JPH064611B2 - Dihydrobenzofuran derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] (In the formula, n represents an integer of 1 to 9) A dihydrobenzofuran derivative [hereinafter, referred to as a dihydrobenzofuran derivative (I)].

Dihydrobenzofuran derivative provided by the present invention
(I) has an excellent anti-oxidant effect, and is a treatment of vitamin E deficiency such as hemolysis and encephalomalacia, which are said to be caused by lipid peroxides and radicals which are peroxidation products of unsaturated lipids in vivo. Alternatively, it is useful as a pharmaceutical for prevention or a synthetic intermediate thereof.

[Conventional technology]

Conventionally, it has been said that the biological activity of vitamin E, such as anti-hemolytic ability, is derived from the antioxidant action, and among vitamin E, α-tocopherol is known to have excellent biological activity. [For example, “Vitaminology [1]” edited by the Japan Vitamin Society (May 6, 1980)
(See pages 177-235). Also, α-tocopherol,
The biological activity of vitamin E such as β-tocopherol, γ-tocopherol, δ-tocopherol is α-tocopherol>β-tocopherol>γ-tocopherol> δ-
Tocopherol decreases in order, but the degree of this activity has been reported to roughly correspond to the degree of antioxidant activity (for example, Bulletin of the Chemical Society of Japan.
ety of Japan), Vol. 59, pp. 3113-3116 (1986)
reference〕.

[Problems to be solved by the invention]

Α-, which has the best biological activity among vitamin E
If it is possible to provide a compound having an antioxidant effect higher than that of tocopherol, it is possible to use the compound as a vitamin E-like drug having a pharmacological action derived from its strong antioxidant effect or a synthetic intermediate thereof. Become.

Therefore, an object of the present invention is to provide a novel compound having a stronger antioxidant effect than α-tocopherol.

[Means for solving problems]

According to the present invention, the above object is achieved by providing a dihydrobenzofuran derivative (I).

The dihydrobenzofuran derivative (I) of the present invention can be produced, for example, by the following method.

(In the formula, n is as defined above and R ¹ and R ² each represent a lower alkyl group.) That is, the ketone represented by the general formula (II) and the general formula (III)
The unsaturated ester represented by the general formula (IV) is obtained by reacting with the Wittig reagent represented by.
Examples of the Witteich reagent include ethyl 2- (diethylphosphono) propionate and 2- (diethylphosphono).
Methyl propionate, methyl 2- (dimethylphosphono) propionate, ethyl 2- (diethylphosphono) propionate and the like are used. This Witteich reaction is carried out, for example, with organic lithium compounds such as n-butyllithium and methyllithium; basic compounds such as alkali metal hydrides such as sodium hydride and potassium hydride, and ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane. To the mixture with and after adding the Witteig reagent under stirring at a temperature in the range of about -30 ° C to about 80 ° C, preferably in the range of about -10 ° C to about 50 ° C, at the temperature in the above range. More about
A solution of phosphoylide is prepared by continuing to stir for 0.5 to 24 hours, then adding about 0 to 100 ketone to the solution.
It is carried out by adding at a temperature in the range of 0 ° C, preferably in the range of about 15-80 ° C, and continuing stirring for about 0.5-24 hours. The ether solvent is preferably in an anhydrous state, and the amount thereof used is preferably about 5 to 50 times the weight of the ketone. The Witteich reagent is usually about 0.5 to 10 mol, preferably about 0.8 to 1 mol of the ketone.
It is used in an amount of 8 mol, more preferably about 1 to 5 mol, and the basic compound is preferably used in an amount of about 0.5 to 1.5 mol per 1 mol of Witteich reagent. The reaction system is preferably replaced with an inert gas such as argon or nitrogen.

Thus, the separation / purification of the unsaturated ester represented by the general formula (IV) from the reaction mixture obtained by the Witteich reaction is used for the separation / purification of the product obtained by the general organic synthesis reaction from the reaction mixture. The same is done by the method described above. For example, the reaction mixture is mixed with water, extracted with a solvent such as hexane, benzene, diethyl ether,
The unsaturated ester can be obtained by distilling the solvent from the extract and subjecting the residue to operations such as chromatography and distillation. Examples of the adsorbent used for chromatography include silica gel, alumina, florisil, and the like, and silica gel is particularly preferable. Hexane, pentane, petroleum ether,
It is preferable to use a solvent prepared by mixing a small amount of a polar solvent such as chloroform, methylene chloride, diethyl ether, methyl acetate and ethyl acetate with a hydrocarbon non-polar solvent such as benzene and toluene.

