JPH0326189B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () The present invention relates to a 3,4-dihydro-2H-benzopyran derivative represented by and a method for producing the same. In the above formula, R ¹ represents a hydrogen atom or a lower alkyl group such as a methyl group, ethyl group, propyl group, butyl group. R ² and R ³ are the same or different and each represents a hydrogen atom; a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group; or a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group; Or ^R2 and ^R3 together form a -CH=CH-CH=CH- group.
R ⁴ represents a hydrogen atom, an acyl group, a methyl group, a t-butyl group, a triphenylmethyl group, a benzyl group or a trimethylsilyl group. Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, and a benzoyl group. The above-mentioned acyl group, methyl group, t-butyl group, triphenylmethyl group, benzyl group and trimethylsilyl group are protecting groups used for the purpose of protecting a hydroxyl group. A is

【formula】

[Formula] or

Represents [formula]. Here, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, or R ⁵ and R ⁶ taken together -
(CH ₂ ) ₄ - represents a group. R ⁷ and R ⁸ are together

【formula】

【formula】

【formula】

[Formula] or

[Formula], R ⁹ represents a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and X represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom. The 3,4-dihydro-2H-benzopyran derivative represented by the general formula () provided by the present invention is a new compound that has not been described in any known literature. Among these 3,4-dihydro-2H-benzopyran derivatives, those in which R ⁴ in the general formula () is a hydrogen atom have an excellent antioxidant effect, and are useful for oxygen-sensitive organic materials such as oils, fats, and rubbers. Useful as an antioxidant for products, plastics, etc. In addition, R ⁴ in the general formula () is an acyl group, a methyl group, a t-
When a butyl group, triphenylmethyl group, benzyl group or trimethylsilyl group is used, a compound having the above-mentioned antioxidant effect can be obtained by replacing these groups with a hydrogen atom by a conventional method. Recently, vitamin E has attracted attention as a highly safe antioxidant, but it has not yet become a general-purpose antioxidant because it is relatively expensive and is easily oxidized and colored. As a result of intensive research to develop a new antioxidant that surpasses vitamin E, the present inventors found that the 3,4-dihydro-2H-benzopyran derivative represented by the general formula () has an antioxidant superior to vitamin E. The present inventors have discovered that these 3,4-dihydro-2H-benzopyran derivatives can be produced at low cost and that they can be used as precursors for compounds that have antioxidative action or antioxidant action, leading to the present invention. According to the invention, the general formula () [In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula (), and R is R ⁴ in the general formula ()
The same as or different from , represents a hydrogen atom, an acyl group, a methyl group, a t-butyl group, a triphenylmethyl group, a benzyl group, or a trimethylsilyl group. ] 2-substituted ethyl alcohol or its reactive derivative represented by the general formula () HOOC-A-COOH ... () [wherein A has the same meaning as in the general formula (). ] The 3,4-dihydro-2H-benzopyran derivative represented by the above general formula () can be produced by reacting the dicarboxylic acid represented by the formula (2) or its reactive derivative. Here, examples of reactive derivatives of 2-substituted ethyl alcohol include halides, alkanesulfonates, arenesulfonates, and carboxylates. Reactive derivatives of dicarboxylic acids include lower alkyl esters, acid halides, acid anhydrides, alkali metal salts, silver salts, or salts of organic tertiary or quaternary bases. 2-substituted ethyl alcohol or its reactive derivative represented by the general formula () and the general formula ()
The reaction with the dicarboxylic acid represented by or its reactive derivative can be carried out under conventionally known general ester synthesis reaction conditions, and representative examples of the ester synthesis reaction are shown below. (Reaction Example A) Reaction between alcohol and dicarboxylic acid dihalide Alcohol () and dicarboxylic acid () halide, preferably dicarboxylic acid dichloride, are reacted in an inert solvent such as benzene, toluene, ether, or chloroform at 1% relative to the alcohol. ~3 molar equivalents of pyridine, triethylamine, etc.
