JPS623134B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a compound represented by the following general formula () or () or a lower alkyl carboxylic acid ester thereof. or [In the formula, R is a lower alkyl group or a lower alkoxy group, and A is -CH ₂ -, -CO- or

[Formula], n is an integer of 2 to 8, X is a hydrogen atom or a hydroxy group that may be protected, and Y is a hydroxy group that may be protected with alkyl, aralkyl, acyl, acetal or silyl. The present inventors have succeeded in synthesizing the above-mentioned novel compounds () and (), and (1) these compounds exhibit remarkable effects on lysosomal membranes, and also have physiological biological resistance-controlling effects, especially immune promotion. (2) These compounds have a simple structure and are suitable for industrial production. (3)
These compounds have moderate hydrophilicity and are easy to formulate, and (4) these compounds are stable against light, acids, etc., and can be more advantageously employed as pharmaceuticals. This discovery led to the completion of the present invention. In formulas () and (), the lower alkyl group represented by R preferably has 4 or less carbon atoms, and specific examples thereof 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 thereof include methoxy, ethoxy, i-propoxy, n-propoxy, and i-butoxy. The integer represented by n is preferably 4 or 5 when R is a lower alkyl group, and preferably 2, 7 or 8 when R is a lower alkoxy 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, such as alkyl, aralkyl, acyl, acetal, and silyl groups. The alkyl group 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 as a protecting group includes benzyl. , As the acyl group as a protecting group, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, especially alkylcarbonyl having 4 or less carbon atoms (for example, 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. Examples of the lower alkyl carboxylic acid esters of compounds () and () include those in which the alkyl moiety has 4 or less carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl. Compounds () and () are produced, for example, by the method shown in the following figure. Compounds () and groups of () have the known general formula () [In the formula, R, It is produced using [in the formula, R has the same meaning as above] as a starting material. The method for producing compounds () and (), 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 such a solvent as long as it does not interfere with the reaction, and specific examples thereof include water, dilute acid or 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, a yellow color image, a color reaction using a leucomethylene blue reagent, or an ultraviolet absorption spectrum may be employed as confirmation means. The reaction temperature and reaction time vary depending on the type of oxidizing agent used, but the reaction temperature is usually about 0° to 25°C, and the reaction time is about 0.5 to 25°C.
About an hour is preferable. 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. Among these, preferred examples include Clemensen reduction using zinc amalgam and hydrochloric acid, Wolff Kiyner reduction in which a ketone is decomposed into hydrazone in the presence of a base, desulfurization reduction with dithioacetate and nickel, and catalytic reduction. be able to. It is usually advantageous to carry out the reaction in the presence of a suitable solvent. Any solvent may be used 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, X=Y=OH in compound (-2)
The compound 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-(CH ₂ ) _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 the anhydride with peroxide. 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 very mild conditions with the generation of carbon dioxide gas, with few side reactions, the desired product is obtained in good yield, and unreacted raw materials are recovered after the reaction 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, compound (-2) in which X=Y=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. The oxidation method in this step may be any method 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. It will be done. The oxidation reaction is generally carried out in the presence of a suitable solvent. Any solvent may be used as long as it does not interfere with the oxidation reaction, and examples include water, dilute acid or alkali solutions, acetone, ethanol, dioxane, ether, acetic acid, and dimethylformamide. The temperature and reaction time in the oxidation reaction vary depending on the type of oxidizing agent, but are generally between 0°C and
Preferably, the temperature is 25°C for 0.5 to 5 hours. Step (14) Oxidize compound (-3) to form compound (-3)
get. The oxidation method in this step is as described in the previous step (13).
It will be carried out in accordance with. 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 acyl (e.g. acetyl, benzyl, benzoyl), acetanol (e.g. tetrahydrofuran)
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. The oxidation reaction in this step is as described in the previous step (13).
It will be carried out in accordance with. Step (18) Compound (-2) is reduced to form compound (-
2) is obtained. 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) When [hereinafter collectively referred to as compound ()] 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 (), ()
or by reacting a reactive derivative thereof at the carboxyl group with alcohol, phenol compound, alkyl halide, aralkyl halide, dialkyl sulfate, diazomethane, etc. 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, propanol, i-propanol, n-butanol,
Examples of the aralkyl halide include i-butanol, methyl iodide and ethyl iodide, and benzyl chloride 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. Reactive derivatives of carboxylic acids include carboxylic anhydrides, carboxylic acid halides, lower alkyl esters of carboxylic acids,
Examples include carboxylates. 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. If the 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 the compound (), (). can lead. The compounds () and () thus obtained can be easily collected by suitable collection methods such as liquid conversion, dissolution, concentration, vacuum distillation, chromatography, crystallization, and recrystallization. sell. Compound () is a new compound that exhibits physiological biological resistance control effects, especially immunostimulatory effects; smooth muscle relaxing effects; and other effects, such as physiological biological resistance control effects in animals including humans, especially as an immune adjuvant. used. 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 or less 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, solubility of the compound, etc. 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. Compound () is also a new compound, and has the same physiological bioresistance control action and action on lysosomal membranes as described for compound ().
