JP2002088061A - New method for producing benzoquinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple and excellent method for producing a benzoquinone derivative useful as a medicine or the like. SOLUTION: This method for producing a benzoquinone derivative represented by the general formula (I) or its pharmaceutically permissible salt is characterized by comprising a step, wherein a heteroaryl derivative represented by the general formula (II) is reacted with a dihalogenobenzoquirione derivative represented by the general formula (III).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a benzoquinone derivative.

[0002]

2. Description of the Related Art A large number of compounds useful as medicines and the like exist in a group of compounds having a structure in which a benzoquinone skeleton is substituted with an aryl or a heteroaryl. For example, Science, 284,
974-977 and 1999 include demethylasteriquinone B1 (demethy
l-Asterriquinone B1) and WO99 / 51225 describe that a compound represented by the following general formula has an antidiabetic effect.

Embedded image (For symbols in the formula, refer to the gazette.)
40,5119-5122,1999 discloses asteriquinone B1 (asterriquon), which is known as a fermentation product having antitumor activity in vivo.
inone B1) and demethylasteriquinone B1 (demethylas
A method for the chemical synthesis of terriquinone B1) has been disclosed.

Embedded image However, since the production methods disclosed in the above-mentioned publications and literatures require many steps, improvement of the production method has been required from the viewpoint of economic efficiency in industrial production.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a simple and excellent method for producing a benzoquinone derivative useful as a medicament or the like.

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a benzoquinone derivative.
We succeeded in establishing a simple manufacturing method and completed the present invention.

That is, the present invention provides the following general formula (I)

Embedded image (The symbols in the formula represent the following meanings: A: aryl or heteroaryl group which may have a substituent, Y: halogen, OH or lower alkyl-O- group

Embedded image m: 0, 1 or 2, R: H, OH, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, heteroaryl, amino, mono- or di-aminoalkyl) or a pharmaceutical preparation thereof A method for producing a chemically acceptable salt comprising a compound of the general formula (II)

Embedded image (The symbols in the formula are as described above), and a general formula (III)

Embedded image (A group in the formula is as described above, Hal is a halogen,
Alk represents a lower alkyl group. A) reacting a dihalogenobenzoquinone derivative represented by the formula (1).

[0005] Further, the present invention relates to a method of preparing the compound of the formula (IV)

Embedded image (The symbols in the formula are as described above.) The aryloxy or heteroaryl group which may have a substituent is reacted with the dialkoxydihalogenobenzoquinone derivative represented by the general formula (III). A process for producing a dihalogenobenzoquinone derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also relates to a novel compound useful as an intermediate in the above-mentioned novel production method, that is, a compound represented by the formula (V) or (VI) or a pharmaceutically acceptable salt thereof. About.

Embedded image

Embedded image

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The manufacturing method of the present invention will be described below in detail.

Embedded image (The symbols in the formula have the above-mentioned meanings.)

First Step The dihalogenobenzoquinone derivative represented by the general formula (III) is obtained by reacting an optionally substituted aryl or heteroaryl with a dialkoxydihalogenobenzoquinone derivative represented by the general formula (IV). It is manufactured by The reaction is usually acetone, dioxane, tetrahydrofuran (THF), cyclohexane, n-hexane, diethyl ether, diisopropyl ether, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, N, N-dimethylformamide (DMF), It is carried out in a conventional solvent such as toluene, pyridine, 4-dimethylaminopyridine (DMAP) or a mixture thereof,
The reaction is performed in any other organic solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature or under heating. This reaction is usually performed in the presence of an organic metal such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium 2,2,6,6-tetramethylpiperidine, and diisopropylamine lithium.

