anhydrous hexane (20
ml) and t-butyllithium (1.57 mol / l
Pentane solution, 4.89 ml, 7.68 mmol) was added dropwise and stirred for 1 hour. Cyclohexanecarbaldehyde (0.93 ml, 7.68 mmol) was added to the reaction suspension, and stirring was continued overnight. After adding 1N hydrochloric acid (10 ml) to stop the reaction,
The mixture was extracted with ethyl acetate, the organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and dried. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (60 g), and a colorless oily matter was obtained from the hexane-ethyl acetate (5: 1 v / v) stream as a colorless oil.
(1-hydroxycyclohexylmethyl) -3,4-dimethoxy-1-methoxymethoxybenzene (0.97 g, 53
%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.3-0.95 (6
H, m), 1.9-1.55 (4H, m), 2.35-2.15 (1H, m), 3.43 (1H, d, J
= 11.5Hz), 3.48 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 4.72
(1H, dd, J = 11.5, 9.1Hz), 5.13 (1H, d, J = 6.7Hz), 5.18 (1
H, d, J = 6.7Hz), 6.73 (1H, d, J = 9.0Hz), 6.82 (1H, d, J = 9.1H
z). IR (neat, cm ^-1 ): 3570, 2940, 2870, 1600, 1495, 145
5, 1430, 1355, 1295, 1260, 1240, 1160, 1100, 1080,
1055, 1020, 975, 940, 930, 900, 870, 845, 805, 76
0, 720.MS m / z: 310 (M ⁺ ), 248 (M-OCH ₃ -OCH ₃ ⁺ ), 227 (MC
₆ H ₁₁ ⁺ ). HRMS (m / z): M ⁺ (C ₁₇ H ₂₆ O ₅ ) calculated 310.1778; analytical
310.1763.

[Reference Example 22]

[0165]

Embedded image

1,2-Dimethoxy-4-methoxymethoxybenzene (0.60 g, 2.75 mmol) was added to anhydrous hexane (15 m
l), and t-butyllithium (1.57 mol / l
Pentane solution, 1.9 ml, 2.98 mmol) was added dropwise and stirred for 30 minutes. At the same temperature, (4aR, 8aR)-
1-formyl-1,2,3,4,4a, 5,6,7,
8,8a-decahydro-8a-methylnaphthalene (496m
g, 2.75 mmol) was added and stirred for 1.5 hours. After adding water, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, and anhydrous magnesium sulfate was added to dry it. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (40 g), and the epimer at the 1-position was 7: 3 from the hexane-ethyl acetate (4: 1 v / v) fraction.
To give a mixture (0.43 g, 41%). This product was again subjected to column chromatography using silica gel (50 g),
Hexane-ethyl acetate (9: 1 v / v) stream (1S,
4aR, 8aR) -1, 2, 3, 4, 4a, 5, 6,
7,8,8a-decahydro-1- (α-hydroxy-
2,3-dimethoxy-6-methoxymethoxybenzyl)
-8a-Methylnaphthalene was obtained.

Main product Colorless oily substance [α] _D ²⁰ = + 17.5 ° (c = 1.41, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.09-1.32 (5H, m), 1.27
(3H, s), 1.39-1.67 (7H, m), 1.70-1.96 (4H, m), 3.48 (3
H, s), 3.82 (3H, s), 3.88 (3H, s), 4.43 (1H, d, J = 10.9
Hz), 5.14 (1H, d, J = 6.9Hz), 5.15 (1H, d, J = 6.9Hz),
5.47 (1H, dd, J = 10.9, 1.1Hz), 6.73 (1H, d, J = 9.1Hz),
6.82 (1H, d, J = 9.1Hz). IR (neat, cm ^-1 ): 3560, 2940, 2870, 1595, 1490, 145
0, 1425, 1385, 1365, 1295, 1255, 1220, 1210, 1160,
1100, 1080, 1050, 1010, 970, 940, 930, 855,800, 7
30, 585.MS m / z: 378 (M ⁺ ), 316 (M-CH ₃ OCH ₂ OH ⁺ ). HRMS (m / z): M ⁺ (C ₂₂ H ₃₄ O ₅ ) calculated 378.2404; analyzed
378.2399. Secondary product colorless oil [α] _D ²⁰ = + 0.92 ° (c = 1.08, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.04 (1H, dt, J = 13.7, 3.
6Hz), 1.14-1.80 (12H, m), 1.17 (3H, s), 1.86 (1H, tt,
J = 13.5, 4.5Hz), 2.03-2.10 (2H, m), 3.48 (3H, s), 3.8
3 (3H, s), 3.88 (3H, s), 4.17 (1H, d, J = 11.3Hz), 5.15
(1H, d, J = 6.9Hz), 5.16 (1H, d, J = 6.9Hz), 5.35 (1H, d
d, J = 11.3, 2.5Hz), 6.74 (1H, d, J = 9.1Hz), 6.85 (1H,
d, J = 9.1Hz). IR (neat, cm ^-1 ): 3570, 2940, 2870, 1595, 1490, 145
5, 1425, 1385, 1360, 1295, 1260, 1240, 1210, 1160,
1095, 1050, 1030, 1005, 970, 950, 930, 840,800, 7
65, 730, 720, 665, 595, 520, 460, 440.MS m / z: 378 (M ⁺ ), 316 (M-CH ₃ OCH ₂ OH ⁺ ). HRMS (m / z): M ⁺ (C ₂₂ H ₃₄ O ₅ ) Calculated 378.2404; Analytical
378.2397.

[Reference Example 23]

[0169]

[Chemical 38]

2- (1-hydroxybutyl) -3,4-
Dimethoxy-1-methoxymethoxybenzene (307.2 m
g, 1.14 mmol) was dissolved in methanol (5 ml), 10% palladium-carbon (24.5 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere at 1 atm. After separating the catalyst by filtration, the catalyst was washed with chloroform, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (20 g), and 2-butyl-3,4-dimethoxy-1- was obtained as a colorless oily substance from a stream of hexane-ethyl acetate (3: 1 v / v). Methoxymethoxybenzene (225.6 mg, 78%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.93 (3H, t,
J = 7.2Hz), 1.60-1.25 (4H, m), 2.66 (2H, t, J = 8.0Hz), 3.4
8 (3H, s), 3.816 (3H, s), 3.819 (3H, s), 5.13 (2H, s), 6.6
7 (1H, d, J = 8.9Hz), 6.78 (1H, d, J = 8.9Hz). IR (neat, cm ^-1 ): 2970, 2940, 2870, 2840, 1600, 149
0, 1470, 1430, 1410, 1380, 1295, 1255, 1230, 1210,
1160, 1120, 1095, 1080, 1050, 1020, 950, 930, 80
0, 740, 720. MS m / z: 254 (M ⁺ ), 224 (M-CH ₂ O ⁺ ). HRMS (m / z): M ⁺ (C ₁₄ H ₂₂ O ₄ ) calculated value 254.1517; Analytical value
254.1540.

