JPH0137384B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel quinone compounds useful as pharmaceuticals. More specifically, the present invention relates to the general formula [In the formula, R is a lower alkyl group or a lower alkoxy group, and A is -CH ₂ -, -CO- or

[Formula], n represents an integer of 2 to 8, X represents a hydrogen atom or an optionally protected hydroxyl group, and Y represents an optionally protected hydroxyl group. ] A general formula characterized by oxidizing the compound or its ester [In the formula, each symbol has the same meaning as above. ] The present invention relates to a method for producing a quinone compound or an ester thereof. The present inventors succeeded in synthesizing the above-mentioned novel compound (1), and (1) this compound exhibits a remarkable effect on the lysosomal membrane, and also has a physiological biological resistance regulating effect, especially an immunostimulatory effect, and (2) This compound has a simple structure and is suitable for industrial production. (3) This compound has moderate hydrophilicity. ease of formulation; and
(4) This compound is stable against light, acids, etc.
The present inventors have discovered that the present invention can be more advantageously employed as a medicine, and have completed the present invention. In formulas () and (), the lower alkyl group represented by R preferably has 4 or less carbon atoms, and specific examples include methyl, ethyl, i-propyl, n-butyl, and i-butyl.
Similarly, the lower alkoxy group represented by R preferably has 4 or less carbon atoms, and specific examples include methoxy, ethoxy, i-propoxy, n-propoxy, and i-butoxy. The integer represented by n is preferably 4,5 when R is a lower alkyl group, and preferably 2,7,8 when R is a lower alkoxyl group. Regarding the formula (), the protecting group for the hydroxy group of X or Y may be any group as long as it can be easily removed, and examples thereof include alkyl, aralkyl, acyl, acetal, and silyl groups. The alkyl group serving as a protecting group preferably has 4 or less carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, etc., and the aralkyl group serving as a protecting group preferably includes benzyl. As the acyl group as a protecting group, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, especially alkylcarbonyl having 4 or less carbon atoms (e.g. acetyl, n-propionyl, n-butyryl, etc.),
As the acetal group as a protecting group, α-tetrahydropyranyl, methoxymethyl, etc. are preferable, and as the silyl group as a protecting group, trimethylsilyl is preferable. The compounds () and esters of () are preferably alkyl carboxylic acid esters, aryl carboxylic acid esters, and aralkyl carboxylic acid esters, and these alkyl, aryl, and aralkyl moieties may be substituted. The alkyl moiety of the alkyl carboxylic acid ester preferably has 4 or less carbon atoms, such as methyl,
Examples include ethyl, n-propyl, i-propyl, n-butyl, and i-butyl. The aryl moiety of the aryl carboxylic acid ester preferably has 7 or less carbon atoms, such as phenyl and p-tosyl. The aralkyl moiety of the aralkyl carboxylic acid ester preferably has 8 or less carbon atoms, such as benzyl and phenethyl. Substituents in these alkyl, aryl, and aralkyl moieties include sulfonyl, carbonyl, formyl, hydroxy, and/or amino groups. In the method of the present invention, compound () can be obtained by oxidizing compound (). Any oxidation method may be used as long as it can convert phenol into quinone without affecting the alcoholic hydroxyl group, and examples of the oxidizing agent include ferric chloride, silver oxide, and nitrosodisulfonate. The oxidation reaction is generally carried out in the presence of a suitable solvent. The solvent may be any solvent as long as it does not interfere with the oxidation reaction, such as water, dilute acid or alkali solutions,
Acetone, ethanol, dioxane, ether,
Examples include acetic acid and dimethylformamide.
The temperature and reaction time in the oxidation reaction vary depending on the type of oxidizing agent, but are generally preferably 0° C. to 25° C. and 0.5 hours to 5 hours. Next, the method of the present invention and the steps for producing its raw material compounds will be illustrated.

[Table] Compounds () and the method for producing (), ie, the steps (1) to (19), will be described in detail below. Step (1) Convert compound () to general formula () (In the formula, n has the same meaning as above) or react with a compound represented by the general formula () (In the formula, Z represents a carboxyl group which may be esterified, Hal represents a halogen atom, and n represents the same meaning as above) to obtain compound (-1). This reaction is preferably carried out in the presence of a catalyst.
As the catalyst, catalysts used in Friedel-Crafts reactions, such as mineral acids such as sulfuric acid, phosphoric acid, and polyphosphoric acid, and Lewis acids such as aluminum chloride and boron trifluoride, are preferably used. Although the reaction proceeds without a solvent, it is usually carried out in an inert organic solvent, such as nitrobenzene, carbon disulfide, tetrachloroethane, etc. The reaction temperature is preferably about 0° to 150°C. Step (2) Compound (-1) is obtained by oxidizing compound (-1). In general, any oxidation means capable of converting phenols into quinones can be conveniently used. Specific examples of oxidizing agents include hydrogen peroxide, peracetic acid, performic acid, perbenzoic acid, potassium permanganate, potassium dichromate, chromic anhydride, potassium nitrosodisulfonate, ferric chloride, and silver oxide. , manganese dioxide, etc.
The reaction is usually carried out in the presence of a suitable solvent. Any solvent may be used as long as it does not interfere with the reaction, and specific examples include water, dilute acid, dilute alkali aqueous solution, acetone, ethanol, dioxane, ether, and acetic acid. The progress of the reaction can be determined by thin layer chromatography. In this case, it can be employed as a means for confirming a yellow color image, a color reaction using a leucomethylene blue reagent, or an ultraviolet absorption spectrum. Although the reaction temperature and reaction time vary depending on the type of oxidizing agent used, the reaction temperature is usually about 0° to 25°C, and the reaction time is preferably about 0.5 to 5 hours. Good results can also be obtained by carrying out the reaction in the presence of a suitable buffer (eg, phosphate buffer). Step (3) Compound (-2) is obtained by reducing compound (-1). As such a reduction method, any method capable of converting the carbonyl group in compound (-1) into a methylene group can be conveniently used. Preferred examples include, for example, Clemensen reduction using zinc amalgam and hydrochloric acid, Wolff Kiyner reduction in which a ketone is decomposed into hydrazone in the presence of an acid group, desulfurization reduction with dithioacetate and nickel, and catalytic reduction. can be mentioned. It is usually advantageous to carry out the reaction in the presence of a suitable solvent. Such a solvent may be any solvent as long as it is not involved in the reaction, but specific examples include ether, methanol,
Examples include ethanol, benzene, toluene, xylene, ethylene glycol, triethylene glycol, and acetic acid. The above-mentioned reduction reaction proceeds easily by a conventional method. Step (4) Compound (-2) is obtained by oxidizing compound (-2). This oxidation reaction is carried out in the same manner as described in step (2). Step (5) Compound (-3) is obtained by reducing compound (-1). The reduction method in this step may be any method as long as it converts the ketone into an alcoholic hydroxyl group without affecting the carboxyl group, such as catalytic reduction, for example, reduction with a reducing agent such as sodium borohydride. Step (6) Compound (-3) is obtained by oxidizing compound (-3). The oxidation method may be any method as long as it converts hydroquinone into quinone without affecting the alcoholic hydroxy group. As the oxidizing agent, ferric chloride, silver oxide, and potassium nitrosodisulfonate are preferred. The oxidation reaction is carried out under similar conditions as described for step (2). Step (7) Compound (-1) is reduced to compound (-2)
get. This reduction reaction is carried out in the same manner as described in step (3) (except for the Wolff Kiyoner reduction and the dithioacetal desulfurization reduction). In this step, a compound in which X=Y=OH in compound (-2) is obtained. Step (8) Compound (-1) is obtained by reducing compound (-1). As the reduction method in this step, any method can be used as long as it converts quinone into hydroquinone without affecting the carbonyl group; for example, a reduction method using hydrosulfite is preferred. In this step, a compound (-1) in which X=Y=OH is obtained. Step (9) The compound () is converted into a peroxide of a carboxylic acid represented by the general formula () Z-( _CH2 ) _o+1 -COOH (wherein Z and n have the same meanings as above) or a peroxide of the carboxylic acid. Compound (-2) is obtained by reacting anhydride with peroxide.
get. The peroxide of the carboxylic acid () or the peroxide of the anhydride of the carboxylic acid may be any one that generates carbon dioxide gas and alkyl radicals when heated,
Such peroxides can be obtained by reacting carboxylic acids, their acid halides, or acid anhydrides with peroxides (eg, hydrogen peroxide, metal salts thereof, lead tetraacetate, etc.). The reaction in this step is preferably carried out in an appropriate inert solvent, such as n-hexane, ligroin, toluene, xylene, acetic acid, or propionic acid. The reaction temperature is preferably about 80° to 100°C, and the reaction time is preferably about 0.5 to 3 hours. This reaction proceeds under extremely mild conditions with the generation of carbon dioxide gas, with few side reactions, and the desired product is obtained in good yield.