The reduction reaction of the unsaturated ester represented by the general formula (IV) to the unsaturated alcohol represented by the general formula (V) is, for example, lithium aluminum hydride, diethyl ether mixed with a reducing agent such as lithium borohydride, Tetrahydrofuran, ether solvent such as 1,2-dimethoxyethane,
Within the range of about -30 ° C to about 30 ° C, preferably about -10 ° C.
It is carried out by adding the unsaturated ester with stirring at a temperature in the range of to about 10 ° C. and continuing the stirring at the temperature in the above range for about 5 minutes to about 12 hours. The ether solvent is preferably in an anhydrous state, and the amount thereof is usually about 5 to 100 times the weight of the unsaturated ester,
The weight is preferably about 10 to 50 times. The amount of the reducing agent used is usually about 0.5 to 10 mol, preferably about 0.6 to 2 mol, based on 1 mol of the unsaturated ester. Controlling the reaction gives suitable results by adding the unsaturated ester as such or in small portions in a solution of the ethereal solvent to the mixture of reducing agent and ethereal solvent.

Separation and purification of the unsaturated alcohol represented by the general formula (V) from the reaction mixture thus obtained by the reduction reaction can be carried out, for example, by the following method. The reaction mixture is treated with a mineral acid such as hydrochloric acid or sulfuric acid or an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and then extracted with a solvent such as hexane, benzene or diethyl ether, and the solvent is extracted from the extract. The unsaturated alcohol represented by the general formula (V) can be obtained by distilling off and subjecting the residue to operations such as chromatography and distillation.

The unsaturated alcohol represented by the general formula (V) is Lars (Lar
s) et al. [Tetrahedron, No. 26
Vol., Pp. 879-886 (1970)], to a dihydrobenzofuran derivative (I) by an acid-catalyzed cyclization reaction with 2,3,5-trimethylhydroquinone. Specifically, for example, unsaturated alcohol and 2,3,5-trimethylhydroquinone are reacted in formic acid in the presence of concentrated sulfuric acid under heating under reflux for about 10 to 100 hours, preferably for about 20 to 60 hours, The obtained reaction mixture was poured into ice water and extracted with a solvent such as hexane, benzene, diethyl ether,
The solvent is distilled off from the extract, and the resulting oily substance is heated under reflux in an alcoholic solvent such as methanol or ethanol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid for about 5 minutes to about 1 hour, preferably about The dihydrobenzofuran derivative (I) can be obtained by reacting for 10 to 20 minutes. The amount of 2,3,5-trimethylhydroquinone used is usually about 0.5 to 5 mol per 1 mol of unsaturated alcohol,
It is preferably about 0.9 to 1.2 mol. It is preferable to use formic acid which has been dehydrated by heating in the presence of phthalic anhydride and then being distilled. The amount of formic acid used is usually about 1 for unsaturated alcohols.
The weight is 0 to 100 times, preferably about 20 to 50 times. The amount of concentrated sulfuric acid used is usually about 0.001 to 0.5 times the weight of the unsaturated alcohol, preferably about 0.01 to 0.
1 times the weight. The alcohol solvent is usually used in an amount of about 10 to 100 times, preferably about 20 to 40 times the weight of the unsaturated alcohol used initially. The amount of the mineral acid used is usually about 0.01 to 1 mol, preferably about 0.1 to 0.5, per mol of the unsaturated alcohol used initially.
It is a mole.

The separation / purification of the dihydrobenzofuran derivative (I) from the reaction mixture thus obtained by the cyclization reaction can be carried out, for example, by the following method. The alcoholic solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was dissolved in diethyl ether, and after washing with water, diethyl ether was distilled off, petroleum ether was added to the residue, and the precipitated unreacted 2,3, By separating 5-trimethylhydroquinone, concentrating the obtained liquid under reduced pressure, and subjecting this concentrate to operations such as chromatography and distillation, the dihydrobenzofuran derivative (I) is generally produced as a by-product. A mixture with the dihydrobenzopyran derivative represented by the formula (VI) [hereinafter, referred to as the dihydrobenzopyran derivative (VI)] is obtained. Separation of these two compounds can be carried out, for example, by liquid chromatography, but particularly, it is convenient to carry out separation by high performance liquid chromatography (hereinafter referred to as HPLC). This HPLC can be carried out by a method usually used for separation / purification of fat-soluble compounds, but especially in normal phase HPLC, for example, Merck of West Germany.
(Merck) Licrosolve (Lickrosorb) Si60, US Waters (Waters) using a silica gel column such as μ-Porasil (μ-Porasil), a mixed solvent of hexane and a small amount of an ether solvent such as tetrahydrofuran. Is preferably used as the mobile phase, and in reversed-phase HPLC, for example, Zorb (Zorb) manufactured by Du Pont of the United States is used.
ax) ODS, Chemcopak manufactured by Chemco Ltd.
It is preferable to use an octadecylsilanized silica gel column such as ODS and a mixed solvent of a hydrophilic organic solvent such as methanol and acetonitrile and a small amount of water as a mobile phase.