[Reference Example 24]

[0173]

[Chemical Formula 39]

2- (1-Hydroxycyclohexylmethyl) -3,4-dimethoxy-1-methoxymethoxybenzene (916 mg, 2.95 mmol) was dissolved in methanol (30 ml) to obtain 10% palladium-carbon (116 mg). Was added, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 24 hours. After separating the catalyst by filtration, the catalyst was washed with chloroform, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (70 g), and 2-cyclohexylmethyl-3,4- as a colorless oily substance from a stream of hexane-ethyl acetate (5: 1 v / v).
Dimethoxy-1-methoxymethoxybenzene (424 mg,
49%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-0.95
(5H, m), 1.8-1.50 (6H, m), 2.54 (2H, d, J = 6.8Hz), 3.48 (3
H, s), 3.805 (3H, s), 3.814 (3H, s), 5.11 (2H, s), 6.67 (1
H, d, J = 9.0Hz), 6.78 (1H, d, J = 8.9Hz). IR (neat, cm ^-1 ): 3010, 2930, 2870, 1600, 1490, 145
0, 1430, 1410, 1340, 1285, 1255, 1230, 1200, 1160,
1135, 1090, 1075, 1060, 1045, 1020, 970, 950, 93
0, 725.MS m / z: 294 (M ⁺ ). HRMS (m / z): M ⁺ (C ₁₇ H ₂₆ O ₄ ) calculated value 294.1829; analyzed value
294.1830.

[Reference Example 25]

[0177]

[Chemical 40]

(1S, 4aR, 8aR) -1,2,3
4,4a, 5,6,7,8,8a-decahydro-1-
(Α-Hydroxy-2,3-dimethoxy-6-methoxymethoxybenzyl) -8a-methylnaphthalene (159 mg,
0.42 mmol) was dissolved in methanol (16 ml), 10% palladium-carbon (160 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere at 1 atm. The catalyst was filtered off, washed with methanol, and the filter wash solution was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and from the hexane-ethyl acetate (15: 1 v / v) fraction (1R, 4
aR, 8aR) -1,2,3,4,4a, 5,6,7,
8,8a-decahydro-1- (2,3-dimethoxy-6
-Methoxymethoxybenzyl) -8a-methylnaphthalene (81 mg, 52%) was obtained as a colorless oil.

[Α] _D ²⁰ = + 25.4 ° (c = 1.11, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.99-1.10 (1H, m), 1.16-
1.31 (6H, m), 1.25 (3H, s), 1.35-1.74 (8H, m), 1.87-1.
96 (1H, m), 2.40 (1H, dd, J = 12.2, 11.2Hz), 2.72 (1H,
dd, J = 12.2, 2.4Hz), 3.48 (3H, s), 3.80 (3H, s), 3.81
(3H, s), 5.10 (1H, d, J = 6.6Hz), 5.11 (1H, d, J = 6.6H
z), 6.67 (1H, d, J = 9.0Hz), 6.77 (1H, dd, J = 9.0Hz). IR (neat, cm ^-1 ): 2940, 2870, 1600, 1490, 1470, 145
0, 1425, 1410, 1385, 1360, 1330, 1285, 1255, 1200,
1155, 1135, 1090, 1065, 1050, 1040, 1020, 960, 93
0, 880, 855, 800, 725, 675. MS m / z: 362 (M ⁺ ), 316 (M-OCH ₃ -CH ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₂₂ H ₃₄ O ₄ ) Calculated 362.2454; Analytical
362.2454.

[Reference Example 26]

[0181]

Embedded image

2-Butyl-3,4-dimethoxy-1-methoxymethoxybenzene (222 mg, 0.87 mmol) was dissolved in methanol (20 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at room temperature overnight. After concentrating the solvent, extract with ethyl acetate,
The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and dried. After distilling off the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (15 g), and 2-butyl as a colorless oily substance was obtained from a fraction of hexane-ethyl acetate (2: 1 v / v). -3,4-Dimethoxyphenol (185 mg, quantitative) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94 (3H, t,
J = 7.2Hz), 1.55-1.30 (4H, m), 2.64 (2H, t, J = 8.0Hz), 3.8
1 (3H, s), 3.82 (3H, s), 4.39 (1H, s), 6.49 (1H, d, J = 8.7H
z), 6.64 (1H, d, J = 8.8Hz). IR (neat, cm ^-1 ): 3410, 2970, 2940, 2880, 2850, 160
5, 1500, 1470, 1430, 1380, 1340, 1295, 1270, 1220,
1165, 1115, 1090, 1040, 970, 940, 885, 800, 740.MS m / z: 210 (M ⁺ ), 195 (M-CH ₃ ⁺ ), 167 (M-CH ₂ CH ₂ CH ₃ ⁺ ),
152 (M-CH ₂ CH ₂ CH ₃ -CH ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₂ H ₁₈ O ₃ ) calculated value 210.1254; analytical value
210.1244.

[Reference Example 27]

[0185]

Embedded image

2-Cyclohexylmethyl-3,4-dimethoxy-1-methoxymethoxybenzene (386.4 mg, 1.
31 mmol) in methanol (20 ml) and concentrated hydrochloric acid (2
ml) was added and the mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with water, and anhydrous magnesium sulfate was added to dry the organic layer. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (25 g), and 2-cyclohexyl was obtained as a colorless oily substance from a fraction of hexane-ethyl acetate (5: 1 v / v). Methyl-
3,4-Dimethoxyphenol (281.6 mg, 86%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.3-0.9 (5
H, m), 1.75-1.5 (6H, m), 2.51 (2H, d, J = 7.0Hz), 3.805 (3
H, s), 3.811 (3H, s), 4.36 (1H, s), 6.50 (1H, d, J = 8.8Hz),
6.65 (1H, d, J = 8.8Hz). IR (neat, cm ^-1 ): 3420, 3010, 2930, 2860, 1605, 150
0, 1470, 1450, 1430, 1340, 1290, 1260, 1220, 1205,
1180, 1135, 1090, 1060, 1040, 975, 965, 950, 900,
885, 800, 740.MS m / z: 250 (M ⁺ ), 167 (MC ₆ H ₁₁ ⁺ ), 152 (MC ₆ H ₁₁ -C
H ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₁₅ H ₂₂ O ₃ ) calculated 250.1568; analytical
250.1568.