Further, after the reaction, unreacted raw materials are recovered without loss. The reaction may also be carried out under conditions in which peroxide is produced in the reaction system, for example, in the presence of a tetravalent lead compound (for example, lead tetraacetate), the compound () and () represented by the formula It is carried out by reacting the carboxylic acid or its anhydride. The reaction is preferably carried out in a suitable inert solvent (e.g. n-hexane, ligroin, toluene, xylene, acetic acid, propionic acid, etc.),
Further, the reaction temperature is preferably 50° to 150°C. Step (10) Compound (-2) is obtained by reducing compound (-2). This reduction method may be any method as long as it converts quinone into hydroquinone; for example, catalytic reduction, reduction using hydrosulfite, etc. are advantageously used. In this step, a compound (-2) in which X=X=OH is obtained. Step (11) Compound (-3) is obtained by reducing compound (-1). As the reduction method in this step, any method that can convert carboxyl groups into alcoholic hydroxy groups may be used. An example of such a reduction method is a method using lithium aluminum hydride. It is generally advantageous to carry out the reduction process in a suitable solvent. Any solvent may be used as long as it does not hinder the reduction reaction, and examples thereof include ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.). Step (12) Compound (-3) is reduced to compound (-2)
get. As the reduction method in this step, any method may be used as long as the benzyl alcoholic hydroxy group can be converted into a hydrogen atom. The reduction is carried out using reduction means known per se, catalytic reduction being particularly preferred.
Palladium, platinum oxide, etc. are advantageously used as the catalyst. It is generally preferred that this reduction be carried out in the presence of a suitable solvent. Any solvent may be used as long as it does not hinder the reduction reaction, and preferred examples include acetic acid and alcohol (eg, methanol, ethanol). This reduction reaction is advantageously carried out, for example, in the presence of an acid (eg hydrochloric acid, perchloric acid). Step (13) Oxidize compound (-2) to form compound (-2)
get. This reaction is the method of the present invention and its description is as described above. Step (14) Oxidize compound (-3) to form compound (-3)
get. This reaction is the method of the present invention and its description is as described above. Step (15) Oxidize compound (-3) to form compound (-1)
get. The oxidation reaction in this step is compound (-3)
It is advantageous to protect the -CH ₂ OH moiety in the protective group, and any protecting group may be used as long as it can be easily removed. Examples of such protecting groups are acyls (e.g. acetyl, benzyl, benzoyl), acetals (e.g. tetrahydrofuranyl)
can be given. Preferred oxidizing agents include manganese dioxide and chromium trioxide. Step (16) Compound (-1) is reduced to compound (-1)
get. The reduction reaction in this step is carried out according to the above-mentioned step (8). In this step, the compound (-
1) A product in which X=Y=OH is obtained. Step (17) Oxidize compound (-1) to form compound (-1)
get. This reaction is the method of the present invention and its description is as described above. Step (18) Compound (-2) is reduced to obtain compound-2). The reduction reaction in this step is carried out according to the above-mentioned step (11). Step (19) Compound (-2) is reduced to compound (-2)
get. The reduction reaction in this step is carried out according to the above-mentioned step (11). Compounds (-1), (-2) and (-3)
[Hereinafter, these are collectively referred to as compound ()] and compounds (-1), (-2) and (-
3) [Hereinafter, these are collectively referred to as compounds ()]
When has a free carboxyl group, it can be converted into compounds () and () having an esterified carboxyl group by esterification by a method known per se. The aforementioned esterification reaction is performed on the compounds (), ()
Alternatively, the reaction is carried out by reacting a reactive derivative thereof at a carboxyl group with an alcohol, phenol compound, alkyl halide, aralkyl halide, dialkyl sulfate, diazomethane, or the like. Examples of reactive derivatives of carboxyl groups include carboxylic acid anhydrides, carboxylic acid halides, carboxylic acid metal salts (eg, sodium salts, calcium salts, silver salts), and the like. Alcohols include methanol, ethanol, n-
Examples of the aralkyl halide include propanol, i-propanol, n-butanol, i-butanol, etc., methyl iodide, ethyl iodide, etc. as the alkyl halide, and benzyl chloride and the like as the aralkyl halide. In compounds () and (), compound (-
3) and (-3) are their

The [Formula] moiety can also be esterified. Such esterification is carried out in the same manner as the esterification of compounds () and () described below. In addition, when the compounds () and () have an esterified carboxyl group, they can be converted into compounds () and () having a free carboxyl group by hydrolysis by means known per se. Such hydrolysis is advantageously carried out, for example, in the presence of mineral acids (sulfuric acid, hydrochloric acid, etc.) or alkalis (sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). Furthermore, the hydrolysis is advantageously carried out in the presence of suitable antioxidants (such as pyrogallol) or reducing agents (such as hydrosulfites). In compounds () and (), compound (-
When 3) and (-3) have an esterified alcoholic hydroxy group, they can be converted into compounds (-3) and (-3) having an alcoholic hydroxy group by hydrolysis. Such hydrolysis is also performed in the same manner as the above-mentioned hydrolysis. When the compounds () and () have an alcoholic hydroxy group, the compounds can be esterified by methods known per se. The esterification is carried out, for example, by reacting the compound () or () having an alcoholic hydroxy group with a carboxylic acid compound or a reactive derivative thereof. Examples of carboxylic acids include alkylcarboxylic acids, arylcarboxylic acids, and aralkylcarboxylic acids. Examples of reactive derivatives of carboxylic acids include carboxylic anhydrides, carboxylic acid halides, lower alkyl esters of carboxylic acids, and carboxylic acid salts. In compounds (-3) and (-3), the above esterification generally involves -CH ₂ OH and

occurs in both parts of [formula], but it is important to choose the conditions, e.g. compound (-3) or (-
It is also possible to esterify only the -CH ₂ OH portion by, for example, setting the ratio of carboxylic acid or its reactive derivative to 3) to 1:1. When compounds () and () have an esterified alcoholic hydroxy group, the compounds () and () having an alcoholic hydroxy group can be obtained by hydrolysis in the same manner as described for compounds () and (). I can guide you. The compound () thus obtained can be easily collected by any suitable collection means known per se, such as liquid conversion, dissolution, concentration, vacuum distillation, chromatography, crystallization, recrystallization, etc. Compound () is a new compound that exhibits physiological bioresistance regulating action, especially immunostimulatory action; smooth muscle relaxing action; and other actions, such as physiological bioresistance regulating action in animals including humans, especially as an immune adjuvant. used as. Furthermore, in the compound (), the compound (-
2) A compound in which R is lower alkyl, and R
Those in which R is a lower alkoxy group and n is 3 or more exhibit a cell lysosomal membrane stabilizing effect, and those in which R is a lower alkoxy group and n is 2 exhibit a lysosomal membrane destabilizing effect. Furthermore, compounds (-1) and (-3) also exhibit remarkable effects on lysosomal membranes. Compound (2) is administered orally or parenterally to animals including humans, either as such or in the form of an appropriate mixture with an appropriate carrier or medium, such as powder, granules, tablets, or injections. Pharmaceutical compositions containing the compound () can be produced by powders, capsules, tablets, granules, injections, or other methods known per se. The vehicle is appropriately selected depending on the route of administration and solubility of the compound. The dosage of the compound () varies depending on the type of target compound, symptoms, etc., and is determined as appropriate; however, when used as an immunostimulant for mammals,
For example, the usual daily dose is about 50μg to 50mg/
Kg, preferably 1-25 mg/Kg, is administered by injection. Reference Example 1 (1) To a solution of 2,3,5-trimethylphenol (where R=H ₃ C, X=H, Y=OH (1.4 g) in tetrachloroethane (10 ml) at 0°C, nitrogen Under a stream of air, a solution of aluminum chloride powder (3.5 g) and ethyl 5-chloroformylpentanoate (3 g) in tetrachloroethane (5 ml) is added, and then heated at 110-120°C for 17 hours.Cold water (50 ml) is added to the reaction mixture. After that, acidify with dilute hydrochloric acid and extract with chloroform (200 ml).The residue obtained from the extract (2.7 g) is added to silicic acid (60 g).