Hereinafter, the evaluation method and the results of the antioxidant effect of the dihydrobenzofuran derivative (I) of the present invention will be described.

Evaluation Method Several people, including two of the inventors, were assigned to the Bulletin of the Chemical Society of Japan (Bulle
tin of the Chemical Society of Japan), Volume 59, Volume 3
The evaluation was performed according to the method for evaluating the antioxidant properties of tocopherols reported on pages 113 to 3116 (1986). That is, an ethanol solution of a test substance of a predetermined concentration and a predetermined concentration of
An ethanol solution of 2,6-di-tert-butyl-4- (4-methoxyphenyl) phenoxyl radical was mixed in an equal volume ratio at a temperature of 25 ° C. to obtain 376 n of the resulting mixed solution.
By spectroscopically tracking the change with time in the decrease in absorption intensity at wavelengths of m and 580 nm by the stopped-flow method, as a measure of the antioxidant activity of the test substance, 2,6- Determine the second-order reaction rate constant in the oxidation reaction of the test substance by di-tert-butyl-4- (4-methoxyphenyl) phenoxyl radical.

Evaluation results The second-order reaction rate constants of the dihydrobenzofuran derivative (I) of the present invention or the mixture of the dihydrobenzofuran derivative (I) and the corresponding dihydrobenzopyran derivative (VI) are α-tocopherol, β-tocopherol, γ- It is shown in Table 1 together with the second-order reaction rate constants of tocopherol and δ-tocopherol.

As is clear from Table 1, the dihydrobenzofuran derivative (I) is used alone or as a dihydrobenzopyran derivative (V
In the mixture with I), all of them showed higher antioxidant activity than tocopherols such as α-tocopherol.

Thus, the dihydrobenzofuran derivative (I) has an excellent antioxidant effect, and a vitamin E-like drug having a pharmacological action derived from the antioxidant action, for example, a drug for treating or preventing vitamin E deficiency or its synthesis. It is useful as an intermediate.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

In the examples, infrared absorption spectrum analysis (hereinafter referred to as I
The R analysis) was performed by a liquid film method, and the ¹ H-nuclear magnetic resonance spectrum analysis (hereinafter, referred to as PMR analysis) was performed in a deuterated chloroform solvent using tetramethylsilane as an internal standard. .

Example 1 (1) 3.2 g of 50% oily sodium hydride and 20 g of anhydrous tetrahydrofuran were placed in a three-necked flask substituted with nitrogen gas.
0m and 2- (diethylphosphono) under stirring
Ethyl propionate 14.3 g was added to anhydrous tetrahydrofuran 2
The solution diluted with 0 m was gradually added dropwise at room temperature, and after completion of the addition, stirring was continued for 1 hour. The reaction mixture was gradually warmed and heated to reflux for about 10 minutes, after which it was added to 6,10,1
A solution prepared by diluting 13.4 g of 4-trimethylpentadecan-2-one with 20 m of anhydrous tetrahydrofuran was added dropwise, and after completion of the addition, heating and refluxing were continued for another hour. The obtained reaction mixture was cooled, a small amount of water was added, and then tetrahydrofuran was distilled off under reduced pressure. About 100 m of water was added to the obtained residue, and extraction was performed 3 times (about 150 m in total) with about 50 m of diethyl ether. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oily substance was purified by column chromatography (adsorbent: about 500 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether) to give 2,3,7,1.
Ethyl 1,15-pentamethyl-2-hexadecenoate 9.0g
Got The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 1720,1210,1100cm ^-1 PMR analysis result δ (ppm): 2.10 (s, 3H, 4.18 (q, 2H, -CO ₂ CH ₂ CH ₃ ) (2) Lithium aluminum hydride 0.98g and anhydrous diethyl ether 250 in a three-necked flask purged with nitrogen gas.
m, and stir under cooling in an ice-water bath for a few minutes.
Ethyl 7,11,15-pentamethyl-2-hexadecenoate 9.0
A solution prepared by diluting g with 25 m of anhydrous diethyl ether was gradually added dropwise. After completion of dropping, stirring was continued at room temperature for 30 minutes. 0.98 g of water in the reaction mixture while cooling in an ice-water bath, 1
0.98 g of a 5% aqueous sodium hydroxide solution and 2.94 g of water were gradually added dropwise. The white precipitate formed was separated with a glass filter, diethyl ether was added to the separated white precipitate and the mixture was stirred, and the mixture was filtered with a glass filter. The organic layers of the liquids were combined, and the solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to column chromatography (adsorbent: about 300 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether). Purified by
2,3,7,11,15-Pentamethyl-2-hexadecene-1-
I got all 6.2g. IR analysis and PMR of this product
The results of the analysis are shown below.