[Reference Example 28]

[0189]

[Chemical 43]

(1R, 4aR, 8aR) -1,2,3
4,4a, 5,6,7,8,8a-decahydro-1-
A methanol solution (6 ml) of (2,3-dimethoxy-6-methoxymethoxybenzyl) -8a-methylnaphthalene (41 mg, 0.11 mmol) was cooled to 0 ° C., and concentrated hydrochloric acid (0.3 m
l) was added. After stirring for 2 hours at room temperature, dilute with water,
Extracted 3 times with ethyl acetate. The organic layer was washed with 3% hydrochloric acid and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and hexane-ethyl acetate (15: 1
v / v) flow fraction (1R, 4aR, 8aR) -1, 2,
3,4,4a, 5,6,7,8,8a-decahydro-1
-(6-Hydroxy-2,3-dimethoxybenzyl)-
8a-Methylnaphthalene (25 mg, 71%) was obtained. Recrystallization from ether-hexane gave colorless crystals.

Mp: 144.5-145.5 ° C. [α] _D ²⁰ = + 26.8 ° (c = 1.16, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.87-1.74 (15H, m), 1.26
(3H, s), 1.87-1.95 (1H, m), 2.30 (1H, dd, J = 13.1, 11.
2Hz), 2.73 (1H, dd, J = 13.1, 2.2Hz), 3.80 (3H, s), 3.8
1 (3H, s), 4.37 (1H, s), 6.51 (1H, d, J = 8.8Hz), 6.65
(1H, d, J = 8.8Hz). IR (neat, cm ^-1 ): 3400, 2940, 2870, 1500, 1470, 145
0, 1430, 1385, 1290, 1260, 1200, 1180, 1160, 1135,
1090, 1065, 1035, 970, 800, 740, 690, 540.MS m / z: 318 (M ⁺ ), 168.HRMS (m / z): M ⁺ (C ₂₀ H ₃₀ O ₃ ) calculated 318.2193; Analysis value
318.2172. Elemental analysis: Calculated (C ₂₀ H ₃₀ O ₃ ): C, 75.43%; H, 9.50%.
Analytical values: C, 75.16%; H, 9.41%.

[Example 6]

[0193]

[Chemical 44]

3,4-dimethoxyphenol (387 mg,
2.51 mmol) in anhydrous tetrahydrofuran (10 ml) was added to sodium hydride (60% in oil, 241 mg, 6.03 mmo)
l) in anhydrous tetrahydrofuran (20 ml) suspension at -78 ° C
, And after stirring for 10 minutes, at the same temperature 2,3-dichloro-
5-methoxy-6-methyl-1,4-benzoquinone (66
6 mg, 3.01 mmol) anhydrous tetrahydrofuran (10 ml)
The solution was added dropwise. The mixture was stirred for 2 hours while raising the temperature to −35 ° C., and further stirred for 2.5 hours at the same temperature. 1 at -50 ℃
The reaction was stopped by adding N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using silica gel (50 g), using hexane-ethyl acetate (2: 1 v / v) flow. Crystals were obtained from the minutes. This product was recrystallized from chloroform-hexane to give 2-chloro-3- (2-hydroxy-4,5-dimethoxyphenyl) -6-methoxy-5-methyl-1,4-benzoquinone (566 as dark purple crystals. mg, 67%) was obtained.

Mp 109.5-111 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 2.00 (3H, s), 3.81 (3H, s),
3.85 (3H, s), 4.08 (3H, s), 5.50 (1H, brs), 6.53 (1H, s),
6.63 (1H, s). IR (KBr, cm ^-1 ): 3450, 3270, 2950, 2850, 1685, 165
5, 1620, 1530, 1455, 1420, 1380, 1320, 1275, 1210,
1170, 1100, 1045, 1000, 920, 880, 840, 765,720, 5
95, 520.MS m / z: 338 (M ⁺ ), 340 (M + 2 ⁺ ), 303 (M-Cl ⁺ ). HRMS (m / z): M ⁺ (C ₁₆ H ₁₅ O ₆ Cl) Calculation Value 338.0555; Analytical value 338.0553.

[Embodiment 7]

[0197]

Embedded image

A solution of 3,4-dimethoxy-2-methylphenol (110.4 mg, 0.66 mmol) in anhydrous tetrahydrofuran (5 ml) was added with sodium hydride (37.8 mg, 1.58 mm).
ol) in anhydrous tetrahydrofuran (5 ml) suspension at -78 ° C
, And after stirring for 30 minutes, at the same temperature 2,3-dichloro-
5-methoxy-6-methyl-1,4-benzoquinone (17
4.1 mg, 7.88 mmol) anhydrous tetrahydrofuran (10 m
l) The solution was added dropwise. The mixture was stirred for 1 hour while the temperature was raised to -35 ° C, and the stirring was continued for 10 minutes at the same temperature. 1 at -50 ℃
The reaction was stopped by adding N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using silica gel (20 g), and hexane-ethyl acetate (3:
Crystals were obtained from the 1 v / v) fraction. This product is chloroform-
Recrystallized from hexane to give 2-chloro-3- (2-hydroxy-4,5-dimethoxy-3-) as dark brown needle crystals.
Methylphenyl) -6-methoxy-5-methyl-1,4
-Benzoquinone (168.2 mg, 73%) was obtained.

Mp 137-138 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 2.00 (3H, s), 2.18 (3H, s),
3.78 (3H, s), 3.84 (3H, s), 4.08 (3H, s), 4.75 (1H, brs),
6.52 (1H, s). IR (KBr, cm ^-1 ): 3470, 3010, 2950, 2860, 1685, 165
5, 1615, 1600, 1490, 1475, 1460, 1380, 1360, 1310,
1290, 1220, 1180, 1145, 1110, 1090, 1055, 1000, 9
80, 960, 910, 880, 840, 805, 760, 720, 700, 660.MS m / z: 352 (M ⁺ ), 354 (M + 2 ⁺ ), 317 (M-Cl ⁺ ). Elemental analysis: Calculated (C ₁₇ H ₁₇ O ₆ Cl): C, 57.88%; H, 4.86
%; Cl, 10.05%. Analysis value: C, 57.98%; H, 4.76%; Cl,
9.97%.

[Embodiment 8]

[0201]

Embedded image

A solution of 2-butyl-3,4-dimethoxyphenol (29.7 mg, 0.14 mmol) in anhydrous tetrahydrofuran (2 ml) was added with sodium hydride (60% in oil, 13.6 mg).
(mg, 0.34 mmol) in anhydrous tetrahydrofuran (2 ml) at −78 ° C., stirred for 10 minutes, and then stirred at the same temperature for 2-butyl-5,6-dichloro-3-methoxy-1,4-benzoquinone. A solution of (44.6 mg, 0.17 mmol) in anhydrous tetrahydrofuran (4 ml) was added dropwise. The mixture was stirred for 1.5 hours while raising the temperature to -20 ° C, and the stirring was continued for another hour at the same temperature.
The reaction was stopped by adding 1N hydrochloric acid at -50 ° C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was silica gel (25 g).
Column chromatography using hexane-
2-butyl-6- (3-butyl-2-hydroxy-) was obtained as a dark brown oily substance from the ethyl acetate (5: 1 v / v) stream.
4,5-Dimethoxyphenyl) -5-chloro-3-methoxy-1,4-benzoquinone (60.7 mg, 98%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, t,
J = 7.1Hz), 0.94 (3H, t, J = 7.0Hz), 1.6-1.3 (8H, m), 2.50
(2H, t, J = 7.6Hz), 2.66 (2H, t, J = 7.9Hz), 3.80 (3H, s), 3.
87 (3H, s), 4.09 (3H, s), 4.80 (1H, s), 6.53 (1H, s). IR (neat, cm ^-1 ): 3500, 2970, 2940, 2870, 1680, 165
0, 1610, 1490, 1470, 1440, 1340, 1300, 1215, 1170,
1115, 990, 955, 910, 880, 840, 760, 740.MS m / z: 436 (M ⁺ ), 438 (M + 2 ⁺ ), 401 (M-Cl ⁺ ). HRMS (m / z): M ⁺ (C ₂₃ H ₂₉ O ₆ Cl) calc. 436.1650; calc. 436.1631.