The eluate obtained from the fractions eluted with chloroform-ether (20:1) (300 ml) was evaporated to dryness, and the resulting residue was recrystallized from ethanol to give ethyl 5- (2'-Hytroxy-3',4',6'-trimethylbenzoyl)pentanoate (-1, R=H ₃ C, X=H, Y=OH, n=4, ethyl ester) (1.9 g) is obtained as colorless needle crystals. Melting point: 72°-73°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450 (OH),
1720 (COOC ₂ H ₅ ), 1610 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 8.76 (CH ₃ , triplet), 8.5−8.1 (CH ₂ ,
multiplet), 8.0−7.6 (CH ₂ , multiplet), 7.89 (nuclear
CH ₃ , singlet), 7.78 (nuclear CH ₃ , singlet), 7.50
(nuclear CH ₃ , singlet), 7.25−7.00 (CH ₂ , multiplet),
5.88 (OCH ₃ , quartet), 3.48 (nuclear proton, singlet) Elemental analysis C ₁₇ H ₂₄ O ₄ Calculated value C 69.83, H 8.27 Actual value C 69.78, H 8.44 (2) Aqueous content of this product (610 mg) Acetone (acetone-
Add 10% sodium hydroxide (10 ml) dropwise to the water (5:1), 12 ml solution with stirring at room temperature. After stirring for 30 minutes, cool to 0°C and add cold water (50ml) to the reaction mixture. cold dilute hydrochloric acid,
When the resulting white precipitate is recrystallized from ethanol, 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (-1, where R=
H ₃ C, X=H, Y=OH, n=4, free form)
(428 mg) was obtained as colorless needle-like crystals. Melting point 146゜−
148℃. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3430 (OH),
1700 (COOH), 1605 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 8.5−8.0 (CH ₂ , multiplet), 8.0−7.3
(CH ₂ , multiplet), 7.88 (nuclear CH ₃ , singlet), 7.78
(nuclear CH ₃ , singlet), 7.47 (nuclear CH ₃ , singlet), 7.2
-6.9 (CH ₂ , multiplet), 3.47 (nuclear proton, singlet) Elemental analysis C ₁₅ H ₂₆ O ₄ Calculated value C 68.16, H 7.63 Actual value C 67.95, H 7.92 Reference example 2 (1) 2, 3, Reference Example 1: 5-trimethylphenol (in the formula, R=H ₃ C, X=H, Y=OH) (0.9 g), aluminum chloride (2.1 g), and ethyl 6-chloroformylhexanoate (1.3 g) (1)
When treated in the same manner as above, ethyl 6-(2'-hydroxy-3',4',6'-trimethylbenzoyl)hexanoate (-1, where R=H ₃ C, X=H,
Y=OH, n=5, ethyl ester) (1.5g)
is obtained as colorless needle crystals. Melting point: 47°-48°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1735
(COOC ₂ H ₅ ), 1610 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 8.76 (CH ₃ , triplet), 8.7−8.0 (CH ₂ ,
multiplet), 8.0−7.4 (CH ₂ , multiplet), 7.88 (nuclear
CH ₃ , singlet), 7.78 (nuclear CH ₃ , singlet), 7.49
(Nuclear CH ₃ , singlet), 7.01 (CH ₂ , triplet), 5.87
(OCH ₂ , quartet), 3.47 (nuclear proton, singlet) Elemental analysis C ₁₆ H ₃₆ O ₄ Calculated value C 70.56, H 8.55 Actual value C 70.23, H 8.72 (2) This product (1 g) is used as a reference example Hydrolysis according to method 1(2) yields 6-(2'-hydroxy-3',4',
6'-trimethylbenzoyl)hexanoic acid (-
In formula 1, R=H ₃ C, X=H, Y=OH, n=
5, free form) (0.8 g) was obtained as colorless needle crystals. Melting point: 119°-125°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1710
(COOH), 1610 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 8.7−8.0 (CH ₂ , multiplet), 8.0−7.3
(CH ₂ , multiplet), 7.86 (nuclear CH ₃ , singlet), 7.75
(nuclear CH ₃ , singlet), 7.47 (nuclear CH ₃ , singlet),
7.06 (CH ₂ , triplet), 3.46 (nuclear proton, singlet) Elemental analysis C ₁₆ H ₂₂ O ₄ Calculated value C 69.04, H 7.97 Actual value C 69.12, H 7.75 Reference example 3 (1) 2, 3, 5 -Trimethylphenol (in the formula, R=H ₃ C, When treated in the same manner as ethyl 9-(2'-hydroxy-
3′,4′,6′-trimethylbenzoyl)nonanoate (-1, where R=H ₃ C, X=H, Y=
OH, n=8, ethyl ester) (2 g) is obtained as colorless needles. Melting point: 48°-50°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450 (OH),
1735 (COOC ₂ H ₅ ), 1610 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 9.0−8.0 (CH ₂ , multiplet), 8.76 (CH ₃ ,
triplet), 8.0−7.4 (CH ₂ , multiplet), 7.88 (nuclear
CH ₃ , singlet), 7.78 (nuclear CH ₃ , singlet), 7.49
(Nuclear CH ₃ , singlet), 7.04 (CH ₂ , triplet), 5.87
(OCH ₃ , quartet), 3.47 (nuclear proton, singlet) Elemental analysis C ₂₁ H ₃₂ O ₄ Calculated value C 72.38, H 9.26 Actual value C 72.32, H 9.56 (2) Refer to this product (1.4 g) When hydrolyzed by the method of Example 1 (2), 9-(2'-hydroxy-3',4',6'-trimethylbenzoyl)nonanoic acid (-1 in the formula
R=H ₃ C, X=H, Y=OH, n=8, free form) (1.2 g) is obtained as colorless needles. melting point
97°−100℃. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450 (OH),
1710 (COOH), 1610 (CO). Nuclear magnetic resonance spectrum (τ value in deuterated chloroform): 8.9−8.0 (CH ₂ , multiplet), 8.0−7.3
(CH ₂ , multiplet), 7.85 (CH ₃ , singlet), 7.77 (nuclear
CH ₃ , singlet), 7.47 (nuclear CH ₃ , singlet), 7.07
(CH ₂ , triplet line), 3.45 (nuclear proton, singlet line) Elemental analysis C ₁₉ H ₂₈ O ₄ Calculated value C 71.22, H 8.81 Actual value C 71.10, H 8.97 Reference example 4 (1) Aluminum chloride (4.08 g) , ethyl 9-
Chloroformyl nonanoate (3.52g) and 3,
4,5-trimethoxytoluene (wherein R=
Add H ₃ CO, X=H, Y=H ₃ CO) (2.21 g) little by little to a solution of nitrobenzene (20 ml) under ice cooling. After stirring at 0°C for 16 hours and at room temperature for 1.5 hours, the mixture was acidified with dilute hydrochloric acid and extracted with ether.
The extract was subjected to hydrolysis silicic acid column chromatography according to the method of Reference Example 1 (2), and 9 was extracted from the fraction eluted with benzene-ether (9:1).
-(2',3',4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (-1 in the formula, R=H ₃ CO,
X=H, Y=OCH ₃ , n=8, free form) (1.82
9-(3',4'-dimethoxy-2'-hydroxy-6'-methylbenzoyl)nonanoic acid (-1, where R=H ₃ CO, X=H, Y=OH,
n=8, free form) (0.67 g) is obtained as colorless needles. Melting point: 75°-76.5°C. Elemental analysis C ₁₉ H ₂₈ O ₆ Calculated value C 64.75, H 8.01 Actual value C 64.87, H 8.06 Reference example 5 3,4,5-trimethoxytoluene (in the formula,
R=H ₃ CO, X=H, Y=H ₃ CO) (2.09 g) and ethyl 5-chloroformylpentanoate (2.66
g) is treated in the same manner as in Reference Example 4, 5-(3',
4'-dimethoxy-2'-hydroxy-6'-methylbenzoyl)pentanoic acid (-1, where R=
H ₃ CO, X=H, Y=OH, n=4, free form)
(1.97 g) Obtained as light brown needles. Melting point 111゜−
112℃. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3250 (OH),
1740 (COOH), 1615 (CO). Elemental analysis C ₁₅ H ₂₀ O ₆ Calculated value C 60.80, H 6.80 Actual value C 60.69, H 6.75 Reference example 6 3,4,5-trimethoxytoluene (in the formula,
R=H ₃ CO, X=H, Y=H ₃ CO) (3.65 g) and succinic anhydride (2.4 g) were dissolved in nitrobenzene (10