IR analysis result νmax: 3300 cm ^-1 PMR analysis result δ (ppm): 4.03 (s, 2H, -CH ₂ -OH) (3) A mixed solution of 200 g of 98% formic acid and 40 g of phthalic anhydride was heated under reflux for 2 hours. 100 g of anhydrous formic acid obtained after distillation, 2,3,7,11,15-pentamethyl-
6.2 g of 2-hexadecen-1-ol and 3.0 g of 2,3,5-trimethylhydroquinone were placed in a three-necked flask, 4 drops of concentrated sulfuric acid was added thereto, and the mixture was heated under reflux for 2 days. After cooling, the reaction mixture was poured into ice water and stirred, and then extracted twice with 200 ml of diethyl ether (400 m in total).
I went. The organic layers were combined, washed several times with water, further washed successively with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily substance was dissolved in 60 m of methanol, 0.6 m of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 15 minutes. After cooling
Methanol was distilled off from the reaction mixture under reduced pressure, and the residue was diluted with 100 m of diethyl ether. This solution with water,
The extract was washed successively with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Petroleum ether (50 m) was added to the obtained residue to separate the precipitated unreacted 2,3,5-trimethylhydroquinone. The liquid was concentrated, and the obtained oil was purified by column chromatography (adsorbent: 200 g of silica gel; developing solvent: mixed solvent of hexane and diethyl ether) to obtain 5.3 g of oil. As a result of HPLC analysis of this oil, it was confirmed that this oil had a retention time of 9.74 minutes and a retention time of 9.74 minutes.
It was found to be a binary mixture with the 10.08 minute component. The analysis conditions for this HPLC are shown below.

HPLC analysis conditions Column: length 250 mm, inner diameter 4 mm Packing agent: Lickrosorb Si60 (particle size: 5 μm) manufactured by Merck, West Germany Reagent: 0.05% n-hexane solution 5 μ Mobile phase: n-hexane Mixed solvent of water and tetrahydrofuran (volume ratio: 99/1) Flow rate: 2 m / min Temperature: 55 ° C A part of this oily substance was collected by HPLC, and the retention time was 9.74 minutes and the retention time was 10.08 minutes. The ingredients were separated from each other. The former is 3,4-dihydro-2,3,5,7,8-pentamethyl-
2- (4,8,12-trimethyltridecyl) -2H-benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI-3)], the latter being 2,3-dihydro-2 , 4,6,7-Tetramethyl-2- (1,5,9,13-tetramethyltetradecyl) benzofuran-5-ol (hereinafter referred to as the dihydrobenzofuran derivative (I-3)) . The results of the PMR analysis of both are shown below.

PMR analysis result of dihydrobenzopyran derivative (VI-3) δ (ppm): 2.30 and 2.65 (each m, each 1H, ) PMR analysis results of dihydrobenzofuran derivative (I-3) δ (ppm): 2.74 and 3.03 (each d, each J = 15.4H)
z, each 1H, ) Further, as a result of PMR analysis of the oil, it was found that the mixing ratio of the dihydrobenzopyran derivative (VI-3) and the dihydrobenzofuran derivative (I-3) in the oil was 50/50. .

Example 2 (1) 2- (diethylphosphono) in Example 1- (1)
By carrying out the reaction and separation and purification in the same manner as in Example 1- (1) except that 11.8 g of methyl 2- (dimethylphosphono) propionate was used instead of 14.3 g of ethyl propionate, 2,3,7, 8.8 g of methyl 11,15-pentamethyl-2-hexadecenoate was obtained. The results of PMR analysis of this product are shown below.

PMR analysis result δ (ppm): 2.11 (s, 3H, _{3.60 (s, 3H, -CO 2} CH 3) (2) Example 1- (2) and 1- (3) 2,3,7,11,15
-Examples 1- (2) and 1- except that 8.8 g of methyl 2,3,7,11,15-pentamethyl-2-hexadecenoate was used instead of 9.0 g of ethyl pentamethyl-2-hexadecenoate.
By carrying out the reaction and separation and purification in the same manner as in (3), a mixture (mixing ratio: 50/50) of the dihydrobenzopyran derivative (VI-3) and the dihydrobenzofuran derivative (I-3) was mixed with 5.
1 g was obtained.