[Embodiment 9]

[0205]

[Chemical 47]

A solution of 2-cyclohexylmethyl-3,4-dimethoxyphenol (17.2 mg, 0.07 mmol) in anhydrous tetrahydrofuran (1 ml) was added with sodium hydride (60%).
in oil, 6.6 mg, 0.17 mmol) was added dropwise to a suspension of anhydrous tetrahydrofuran (1 ml) at −78 ° C., and the mixture was stirred for 10 minutes and then at the same temperature 2,3-dichloro-5-cyclohexylmethyl-6-methoxy. -1,4-benzoquinone (25.0 mg,
A solution of 0.08 mmol) in anhydrous tetrahydrofuran (2 ml) was dropped. The mixture was stirred for 1.5 hours while raising the temperature to -20 ° C, and the stirring was continued for another hour at the same temperature. The reaction was stopped by adding 1N hydrochloric acid at -50 ° C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using silica gel (20 g), hexane-ethyl acetate (5: 1 v /
2-Chloro-5-as a dark brown oil from the stream of v).
Cyclohexylmethyl-3- (3-cyclohexylmethyl-2-hydroxy-4,5-dimethoxyphenyl)-
6-Methoxy-1,4-benzoquinone (30.1 mg, 85%)
I got

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.8-0.9 (22
H, m), 2.40 (2H, d, J = 7.0Hz), 2.53 (2H, d, J = 6.7Hz), 3.80
(3H, s), 3.86 (3H, s), 4.07 (3H, s), 4.77 (1H, s), 6.55 (1
H, s). IR (neat, cm ^-1 ): 3520, 2930, 2860, 1680, 1650, 161
0, 1490, 1450, 1360, 1330, 1310, 1210, 1170, 1080,
1045, 980, 960, 910, 880, 850, 760, 740.MS m / z: 516 (M ⁺ ), 518 (M + 2 ⁺ ), 481 (M-Cl ⁺ ). HRMS (m / z): M ⁺ (C ₂₉ H ₃₇ O ₆ Cl) calc. 516.2277; calc. 516.2289.

[Embodiment 10]

[0209]

Embedded image

(1R, 4aR, 8aR) -1, 2, 3,
4,4a, 5,6,7,8,8a-decahydro-1-
(6-hydroxy-2,3-dimethoxybenzyl) -8
A solution of a-methylnaphthalene (17 mg, 0.053 mmol) in tetrahydrofuran (0.5 ml) was added with sodium hydride (60 mg).
% in oil, 5.2 mg, 0.13 mmol) in anhydrous tetrahydrofuran (2 ml) suspension at -78 ° C, and after stirring for 10 minutes,
(1R, 4aR, 8aR) -1, 2, 3, at the same temperature
4,4a, 5,6,7,8,8a-decahydro-1-
[6- (2,3-Dichloro-5-methoxy-1,4-benzoquinonyl) methyl] -8a-methylnaphthalene (24
mg, 0.065 mmol) anhydrous tetrahydrofuran (0.5 m
l) The solution was added dropwise. The mixture was stirred for 4 hours while the temperature was raised to -15 ° C, and the stirring was continued for another hour at the same temperature. 1 at -50 ℃
The reaction was stopped by adding N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using silica gel (10 g), using hexane-ethyl acetate (12: 1 v / v) flow. 2-chloro-5- [1-[(1
R, 4aR, 8aR) -1,2,3,4,4a, 5
6,7,8,8a-decahydro-8a-methylnaphthyl] methyl] -3- [3- [1-[(1R, 4aR, 8
aR) 1,2,3,4,4a, 5,6,7,8,8a-
Decahydro-8a-methylnaphthyl] methyl] -2-hydroxy-4,5-dimethoxyphenyl] -6-methoxy-1,4-benzoquinone (33 mg, 94%) was obtained as a black powder.

[Α] _D ²⁰ = -88.2 ° (c = 0.034, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.90-1.75 (30H, m), 1.1
9 (3H, s), 1.25 (3H, s), 1.86-1.98 (2H, m), 2.22-2.40
(1H, m), 2.29 (1H, dd, J = 12.0, 10.9Hz), 2.58 (1H, d
d, J = 12.0, 2.2Hz), 2.77 (1H, d, J = 11.2Hz), 3.80 (3H,
s), 3.86 (3H, s), 4.06 (3H, s), 4.70 (1H, br s, W _1/2 =
9.6Hz), 6.54 (1H, s). IR (KBr, cm ^-1 ): 3510, 2940, 2870, 1680, 1655, 161
0, 1490, 1470, 1460, 1320, 1300, 1215, 1170, 1070,
845, 760.MS m / z: 654 (M ⁺ +2), 652 (M ⁺ ), 616 (M-HCl ⁺ ). HRMS (m / z): M ⁺ (C ₃₉ H ₅₃ O ₆ Cl) calculation Value 652.3528; Analytical value 652.3552.

[Embodiment 11]

[0213]

[Chemical 49]

Amberlite® IRA-90
0 (OH type) (986 mg) was suspended in chloroform (3 ml), and 2-chloro-3- (2-hydroxy-4,5) was added at 0 ° C.
-Dimethoxyphenyl) -6-methoxy-5-methyl-
A chloroform (5 ml) solution of 1,4-benzoquinone (28.4 mg, 0.084 mmol) was added dropwise. After stirring at the same temperature for 3.5 hours, the resin was filtered off and washed with chloroform. The filter wash solution was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel (8 g) to give crystals from the chloroform fraction. This product was recrystallized from chloroform-hexane to give red crystals, 3,7,8-trimethoxy-2-
Methyldibenzofuran-1,4-dione (13.5 mg, 53
%).