The desired 3,4-dihydro-2H-benzopyran derivative () is obtained by reacting at room temperature in the presence of a class amine. (Reaction example 2) Reaction between alcohol and acid anhydride Alcohol () and acid anhydride of dicarboxylic acid () are mixed in an inert solvent such as benzene, toluene, xylene, hexane, etc., preferably sulfuric acid or p-toluenesulfonic acid. The desired 3,4-dihydro-2H-benzopyran derivative () is obtained by reacting at room temperature or with heating in the presence of an acid such as pyridine or a tertiary amine such as pyridine or triethylamine, followed by dehydration condensation. . (Reaction example C) Reaction of alcohol and dicarboxylic acid Alcohol () and dicarboxylic acid () are reacted with dicyclohexylcarbodiimide or 2-chloro-1-methylpyridinium iodide in an inert solvent such as benzene, toluene, or xylene. In the presence of a dehydration condensation agent such as triethylamine,
The desired 3,
4-dihydro-2H-benzopyran derivative ()
get. (Reaction example d) Reaction between alcohol and lower alkyl ester of dicarboxylic acid Alcohol () and lower alkyl ester of dicarboxylic acid () are transesterified using a suitable transesterification catalyst,
For example, in the presence of p-toluenesulfonic acid or a titanium metal compound such as tetramethyl titanate, a heating reaction is performed in an inert solvent such as toluene or xylene, and the low-boiling alcohol generated is removed from the reaction system. The desired 3,4-dihydro-2H-benzopyran derivative () is obtained. (Reaction example e) Reaction of alcohol halide, alkanesulfonate or arenesulfonate with alkali metal salt, silver salt or organic tertiary or quaternary base salt of dicarboxylic acid Halide, alkanesulfonate or arenesulfonate of alcohol () and a dicarboxylic acid () with an alkali metal salt, silver salt, or salt of an organic tertiary or quaternary base in a solvent such as dimethylformamide, benzene, acetone, etc., at room temperature or under heating to achieve the desired purpose. 3,4
-dihydro-2H-benzopyran derivative () is obtained. 3,4 obtained by the above ester synthesis reaction
The -dihydro-2H-benzopyran derivative can be separated and recovered by a conventional method. For example, water is added to the reaction mixture, then extracted with ether etc., the extract is washed with water, dried, the solvent is distilled off, and the residue is recrystallized or purified by column chromatography. A 3,4-dihydro-2H-benzopyran derivative represented by the formula () can be obtained. 2- represented by the general formula () used as a raw material
Most substituted ethyl alcohols are compounds known per se (see JP-A-49-88876 and JP-A-56-145282), but according to the method previously discovered by the present inventors, General formula () [In the formula, R, R ¹ , R ² and R ³ have the same meanings as in the general formula (). ] Hydroquinone or its derivative shown and 4-
It can be easily obtained by reacting methyl-5,6-dihydro-2H-pyran in the presence of a Lewis acid (see JP-A-57-83654). Examples of Lewis acids used in this condensation reaction include boron trifluoride/ether complex, aluminum chloride, aluminum bromide, ferrous chloride, ferric chloride, stannous chloride, stannic chloride, zinc chloride, and sulfuric acid. , p-toluenesulfonic acid, etc., but preferably aluminum chloride,
It is a boron trifluoride/ether complex. The amount of Lewis acid used is 0.1 to 2 times, preferably 0.5 to 1.0 times, the amount of hydroquinone or its derivative represented by the general formula (). This condensation reaction is preferably carried out in a solvent, for example 1,2-
Hydrogen halides such as dichloroethane, dichloromethane, chloroform, 1,1,2-trichloroethylene, carbon tetrachloride, chlorobenzene;
Hydrocarbons such as benzene, toluene, xylene, cyclohexane, n-hexane, ligroin;
Nitrogen-containing compounds such as nitromethane, nitrobenzene, benzonitrile, and acetonitrile; oxygen-containing compounds such as methyl ethyl ketone, ethyl acetate, butyl acetate, and mixtures thereof can be used as the solvent, and 1,2-dichloroethane is particularly preferred. The amount of solvent used is approximately 2 to 100% of the hydroquinone or its derivative represented by the general formula ().
twice the weight, preferably about 5 to 20 times the weight. This condensation reaction is usually carried out at -40°C to 150°C, preferably at 0°C.