Example 3 (1) An example except that 9.9 g of 6,10-dimethylundecane-2-one was used in place of 13.4 g of 6,10,14, -trimethylpentadecan-2-one in Example 1- (1). 1- (1)
The reaction was carried out in the same manner as in. The obtained reaction mixture was cooled, poured into ice water (about 1) and stirred, and then extracted with about 100 m of diethyl ether three times (about 300 m in total).
I went. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily substance was purified by column chromatography (adsorbent: about 500 g of silica gel; developing solvent: mixed solvent of hexane and diethyl ether), and ethyl 2,3,7,11-tetramethyl-2-dodecenoate. 6.5 g was obtained. IR analysis and PMR of this product
The results of the analysis are shown below.

IR analysis result νmax: 1720,1210,1100cm ^-1 PMR analysis result δ (ppm): 2.10 (s, 3H, 4.18 (q, 2H, -CO ₂ CH ₂ CH ₃ ) (2) Lithium aluminum hydride 0.87g and anhydrous diethyl ether 200 in a three-necked flask replaced with nitrogen gas.
m, and mix with ice water while stirring under cooling for 2, 3,
A solution prepared by diluting 6.5 g of ethyl 7,11-tetramethyl-2-dodecenoate with 20 m of anhydrous diethyl ether was gradually added dropwise. After completion of dropping, stirring was continued at room temperature for 30 minutes. 0.87 g of water, 0.87 g of 15% aqueous sodium hydroxide solution and 2.61 g of water were gradually added dropwise to the reaction mixture while cooling with an ice water bath. The white precipitate formed was separated with a glass filter, diethyl ether was added to the separated white precipitate and the mixture was stirred, and the mixture was filtered with a glass filter.
After the organic layers of the liquids were combined and the solvent was distilled off under reduced pressure, the obtained oily substance was subjected to column chromatography (adsorbent: about 250 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether). Purified by 2,3,7,11
-4.8 g of tetramethyl-2-dodecen-1-ol were obtained. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 3300 cm ^-1 PMR analysis result δ (ppm): 4.02 (s, 2H, -CH ₂ OH) (3) In Example 1- (3), 2,3,7,11,15-pentamethyl- 2-hexadecen-1-ol 2,3, instead of 6.2 g
7,11-Tetramethyl-2-dodecen-1-ol 4.8g
Reaction and separation / purification were carried out in the same manner as in Example 1- (3) except that was used to obtain 3.7 g of an oily substance. As a result of HPLC analysis of this oily substance, it was found that this oily substance was a mixture of two components, a component having a retention time of 24.92 minutes and a component having a retention time of 26.95 minutes. The analysis conditions in this HPLC are shown below.

HPLC analysis conditions Column: length 250 mm, inner diameter 4 mm Packing agent: Licrosolve (Li manufactured by Merck, West Germany)
ckrosorb) Si60 (particle size: 5 μm) Reagent: 0.05% n-hexane solution 5 μ Mobile phase: Mixed solvent of n-hexane and tetrahydrofuran (volume ratio: 99.75 / 0.25) Flow rate: 2 m / min Temperature: 55 ℃ A part of this oily substance was collected by HPLC and the retention time was 2
The component at 4.92 minutes and the component at a retention time of 26.95 minutes were separated. The former is 3,4-dihydro-2,3,5,7,8-pentamethyl-2- (4,8-dimethylnonyl) -2H-benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI- 2)] and the latter is 2,3-dihydro-2,4,6,7-tetramethyl-2- (1,5,9-trimethyldecyl) benzofuran-5-ol [hereinafter referred to as dihydro Benzofuran derivative (I-2)]. The results of the PMR analysis of both are shown below.

PMR analysis result of dihydrobenzopyran derivative (VI-2) δ (ppm): 2.26 and 2.61 (each m, each 1H, PMR analysis results of dihydrobenzofuran derivative (I-2) δ (ppm): 2.71 and 3.01 (d respectively, 1H each, Further, as a result of PMR analysis of the oily matter, the mixing ratio of the dihydrobenzopyran derivative (VI-2) and the dihydrobenzofuran derivative (I-2) in the oily matter was 35/65.
It turned out to be

Example 4 (1) Example 1- () except that 6.4 g of 6-methylheptadecane-2-one was used in place of 13.4 g of 6,10,14 trimethylpentadecan-2-one in Example 1- (1). By carrying out the reaction and post-treatment of the reaction mixture in the same manner as in 1)
7.4 g of oil was obtained (the oil was not purified by chromatography).