Second Step Among the benzoquinone derivatives represented by the general formula (I), the compound in which Y is a halogen is obtained by adding the compound represented by the general formula (III) to the dihalogenobenzoquinone derivative represented by the general formula (III). Produced directly by reacting an aryl. The reaction is usually acetone, dioxane, tetrahydrofuran (THF), cyclohexane, n-hexane, diethyl ether, diisopropyl ether, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, N, N-dimethylformamide (DMF),
Toluene, pyridine, 4-dimethylaminopyridine (DMAP)
And the like, but also in any other organic solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and is usually cooled,
The reaction is performed at room temperature or under heating. This reaction is usually performed with n-
Butyllithium, sec-butyllithium, tert-butyllithium, 2,2,6,6-tetramethylpiperidine lithium salt,
It is carried out in the presence of an organic metal such as diisopropylamine lithium salt.

Among the benzoquinone derivatives represented by the general formula (I), the compound wherein Y is a lower alkyl-O-group is obtained by reacting the compound obtained in the second step (Y = halogen) with a lower alcohol at room temperature. It can be manufactured by doing. This reaction is usually performed with an alkali metal hydroxide (for example,
Sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), tri (lower) alkylamines (eg, trimethylamine, triethylamine, etc.), pyridine or derivatives thereof (eg, picoline) , Lutidine, 4-dimethylaminopyridine, etc.), the presence of an inorganic or organic base such as N- (lower) alkylmorpholine (eg, N-methylmorpholine), N, N-di (lower) alkylbenzylamine, etc. Done below.

Among the benzoquinone derivatives represented by the general formula (I), the compound wherein Y is an OH group is the compound obtained in the second step (Y = halogen) or the compound obtained in the third step (Y = -O-lower alkyl) is converted to ethanol, methanol, acetone, dioxane, tetrahydrofuran (TH
It can be produced by adding distilled water if necessary in an organic solvent such as F), diethyl ether, diisopropyl ether, acetonitrile and heating. This reaction is usually carried out using an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), a tri (lower) alkylamine (eg, trimethylamine). ,
Triethylamine, etc.), pyridine or a derivative thereof (eg, picoline, lutidine, 4-dimethylaminopyridine, etc.), N- (lower) alkylmorpholine (eg, N-methylmorpholine), N, N-di (lower) alkylbenzyl The reaction is performed in the presence of an inorganic or organic base such as an amine.

In the definition of the general formula in the present specification, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Accordingly, a "lower alkyl group" is an alkyl group having 1 to 6 carbon atoms, and specifically, for example, these structural isomers such as methyl, ethyl, propyl, butyl, pentyl (amyl), hexyl, and isopropyl. , Preferably having 1 to 3 carbon atoms.
Alkyl groups. The “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl group or These structural isomers such as an allyl group are preferable, and preferably have 3 carbon atoms.
From 4 to 4 alkenyl groups. "Lower alkynyl group"
Is an alkynyl group having 2 to 6 carbon atoms, specifically, for example, ethynyl, 1-propynyl, 1-butynyl,
These structural isomers such as a 1-pentynyl, 1-hexynyl or 2-propynyl group are exemplified, and preferably have 3 carbon atoms.
From 4 to 4 alkynyl groups.

The "cycloalkyl group" is a saturated hydrocarbon ring group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. "Aryl group" means an aromatic hydrocarbon ring group,
Aryl having 6 to 14 carbon atoms is preferable, and specific examples include phenyl, naphthyl, indenyl, anthryl, and phenanthryl. “Heteroaryl” includes 1 to 4 heteroatoms selected from O, S and N.
And an aromatic ring group containing 5- to 6-membered heteroaryl (for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazyl). Fused bicyclic heteroaryl (eg, naphthyridinyl, pyridopyrimidinyl, etc.), and also heteroaryl fused to a benzene ring (eg, quinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, indolyl, benzimidazolyl, imidazopyridyl, benzofuranyl, Benzoxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, benzothienyl and the like). Further, oxobenzofuranyl and the like in which oxo is substituted on these rings are also included.