It can be used as a medicine in exactly the same manner as compound (). Furthermore, compound () can also be used as an intermediate for the production of compound (). Reference Example 1 (1) Add 2,3,5-trimethylphenol (in the formula, R=H ₃ C, X=H, Y=OH) (1.4 g) to a solution of tetrachloroethane (10 ml) at 0°C. Aluminum chloride powder (3.5g) under bare air flow
and ethyl 5-chloroformylpentanoate (3 g) in tetrachloroethane (5 ml) and then heated at 110-120°C for 17 hours. After adding cold water (50 ml) to the reaction solution, acidify with dilute hydrochloric acid and extract with chloroform (200 ml).
The residue (2.7 g) obtained from the extract was subjected to column chromatography using silicic acid (60 g) and chloroform-ether (20:1) (300 g).
The eluate obtained from the fraction eluted with
6′-trimethylbenzoyl)pentanoate (-1 in the formula, R=H ₃ C, X=H, Y=OH, n
=4, ethyl ester) (1.9 g) is obtained as colorless needles. Melting point: 72° to 73°C. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450
₍ OH), 1720 ( _COOC2H5 ), 1610 (CO). Nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.76 (CH ₃ , triple line), 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 Measured value C 69.83, H 8.27 Actual value C 69.78, H 8.44 (2) Aqueous 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,
The resulting white precipitate is recrystallized from ethanol to give 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 in deuterated chloroform
Value): 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 calculation Value C 68.16, H 7.63 Actual value C 67.95, H 7.92 Reference example 2 (1) 2,3,5-trimethylphenol (in the formula, R= _H3C , X=H, Y=OH) (0.9g), Reference Example 1 Aluminum chloride (2.1g) and ethyl 6-chloroformylhexanoate (1.3g)
(1). When treated in the same manner, ethyl 6-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl)
Hexanoate (-1, where R=H ₃ C, X=
H, Y=OH, n=5, ethyl ester) (1.5
g) is obtained as colorless needles. Melting point 47°−48
℃. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 1735
(COOC ₂ H ₅ ), 1610 (CO) nuclear magnetic resonance spectrum (τ in deuterated chloroform
Value): 8.76 (CH ₃ , triple line), 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 ₁₈ H ₃₆ O ₄ Calculated value C 70.56, H 8.55 Actual value C 70.23, H 8.72 (2) This product ( 1g) according to the method of Reference Example 1(2), 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 in deuterium chloroform
Value): 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, X=H, Y=OH) (1.5 g), aluminum chloride (3.5 g), ethyl 9-chloroformyl nanoate (3 g) was treated in the same manner as in Reference Example 1 (1) to yield ethyl 9-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl) nonanoate (-1 In the formula), 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 spectra (τ in deuterium chloroform
Value): 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) This product ( 1.4g) was hydrolyzed by the method of Reference Example 1(2) to produce 9-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl)nonanoic acid (-1,
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 in deuterium chloroform
Value): 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), 3.45 (nuclear proton, singlet) 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 (4.08g) was dissolved in 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-
(2′・3′・4′-trimethoxy-6′-methylbenzoyl)nonanoic acid (-1 in the formula, R=H ₃ CO,
=H, Y=OCH ₃ , n=8, free form) (1.82g)
However, from the fraction eluted with benzene-ether (5.7:1), 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= _H3CO , X=H, Y= _H3CO ) (2.09g) and ethyl 5-chloroformylpentanoate (2.66
When 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,
=H, Y=OH, n=4, free form) (1.97 g) is obtained as light brown needles. Melting point: 111°-112°C. 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 removed under reduced pressure. The residue was recrystallized from methanol to give 3-(2'-hydroxy-3'·4'-dimethoxy-6'-memethylbenzoyl)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 deuterium 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
Value): 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 in the formula, 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= _H3CO , 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.