Perform at ~100°C. The 2-substituted ethyl alcohol represented by the general formula () can be converted into a reactive derivative of the 2-substituted ethyl alcohol by halogenation, alkanesulfonylation, arenesulfonylation, or acylation using a conventional method. can. Further, the dicarboxylic acid represented by the general formula () and its reactive derivative, which are one of the raw materials, are known compounds. The 2-substituted ethyl alcohol represented by the general formula () or its reactive derivative used as a raw material in the method for producing the 3,4-dihydro-2H-benzopyran derivative represented by the general formula () of the present invention is as described above. Although it is easily derived from 4-methyl-5,6-dihydro-2H-pyran, the 4-methyl-5,6-dihydro-2H-
Pyran is produced in large amounts as a by-product when producing isoprene from isobutene and formalin, and can also be synthesized by reacting tertiary butanol with an aqueous formaldehyde solution in the presence of an acid catalyst.
It is easily and inexpensively available. The present invention will be specifically described below with reference to Examples and Test Examples. Example 1 3,4-dihydro-2-hydroxyethyl-
2,5,7,8-tetramethyl-2H-benzopyran-6-ol 10g, dimethyl maleate 3.16
A solution consisting of 0.6 g, P-toluenesulfonic acid, 0.16 g of hydroquinone, and 100 ml of toluene was heated, and the methanol produced was gradually distilled out of the system. The resulting reaction solution was poured into water and extracted with diethyl ether. After washing the extract with water and drying, the low-boiling substances were distilled off under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography to obtain di[2-(3,
4-dihydro-6-hydroxy-2,5,7,8
-tetramethyl-2H-benzopyranyl)ethyl]
5.93g of maleate was obtained (yield 51%). FD mass spectrum: [M] ⁺ 580 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.2 (s, 6H); 1.6-2.3 (m, 26H); 2.56
(t, J=7Hz, 4H); 4.1~4.6 (m,
6H); 6.1 to 6.25 (m, 2H) Example 2 Di[2-(3,4 −
9.04 g of dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl itaconate was obtained (yield 76%). FD mass spectrum: [M] ⁺ 594 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.22 (s, 6H); 1.6-2.2 (m, 26H); 2.57
(t, J=7Hz, 4H); 3.3 (s, 2H); 4.1
~4.5 (m, 6H); 5.67 (s, 1H); 6.3 (s,
1H) Example 3 3,4-dihydro-2-hydroxyethyl-
2,5,7,8-tetramethyl-2H-benzopyran-6-ol 5.0 g, 4-cyclohexene-
A solution consisting of 1.70 g of 1,2-dicarboxylic acid, 0.16 g of P-toluenesulfonic acid, 0.04 g of hydroquinone and 100 ml of toluene was heated, and the water produced was distilled out of the system. After cooling, water was added and extracted with diethyl ether, and the resulting extract was washed with water. The concentrate obtained by drying over anhydrous magnesium sulfate and distilling off the low-boiling substances under reduced pressure was purified by silica gel column chromatography to obtain di[2-(3,4-dihydrohydrocarbon) having the following physical properties. -6-hydroxy-2,5,7,8-tetramethyl-2H
-benzopyranyl)ethyl] 5.12 g of 4-cyclohexene-1,2-dicarboxylate (yield: 81%). FD mass spectrum: [M] ⁺ 634 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.2 (s, 6H); 1.6 ~ 3.1 (m, 36H); 4.06 ~
4.4 (m, 6H); 5.62 (s, 2H) Example 4 3,4-dihydro-2-hydroxyethyl-
2,5,7,8-tetramethyl-2H-benzopyran-6-ol 5.0 g, 5-norbornene-2,
A solution consisting of 1.64 g of 3-dicarboxylic anhydride, 0.1 g of P-toluenesulfonic acid, 0.1 g of hydroquinone, and 100 ml of toluene was heated, and the water produced was distilled out of the system. After cooling, water was added and extracted with diethyl ether, and the resulting extract was washed with water. The concentrate obtained by drying over anhydrous magnesium sulfate and distilling off the low-boiling substances under reduced pressure was purified by silica gel column chromatography to obtain di[2-(3,4-dihydrohydrocarbon) having the following physical properties. -6-hydroxy-2,5,7,8-tetramethyl-2H
-benzopyranyl)ethyl]5-norbornene-
5.1g of 2,3-dicarboxylate was obtained (yield
79%). FD mass spectrum: [M] ⁺ 646 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.2 (s, 6H); 1.4-3.3 (m, 36H); 4.0-
4.5 (m, 4H); 4.6-4.83 (m, 2H); 4.87
(s, 2H) Examples 5 to 11 In Example 4, 5-norbornene-2,3-
1.52 g of 2-cyclohexene-1,2-dicarboxylic anhydride, 1.54 g of cyclohexane-1,2-dicarboxylic anhydride instead of 1.64 g of dicarboxylic anhydride
g, citraconic anhydride 1.12g, norbornane-
2,3-dicarboxylic anhydride 1.66g, 1,4,
3.71 g of 5,6,7,7-hexachloro-5-norbornene-2,3-dicarboxylic anhydride, 1.66 g of 4-methyl-4-cyclohexene-1,2-dicarboxylic anhydride or 5-methyl-5- The corresponding 3,4-dihydro-2H-benzopyran derivatives were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 4, except that 1.78 g of norbornene-2,3-dicarboxylic anhydride was used. The results are shown in Table 1.