In the present invention, aryl and heteroaryl substituents, or Is not particularly limited as long as it is a substituent usually used as a substituent of these groups. These substituents, for example, a) halogen, cyano, nitro; oxo; ^{carboxy; b) -O-R 3;} -CO-R 3; -CO-N (R 3) -
^{R 4; -CO-O-R} 3; -CO-S (O) n -R 3; c) -N (R 3) -R 4; -N (R 3) -CO-R 4; -N
^{(R 3) -S (O)} n -R 4; 1- pyrrolidinyl; piperidino; morpholino; _{piperazinyl; d) -S (O) n} -R 4; -S (O) n -N (R 3) -R ^4; e) lower alkyl; lower alkenyl; lower alkynyl;
Cycloalkyl; aryl; heteroaryl; (these are halogen, carboxyl, —O—R ³ , —N (R ³ ) —
^{R 4, -N (R 3)} -CO-R 4, -N (R 3) -SO n -
R ⁴ , lower alkyl; which may be substituted with a substituent selected from the group consisting of lower alkenyl, lower alkynyl, cycloalkyl, aryl, and heteroaryl). (Here, R ³ and R ⁴ each represent a hydrogen atom, lower alkyl, cycloalkyl, aryl or heteroaryl, and n represents 0, 1 or 2.) “Halogen atom” is F, Cl, Br, I means

The compounds of the present invention have optical isomers (optically active substances, diastereomers, etc.) depending on the kind of the group. Further, some of the compounds of the present invention have an amide bond, and tautomers based on the amide bond also exist. The present invention includes a separated form or a mixture of these isomers. The compound (I) of the present invention may form a salt with an acid or a base depending on the type of the substituent. Such salts are pharmaceutically acceptable salts, and specifically include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionic acid. Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, Inorganic bases such as potassium, magnesium, calcium, aluminum,
Examples thereof include salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts. Further, the present invention provides a compound (I) of the present invention.
And various hydrates, solvates, and polymorphs of the salts thereof. Formula (I) obtained by conventional means
The present invention also encompasses prodrugs of the above-mentioned substances.

[0016]

EXAMPLES The present invention will be described in more detail with reference to Examples of the production of asteriquinone B1 and demethylasteriquinone B1. However, the present invention is not limited to these examples, and is a production method that can be used widely for the benzoquinone derivative represented by the general formula (I). The nuclear magnetic resonance spectrum ( ¹ H-NMR) described as a physical property was measured by the solvent CDCl ₃ , TMS internal standard δ; ppm, and mass spectrometry (MS) by the fast atom bombardment method, unless otherwise specified. Reference Example 1 (1) 8.10 g (69.1 mmol) of indole was mixed with 120 ml of carbon tetrachloride.
And 12.0 g (89.9 mmol) of N-chlorosuccinimide was added thereto while stirring under ice cooling, followed by stirring for 1 hour. The insolubles were filtered off, the filtrate was washed with 600 ml of chloroform, and the solvent of the filtrate was distilled off under reduced pressure to obtain 8.59 g of 3-chloroindole as a red solid (yield: 82%). ^{1 H-NMR: 7.08 (dd} , J = 8.0 & 8.0Hz, 1H), 7.16 (dd, J = 8.0 & 8.0H
z, 1H), 7.22 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.49 (d, J = 8.0H
z, 1H), 8.03 (br s, 1H) Rf value: 0.54 (hexane: ethyl acetate = 2: 1) (2) In an argon atmosphere, 2.20 g of 3-chloroindole (1
(4.5 mmol) in 44 ml of anhydrous THF.
4.0 ml (29 mmol) and 5.3 g (30 mmol) of prenyl-9-borabicyclo [3.3.1] nonane were added. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 15: 1).
To give 1.92 g of compound 1 as a colorless oil (yield 72%). ¹ H-NMR (acetone-d ₆ ): 1.36 (s, 6H), 4.88 (dd, J = 1.4 & 12.0H
z, 1H), 4.91 (dd, J = 1.4 & 19.0Hz, 1H), 5.98 (dd, J = 12.0 & 19.0
Hz, 1H), 6.09 (dd, J = 0.5 & 2.4Hz, 1H), 6.81 (ddd, J = 0.5,8.0 &
8.0Hz, 1H), 6,87 (ddd, J = 0.5,8.0 & 8.0Hz, 1H), 7,16 (dd, J =
0.5 & 8.0Hz, 1H), 7,33 (dd, J = 0.5 & 8.0Hz, 1H), 9.80 (br s, 1
H) Rf value: 0.56 (hexane: ethyl acetate = 8: 1)