Reflux for an hour. 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
= _H3CO , 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℃. 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
℃. 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 deuterated 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 (
-1, where R=H ₃ CO, X=H, Y=OH, n=
8. Methyl ester) (120 mg) in acetic acid (17 ml) was shaken in a stream of steam at 50°-60°C in the presence of 5% palladium-carbon. The catalyst was removed 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 give methyl 10-(3'4'-dimethoxy-2'-hydroxy-
6'-Methylphenyl)decanoate (-2 in which 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) in 0.5% NaOH solution (3.3 ml) at 20°C.
While stirring, add potassium nitrosodisulfonate (0.4g) and stir for 10 minutes. The reaction solution was diluted with cold water (100 ml) under ice-cooling, diluted with dilute hydrochloric acid, and then extracted 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
where 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'-cacarboxy-
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
Values): 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 (-
2 in which R=H ₃ CO, X=Y=OH, n=4, free form) is obtained. 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 ( _CH3 , multiplet), 7.87
( _CH3 , singlet), 7.75−7.27 (nuclear _CH2 ,
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 In the formula, R=H ₃ C, n=4, free form)
(10 mg) in acetic acid (2 ml) was added with 5% palladium-
4 at 65°-70°C in a stream of hydrogen in the presence of carbon (12 mg)
Stir the time. When the catalyst was removed and the liquid was concentrated under reduced pressure, 2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (in the formula -2,
R=H ₃ C, X=Y=OH, n=4, free form) 9 mg
was gotten. 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
-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 formula, 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) in Reference example 21 It was similarly reduced to give 2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (-2,
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,
Dissolve R=H ₃ CO, X=H, Y=OH, n=4, free form) in 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 by a conventional method to obtain 2.3-
Dimethoxy-5-methyl-6-(5'-carboxypentyl)hydroquinone (-2, where R=
H ₃ CO, X=Y=OH, n=4, free form) was obtained as a colorless oil. Reference 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- by oxidation according to
(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 deuterated 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 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 deuterated 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 value C 69.08, H 8.04 Reference example 27 10-(2'-Hydroxy- 3′・4′・6′-trimethylphenyl)decanoic acid (-2, where R=H ₃ C, X
=H, Y=OH, n=8, free form) (0.4g) was oxidized according to the method of Reference Example 25 to give 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 deuterated 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 value C 71.19, H 8.80 Reference example 28 10−(3′・4′ -dimethoxy-2'-hydroxy-
6'-methylphenyl)decanoic acid (-2, where R
= _H3CO , X=H, Y=OH, n=8, free form)
(97mg) in 1% sodium hydroxide solution (0.67ml)
A solution of potassium nitrosodisulfonate (800 mg) in water (10 ml) was added to a mixed solution of and acetone (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified 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, where R=
H ₃ CO, n=8, free form) (99 mg) is 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,
When R=H ₃ CO, X=H, Y=OH, n=4, free form) (84 mg) is oxidized according to Reference Example 28, 2.
3-dimethoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone(-2
where 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 give 2.3-
Dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (-2, R= _H3CO , 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 (-
In formula 2, R=H ₃ CO, X=H, Y=OH, n=
8, methyl ester) according to Reference Example 28, 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'-
10% ferric chloride solution (15 ml) was added to (carboxypentyl)hydroquinone (-2 formula, R=H ₃ CO, X=Y=OH, n=4, free form) (8 mg) and mixed. Extract with ether, wash the extract with water, dry and evaporate under reduced pressure. The residue was dissolved in silicic acid (1
The fraction eluted with chloroform-ethanol (49:1) was subjected to column chromatography using g) and recrystallized from ether-hexane to obtain 2.3-
Dimethoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone (-2, R= _H3CO , n=4, free form) (6.7 mg) is obtained as an orange crystal. . 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 (10
ml) solution dropwise at 25°C. After stirring for 2.5 hours, the reaction solution was diluted with cold water (300 ml), acidified 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 obtain 2.
3,5-trimethyl-6-[5'-(0-formylphenyl)oxycarbonylpentyl]-1,4-
Benzoquinone (-2 in the formula, R = H ₃ C, n = 4,
0-formylphenolate) (1.3 g) is obtained as a yellow oil. This product (1.1g) of acetone (25
ml) Add standard Jones reagent (2 ml) to the solution 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).
3,5-trimethyl-6-[5'-(0-carboxyphenyl)oxycarbonylpentyl]-1,4
-Benzoquinone (-2 in the formula, R=H ₃ C, n=
4,0-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 under reflux in benzene for 19 hours. Insoluble materials were removed, the liquid was concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 2,3,5-trimethyl-6-
(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) in CH ₃ OH-HCl (5 ml) according to Reference Example 13.