ml) and tetrachloroethane (30 ml), and add aluminum chloride powder (7.2 g) little by little while stirring under ice-cooling. Then, the mixture was left at room temperature for 4 days, diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ether. Extract the ether layer with 10% sodium carbonate solution. The sodium carbonate extract is washed with ether to remove nitrobenzene and tetrachloroethane, and the aqueous layer is acidified with dilute hydrochloric acid. The precipitated oil was extracted with ethyl acetate, washed with water, dried,
The solvent is distilled off under reduced pressure. The residue was recrystallized from methanol to give 3-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)propionic acid (
-1, where R=H ₃ CO, X=H, Y=OH, n=
2. Free form) (1 g) was obtained as pale yellow crystals. melting point
145°−147°C. Elemental analysis C ₁₈ H ₁₆ O ₆ Calculated value C 58.20, H 6.01 Actual value C 58.07, H 5.98 Reference example 7 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (-1 In the formula, R=
H ₃ C, X=H, Y=OH, n=4, free form) (262
mg), water (16 ml), toluene (20 ml), concentrated hydrochloric acid (4
ml), zinc amalgam made from zinc (2 g) and refluxed for 16 hours. Meanwhile, concentrated hydrochloric acid (6 ml)
Add in 3 times. After cooling, dilute with water and extract with ether. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain 6-(2'-hydroxy-3',
4′,6′-trimethylphenyl)hexanoic acid (−
In formula 2, R=H ₃ C, X=H, Y=OH, n=4,
Free form) (251 mg) is obtained as colorless needles. melting point
96°−108°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400 (OH),
1700 (COOH). Nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.8−8.0 (CH ₂ , multiplet), 7.9−7.2 (CH ₂ , multiplet), 7.90 (nuclear CH ₃ , singlet), 7.80 (nuclear CH ₃ , singlet), 3.41 (nuclear proton, Singlet) Elemental analysis C ₁₅ H ₂₂ O ₃ Calculated value C 71.97, H 8.86 Actual value C 71.67, H 9.02 Reference example 8 6-(2′-hydroxy-3′,4′,6′-trimethylbenzoyl)hexanoic acid (-1, where R=
H ₃ C, X=H, Y=OH, n=5, free form) (326
mg) was reduced according to Reference Example 7, resulting in 7-
(2'-Hydroxy-3',4',6'-trimethylphenyl)heptanoic acid (-2, where R=H ₃ C, X=
H, Y=OH, n=5, free form) (250 mg) is obtained as colorless needles. Melting point: 91°-104°C Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450 (OH),
1710 (COOH) Nuclear magnetic resonance spectrum (τ in deuterated chloroform
Values): 8.9−8.1 (CH ₂ , multiplet), 8.0−7.2 (CH ₂ , multiplet), 7.87 (nuclear CH ₃ , singlet), 7.78 (nuclear CH ₃ , singlet), 3.42 (nuclear proton, Singlet) Elemental analysis C ₁₆ H ₂₄ O ₃ Calculated value C 72.69, H 9.15 Actual value C 72.48, H 9.08 Reference example 9 9-(2'-hydroxy-3',4',6'-trimethylbenzoyl)nonanoic acid (-1, where R=H ₃ C,
When X=H, Y=OH, n=8, free form) (1.1 g) was reduced according to the method of Reference Example 7, 10-
(2'-Hydroxy-3',4',6'-trimethylphenyl)decanoic acid (-2, where R=H ₃ C, X=H,
Y=OH, n=8, free form) (0.4 g) is obtained as a colorless oil. Reference example 10 9-(3',4'-dimethoxy-2'-hydroxy-
6′-methylbenzoyl)nonanoic acid (-1 in the formula,
R=H ₃ CO, X=H, Y=OH, n=8, free form)
(254 mg), zinc amalgam (560 mg), toluene (1 ml), 35% hydrochloric acid (0.5 ml) and a small amount of water are refluxed for 15 hours. The toluene layer was separated, the aqueous layer was extracted with ether, the toluene and ether solutions were combined, washed with water, dried, and the solvent was evaporated to dryness under reduced pressure. The resulting residue was recrystallized from ligroin to form colorless powder crystals.
-(3',4'-dimethoxy-2'-hydroxy-6'-methylphenyl)decanoic acid (-2, where R=
H ₃ CO, X=H, Y=OH, n=8, free form)
(140mg) is obtained. Melting point 62.5°-66°C Nuclear magnetic resonance spectrum (τ in deuterated chloroform
value): 8.80−8.13 (CH ₂ , multiplet), 7.78 (nuclear CH ₃ ,
singlet), 7.57 (COCH ₂ , CH ₂ CO, triplet), 6.20
(OCH ₃ singlet), 6.16 (OCH ₃ , singlet), 4.77 (nuclear proton, singlet) Elemental analysis C ₁₉ H ₃₀ O ₅ Calculated value C 67.43, H 8.94 Actual value C 67.50, H 8.89 Reference example 11 5 -(3',4'-dimethoxy-2'-hydroxy-
When 6'-methylbenzoyl)pentanoic acid (-1 formula, R=H ₃ CO, X=H, Y=OH, n=4, free form) (149 mg) was reduced according to Reference Example 10, 6- (3′,4′-dimethoxy-2′-hydroxy-
6'-methylphenyl)hexanoic acid (-2 in the formula,
R=H ₃ CO, X=H, Y=OH, n=4, free form)
(60 mg) is obtained as colorless crystals. Melting point: 38°-44°C. Elemental analysis C ₁₅ H ₂₂ O ₅ Calculated value C 63.81, H 7.85 Actual value C 63.54, H 7.70 Reference example 12 3-(2'-hydroxy-3',4'-dimethoxy-
6′-Methylbenzoyl)propionic acid (-1 formula, R=H ₃ CO, X=H, Y=OH, n=2, free form) (536 mg), zinc amalgam (1 g), concentrated hydrochloric acid (1 ml) A mixture of , water (2 ml) and toluene (2 ml) is heated to reflux for 5 hours. After cooling, the reaction mixture was extracted with ether, washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-hexane to give 4-(3',4'-dimethoxy-2'-hydroxy-6'-
methylphenyl)butyric acid (-2, where R=
H ₃ CO, X=H, Y=OH, n=2, free form)
(340 mg) was obtained as colorless needle-like crystals. Melting point: 98°-100°C. Elemental analysis C ₁₃ H ₁₈ O ₅ Calculated value C 61.40, H 7.14 Actual value C 61.35, H 7.01 Reference example 13 9-(3',4'-dimethoxy-2'-hydroxy-
6′-methylbenzoyl)nonanoic acid (-1 in the formula,
R=H ₃ CO, X=H, Y=OH, n=8, free form)
(197 mg) was dissolved in saturated CH ₃ OH-HCl (7 ml) and stirred at room temperature for 20 minutes. The residue obtained by distilling off CH ₃ OH under reduced pressure was recrystallized from hexane-ether to give methyl 9-(3',4'-dimethoxy-2'-hydroxy-6'-methylbenzoyl) nonanoate (-1 In the formula, R=H ₃ CO, X=H, Y=OH, n
=8, methyl ester) (195 mg) is obtained as colorless needles. Melting point: 49°-53°C Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1740
(COOCH ₃ ), 1620 (CO) nuclear magnetic resonance spectrum (τ in deuterium chloroform
value): 8.82−8.13 (CH ₂ , multiplet), 7.68 (CH ₂ CO,
triplet), 7.57 (CH ₃ , singlet), 7.10 (COCH ₂ , triplet), 6.33 (COOCH ₃ , singlet), 6.15 (OCH ₃ singlet), 6.10 (OCH ₃ , singlet), 3.67 ( nuclear proton,
Singlet), -0.03 (OH, singlet) Elemental analysis C ₂₀ H ₃₀ O ₆ Calculated value C 65.55, H 8.25 Actual value C 65.58, H 8.17 Reference example 14 Methyl 9-(3',4'-dimethoxy-2 '-Hydroxy-6'-methylbenzoyl) nonanoate (-
In formula 1, R=H ₃ CO, X=H, Y=OH, n=8,
A solution of methyl ester (120 mg) in acetic acid (17 ml) was shaken in a hydrogen stream at 50°-60°C in the presence of 5% palladium on carbon. The catalyst was filtered off and acetic acid was distilled off under reduced pressure.