(2) In place of the solution prepared by diluting 9.0 g of ethyl 2,3,7,11,15-pentamethyl-2-hexadecenoate with 25 m of anhydrous diethyl ether in Example 1- (2), Example 4- (1) was used.
7.4 g of the oily product obtained in step 20 m of anhydrous diethyl ether
The reaction and separation and purification were carried out in the same manner as in Example 1- (2) except that the solution diluted with was used to prepare 2,3,7-
3.0 g of trimethyl-2-octen-1-ol was obtained.
The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 3300 cm ^-1 PMR analysis result δ (ppm): 4.15 (s, 2H, -CH ₂ -OH) (3) A mixed solution of 200 g of 98% formic acid and 40 g of phthalic anhydride was heated under reflux for 2 hours. Then, 100 g of anhydrous formic acid obtained by distillation, 3.0 g of 2,3,7-trimethyl-2-octen-1-ol and 2.65 g of 2,3,5-trimethylhydroquinone were placed in a three-necked flask. , This is concentrated sulfuric acid 3
After adding a drop, the mixture was heated under reflux for 2 days. After cooling, the reaction mixture was poured into ice water and stirred, and then diethyl ether 1 was added.
Extraction was performed twice using 50 m (300 m in total).
The organic layers were combined, washed several times with water, further washed successively with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily substance was dissolved in 50 m of methanol, 0.5 m of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 15 minutes. After cooling, methanol was distilled off from the reaction mixture under reduced pressure, and the residue was diluted with 100 ml of diethyl ether. The solution was washed successively with water, aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Petroleum ether (50 m) was added to the obtained residue to precipitate the unreacted 2,
Separated 3,5-trimethylhydroquinone. The liquid was concentrated, and the resulting oil was purified by column chromatography (adsorbent: silica gel 200 g; developing solvent: mixed solvent of hexane and diethyl ether) to obtain 2.6 g of an oil. This oil was analyzed by HPLC under the same analytical conditions as in Example 3- (3), and as a result, it was found that this oil was a mixture of two components, a component having a retention time of 27.80 minutes and a component having a retention time of 30.72 minutes. found. A part of this oily substance was separated by HPLC to separate a component with a retention time of 27.80 minutes and a component with a retention time of 30.72 minutes. The former is
3,4-dihydro-2,3,5,7,8-pentamethyl-2- (4-
Methylpentyl) -2H-benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI-1)
The latter is a 2,3-dihydro-2,4,6,7-tetramethyl-2- (1,5-dimethylhexyl) benzofuran-5-ol [hereinafter referred to as a dihydrobenzofuran derivative (I -1)]]. The results of the PMR analysis of both are shown below.

PMR analysis results of dihydrobenzopyran derivative (VI-1) δ (ppm): 2.26 and 2.61 (each m, each 1H, PMR analysis result of dihydrobenzofuran derivative (I-1) δ (ppm): 2.71 and 2.99 (each d, each 1H, As a result of PMR analysis of the oily matter, the mixing ratio of the dihydrobenzopyran derivative (VI-1) and the dihydrobenzofuran derivative (I-1) in the oily matter was 44/56.
It turned out to be

Example 5 (1) In Example 1- (1), 13.4 g of 6,10,14-trimethylpentadecan-2-one was added to anhydrous tetrahydrofuran 2
Example 1-Except that a solution prepared by diluting 16.9 g of 6,10,14,18-tetramethylnonadecan-2-one with 25 m of anhydrous tetrahydrofuran was used instead of the solution diluted to 0 m.
Reaction and separation and purification were carried out in the same manner as in (1) to obtain 10.5 g of ethyl 2,3,7,11,15,19-hexamethyl-2-eicosenoate. IR analysis and PMR of this product
The results of the analysis are shown below.