Reference Example 2 In an argon atmosphere, 150 g of neutral alumina in which 15.0 ml (293 mmol) of bromine was adsorbed was added to 10.0 g (59.5 mmol) of 2,5-dimethoxy-1,4-benzoquinone and mixed well. After that, it was vibrated for 2 days with an ultrasonic cleaner. After adding 1.5 l of chloroform, the mixture was filtered using celite to remove alumina. The filtrate was washed with a 25% aqueous sodium thiosulfate solution (500 ml × 3). After separating the organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 9.79 g of compound 2 as an orange-red solid (yield). 51%). ¹ H-NMR: 4.00 (s, 6H) Rf value: 0.50 (hexane: ethyl acetate = 4: 1)

Reference Example 3

Embedded image (1) 17.6 g (80.2 mmol) of 2-iodin-1-aniline was added to TH
F, dissolve in 176 ml, stir at room temperature, diisopropylethylamine 14.0 ml (80.2 mmol), dicarbonate-di-t-
52.5 g (240 mmol) of butyl were added. After refluxing for 5 days, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only, then hexane: chloroform = 1: 1) to obtain 22.0 g of compound 3 as a pale yellow oil (yield 86%). ^{1 H-NMR: 1.54 (s} , 9H), 6.76 (t, J = 7.7Hz, 1H), 6.81 (br, 1H),
7.31 (t, J = 7.9Hz, 1H), 7.74 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1
Hz, 1H) Rf value: 0.40 (hexane: chloroform = 2: 1) (2) Compound 3 25.6 g (80.2 mmol) in an argon atmosphere
Was dissolved in 78.8 ml of triethylamine and, while stirring at room temperature, 0.92 g (4.80 mmol) of copper iodide and 3.39 g of bistriphenylphosphinepalladium (II) dichloride (4.80 mm
ol). After stirring for 5 minutes, 15.6 ml (114 mmol) of trimethylsilylacetylene was added dropwise over 5 minutes. After stirring for 30 minutes, the mixture was filtered using Celite. Things
After washing with 500 ml of THF, the filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give Compound 4 (20.3 g) as an orange oil (yield: 88%). ^{1 H-NMR: 0.29 (s} , 9H), 1.53 (s, 9H), 6.93 (t, J = 7.7Hz, 1H), 7.
37-7.26 (m, 3H), 8.10 (d, J = 8.4Hz, 1H). Rf value: 0.60 (hexane: chloroform = 1: 1)