When esterified with 2,3-dimethoxy-5
-Methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone (-2, where R=
H ₃ CO, n=8, 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 diluted 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, dried, and the ether was distilled off under reduced pressure to give 2,3-dimethoxy-5-methyl-6-
(9′-carboxynonyl)-1,4-benzoquinone (-2 formula, R=H ₃ CO, n=8, free form) 8
I got mg. 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) 9 mg 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 and stir at 85℃ for another 2 hours. 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 give 2,3-dimethoxy-5-methyl-6-(8'-ethoxycarbonyloctyl)-1.
4-benzoquinone (-2 in the formula, R=H ₃ CO, n
=7, ethyl 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 value in carbon tetrachloride):
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 ₃ 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, ethyl 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, where 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 Example 1 Ethyl 5-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl) pentanoate (-1 A solution of R=H ₃ C, X=H, Y=OH, n=4, ethyl ester) (0.4 g) in tetrahydrofuran (100 ml) is reduced 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 removed, the liquid 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= _H3C , X=H, Y=OH, n=4, free form)
(0.32 g) are 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 Example 2 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 fraction, 6-hydroxy-6-(2'-hydroxy-
3′・4′・6′-trimethylphenyl)hexanoic acid (-3 in the formula, 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 in the formula, 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 Example 1. Reference example 40 6-hydroxy-6-(2′-hydroxy-3′・
4′・6′-trimethylphenyl)hexanoic acid (−
In formula 3, R=H ₃ C, X=H, Y=OH, n=4,
Free form) (0.158 g) is dissolved in 5% sodium hydroxide solution (2 ml) and water (7 ml), to which 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 ethyl 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 and eluted with chloroform-methanol (20:1). The product was converted into ethyl acetate.
Recrystallized from hexane (1:2) to obtain 2,3,5-trimethyl-6-(5'-carboxy-1'-hydroxypentyl)-1,4-benzoquinone (-3, where R=H ₃ C , n=4, free form) (0.128 g) are obtained as brown needles. Melting point 130-131.5℃. Elemental analysis value C ₁₅ H ₂₀ O ₅ Calculated value C 64.27, H 10.24 Actual value C 64.03, H 7.22 Example 3 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 removed and the liquid is evaporated to dryness. The residue was subjected to silica gel column chromatography and eluted with chloroform-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 Observed C 76.08, H 10.33 From the second fraction, starting material (2.31 g)
is collected. Example 4 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 yield 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 5 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) solution of potassium nitrosodisulfonate (0.5
g), 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 ethyl acetate-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) is 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−
0, broad) Mass spectrum (m/e) C ₁₅ H ₂₂ O ₄ :M ⁺ (266) Example 6 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4 -benzoquinone (
−3, where R=H ₃ C, n=4, free form) (1.17
A solution of acetic anhydride (0.473 g) in pyridine (5 ml) was added dropwise to a solution of g) in dry pyridine (15 ml) at 5°C with stirring. Leave the mixture at room temperature overnight,
The solvent was distilled off and the residue was separated into two fractions by silica gel chromatography and eluted with methylene chloride-diethyl ether (9:1). 2,3,5-trimethyl-6- from the first fraction
(1', 6'-diacetoxyhexyl)-1, 4-benzoquinone (-3, where R=H ₃ C, n=4, -
_CH2OH and

Diacetate (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 deuterated chloroform
Value): 8.50 (CH ₂ , Broad), 7.99, 7.98,
7.95, 6.85 (nuclear CH ₃ , OCOCH ₃ ), 5.96 (CH ₂ −
0, triple line), 4.05 (CH-O, triple line) 2.05 (CH-O, triple line) from the second fraction of chromatography
3,5-trimethyl-6-(6'-acetoxy-
1'-Hydroxyhexyl)-1,4-benzoquinone (-3, where R= _H3C , n=4, acetate in _-CH2OH ) (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 deuterated chloroform
Value): 8.50 (CH ₂ , Broad), 7.99, 7.98,
7.97 (nuclear CH ₃ , OCOCH ₃ ), 5.96 (CH ₂ -O, triplet), 4.05 (CH - O, triplet) Mass spectrum (m/e) C ₁₇ H ₂₄ O ₅ :M ⁺ (308) Implementation Example 7 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. Jones' 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 yields 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) Example 8 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1. 2N aqueous sodium hydroxide to a stirred mixture of 4-benzoquinone (-1, where R= _H3C , n=4, acetate) (0.5 g), sodium hydrosulfite (1 g), 30% aqueous methanol (20 ml) (1.6 ml) was added dropwise at 5°C. Leave the mixture at the same temperature for 3 hours,
After distilling off the methanol and acidifying with phosphoric acid, the product is extracted with ethyl acetate. Wash the organic layer with water,
Dry over anhydrous sodium sulfate and evaporate 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 in the formula, 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) (0.265
g) 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 9 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-hydroquinone (-
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 in the formula, 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 line), 6.37 (CH ₂ -O, triplet line) Mass spectrum (m/e) C ₁₅ H ₂₀ O ₄ :M ⁺ (264) Reference example 41 2,3-dimethoxy-5-methyl- 6-(3'-
carboxypropyl)-1,4-benzoquinone (-2 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 obtained by distilling off the solvent was subjected to silica gel chromatography and eluted with chloroform to obtain 2,3-dimethoxy-5.
-Methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (-2, where R=
H ₃ CO, n=2, ethyl 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 ( _CH3 , 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 10 A solution of lithium aluminum hydride (0.5 g) in diethyl ether (5 ml)・3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (-2 in the formula,
R= _H3CO , n=2, ethyl ester) (0.78g)
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 with 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) 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
value): 8.62−8.24 (CH ₂ , multiplet), 8.10
(OH, singlet), 7.98 (nuclear CH ₃ , singlet), 7.50
(nuclear CH ₂ , triplet), 632 (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 11 2,3-dimethoxy-5-methyl-6-(9'-
When 0.1 g of methoxycarbonyl)-1,4-benzoquinone (-2 in the formula, R=H ₃ CO, n=8, methyl ester) was treated with lithium aluminum hydride in the same manner as in Example 10, 2.3- Dimethoxy-5-methyl-6-(10'-hydroxydecyl)-
Hydroquinone (-2, where R=H ₃ CO, X=Y
=OH, n=8, free form), and this product was treated with ferric chloride as in Example 10 and recrystallized from ligroin to give 2,3-dimethoxy-5
-Methyl-6-(10'-hydroxydecyl)-1.
4-benzoquinone (-2 in the formula, R=H ₃ CO, n
= 8, free form) (0.065 g) are obtained as orange needles.
Melting point 46-50℃ Elemental analysis C ₁₉ H ₂₀ O ₅ Calculated value C 67.43, H 8.94 Actual value C 67.41, H 8.94 Example 12 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 Calculation formula C 66.30, H 8.48 Actual value C 66.12, H 8.59 Reference example 42 2.3.5-trimethyl-6-(5'-carboxypentyl)-1.4- To a solution of benzoquinone (-2 formula, R=H ₃ C, n=4, free form) (0.21 g) in ethanol (10 ml) was added dropwise 3 drops of concentrated sulfuric acid with stirring under ice cooling, and the mixture was left 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'-ethoxycarbonylpentyl)-1,4-benzoquinone (-2
In the formula, 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 , triple line), 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 13 2.3.5-trimethyl-6-(5'-ethoxycarbonylpentyl )-1,4-benzoquinone (-2 formula, R = H ₃ C, n = 4, ethyl ester) (0.1 g) in diethyl ether (10 ml) was treated with lithium aluminum hydride in the same manner as in Example 10. Then, 2,3,5-trimethyl-6-(6'hydroxyhexyl)-hydroquinone (-2 formula, R=H ₃ C, n=4, free form) is obtained. The product was treated with ferric chloride as in Example 10,
Recrystallization from diethyl ether-hexane yields 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (-2, R= _H3C , 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 43 An actual prescription example when the compound of the present invention is used for bioresistance control action is 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 (1) added to (2) , heat to about 40℃ to dissolve (1) into (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】

[Table] (b) Experimental method The effect on rat liver lysosomal membranes was measured according to the method of Watanabe et al. [Chem.Pharm.Bull., 22, 183 (1974)]. That is, after incubating the liver lysosomal fraction and the DMF solution of the specimen at 37°C for 90 minutes, the leaked hydrolytic enzyme (β
- glucuronidase and acid phosphatase) activities were measured and expressed as a percentage of the activity in the absence of compound addition. (c) Experimental results

【table】

Claims (1)

[Claims] 1. General formula or [Wherein, R is a lower alkyl group or a lower alkoxy group, A is -CH ₂ -, -CO- or [Formula], n is an integer of 2 to 8, and X is a hydrogen atom or a protected Y represents a hydroxy group which may be protected. ] A compound represented by or its lower alkyl carboxylic acid ester.