Mp 217-218 ° C. (decomposition). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03 (3H, s), 3.96 (3H,
s), 3.97 (3H, s), 4.08 (3H, s), 7.04 (1H, s), 7.43 (1H,
s). IR (KBr, cm ^-1 ): 1675, 1645, 1610, 1565, 1505, 149
0, 1445, 1375, 1110, 1085, 1025, 1000, 920, 880, 8
50, 805, 760, 580. MS m / z: 302 (M ⁺ ), 287 (M-CH ₃ ⁺ ). Elemental analysis: Calculated (C ₁₆ H ₁₄ O ₆ ): C, 63.57%; H, 4.67 %.
Analytical values: C, 63.44%; H, 4.56%.

[Embodiment 12]

[0219]

Embedded image

Amberlite® IRA-90
0 (OH type) (611 mg) was suspended in chloroform (2 ml), and 2-chloro-3- (2-hydroxy-4,5) was added at 0 ° C.
-Dimethoxy-3-methylphenyl) -6-methoxy-
5-methyl-1,4-benzoquinone (17.7 mg, 0.05 mm
ol) in chloroform (3 ml) was added dropwise. After stirring at the same temperature for 2 hours, the resin was filtered off and washed with chloroform. The filter wash solution was concentrated under reduced pressure, and the residue was silica gel (8 g).
Was subjected to column chromatography, and crystals were obtained from the chloroform fraction. This product was recrystallized from chloroform-hexane to give orange needle crystals.
8-trimethoxy-2,6-dimethyldibenzofuran-
1,4-dione (12.7 mg, 80%) was obtained.

Mp 182-183.5 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04 (3H, s), 2.46 (3H,
s), 3.87 (3H, s), 3.94 (3H, s), 4.08 (3H, s), 7.35 (1H,
s). IR (KBr, cm ^-1 ): 3460, 2940, 2870, 1675, 1660, 162
0, 1575, 1500, 1470, 1420, 1390, 1380, 1300, 1245,
1225, 1120, 1095, 1065, 1005, 980, 920, 845,800,
750, 715, 685. MS m / z: 316 (M ⁺ ), 301 (M-CH ₃ ⁺ ). Elemental analysis: Calculated (C ₁₇ H ₁₆ O ₆ ): C, 64.55%; H, 5.09%.
Analytical values: C, 64.58%; H, 4.98%.

[Example 13]

[0221]

[Chemical 51]

Amberlite® IRA-90
0 (OH type) (1.04 g) was suspended in chloroform (2.5 ml), and 2-butyl-6- (3-butyl-2-hydroxy-4,5-dimethoxyphenyl) -5-chloro- was prepared at 0 ° C.
3-methoxy-1,4-benzoquinone (30.4 mg, 0.07
A solution of (mmol) in chloroform (4 ml) was added dropwise. After stirring at the same temperature for 1 hour, the resin was filtered off and washed with chloroform. The filter wash solution was concentrated under reduced pressure, and the residue was silica gel (25 g).
Was subjected to column chromatography, and crystals were obtained from a fraction of chloroform. This product was recrystallized from hexane to give 2,6-dibutyl-3,6 as orange needle crystals.
7,8-Trimethoxydibenzofuran-1,4-dione (27.5 mg, 99%) was obtained.

Mp 101-103 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.94 (6H, t, J = 7.4), 1.52
-1.36 (6H, m), 1.70-1.62 (2H, m), 2.52 (2H, t, J = 7.8Hz),
2.92 (2H, t, J = 7.7), 3.90 (3H, s), 3.95 (3H, s), 4.09 (3H,
s), 7.39 (1H, s). IR (KBr, cm ^-1 ): 2970, 2940, 2880, 1675, 1650, 157
0, 1465, 1430, 1340, 1290, 1240, 1130, 1105, 1075,
1040, 835.MS m / z: 400 (M ⁺ ), 357 (M-CH ₂ CH ₂ CH ₃ ⁺ ), 358 (M-CH ₂ = CHC
H ₃ ⁺ ). Elemental analysis: Calculated (C ₂₃ H ₂₈ O ₆ ): C, 68.98%; H, 7.05%.
Analytical values: C, 68.81%; H, 7.16%.

[Embodiment 14]

[0225]

Embedded image

Amberlite® IRA-90
0 (OH type) (5.04 g) was suspended in chloroform (14 ml) and stirred at 0 ° C. for 10 minutes, and then 2-chloro-5-cyclohexylmethyl-3- (3-cyclohexylmethyl-2).
-Hydroxy-4,5-dimethoxyphenyl) -6-methoxy-1,4-benzoquinone (173.1 mg, 0.33 mmo
A solution of l) in chloroform (28 ml) was added dropwise. After stirring at the same temperature for 2.5 hours, the resin was filtered off and washed with chloroform. The filter wash solution was concentrated under reduced pressure and the residue was washed with silica gel (40
g) was used for column chromatography, and crystals were obtained from the chloroform fraction. This product was recrystallized from hexane to give 2,6-dicyclohexylmethyl-3,7,8-trimethoxydibenzofuran-1,4 as red crystals.
-Dione (140.2 mg, 87%) was obtained.

Mp 133-135 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.3-1.0 (10H, m), 1.8-1.
5 (12H, m), 2.43 (2H, d, J = 7.2Hz), 2.81 (2H, d, J = 7.4Hz),
3.88 (3H, s), 3.95 (3H, s), 4.09 (3H, s), 7.41 (1H, s). IR (KBr, cm ^-1 ): 2930, 2860, 1675, 1655, 1610, 157
0, 1500, 1460, 1425, 1300, 1275, 1235, 1170, 1135,
1110, 1070, 1040, 990, 950, 910, 850, 795.MS m / z: 480 (M ⁺ ), 398 (MC ₆ H ₁₀ ⁺ ), 397 (MC ₆ H ₁₁ ⁺ ). Elemental analysis: Calculated (C ₂₉ H ₃₆ O ₆ ): C, 72.48%; H, 7.55%.
Analytical values: C, 72.50%; H, 7.75%.

[Embodiment 15]

[0229]

Embedded image

Amberlite® IRA-90
0 (OH type) (660 mg) was added to tetrahydrofuran (10 m
l) and suspended at 0 ° C. in 2-chloro-5- [1-[(1
R, 4aR, 8aR) -1,2,3,4,4a, 5
6,7,8,8a-decahydro-8a-methylnaphthyl] methyl] -3- [3- [1-[(1R, 4aR, 8
aR) 1,2,3,4,4a, 5,6,7,8,8a-
A solution of decahydro-8a-methylnaphthyl] methyl] -2-hydroxy-4,5-dimethoxyphenyl] -6-methoxy-1,4-benzoquinone (33 mg, 0.051 mmol) in tetrahydrofuran (1 ml) was added dropwise. 30 at the same temperature
After stirring for a minute and further at room temperature for 45 minutes, the resin was filtered off and washed with chloroform. The filtrate was concentrated under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and 2,6-bis [1- [from the hexane-ethyl acetate (20: 1 v / v) fraction was collected). (1R, 4aR, 8aR) 1,
2,3,4,4a, 5,6,7,8,8a-decahydro-8a-methylnaphthyl] methyl] -3,7,8-trimethoxydibenzofuran-1,4-dione (24 mg, 77
%). This product was recrystallized from ether-hexane to give red crystals.