(3) Compound 4 10.5 g in an argon atmosphere
(36.2 mmol) dissolved in diethyl ether (105 ml),
Then, 52.8 ml (79.7 mmol) of a 1.51 M t-butyllithium-n-pentane solution was added dropwise over 20 minutes while stirring. After stirring for 3 hours while maintaining the temperature at -20 ° C, the mixture was cooled to -78 ° C, and 5.01 ml of 4-bromo-2-methyl-2-butene (43.5 mmo
l) was added. After stirring at −78 ° C. for 15 minutes, at −20 ° C. for 45 minutes, and then at room temperature for 1 hour, the mixture was neutralized with 3 ml of acetic acid, and the solvent was distilled off under reduced pressure. 60 ml of distilled water was added to the residue and extracted with chloroform (300 ml × 1,150 ml × 1). After washing the combined organic layer with a saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (toluene: chloroform = 5: 1) to give Compound 5 (10.8 g) as a pale yellow solid (yield 86).
%). ¹ H-NMR: 0.25 (s, 9H), 1.49 (s, 9H), 1.71 (s, 3H), 1.73 (s, 3
H), 3.35 (d, J = 7.0Hz, 2H), 5.21-5.18 (m, 1H), 6.33 (br s, 1
H), 7.09 (t, J = 7.7Hz, 1H), 7.18 (d, J = 7.3Hz, 1H), 7.31 (d, J =
7.7 Hz, 1H) Rf value: 0.46 (hexane: chloroform = 1: 1) (4) Under an argon atmosphere, compound 5 10.8 g (31.2 mmol)
Dissolve in 323 ml of ethanol and stir at room temperature.
Sodium ethoxide (8.44 g, 156 mmol) was added, and the mixture was heated under reflux for 7.5 hours. After neutralizing by adding 7.7 ml of acetic acid, the mixture was filtered using celite, and the residue was washed with 100 ml of ethanol. The combined filtrate and washings were concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: chloroform: ethyl acetate = 12: 1: 1) to obtain 4.38 g of compound 6 as a pale yellow solid (yield: 76).
%). ^{1 H-NMR: 1.78 (s} , 3H), 1.83 (s, 3H), 3.58 (d, J = 7.0Hz, 2H), 5.
45-5.39 (m, 1H), 6.56 (dd, J = 2.2 & 2.9Hz, 1H), 7.08-6.98 (m, 1H)
2H), 7.20 (t, J = 2.6 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 8.16 (br
s, 1H) Rf value: 0.41 (hexane: chloroform: ethyl acetate = 1)
2: 1: 1)

[0020]

Embedded image Example 1 Under an argon atmosphere, 837 mg (4.52 mmol) of Compound 1 was dehydrated.
Dissolve in 16.7 ml of THF, and at -78 ° C, 1.07 M s-butyllithium-cyclohexane, n-hexane solution 5.77 ml (5.88 mmo
l) was added dropwise over 10 minutes and stirred for 1 hour. To this solution was added dropwise 23.6 ml of a solution of 1.18 g (3.62 mmol) of compound 2 in anhydrous THF over 12 minutes, followed by stirring at -78 ° C for 30 minutes and then at room temperature for 30 minutes. After neutralizing with 0.3 ml of acetic acid and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: chloroform: ethyl acetate = 12: 2: 1) to obtain 1.06 g of compound 7 as a dark blue color. Obtained as a solid (61% yield). FAB-MS (m / z): 478 ([M + H] ⁺ ) ¹ H-NMR (acetone-d ₆ ): 1.46 (s, 6H), 4.23 (s, 3H), 5.02 (dd, J
= 11.0 & 1.0Hz, 1H), 5.04 (dd, J = 18.0 & 1.0Hz, 1H), 6.06 (dd, J
= 18.0 & 11.0Hz, 1H), 6.96 (dd, J = 8.0 & 8.0Hz, 1H), 7.06 (dd, J
= 8.0 & 8.0Hz, 1H), 7.19 (d, J = 8.0Hz, 1H), 7.34 (d, J = 8.0Hz, 1
H), 10.36 (br s, 1H) Rf value: 0.44 (hexane: chloroform: ethyl acetate = 6:
2: 1)