IR analysis result νmax: 1725, 1210, 1100 cm ^-1 PMR analysis result δ (ppm): 2.08 (s, 3H, ) 4.16 (q, 2H, -CO ₂ CH ₂ CH ₃ ) (2) 0.95 g of lithium aluminum hydride and anhydrous diethyl ether in a three-necked flask replaced with nitrogen gas.
m, and stir under cooling in an ice-water bath for a few minutes.
Ethyl 7,11,15,19-hexamethyl-2-eicosenoate 1
A solution prepared by diluting 0.5 g with 25 m of anhydrous diethyl ether was gradually added dropwise. After completion of dropping, stirring was continued at room temperature for 30 minutes. Water 0.95 in the reaction mixture while cooling in an ice-water bath
g, 0.95 g of 15% sodium hydroxide aqueous solution and 2.85 of water
g was gradually added dropwise. The white precipitate formed was separated with a glass filter, diethyl ether was added to the separated white precipitate and the mixture was stirred, and the mixture was filtered with a glass filter. The organic layers of the liquids were combined, and the solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to column chromatography (adsorbent: about 300 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether). To give 7.3 g of 2,3,7,11,15,19-hexamethyl-2-eicosen-1-ol. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 3300 cm ^-1 PMR analysis result δ (ppm): 4.01 (s, 2H, -CH ₂ -OH) (3) In Example 1- (3), 2,3,7,11,15-pentamethyl -2-hexadecen-1-ol 2,3, instead of 6.2 g
Example 1, except that 7.3 g of 7,11,15,19-hexamethyl-2-eicosen-1-ol was used and the amount of 2,3,5-trimethylhydroquinone used was changed from 3.0 g to 2.9 g.
The reaction and separation and purification were carried out in the same manner as in (3) to obtain 3.4 g of an oily substance. Part of this oil is HPL
Fractionated with C, 2,3-dihydro-2,3,5,7,8-pentamethyl-2- (4,8,12,16-tetramethylheptadecyl) -2
H-benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI-4)] and 2,3-dihydro-2,4,6,7-tetramethyl-2- (1,5,9 , 13,17-Pentamethyloctadecyl) benzofuran-5-ol [hereinafter, this is referred to as a dihydrobenzofuran derivative (I-4)] was fractionated. The results of PMR analysis of these compounds are shown below.

PMR analysis results of dihydrobenzopyran derivative (VI-4) δ (ppm): 2.22 and 2.61 (each m, each 1H, PMR analysis result of dihydrobenzofuran derivative (I-4) δ (ppm): 2.71 and 3.00 (each d, each 1H, Further, as a result of PMR analysis of the oily matter, the oily matter was a mixture of the dihydrobenzopyran derivative (VI-4) and the dihydrobenzofuran derivative (I-4), and the mixing ratio of the former and the latter was 46 /. It turned out to be 54.

Example 6 (1) In Example 1- (1), 6,10,14-trimethylpentadecan-2-one was replaced with 6,10,14,18,22-pentamethyltrieicosan-2-one instead of 13.4 g. Reaction and separation and purification were carried out in the same manner as in Example 1- (1) except that 20.4 g was used to give 2,3,7,11,15,19,23-heptamethyl-
14.5 g of ethyl 2-tetraeicosenoate was obtained. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 1720,1210,1100cm ^-1 PMR analysis result δ (ppm): 2.09 (s, 3H, 4.17 (q, 2H, -CO ₂ CH ₂ CH ₃ ) (2) Lithium aluminum hydride 1.12g and anhydrous diethyl ether 250 in a three-neck flask purged with nitrogen gas.
m, and stir under cooling in an ice-water bath for a few minutes.
A solution prepared by diluting 14.5 g of ethyl 7,11,15,19,23-ethylheptamethyl-2-tetraeicosenoate with 25 m of anhydrous diethyl ether was gradually added dropwise. After completion of dropping, stirring was continued at room temperature for 30 minutes. While cooling in an ice-water bath, 1.12 g of water, 1.12 g of 15% aqueous sodium hydroxide solution and 3.36 g of water were gradually added dropwise to the reaction mixture. The white precipitate formed was separated with a glass filter, diethyl ether was added to the separated white precipitate and the mixture was stirred, and the mixture was filtered with a glass filter. The organic layers of the liquids were combined, and the solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to column chromatography (adsorbent: about 300 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether). , 2,3,7,11,15,19,23-heptamethyl-2-
10.6 g of tetraeicosen-1-ol was obtained. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 3300 cm ^-1 PMR analysis result δ (ppm): 4.04 (s, 2H, -CH ₂ -OH) (3) In Example 1- (3), 2,3,7,11,15-pentamethyl -2-hexadecen-1-ol 2,3, instead of 6.2 g
By carrying out the reaction and separation and purification in the same manner as in Example 1- (3) except that 9.0 g of 7,11,15,19,23-heptamethyl-2-tetraeicosen-1-ol was used, 6.9 g was obtained.
An oily substance was obtained. A part of this oily substance was collected by HPLC to give 3,4-dihydro-2,3,5,7,8-pentamethyl-2-
(4,8,12,16,20-pentamethylheneicosyl) -2H
-Benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI-5)] and 2,3-dihydro-2,4,6,7-tetramethyl-2- (1,5,9, 13,17,21-hexamethyldocosyl) benzofuran-5-ol [hereinafter, referred to as dihydrobenzofuran derivative (I-5)] was fractionated. The results of PMR analysis of these compounds are shown below.