The residue was subjected to column chromatography using silicic acid (6 g) and eluted with chloroform to yield methyl 10
-(3',4'-dimethoxy-2'-hydroxy-6'-methylphenyl)decanoate (-2, where R=
H ₃ CO, X=H, Y=OH, n=8, methyl ester) (90 mg) is obtained as a colorless oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3450 (OH),
1740 (COOCH ₃ ) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
value): 8.90−8.13 (CH ₂ , multiplet), 7.83−7.43 (nuclear
CH ₃ , CH ₂ CO, multiplet), 7.73 (nuclear CH ₃ , singlet), 6.37 (COOCH ₃ , singlet), 6.20 (OCH ₃ , singlet), 6.15 (OCH ₃ , singlet), 4.20 ( OH, singlet), 3.73 (nuclear proton, singlet) Reference example 15 5-(2'hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (-1, where R=H ₃ C,
X=H, Y=OH, n=4, free form) (48 mg)
Potassium nitrosodisulfonate (0.4%) dissolved in 0.5% NaOH solution (3.3ml) and stirred at 20°C
Add g) and stir for 10 minutes. The reaction solution was diluted with cold water (100 ml) under ice cooling to make dilute acidic acid, and then
Extract with ether. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane-ethyl acetate (2:1) to give 2,3,5-trimethyl-6-(5'-carboxy-1 '-oxopentyl)-1,4-benzoquinone (-1 in the formula,
R=H ₃ C, n=4, free form) (42 mg) is obtained as yellow needles. Melting point: 96.5°-98.5°C. Reference example 16 5-(3',4'-dimethoxy-2'-hydroxy-
6'-Methylbenzoyl)pentanoic acid (-1 formula, R = H ₃ CO, X = H, Y = OH, n = 4, free form) (57 mg) was oxidized according to Reference Example 15,
2,3-dimethoxy-5-methyl-6-(5'-carboxy-
1′-oxopentyl)-1,4-benzoquinone (-1, R=H ₃ CO, n=4, free form) (32
mg) as orange-red crystals. Melting point: 48°-54°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1710
(COOH), 1710 (CO), 1675, 1655, 1610 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.31 (CH ₂ , multiplet), 8.07 (CH ₃ , singlet),
7.63 (CH ₂ CO, multiplet), 7.35 (COCH ₂ , multiplet),
6.01 (OCH ₃ , singlet) Elemental analysis C ₁₅ H ₁₈ O ₇ Calculated value C 58.06, H 5.85 Actual value C 57.89, H 5.90 Reference example 17 2,3-dimethoxy-5-methyl-6-(5'-
Carboxy-1'-oxopentyl)-1,4-benzoquinone (-1, where R=H ₃ CO, n=4,
A zinc amalgam made from free form) (12 mg), toluene (1 ml), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and zinc (0.1 g) was added and refluxed for 20 hours. After cooling, it was extracted with ether, washed with water, dried, and the solvent was distilled off under reduced pressure to give 2,3-dimethoxy-5-methyl-6-
(5′-carboxypentyl)hydroquinone (-
In formula 2, R=H ₃ CO, X=, Y=OH, n=4,
free form). Infrared absorption spectrum ν ^film _nax cm ^-1 : 3500 (OH),
1715 (COOH) Nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.75−8.20 (CH ₂ , multiplet), 7.87 (CH ₃ , singlet), 7.75−7.27 (nuclear CH ₂ , CH ₂ COO, multiplet),
6.13 (OCH ₃ , singlet) Reference example 18 2,3,5-trimethyl-6-(5'carboxy-1'-oxopentyl)-1,4-benzoquinone (-1, where R=H ₃ C, n=4, free form) (10
mg) in acetic acid (2 ml) was added to palladium-carbon (12
Stir at 65°-70°C for 4 hours in the presence of 50 mg) in a hydrogen stream. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to produce 2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (-2, where R=
H ₃ C, X=Y=OH, n=4, free form) (9 mg)
is obtained. Melting point: 145°-153°C. Reference example 19 2,3-dimethoxy-5-methyl-6-(5'-
Carboxy-1'-oxopentyl)-1,4-benzoquinone (-1, where R=H ₃ CO, n=4,
Dissolve free form (26 mg) in a mixture of ether (2 ml) and ethyl acetate (2 ml), add hydrosulfite (300 mg) dissolved in water (5 ml), and shake. The organic layer was separated, washed with water, dried, and the solvent was distilled off under reduced pressure to give 2,3-dimethoxy-5-methyl-6-
(5'-carboxy-1'-oxopentyl)hydroquinone (-1, where R=H ₃ CO, X=Y=OH,
n=4, free form) was obtained as pale yellow crystals. melting point
110°-115°C. Reference example 20 2,3,5-trimethyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone (-1 formula, R=H ₃ C, n=4, free form)
(10 mg) was reduced according to Reference Example 19, and 2,3,5-
Trimethyl-6-(5'-carboxy-1'-oxopentyl)hydroquinone (-1, where R=
H ₃ C, X=Y=OH, n=4, free form) was obtained as pale yellow crystals. Melting point: 106°-108°C. Reference example 21 2,3-dimethoxy-5-methyl-6-(5'-
carboxypentyl)-1,4-benzoquinone (-2, R=H ₃ CO, n=4, free form) (84
mg) of hydrosulfite (1 mg) in ether.
Shake and mix with aqueous solution (10 ml) of g), separate the ether layer, and treat by conventional method to obtain 2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl).
Hydroquinone (-2 in the formula, R=H ₃ CO, X=Y
=OH, n=4, free form) 69 mg was obtained as a colorless oil. Reference Example 22 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2 formula, R=H ₃ C, n=4, free form) was added to Reference Example 21. Similar reduction was performed to produce 2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (-2 in the formula,
R=H ₃ C, n=4, free form) was obtained as colorless crystals.
Melting point: 145°-153°C. Reference example 23 6-(3',4'-dimethoxy-2'-hydroxy-
6'-methylphenyl)hexanoic acid (-2 in the formula,
R=H ₃ CO, X=H, Y=OH, n=4, free form)
Dissolve in a 5% sodium hydroxide solution, add an aqueous solution of potassium persulfate, and stir at room temperature for 24 hours. The reaction solution was acidified with hydrochloric acid and extracted with ether. The ether extract was treated in a conventional manner to obtain 2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl).
Hydroquinone (-2 in the formula, R=H ₃ CO, X=Y
=OH, n=4, free form) was obtained as a colorless oil. Reference example 24 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (-2 in the formula, R=H ₃ C,
X=H, Y=OH, n=4, free form) as reference example 23
2,3,5-trimethyl-6-
(5′-carboxypentyl)hydroquinone (-
2, R=H ₃ C, X=Y=OH, n=4, free form) was obtained as colorless crystals. Melting point: 145°-153°C. Reference example 25 6-(2′-hydroxy-3′,4′,6′-trimethylphenyl)hexanoic acid (-2 in the formula, R=H ₃ C,
Potassium nitrosodisulfonate (900 mg) was added to a solution of X=H, Y=OH, n=4, free form) (111 mg) in 1% sodium hydroxide (5 ml) and water (3 ml), and the mixture was stirred at room temperature. 0 after stirring for 30 minutes
Cool to ℃, add cold water (50 ml), and acidify with dilute hydrochloric acid to form a yellow precipitate. When this precipitate was recrystallized from hexane-ethyl acetate (10:1), 2,3,5
-trimethyl-6-(5'-carboxypentyl)-
1,4-benzoquinone (-2 in the formula, R=H ₃ C,
n=4, free form) (110 mg) is obtained as yellow needles. Melting point: 81°-82°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1705
(COOH), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.8-8.1 (CH ₂ , multiplet), 8.00 (nuclear CH ₃ , singlet), 7.9-7.3 (CH ₂ , multiplet) Elemental analysis C ₁₅ H ₂₀ O ₄ Calculated value C 68.16, H 7.63 Actual measurement Value C 68.19, H 7.61 Reference example 26 7-(2'-hydroxy-3',4',6'-trimethylphenyl)heptanoic acid (-2, where R=H ₃ C,
When X=H, Y=OH, n=5, free form) (102 mg) was oxidized according to the method of Reference Example 25, 2,3,
5-trimethyl-6-(6'-carboxyhexyl)
-1,4-benzoquinone (-2, where R=
H ₃ C, n=5, free form) (82 mg) is obtained as yellow needles. Melting point: 71°-72°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1710
(COOH), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.9-8.1 (CH ₂ , multiplet), 7.98 (nuclear CH ₃ , singlet), 7.9-7.3 (CH ₂ , multiplet) Elemental analysis C ₁₆ H ₂₂ O ₄ calculated value C 69.04, H 7.97 Actual measurement Value C 69.08, H 8.04 Reference example 27 10-(2'-hydroxy-3',4',6'-trimethylphenyl)decanoic acid (-2, R=H ₃ C,
=H, Y=OH, n=8, free form) (0.4g) was oxidized according to the method of Reference Example 25 to produce 2,3,5
-trimethyl-6-(9'-carboxynonyl)-
1,4-benzoquinone (-2 in the formula, R=H ₃ C,
n=8, free form) (147 mg) is obtained as a yellow oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 1705
(COOH), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.9-8.1 (CH ₂ , multiplet), 8.00 (nuclear CH ₃ , singlet), 8.0-7.3 (CH ₂ , multiplet) Elemental analysis C ₁₉ H ₂₈ O ₄ calculated value C 71.22, H 8.81 Actual measurement Value C 71.19, H 8.80 Reference example 28 10-(3',4'-dimethoxy2'-hydroxy-6'-
methylphenyl)decanoic acid (-2, where R=
H ₃ CO, X=H, Y=OH, n=8, free form) (97
A solution of potassium nitrosodisulfonate (800 mg) in water (10 ml) was added to a mixed solution of 1% sodium hydroxide solution (0.67 ml) and acetone (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was made acidic with dilute hydrochloric acid and then extracted with ether. The extract was washed with water, dried, and then evaporated to dryness to give 2,3-dimethoxy-5.
-Methyl-6-(9'-carboxynonyl)-1,4
-Benzoquinone (-2 in the formula, R=H ₃ CO, n=
8, free form) (99 mg) was obtained as orange needles.