Example 2 Under an argon atmosphere, 291 mg (1.57 mmol) of Compound 6 was dehydrated.
Dissolve in 5.82 ml of THF, and at -78 ° C, 2.00 ml of a 1.02 M s-butyllithium-cyclohexane, n-hexane solution (2.04 mmo
l) was added dropwise over 10 minutes and stirred for 1 hour. To this solution, 12.4 ml of a solution of 619 mg (1.29 mmol) of compound 7 in anhydrous THF was added dropwise over 12 minutes, followed by stirring at -78 ° C for 1 hour and then at room temperature for 30 minutes. After neutralizing with 0.1 ml of acetic acid and evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography (hexane: chloroform: ethyl acetate = 12: 2: 1).
To give 574 mg of compound 8 as a purple solid (yield
70%). FAB-MS (m / z): 631 ([M + H] ⁺ ) ¹ H-NMR (acetone-d ₆ ): 1.48 (s, 6H), 1.73 (s, 3H), 1, 75 (s, 3
H), 3.64 (d, J = 7.0Hz, 2H), 5.06 (dd, J = 11.0 & 1.0Hz, 1H), 5.0
9 (dd, J = 18.0 & 1.0Hz, 1H), 5.42-5.47 (m, 1H), 6.09 (dd, J = 1
8.0 & 11.0Hz, 1H), 6.91-7.07 (m, 5H), 7.27 (d, J = 8.0Hz, 1H),
7.34 (d, J = 8.0Hz, 1H), 7.67 (d, J = 3.0Hz, 1H), 10.37 (br s, 1H
H), 10.80 (brs, 1H) Rf value: 0.28 (hexane: chloroform: ethyl acetate = 6:
2: 1) Example 3 52.5 mg (83.0 μmol) of compound 8 was dissolved in 26.3 ml of methanol, 33 mg (830 μmol) of sodium hydroxide was added, and the mixture was stirred at room temperature for 4 hours. After CG50 was added for neutralization, the mixture was further stirred at room temperature for 10 minutes. After removing CG50 by cotton filtration, the filtrate was concentrated under reduced pressure to distill off the solvent. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1), and asteriquinone B1 33.0 mg
Was obtained as a red-purple solid (74% yield). FAB-MS (m / z): 535 ([M + H] ⁺ ) ¹ H-NMR: 1.48 (s, 6H), 1.79 (s, 3H), 1.83 (s, 3H), 3.60 (d, J =
6.0Hz, 2H), 3.68 (s, 3H), 3.80 (s, 3H), 5.06 (d, J = 10.5Hz, 1
H), 5.12 (d, J = 17.4Hz, 1H), 5.43 (brt, J = 6.0Hz, 1H), 6.09
(dd, J = 17.4 & 10.5Hz, 1H), 7.02-7.16 (m, 4H), 7.26 (dd, J = 8.
0 & 8.0Hz, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.40 (d, J = 8.0Hz, 1H),
7.56 (d, J = 2.7 Hz, 1H), 8.10 (brs, 1H), 8.50 (brs, 1H) Rf value: 0.50 (toluene: ethyl acetate = 5: 1)

Example 4 12.0 mg (18.9 μmol) of compound 8 was dissolved in 2.4 ml of dioxane, and 1.2 ml of distilled water was added.
g (190 μmol) was added and the mixture was refluxed for 2 hours. After returning to room temperature, Dowex 50W-X8 was added and neutralized. After removing insolubles by cotton filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1) to obtain 2.9 mg of demethylasteriquinone B1 as a reddish purple solid (yield 30.2%). FAB-MS (m / z): 507 ([M + H] ⁺ ) mp: 203-204 ° C (decomp.) ¹ H-NMR (acetone-d ₆ ): 1.52 (s, 6H), 1.75 (s, 3H), 1.77 (s, 3
H), 3.64 (d, J = 7.0Hz, 2H), 5.00 (dd, J = 10.4 & 1.0Hz, 1H), 5.0
9 (dd, J = 17.0 & 1.0Hz, 1H), 5.48 (m, 1H), 6.16 (dd, J = 17.0 & 1
0.5Hz, 1H), 6.91-7.06 (m, 4H), 7.28 (d, J = 7.8Hz, 1H), 7.32
(d, J = 7.8Hz, 1H), 7.44 (dd, J = 7.0 & 1.0Hz, 1H), 7.62 (d, J = 3.
0Hz, 1H), 10.07 (brs, 1H), 10.44 (brs, 1H) Rf value: 0.33 (toluene: ethyl acetate: acetic acid = 20: 10: 0.
9) Example 5 91.2 mg (171 μmol) of asteriquinone B1 was added to ethanol 1
The solution was dissolved in 8.2 ml, 9.2 ml of a 1 N aqueous solution of potassium hydroxide was added, and the mixture was refluxed for 2 hours. After returning to room temperature, Dowex50W-X8 was added and neutralized. After removing insolubles by cotton filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1), and demethylasteriquinone B1 was obtained as a reddish purple solid.
67.3 mg was obtained (78% yield).