Mp: 251.0-253.5 ° C. [Α] _D ²⁰ = -212 ° (c = 0.033, chloroform). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.99-1.77 (30H, m), 1.2
6 (3H, s), 1.33 (3H, s), 1.87-1.98 (2H, m), 2.31 (1H,
t, J = 12.0Hz), 2.60 (1H, dd, J = 12.0, 2.5Hz), 2.61 (1
H, dd, J = 12.8, 11.4Hz), 3.02 (1H, dd, J = 12.8, 2.1H
z), 3.88 (3H, s), 3.94 (3H, s), 4.08 (3H, s), 7.41 (1
H, s). ¹³ C-NMR (MHz, CDCl ₃ ) δ: 184.5, 172.7, 156.5, 15
2.9, 151.7, 150.5, 149.6, 134.1, 122.6, 122.4, 11
7.5, 100.9, 61.3, 61.1, 56.1, 49.5, 49.0, 42.3, 4
2.1, 36.7, 36.5, 28.3, 27.93, 27.89, 27.6, 27.3, 2
6.7, 26.4, 25.3, 25.1, 25.0, 24.5, 24.4, 24.0, 22.
0, 20.93, 20.90. IR (neat, cm ^-1 ): 2940, 2880, 1680, 1660, 1570, 147
0, 1310, 1300, 1255, 1080, 1040, 985, 765.MS m / z: 616 (M ⁺ ), 466.HRMS (m / z): M ⁺ (C ₃₉ H ₅₂ O ₆ ) calculated 616.3761; Analysis value
616.3789.

[Example 16]

[0233]

[Chemical 54]

Aluminum chloride (176 mg, 1.32 mmol)
Is suspended in methylene chloride (4 ml), and it is allowed to stand at room temperature for 3,7,8-
Trimethoxy-2-methyldibenzofuran-1,4-dione (40.5 mg, 0.13 mmol) in methylene chloride (10 ml)
The solution was added dropwise. The mixture was heated under reflux for 1 hour, allowed to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with silica gel (70
g) was subjected to column chromatography to obtain 3,7-dihydroxy-8-methoxy- as a dark red powder from a stream of hexane-ethyl acetate-acetic acid (1: 2: 0.01 v / v).
2-methyldibenzofuran-1,4-dione (27.3 mg,
74%).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.81 (3H,
s), 3.85 (3H, s), 7.11 (1H, s), 7.28 (1H, s), 10.18 (1H, b
rs), 10.8 (1H, brs). IR (KBr, cm ^-1 ): 3420, 3350, 1670, 1645, 1630, 160
0, 1565, 1485, 1440, 1390, 1335, 1290, 1220, 1180,
1140, 1080, 1020, 1000, 870, 850, 770, 760, 710.MS m / z: 274 (M ⁺ ), 259 (M-CH ₃ ⁺ ), 246 (M-CO ⁺ ), 231 (MC
H ₃ -CO ⁺ ) .HRMS (m / z): M ⁺ (C ₁₄ H ₁₀ O ₆ ) calculated 274.0476; measured
274.0476.

[Embodiment 17]

[0237]

[Chemical 55]

Aluminum chloride (515 mg, 3.86 mmol)
Suspended in methylene chloride (15 ml) and allowed to stand at room temperature for 3,7,8
-Trimethoxy-2,6-dimethyldibenzofuran-
A solution of 1,4-dione (58.3 mg, 0.18 mmol) in methylene chloride (5 ml) was added dropwise. After heating under reflux for 1 hour, allow to cool,
After adding 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (70 g) to give a dark red powder from the hexane-ethyl acetate-acetic acid (1: 1: 0.002 v / v) fraction. 3,7-dihydroxy-8-methoxy-2,6
-Dimethyldibenzofuran-1,4-dione (37.6 mg,
71%).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.83 (3H,
s), 2.29 (3H, s), 3.89 (3H, s), 7.23 (1H, s), 9.59 (1H,
s), 10.85 (1H, brs). IR (KBr, cm ^-1 ): 3440, 2970, 2930, 1655, 1620, 156
5, 1515, 1480, 1410, 1380, 1340, 1300, 1280, 1220,
1180, 1120, 1090, 1060, 980, 960, 870, 845,800, 7
60, 740, 700, 600.MS m / z: 288 (M ⁺ ), 273 (M-CH ₃ ⁺ ), 260 (M-CO ⁺ ), 245 (MC
H ₃ -CO ⁺ ) .HRMS (m / z): M ⁺ (C ₁₅ H ₁₂ O ₆ ) calculated 288.0633; analytical
288.0634.

[Embodiment 18]

[0241]

[Chemical 56]

Aluminum chloride (114.2 mg, 0.86 mmo
l) was suspended in methylene chloride (4 ml), and the suspension was stirred at room temperature for 2,6-
Dibutyl-3,7,8-trimethoxydibenzofuran-
A solution of 1,4-dione (17.4 mg, 0.043 mmol) in methylene chloride (1 ml) was added dropwise. After heating under reflux for 30 minutes, the mixture was allowed to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (15 g), and hexane-ethyl acetate-acetic acid (2: 1: 0.01 v / v).
2,6-dibutyl-3, as a dark red powder from the
7-dihydroxy-8-methoxydibenzofuran-1,
4-dione (11.1 mg, 69%) was obtained.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.87 (3H,
t, J = 7.1Hz), 0.89 (3H, t, J = 7.1Hz), 1.7-1.2 (8H, m), 2.3
5 (2H, t, J = 7.0Hz), 2.79 (2H, t, J = 7.5Hz), 3.89 (3H, s),
7.23 (1H, s), 9.52 (1H, s), 10.8 (1H, brs). IR (KBr, cm ^-1 ): 3530, 3340, 2970, 2940, 2880, 167
0, 1650, 1615, 1570, 1515, 1470, 1435, 1340, 1320,
1285, 1230, 1120, 1100, 1070, 1020, 870, 750, 70
0.MS m / z: 372 (M ⁺ ), 329 (M-CH ₂ CH ₂ CH ₃ ⁺ ), 330 (M-CH ₂ = CHC
H ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₂₁ H ₂₄ O ₆ ) calculated 372.1570; analyzed
372.1551.