Melting point: 59°-60.5°C. Nuclear magnetic resonance spectrum (τ in deuterated chloroform
value): 8.82−8.25 (CH ₂ , multiplet), 8.00 (nuclear CH ₃ ,
singlet), 7.65 (nuclear CH ₂ , CH ₂ CO, triplet), 6.03
(OCH ₃ , singlet), 0.22 (COOH, wide range) Elemental analysis C ₁₉ H ₂₈ O ₆ Calculated value C 64.75, H 8.01 Actual value C 64.27, H 8.24 Reference example 29 6-(3',4'-dimethoxy- 2'-Hydroxy-
6'-methylphenyl)hexanoic acid (-2 in the formula,
R=H ₃ CO, X=H, Y=OH, n=4, free form)
(84mg) was oxidized according to Reference Example 28 to produce 2,3-
Dimethoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2 in the formula,
R=H ₃ CO, n=4, free form) (76 mg) was obtained as orange granular crystals. Melting point: 82°-86°C. Nuclear magnetic resonance spectrum (τ in deuterated chloroform
value): 8.73−8.20 (CH ₂ , multiplet), 7.97 (nuclear CH ₃ ,
singlet), 7.60 (nuclear CH ₂ , CH ₂ CO, triplet), 6.00
(OCH ₃ , singlet), -0.55 (COOH, wide range) Elemental analysis C ₁₅ H ₂₀ O ₆ Calculated value C 60.80, H 6.80 Actual value C 60.60, H 6.81 Reference example 30 4-(3',4'-dimethoxy -2′-hydroxy-
6'-methylphenyl)butyric acid (-2, where R=
H ₃ CO, X=H, Y=OH, n=2, free form)
(254 mg) was oxidized according to Reference Example 28 to produce 2,3-
dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (-2 in the formula,
R=H ₃ CO, n=2, free form) (220 mg) is obtained as orange needles. Melting point: 74°-75°C. Elemental analysis C ₁₃ H ₁₆ O ₆ Calculated value C 58.20, H 6.01 Actual value C 58.03, H 5.77 Reference example 31 Methyl 10-(3',4'-dimethoxy-2'-hydroxy-6'-methylphenyl)decanoate (- 2
In the formula, R=H ₃ CO, X=H, Y=OH, n=8,
2,3-dimethoxy-5-methyl-6-
(9'-Methoxycarbonylnonyl)-1,4-benzoquinone (-2 in formula R=H ₃ CO, n=8, methyl ester) is obtained as orange needles. melting point
37°−37.5℃. Elemental analysis C ₂₀ H ₃₀ O ₆ Calculated value C 65.55, H 8.25 Actual value C 65.44, H 8.36 Reference example 32 2,3-dimethoxy-5-methyl-6-(5'-
carbonylpentyl) hydroquinone (-2 formula, R=H ₃ CO, X=Y=OH, n=4, free form)
Add 10% ferric chloride solution (15 ml) to (8 mg) and shake. Extract with ether, wash the extract with water, dry and evaporate under reduced pressure. The residue was subjected to column chromatography using silicic acid (1 g), and the fraction eluted with chloroform-ethanol (49:1) was recrystallized from ether-hexane to give 2,3-dimethoxy-5-methyl- 6-(5'-carboxypentyl)-1,4-benzoquinone (-2, where R
=H ₃ CO, n=4, free form) (6.7 mg) is obtained as orange crystals. Melting point: 83°-85°C. Reference example 33 2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (-2, where R=
Dissolve 9 _mg of H 3 C, 6 mg of 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2 formula, R= _H3C , n=4, free form) was obtained as a yellow oil. Reference example 34 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2 formula, R = H ₃ C, n = 4, free form) (1.0 g) and A solution of acid chloride (1.01 g) synthesized from oxalyl chloride (5 ml) in dry benzene (10 ml),
salicylaldehyde (0.6g) in pyridine (10ml)
Add dropwise to the solution at 25°C. After stirring for 2.5 hours,
The reaction solution was diluted with cold water (300 ml), diluted with dilute hydrochloric acid, and extracted twice with ether (300 ml). The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with chloroform to give 2,3,5-trimethyl-6-[5'-( o-Formylphenyl)oxycarbonylpentyl]-1,4-benzoquinone (-2 in which R= _H3C , n=4, o-formylphenolate) (1.3 g) is obtained as a yellow oil. Add standard Jones reagent (2 ml) to a solution of this product (1.1 g) in acetone (25 ml) while stirring while cold, stir for 100 minutes, dilute with cold water (500 ml), and extract with ethyl acetate (500 ml). After washing the extract with water and drying, the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography using silica gel (50 g) to obtain 2,3,5-trimethyl-6-[5'-( o-carboxyphenyl)oxycarbonylpentyl]-1,4-benzoquinone (-2 in which R= _H3C , n=4, o-carboxyphenolate) (1.1 g) is obtained as a yellow oil. Reference example 35 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2 formula, R = H ₃ C, n = 4, free form) (200 mg), chloride Benzyl (400 mg) and silver oxide (283 mg) are heated to reflux in benzene for 19 hours. Insoluble matters were removed by filtration, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography.
(5'-benzyloxycarbonylpentyl)-1,
4-benzoquinone (-2 in the formula, R=H ₃ C, n=
4, benzyl ester) was obtained as a yellow oil. yield
189mg Reference example 36 2,3-dimethoxy-5-methyl-6-(9'-
carboxynonyl)-1,4-benzoquinone (
-2 formula, R = H ₃ CO, n = 8, free form) (40 mg)
When esterified with CH ₃ OH-HCl (5 ml) according to Reference Example 13, 2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,
4-benzoquinone (-2, where R=H ₃ CO, n
=8, the methyl ester (42 mg) is obtained as orange needles. Reference example 37 2,3-dimethoxy-5-methyl-6-(9'-
Methoxycarbonylnonyl)-1,4-benzoquinone (-2, R=H ₃ CO, n=8, methyl ester) (17 mg), pyrogallol (160 mg) in methanol solution with 10% methanolic potassium hydroxide (4 ml) ) and heated under reflux for 2 hours. The reaction solution was made acidic with hydrochloric acid and extracted with ether. The ether extract was shaken with a 10% ferric chloride solution, the ether layer was separated, washed with water, and after drying, the ether was distilled off under reduced pressure.
2,3-dimethoxy-5-methyl-6-(9'-carbonylnonyl)-1,4-benzoquinone(-
In formula 2, 8 mg of R=H ₃ CO, n=8, free form) was obtained. Reference example 38 9-(2',3',4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (-1, where R=Y=
H ₃ CO, X=H, n=8, free form) 9mg as a reference example
10 using zinc amalgam (20 mg), followed by oxidation with 30% hydrogen peroxide in acetic acid (1 ml). Water was added to the resulting reaction solution and ether (50%
ml), the extract was washed with water, dried, and the ether was distilled off to give 2,3-dimethoxy-5-methyl-6
-(9'-carboxynonyl)-1,4-benzoquinone (-2 formula, R=H ₃ CO, n=8, free form)
I got it. Reference Example 39 Disebacoyl peroxide diethyl ester (920 mg) was added to a solution of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (in the formula, R=H ₃ CO) (364 mg) in acetic acid (2 ml) at 85°C. ) little by little,
Stir for another 2 hours at 85°C. After cooling, water was added to the reaction mixture and extracted with ether. The ether extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and then the ether was distilled off under reduced pressure. The obtained orange oil was subjected to column chromatography using silica gel and eluted with hexane-ether to obtain 2,3-dimethoxy-5-methyl-6-
(8'-Ethoxycarbonyloctyl)-1,4-benzoquinone (-2, where R=H ₃ CO, n=7,
ether ester) (179 mg) was obtained as an orange oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 1730 (ester), 1660, 1650, 1615 (quinone) Nuclear magnetic resonance spectrum (τ in carbon tetrachloride
Value): 8.76 (CH ₃ , triple line), 8.66 (CH ₂ , wide range),
8.04 (nuclear CH ₃ , singlet), 7.77 (nuclear CH ₂ , triplet),
7.80-7.37 (CH ₂ COO, wide range), 6.05 (CH ₃ O, singlet), 5.95 (COOCH ₂ , quartet) Elemental analysis C ₂₀ H ₃₀ O ₆ Calculated value C 65.55, H 8.25 Actual value C 65.02, H 8.07 2,3-dimethoxy-5-methyl-6-(8'-
30% potassium hydroxide solution containing hydrosulfite in an ether solution (1 ml) of ethoxycarbonyloctyl)-1,4-benzoquinone (-2, R = H ₃ CO, n = 7, ether ester) (80 mg) (2 ml) and heated under reflux for 1 hour. After cooling, the reaction solution was acidified with hydrochloric acid and extracted with ether. Wash the ether extract with water and shake it with the ferric chloride solution. The ether layer was washed with water, dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. The obtained residue was crystallized from ether-hexane to give 2,3-dimethoxy-5-methyl-6-(8'-carboxy-
octyl)-1,4-benzoquinone (-2 in the formula,
R=H ₃ CO, n=7, free form) (53 mg) is obtained as orange needles. Melting point: 39°-40.5°C. Elemental analysis C ₁₈ H ₂₆ O ₆ Calculated value C 63.88, H 7.74 Actual value C 63.60, H 7.88 Reference example 40 Ether 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoate (-1 A solution of R=H ₃ C, X=H, Y=OH, n=4, eral ester) (0.4 g) in tetrahydrofuran (100 ml) was refluxed with lithium aluminum hydride (0.5 g) under heating for 1 hour. . Hydrous ethyl acetate is added to decompose the excess lithium aluminum hydride, and a saturated solution of sodium sulfate (5 ml) is added. The formed inorganic salt was filtered off, the filtrate was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to give 1-
(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (-3 in the formula,
R=H ₃ C, X=H, Y=OH, n=4, free form)
(032g) is obtained as colorless needles. Melting point 135゜−
136℃. Elemental analysis C ₁₅ H ₂₄ O ₃ Calculated value C 71.39, H 9.59 Actual value C 71.38, H 9.54 Reference example 41 5-(2'-Hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (-1, where R=
H ₃ C, X=H, Y=OH, n=4, free form) (4.9
A solution of g) in dry tetrahydrofuran (10ml) is added at room temperature. Stir under reflux for 2 hours and bring the mixture to 0.