Example 6 23.2 mg (36.7 μmol) of compound 8 was dissolved in 3.5 ml of ethanol, 3.5 ml of distilled water was added, and 20.6 mg of KOH (367 μmol) was added.
l) was added and the mixture was refluxed for 1 hour. After returning to room temperature, Dowex 50W
-X8 was added to neutralize. After filtering the cotton to remove insoluble matter,
The filtrate was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (toluene: ethyl acetate = 20: 1, 1
(Fraction 0.6 ml). The fractions of Nos. 17 to 35 were collected to obtain 7.5 mg of compound 9 as a purple solid in a yield of 36%. Next, fractions of Nos. 41 to 60 were collected to obtain 3.4 mg of demethylasteriquinone B1 as a red-purple solid in a yield of 18%. Compound 9 FAB-MS (m / z): 569 ([M + H] ⁺ ) ¹ H-NMR (acetone-d ₆ ): 1.52 (s, 6H), 1.76 (s, 3H), 1.78 (s, 3)
H), 3.65 (d, J = 7.0Hz, 2H), 5.01 (br d, J = 10.4Hz, 1H), 5.11
(br d, J = 17.0Hz, 1H), 5.48 (m, 1H), 6.17 (dd, J = 17.0 & 10.4H
z, 1H), 6.90-7.08 (m, 4H), 7.28 (d, J = 7.8Hz, 1H), 7.33 (d, J =
7.8Hz, 1H), 7.45 (brd, J = 7.0Hz, 1H), 7.62 (d, J = 3.0Hz, 1H),
10.05 (br s, 1H), 10.46 (br s, 1H) Rf value: 0.55 (toluene: ethyl acetate = 5: 1)

[0024]

The production method of the present invention is a novel method for producing a benzoquinone derivative which is simpler and superior to conventional production methods.
Compared with the method for producing asteriquinone B1 covering 12 steps described in Tetrahedron Letters, 40, 5119-5122, 1999,
According to the production method of the present invention disclosed in the examples, production can be carried out in as few as 6 or 7 steps, so that the production method is excellent in terms of yield, production cost and time.

Claims (4)

[Claims] 1. A compound represented by the following general formula (I): (The symbols in the formula represent the following meanings: A: aryl or heteroaryl group which may have a substituent, Y: halogen, OH or lower alkyl-O- group m: 0, 1 or 2, R: H, OH, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, heteroaryl, amino, mono- or di-aminoalkyl) or a pharmaceutical preparation thereof A process for the production of a chemically acceptable salt comprising a compound of the general formula (II): (The symbols in the formula are as described above.) And a general formula (III) (A group in the formula is as described above, Hal is a halogen,
Alk represents a lower alkyl group. A) reacting a dihalogenobenzoquinone derivative represented by the formula (1). 2. A compound of the general formula (IV) (The symbols in the formula are as described above.) The aryloxy or heteroaryl group, which may have a substituent, is reacted with the dialkoxydihalogenobenzoquinone represented by the general formula (III). The method according to claim 1, further comprising a step of producing a dihalogenobenzoquinone derivative. 3. A compound represented by the formula (V) or a pharmaceutically acceptable salt. Embedded image 4. A compound represented by the formula (VI) or a pharmaceutically acceptable salt. Embedded image