PMR analysis results of dihydrobenzopyran derivative (VI-5) δ (ppm): 2.26 and 2.62 (each m, each 1H, PMR analysis result of dihydrobenzofuran derivative (I-5) δ (ppm): 2.71 and 3.00 (each d, each 1H, Further, as a result of PMR analysis of the oily matter, the oily matter was a mixture of the dihydrobenzopyran derivative (VI-5) and the dihydrobenzofuran derivative (I-5), and the mixing ratio of the former and the latter was 44 / It turned out to be 56.

Example 7 (1) 6,10,14,18,22,26,3 in place of 13.4 g of 6,10,14-trimethylpentadecan-2-one in Example 1- (1)
0,34,38-Nonamethylnonatriacontan-2-one 34.
2,3,7,11,15,19,23,27,3 by carrying out the reaction and separation and purification in the same manner as in Example 1- (1) except that 4 g is used.
20.1 g of ethyl 1,35,39-undecamethyl-2-tetracontenoate was obtained. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 1725, 1210, 1100 cm ^-1 PMR analysis result δ (ppm): 2.10 (s, 3H, ) 4.18 (q, 2H, -CO ₂ CH ₂ CH ₃ ) (2) Lithium aluminum hydride 0.99g and anhydrous diethyl ether 250 in a three-necked flask purged with nitrogen gas.
m, and stir under cooling in an ice-water bath for a few minutes.
20.1 g of ethyl 7,11,15,19,23,27,31,35,39-undecamethyl-2-tetracontenoate was added to anhydrous diethyl ether 2
The solution diluted with 5 m was gradually added dropwise. After the dropping is completed,
Stirring was continued for 30 minutes at room temperature. Water 0.99 g, 15% aqueous sodium hydroxide solution in the reaction mixture while cooling in an ice-water bath
0.99 g and 2.97 g of water were gradually added dropwise. The white precipitate formed was separated with a glass filter, diethyl ether was added to the separated white precipitate and the mixture was stirred, and the mixture was filtered with a glass filter. The organic layers of the liquids were combined, and the solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to column chromatography (adsorbent: about 300 g of silica gel; developing solvent: a mixed solvent of hexane and diethyl ether). Purified by 2,3,7,11,15,19,23,27,31,
14.0 g of 35,39-undecamethyl-2-tetraconten-1-ol was obtained. The results of IR analysis and PMR analysis of this product are shown below.

IR analysis result νmax: 3300 cm ⁻¹ PMR analysis result δ (ppm): 4.02 (s, 2H, -CH ₂ OH) (3) In Example 1- (3), 2,3,7,11,15-pentamethyl- 2-hexadecen-1-ol 2,3, instead of 6.2 g
Reaction, separation and purification in the same manner as in Example 1- (3) except that 14.0 g of 7,11,15,19,23,27,31,35,39-undecamethyl-2-tetraconten-1-ol was used. By doing, 8.2 g of an oily substance was obtained. Part of this oil is H
Fractionated by PLC, 3,4-dihydro-2,3,5,7,8-pentamethyl-2- (4,8,12,16,20,24,28,32,36-nonamethylheptatriacone Cyl) -2H-benzopyran-6-ol [hereinafter referred to as dihydrobenzopyran derivative (VI-
9)] and 2,3-dihydro-2,4,6,7-tetramethyl-2- (1,5,9,13,17,21,25,29,33,37-decamethyloctatria Contyl) benzofuran-5-ol [hereinafter,
This is referred to as a dihydrobenzofuran derivative (I-9)]
And separated. The results of PMR analysis of these compounds are shown below.

PMR analysis result of dihydrobenzopyran derivative (VI-9) δ (ppm): 2.24 and 2.63 (each m, each 1H, PMR analysis result of dihydrobenzofuran derivative (I-9) δ (ppm): 2.73 and 3.02 (each d, each 1H, Further, as a result of PMR analysis of the oily substance, the oily substance was a mixture of the dihydrobenzopyran derivative (VI-9) and the dihydrobenzofuran derivative (I-9), and the mixing ratio of the former and the latter was 42 / It turned out to be 58.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The present invention provides a dihydrobenzofuran derivative (I) having an excellent antioxidant effect as compared with tocopherols such as α-tocopherol. The dihydrobenzofuran derivative (I) is useful as a vitamin E-like drug having various pharmacological actions derived from antioxidant action or a synthetic intermediate thereof.

Claims (1)

[Claims] 1. A general formula (In formula, n represents the integer of 1-9) The dihydrobenzofuran derivative shown by these.