Cool to ℃. Acidify with cold dilute hydrochloric acid and extract with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was subjected to silica gel column chromatography and eluted with carbon tetrachloride-acetone (5:1). From the first flank, 6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (-3, where R=H ₃ C, X=H, Y =OH,n
=4, free form) (0.45 g) is obtained as colorless needles. Melting point: 165°-166°C. Elemental analysis C ₁₅ H ₂₂ O ₄ Calculated value C 67.64, H 8.33 Actual value C 67.63, H 8.13 From the second fraction, 1-(2'-hydroxy
3′,4′,6′-trimethylphenyl)-1,6-hexanediol (-3, where R=H ₃ C, X=H,
Y=OH, n=4, free form) (2.5 g) is obtained.
This compound was consistent with the compound obtained in Reference Example 40. Reference example 42 6-hydroxy-6-(2'-hydroxy-3',
4′,6′-trimethylphenyl)-1,6-hexanoic acid (-3, where R=H ₃ C, X=H, Y=
OH, n=4, free form) (0.158 g) was dissolved in 5% sodium hydroxide solution (2 ml) and water (7 ml), and potassium nitrosodisulfonate (1
g) is added with stirring at room temperature. After stirring for 1 hour, the mixture is cooled to 0° C., acidified with cold dilute hydrochloric acid, and extracted with ether acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to silica gel column chromatography,
Elute with chloroform-methanol (20:1). The product was recrystallized from ethyl acetate-hexane (1:2) to give 2,3,5-trimethyl-6-(5'-
Carboxy-1'-hydroxypentyl)-1,4
-Benzoquinone (-3 in the formula, R=H ₃ C, n=
4. Free form) (0.128 g) was obtained as brown needle crystals. Melting point 130-131.5℃. Elemental analysis C ₁₅ H ₂₀ O ₅ Calculated value C 64.27, H 10.24 Actual value C 64.03, H 7.22 Reference example 43 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6 -hexanediol (-3
An acetic acid solution (150 ml) of R=H ₃ C, X=H, Y=OH, n=4, free form) (5.43 g) was added to 5% palladium-carbon (4.79 g) at room temperature in a hydrogen stream. and stir until absorption of hydrogen gas is completed. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue was subjected to silica gel column chromatography and chloroform-
Elute with methanol (100:1). From the first fraction, 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (-2 in the formula,
R=H ₃ C, X=H, Y=OH, n=4, free form)
(0.872 g) are obtained as colorless needles. melting point 81
−82℃. Elemental Analysis C ₁₅ H ₂₄ O ₂ Calculated C 76.22, H 10.24 Found C 76.08, H 10.33 Starting material (2.31 g) is recovered from the second fraction. Example 1 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (-2, where R=
H ₃ C, X=H, Y=OH, n=4, free form) (0.02
Add potassium nitrosodisulfonate (0.2 g) to a solution of g) in 1% sodium hydroxide (25 ml) at room temperature with stirring. After stirring for 1 hour, the mixture was
Cool to °C, acidify with cold dilute sulfuric acid, and extract with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (-2, where R=H ₃ C, n=4, free form) (0.02 g) is obtained as yellow needles.
Melting point 43-45℃. Example 2 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (-3
where R=H ₃ C, X=H, Y=OH, n=4, free form) (0.32 g) in dimethylformamide (20 ml)
Potassium nitrosodisulfonate (0.5g) in the solution,
Add a solution of dipotassium phosphate (0.5 g) in water (50 ml) all at once. The mixture is stirred at room temperature for 3 hours and the product is extracted with diethyl ether. The diethyl ether layer is washed with water and dried over anhydrous sodium sulfate. The residue after evaporation of the solvent was subjected to silica gel chromatography and eluted with acetic acid ether-diethyl ether (4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1. ,4
-Benzoquinone (-3 in the formula, R=H ₃ C, n=
4, free form) (0.26 g) was obtained as a yellow oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3400 (OH),
1640 (quinone) nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.55 (CH ₂ , broad) 8.00 (nuclear CH ₃ , singlet), 6.40 (nuclear CH ₂ , triplet), 5.35 (CH-O, broad) Mass spectrum (m/e) C ₁₅ H ₂₂ O ₄ :M ⁺
(266) Reference example 44 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (
-3 formula, R = H ₃ C, n = 4, free form) (1.17 g)
Acetic anhydride (0.473
A solution of g) in pyridine (5 ml) was added dropwise at 5°C with stirring. The mixture was left overnight at room temperature, the solvent was distilled off, and the residue was chromatographed on silica gel.
The two fractions were separated and eluted with methylene chloride-diethyl ether (9:1). From the first fraction 2,3,5-trimethyl-6-(1',
6'-diacetoxyhexyl)-1,4-benzoquinone (-3, where R=H ₃ C, n=4, -
CH ₂ OH and diacetate in the moiety of -CH- | OH) (0.265 g) is obtained as a yellow oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 1740, 1370,
1250, 1040 (OCOCH ₃ ), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.50 (CH ₂ , broad), 7.99, 7.98, 7.95,
6.85 (nuclear _CH3 , _OCOCH3 ), 5.96 ( _CH2 -O, triplet), 4.05 (CH-O, triplet) 2,3,5-trimethyl-6-(6 '-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone (-3, where R=H ₃ C, n=4, -
Acetate in CH ₂ OH) (0.769 g) is obtained as a yellow oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3500 (OH),
1740, 1250, 1040 (OCOCH ₃ ), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
value): 8.50 (CH ₂ , broad), 7.99, 7.98, 7.97 (nuclear
_CH3 , _OCOCH3 ), 5.96 ( _CH2 -O, triple line),
4.05 (CH-O, triplet) Mass spectrum (m/e) C ₁₇ H ₂₄ O ₅ :M ⁺
(308) Reference example 45 2,3,5-trimethyl-6-(6'-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone (-3, where R=H ₃ C, n=4, −
A solution of acetone (0.74 g) in CH ₂ OH in acetone (20 ml) was diluted with John's reagent (0.6 ml).
Oxidize for 5 minutes at °C. John's reagent is prepared by dissolving chromium trioxide (26.72 g) in concentrated sulfuric acid (23 ml) and adding water to make a total volume of 100 ml. Water is added to the reaction solution, and the product is extracted with diethyl ether. The organic layer is washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel chromatography and eluted with methylene chloride. Recrystallization from petroleum ether gives 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-
1,4-benzoquinone (-1 in the formula, R=H ₃ C,
n=4, acetate) (0.638 g) is obtained as yellow crystals. Melting point: 57℃. Mass spectrum (m/e) C ₁₇ H ₂₂ O ₅ :M ⁺
(306) Reference example 46 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (-1, where R=H ₃ C, n=4, acetate) (0.5 g), sodium hydrosulfite (1 g), and 30 g% aqueous methanol (20 ml) was added 2N aqueous sodium hydroxide (1.6 ml) at 5°C.
Drip with. After leaving the mixture at the same temperature for 3 hours, distilling off the methanol and acidifying with phosphoric acid, the product is extracted with ether acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to give 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)hydroquinone (-1, where R=H ₃ C, X=
Y=OH, n=4, acetate) (0.075 g) is obtained. Furthermore, by elution with the same solvent, 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)hydroquinone (-1, where R=H ₃ C, X=Y=OH, n = 4, free form)
(0.265g) is obtained. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3450 (OH),
1690 (quinone) nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.40 (CH ₂ , broad), 7.90 (nuclear CH ₃ , singlet), 7.83 (nuclear CH ₃ , singlet), 7.70 (nuclear CH ₃ , singlet), 7.15 (COCH ₂ , broad), 6.40 ( _CH2 -O,
Broad) Example 3 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)hydroquinone (-1
A solution of R=H ₃ C, X=Y=OH, n=4, free form) (0.1 g) in diethyl ether (10 ml) is stirred at room temperature for 2 hours with 3% aqueous ferric chloride. Separate the organic layer and extract the aqueous layer with ethyl acetate. The organic layer and ethyl acetate extract were combined and washed with water.
Dry over anhydrous sodium sulfate and evaporate to dryness. The residue was subjected to silica gel chromatography and eluted with diethyl ether to give 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl).