[Embodiment 19]

[0245]

[Chemical 57]

Aluminum chloride (52.1 mg, 0.39 mmol)
Was suspended in methylene chloride (2 ml), and 2,6-dicyclohexylmethyl-3,7,8-trimethoxydibenzofuran-1,4-dione (9.2 mg, 0.019 mmol) in methylene chloride (2 ml) was suspended at room temperature. Was dripped. After heating under reflux for 30 minutes, the mixture was allowed to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (30 g) to give a dark red powder from the hexane-ethyl acetate-acetic acid (2: 1: 0.01 v / v) fraction. , 2,6-dicyclohexylmethyl-
3,7-dihydroxy-8-methoxydibenzofuran-
1,4-dione (6.1 mg, 70%) was obtained.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.3-0.8
(10H, m), 1.8-1.4 (12H, m), 2.26 (2H, d, J = 7.0Hz), 2.70
(2H, d, J = 6.8Hz), 3.90 (3H, s), 7.26 (1H, s), 9.50 (1H,
s), 10.78 (1H, brs). IR (KBr, cm ^-1 ): 3530, 3400, 2930, 2860, 1670, 165
0, 1615, 1570, 1520, 1470, 1440, 1340, 1290, 1280,
1260, 1230, 1200, 1180, 1140, 1110, 1080, 1070, 1
025, 985, 850, 750.MS m / z: 452 (M ⁺ ), 369 (MC ₆ H ₁₁ ⁺ ), 370 (MC ₆ H ₁₀ ⁺ ). HRMS (m / z): M ⁺ (C ₂₇ H ₃₂ O ₆ ) Calculated value 452.2196; Analytical value
452.2186.

[Embodiment 20]

[0249]

Embedded image

3,7-Dihydroxy-8-methoxy-2
-Methyldibenzofuran-1,4-dione (12.6 mg,
0.046 mmol) was dissolved in methylene chloride (15 ml), and boron tribromide (0.043 ml, 0.46 mmol) was added dropwise at room temperature.
After stirring at the same temperature for 7 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was reprecipitated from ether-ethyl acetate-hexane to give 3,7,8-trihydroxy-2-methyldibenzofuran-1,4-dione (5.9 mg, 49%) was obtained.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82 (3H,
s), 7.08 (1H, s), 7.30 (1H, s), 9.75 (1H, brs), 10.07 (1
H, brs), 10.80 (1H, brs). IR (KBr, cm ^-1 ): 3520, 3350, 1720, 1670, 1630, 160
0, 1560, 1480, 1410, 1390, 1335, 1290, 1230, 1180,
1140, 1085, 1000, 870, 810, 770, 755, 730, 700, 6
30, 580, 500. MS m / z: 260 (M ⁺ ), 232 (M-CO ⁺ ). HRMS (m / z): M ⁺ (C ₁₃ H ₈ O ₆ ) calculated value 260.0319; Analytical value
260.0303.

[Example 21]

[0253]

Embedded image

3,7-Dihydroxy-8-methoxy-
2,6-Dimethyldibenzofuran-1,4-dione (2
5.8 mg, 0.089 mmol) was dissolved in methylene chloride (40 ml), and boron tribromide (0.169 ml, 1.79 mmol) was added dropwise at 0 ° C. After heating under reflux for 17 hours, the mixture was allowed to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was reprecipitated from ethyl acetate-hexane to give a dark red powder of 3,7,8-
Trihydroxy-2,6-dimethyldibenzofuran-
1,4-dione (12.8 mg, 52%) was obtained.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82 (3H,
s), 2.28 (3H, s), 7.21 (1H, s), 9.35 (1H, brs), 10.08 (1
H, brs), 10.80 (1H, brs). IR (KBr, cm ^-1 ): 3520, 3420, 3150, 2940, 1730, 167
0, 1630, 1565, 1530, 1470, 1405, 1385, 1320, 1300,
1260, 1230, 1170, 1110, 1090, 1020, 980, 880, 86
0, 800, 760, 740, 500. MS m / z: 274 (M ⁺ ), 246 (M-CO ⁺ ). HRMS (m / z): M ⁺ (C ₁₄ H ₁₀ O ₆ ) calculated 274.0475; Analysis value
274.0469.

[Embodiment 22]

[0257]

Embedded image

2,6-dibutyl-3,7-dihydroxy-8-methoxydibenzofuran-1,4-dione (6.7
mg, 0.018 mmol) in methylene chloride (10 ml),
Boron tribromide (0.034 ml, 0.36 mmol) was added dropwise at room temperature. After heating under reflux for 7 hours, allowing to cool, and adding 1N hydrochloric acid,
It was extracted with ethyl acetate. After washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g) to obtain a powder from a hexane-ethyl acetate-acetic acid (1: 1: 0.01 v / v) fraction. It was Furthermore, reprecipitation from ethyl acetate-hexane gave a dark red powder,
2,6-Dibutyl-3,7,8-trihydroxydibenzofuran-1,4-dione (4.8 mg, 75%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.88 (3H,
t, J = 7.2), 0.91 (3H, t, J = 7.3Hz), 1.42-1.26 (6H, m), 1.6
2-1.54 (2H, m), 2.35 (2H, t, J = 7.7Hz), 2.79 (2H, t, J = 7.7H
z), 7.22 (1H, s), 9,28 (1H, s), 10.15 (1H, s), 10.73 (1H,
s). IR (KBr, cm ^-1 ): 3530, 3360, 2970, 2940, 2880, 166
0, 1630, 1570, 1465, 1330, 1290, 1260, 1230, 1160,
1120, 1095, 1015, 860, 750, 490.MS m / z: 358 (M ⁺ ), 315 (M-CH ₂ CH ₂ CH ₃ ⁺ ), 316 (M-CH ₂ = CHC
H ₃ ⁺ ). HRMS (m / z): M ⁺ (C ₂₀ H ₂₂ O ₆ ) calculated 358.1414; analyzed
358.1390.

[Example 23]

[0261]

[Chemical formula 61]

2,6-dicyclohexylmethyl-3,7
-Dihydroxy-8-methoxydibenzofuran-1,4
− Dione (4.9 mg, 0.011 mmol) was added to methylene chloride (10 m
l) and dissolve at room temperature in boron tribromide (0.04 ml, 0.43 mmo
l) was added dropwise. After heating under reflux for 6 hours, the mixture was allowed to cool, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (10 g), and a dark red powder was obtained from the hexane-ethyl acetate-acetic acid (1: 1: 0.01 v / v) fraction. As 2,6-dicyclohexylmethyl-3,7,8-trihydroxydibenzofuran-1,4-dione (2.5 m
g, 53%) was obtained.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.2-0.8
(10H, m), 1.7-1.4 (12H, m), 2.25 (2H, d, J = 6.5Hz), 2.68
(2H, d, J = 7.2Hz), 7.21 (1H, s), 9.24 (1H, brs), 10.18 (1
H, brs), 10.67 (1H, brs). IR (KBr, cm ^-1 ): 3520, 3180, 2930, 2860, 1660, 163
0, 1615, 1565, 1465, 1450, 1325, 1300, 1280, 1250,
1225, 1180, 1160, 1130, 1080, 1060, 1010, 860, 76
0, 740, 490.MS m / z: 438 (M ⁺ ), 355 (MC ₆ H ₁₁ ⁺ ), 356 (MC ₆ H ₁₀ ⁺ ). HRMS (m / z): M ⁺ (C ₂₆ H ₃₀ O ₆ ) Calculated 438.2040; Analytical
438.2024.