-1,4-benzoquinone (-1, where R=
H ₃ C, n=4, free form) (0.088 g) is obtained as a yellow oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3450 (OH),
1690 (CO), 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.50 (CH ₂ , broad), 8.06 (nuclear CH ₃ , singlet), 7.97 (nuclear CH ₃ , singlet), 7.40 (COCH ₂ , triplet), 6.37 (CH ₂ -O, triplet) Mass spectrum (m/e) C ₁₅ H ₂₀ O ₄ :M ⁺
(264) Reference example 47 2,3-dimethoxy-5-methyl-6-(3'-
carboxypropyl)-1,4-benzoquinone (-2 in the formula, R = H ₃ CO, n = 2, free form) (0.8
g) of ethanol saturated with dry hydrogen chloride (3
ml) The solution is stirred at room temperature for 1 hour. The residue after distilling off the solvent was subjected to silica gel chromatography,
Elution with chloroform yields 2,3-dimethoxy-
5-Methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (-2, where R
=H ₃ CO, n=2, ether ester) (0.88 g) is obtained as an orange oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 1730
(COOC ₂ H ₅ ), 1660, 1640, 1610 (quinone) Nuclear magnetic resonance spectrum (τ in deuterium chloroform
Value): 8.74 (CH ₃ , triplet), 8.56−8.00 (CH ₂ , multiplet), 7.96 (nuclear CH ₃ , singlet), 7.65 (CH ₂ COO,
triplet), 7.46 (nuclear CH ₂ , triplet), 5.99 (OCH ₃ ,
Singlet), 5.86 (COOCH ₂ , quartet) Elemental analysis C ₁₅ H ₂₀ O ₆ Calculated value C 60.80, H 6.80 Actual value C 61.26, H 7.12 Example 4 Diethyl ether of lithium aluminum hydride (0.5 g) 5 ml) solution of 2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (-2 in the formula,
R=H ₃ CO, n=2, ethyl ester) (0.78 g)
A solution of 1 in diethyl ether (10 ml) was added dropwise under ice-cooling and stirring. After stirring for 1 hour at room temperature, the mixture is acidified with dilute hydrochloric acid. Separate the diethyl ether layer and extract the aqueous layer with diethyl ether. The diethyl ether layer and the extract are combined and washed with water. After drying over anhydrous sodium sulfate and evaporating diethyl ether to dryness, 2,3-dimethoxy-5-methyl-
6-(4'-hydroxybutyl)-hydroquinone (
-2 formula, R= _H3CO , n=2, free form) is obtained. A solution of the above product in diethyl ether is stirred with 16% aqueous ferric chloride (10 ml). The diethyl ether layer is separated, washed with water, and dried over anhydrous sodium sulfate. The residue after removing the solvent was subjected to silica gel chromatography and eluted with chloroform to give 2,3-dimethoxy-5-methyl-6-
(4'-Hydroxybutyl)-1,4-benzoquinone (-2 formula, R=H ₃ CO, n=2, free form)
(0.52 g) of an orange oil is obtained. Infrared absorption spectrum ν ^film _nax cm ^-1 : 3400 (OH),
1660, 1640, 1610 (quinone) Nuclear magnetic resonance spectrum (τ in deuterated chloroform
values): 8.62−8.24 (CH ₂ , multiplet), 8.10 (OH, singlet), 7.98 (nuclear CH ₃ , singlet), 7.50 (nuclear CH ₂ , triplet), 6.32 (CH ₂ O, triplet) ), 6.00 (OCH ₃ , singlet) Elemental analysis C ₁₃ H ₁₈ O ₅ Calculated value C 61.40, H 7.14 Actual value C 61.47, H 7.32 Example 5 2,3-dimethoxy-5-methyl-6-(9' −
methoxycarbonyl)-1,4-benzoquinone(-
In formula 2, R=H ₃ CO, n=8, methyl ester)
(0.1 g) was treated with lithium aluminum hydride in the same manner as in Example 4 to produce 2,3-dimethoxy-5-
Methyl-6-(10′-hydroxydecyl)-hydroquinone (-2 in the formula, R=H ₃ CO, X=Y=OH,
n=8, free form) is obtained. This product was treated with ferric chloride as in Example 4 and recrystallized from ligroin, resulting in 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone ( - In formula 2, R=H ₃ CO, n=8,
Free form) (0.065 g) was obtained as orange needles. Melting point 46−50
°C Elemental analysis C ₁₉ H ₂₀ O ₅ Calculated value C 67.43, H 8.94 Actual value C 67.41, H 8.94 Reference example 48 2,3-dimethoxy-5-methyl-6-(10'-
Hydroxydecyl)-1,4-benzoquinone (
-2 formula, R=H ₃ CO, n=8, free form) (0.03
Add acetic anhydride (0.01 ml) to a solution of g) in pyridine (0.1 ml) under ice-cooling and stirring. After stirring for 1 hour at room temperature, the mixture is diluted with water and the aqueous solution is extracted with diethyl ether. The extract is thoroughly washed with water, dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and dried over anhydrous sodium sulfate. Recrystallization of the solvent-removed residue from aqueous ethanol yields 2,3-
Dimethoxy-5-methyl-6-(10'-acetoxydecyl)-1,4-benzoquinone (-2 in the formula,
R=H ₃ CO, n=8, acetate) (0.031 g) is obtained as orange crystals. Melting point 38℃. Elemental analysis C ₂₁ H ₃₂ O ₆ Calculated value C 66.30, H 8.48 Actual value C 66.12, H 8.59 Reference example 49 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (- In formula 2, 3 drops of concentrated sulfuric acid were added dropwise to a solution of R=H ₃ C, n=4, free form) (0.21 g) in ethanol (10 ml) under ice cooling and stirring, and the mixture was allowed to stand for 12 hours. After adding water, the reaction mixture is extracted with diethyl ether, and the diethyl ether layer is washed with water and dried over anhydrous sodium sulfate. The residue after removing the solvent was subjected to silica gel chromatography and eluted with chloroform.
3,5-trimethyl-6-(5'-carbonylpentyl)-1,4-benzoquinone (-2, where R
=H ₃ C, n=4, ethyl ester) (0.2 g) is obtained as an orange oil. Infrared absorption spectrum ν ^film _nax cm ^-1 : 1640 (quinone) Nuclear magnetic resonance spectrum (τ in deuterated chloroform
value): 8.76 (CH ₃ , triplet), 8.80−8.30 (CH ₂ , multiplet), 8.0 (nuclear CH ₃ , singlet), 8.00−7.30 (nuclear
CH ₂ , CH ₂ COO, multiplet), 5.88 (COOCH ₂ , quartet) Elemental analysis C ₁₇ H ₂₄ O ₄ Calculated value C 69.83, H 8.27 Actual value C 69.85, H 8.36 Example 6 2, 3, 5 A solution of -trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (-2 formula, R= _H3C , n=4, ethyl ester) (0.1 g) in diethyl ether (10 ml) was added. When treated with lithium aluminum hydride in the same manner as in Example 4, 2,3,5-trimethyl-6-(6'-
Hydroxyhexyl)-hydroquinone (-2 in the formula, R= _H3C , n=8, free form) is obtained. The product was treated with ferric chloride as in Example 4,
Recrystallization from diethyl ether-hexane yields 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (-2,
R=H ₃ C, n=4, free form) is obtained as yellow needles. Melting point 43-45℃ Elemental analysis C ₁₅ H ₂₂ O ₃ Calculated value C 71.97, H 8.86 Actual value C 72.33, H 8.58 Reference example 50 Actual formulation examples when using the compound of the present invention for bioresistance control action are as follows. It is as follows. A Capsule a (1) 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone
20mg (2) Corn oil 150mg 170mg/capsule Add (1) to (2) and heat to approximately 40℃ to dissolve (1) in (2). Pack the whole thing into a gelatin capsule. b (1) 2,3-dimethoxy-5-methyl-6-
(4'-Hydroxybutyl)-1,4-benzoquinone 20mg (2) Corn oil 150mg 170mg/capsule Fill into capsules in the same manner as A-a). Experimental example 1 (Action on lysosomal membrane) A. Test compound

[Table] B. Experimental method The effect on rat liver lysosomal membranes was measured according to the method of Watanabe et al. [Chem.Pharm.Bull., 22183 (1974)]. That is, after incubating the liver lysosomal fraction and the DMF solution of the specimen at 37°C for 90 minutes, the activities of the hydrolytic enzymes (β-glucuronidase and acid phosphatase) leaked out were measured, and the activity was compared with that in the case where no compound was added. Expressed as a percentage. C Experiment results

【table】

Claims (1)

[Claims] 1. General formula [Wherein, R is a lower alkyl group or a lower alkoxy group, A is -CH ₂ -, -CO- or [Formula], n is an integer from 2 to 8, and X is a hydrogen atom or a protected Y represents a hydroxyl group which may be protected. ] A general formula characterized by oxidizing the compound or its ester [In the formula, each symbol has the same meaning as above. ] A method for producing a quinone compound or an ester thereof.