[Embodiment 24]

[0265]

Embedded image

2,6-bis [1-[(1R, 4aR, 8
aR) 1,2,3,4,4a, 5,6,7,8,8a-
Decahydro-8a-methylnaphthyl] methyl] -3,
7,8-Trimethoxydibenzofuran-1,4-dione (7.7 mg, 0.012 mmol) was dissolved in methylene chloride (12 ml), and boron tribromide (0.024 ml, 0.25 mmol) was added dropwise at 0 ° C. After stirring at temperature for 4 hours, the temperature was raised to room temperature. After further stirring for 4 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (hexane-ethyl acetate-methanol = 8: 1: 1 v / v) to give 2,6-bis [[black powder]. 1-[(1R, 4aR, 8aR)
1,2,3,4,4a, 5,6,7,8,8a-decahydro-8a-methylnaphthyl] methyl] -3,7,8-
Trihydroxydibenzofuran-1,4-dione (5.5
mg, 77%) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.93-1.7
0 (30H, m), 1.19 (3H, s), 1.26 (3H, s), 1.82-1.91 (2H,
m), 2.42-2.52 (2H, m), 2.93 (1H, dd, J = 6.5, 1.0Hz),
7.21 (1H, s), 9.20 (1H, Br s, W _1/2 = 144Hz), 10.30 (1
H, Br s, W _1/2 = 130Hz), 10.50 (1H, Br s, W _1/2 = 144Hz).
.IR (neat, cm ^-1 ): 3400, 2940, 2880, 1670, 1640, 162
0, 1570, 1470, 1455, 13250, 1290, 1090, 1070, 860,
760.MS m / z: 574 (M ⁺ ), 424. HRMS (m / z): M ⁺ (C ₃₆ H ₄₆ O ₆ ) calculated value 574.3291; analytical value
574.3279.

[0268]

[Test Example 1] (Malignant tumor cell growth inhibition test) Mouse lymphocytic leukemia cells (P388) were treated with 2-hydroxyethyl disulfide 5
μM, kanamycin sulfate 100 μg / ml was added 1
In addition to RPMI-1640 medium containing 0% fetal bovine serum,
The cultured cells were adjusted to 1 × 10 ⁴ cells / ml, and
4-benzoquinone derivatives (I) and (II) and dibenzofuran-1,4-dione derivative (III) were added to a predetermined concentration, and a CO ₂ incubator (CO ₂ 5%, humidity 1
The cells were cultured at 00%, 37 ° C) for 4 days. The number of surviving cells was measured by the MTT colorimetric method, and the 50% cell growth inhibitory concentration (IC ₅₀ ) was determined from the growth inhibition rate relative to the control group. Table 1 shows the results.

[0269]

Table 1. IC _{50 of} 1,4-benzoquinone derivatives (I) and (II) and dibenzofuran-1,4-dione derivative (III) against mouse lymphocytic leukemia cells (P388). ───────────────────────────── Compound (Example No.) IC ₅₀ (μg / ml) ───────── ─────────────────────────── 2,3-dichloro-5-methoxy-6-methyl-1,4-benzoquinone (1) 3 .6 2-Butyl-5,6-dichloro-3-methoxy-1,4-benzoquinone (2) 3.3 2,3-dichloro-5-cyclohexylmethyl-6-methoxy-1,4-benzoquinone (3) 3.5 2-chloro-3- (2-hydroxy-4,5-dimethoxyphenyl) -6-methoxy-5-methyl -1,4-benzoquinone (6) 0.32 2-chloro-3- (2-hydroxy-4,5-dimethoxy-3-methylphenyl) -6-methoxy-5-methyl-1,4-benzoquinone ( 7) 0.32 2-butyl-6- (3-butyl-2-hydroxy-4,5-dimethoxyphenyl) -5-chloro-3-methoxy-1,4-benzoquinone (8) 0.37 2-chloro -5-Cyclohexylmethyl-3- (3-cyclohexylmethyl-2-hydroxy-4,5-dimethoxyphenyl) -6-methoxy-1,4-benzoquinone (9) 0.36 ───────── ──────────────────────────

[0270]

[Table 2] (continued from Table 1) ──────────────────────────────────── Compound (Example No. ) IC ₅₀ (μg / ml) ─────────────────────────────────── 3,7,8-trimethoxy 2-Methyldibenzofuran-1,4-dione (11) 0.41 3,7,8-trimethoxy-2,6-dimethyldibenzofuran-1,4-dione (12) 0.33 3,7-dihydroxy- 8-Methoxy-2-methyldibenzofuran-1,4-dione (16) 4.2 3,7-Dihydroxy-8-methoxy-2,6-dimethyldibenzofuran-1,4-dione (17) 4.52 , 6-Dibutyl-3,7-dihydroxy-8-methoxydibenzofuran-1,4-dione (18) 3.4 2,6-Dicyclohexylmethyl-3,7-dihydroxy-8-methoxydibenzofuran-1,4-dione (19) 3.5 3,7,8-trihydroxy-2-methyldibenzofuran-1,4-dione ( 20) 3.2 3,7,8-trihydroxy-2,6-dimethyldibenzofuran-1,4-dione (21) 3.7 2,6-dibutyl-3,7,8-trihydroxydibenzofuran-1, 4-dione (22) 3.2 2,6-dicyclohexylmethyl-3,7,8-trihydroxydibenzofuran-1,4-dione (23) 2.9 2,6-bis [1-[(1R, 4aR , 8aR) 1,2,3,4,4a, 5,6,7,8,8a-decahydro-8a-methylnaphthyl] methyl] -3,7,8-trimethoxydibenzofuran-1,4-di ON (24) 3.5 ───────────────────────────────────

Claims (4)

[Claims] 1. The following general formula (I): (In the formula, R ¹ and R ² represent a halogen atom selected from the group consisting of a chlorine atom, a bromine atom and an iodine atom, R ³ represents an alkyl group or a cycloalkylmethyl group, and R ⁴ represents a hydrogen atom or a methyl group. Represents a 1,4-benzoquinone derivative. 2. The following general formula (II): (In the formula, R ² , R ³ and R ⁴ are the same as above, R ⁵ represents a hydrogen atom, an alkyl group or a cycloalkylmethyl group, and R ⁶ and R ⁷ represent a hydrogen atom or a methyl group.) The 1,4-benzoquinone derivative represented by: 3. The following general formula (III): (In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above.) A dibenzofuran-1,4-dione derivative. 4. An antitumor comprising the 1,4-benzoquinone derivative according to claim 1 or 2, the dibenzofuran-1,4-dione derivative according to claim 3, or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.