【table】

[Table] Example 12 3,4-dihydro-2-hydroxyethyl-
1.53 g of fumaric acid dichloride was added dropwise to a solution consisting of 5.0 g of 2,5,7,8-tetramethyl-2H-benzopyran-6-ol, 1.6 g of pyridine, and 40 ml of methylene chloride, and the mixture was stirred at room temperature for 4 hours. The resulting reaction solution was poured into water and extracted with diethyl ether. After washing the extract with water and drying, the low boiling point substances were distilled off under reduced pressure, and the resulting concentrate was purified by column chromatography to produce the following.
5.14 g of di[2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl] fumarate having an FD mass spectrum was obtained (yield 89%). FD mass spectrum: [M] ⁺ 580 Examples 13-20 In Example 1, 3,4-dihydro-2-hydroxyethyl-2,5,7,8-tetramethyl-
The corresponding 3,4-
A dihydro-2H-benzopyran derivative was obtained. The results are shown in Table 2.

[Table] Example 21 In Example 12, 3,4-dihydro-2-hydroxyethyl-2,5,7,8-tetramethyl-
2H-benzopyran-6-ol instead of 5.0g
-(6-acetoxy-3,4-dihydro-2-methyl-2H-benzopyranyl)By performing the reaction and separation and recovery in the same manner as in Example 12, except for using 5.0 g of ethanol, a diacetate having the following FD mass spectrum was obtained. [2-(6-acetoxy-3,4-dihydro-2-methyl-2H-benzopyranyl)ethyl)
5.26g of fumarate was obtained (yield 91%). FD mass spectrum: [M] ⁺ 580 Test Examples 1 to 19 The test compounds shown in Table 3 were added to ethyl linoleate at a concentration of 0.020 per 100 g of the ethyl linoleate.
g was added and mixed to create a sample solution. 20ml of these samples were tested using an AOM (Antioxygen method) test device under AOM conditions (97.8°C, aeration 2.33°C).
cc/sec) and POV (peroxide value)
The time to reach 100meq/Kg was measured. The results are shown in Table 3.

【table】

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. ^{R 2} and R ³ are the same or different, a hydrogen atom,
Represents a lower alkyl group or a lower alkoxy group, or R ² and R ³ together represent -CH=CH-CH
Forms a =CH- group. R ⁴ represents a hydrogen atom, an acyl group, a methyl group, a t-butyl group, a triphenylmethyl group, a benzyl group or a trimethylsilyl group, and A represents [Formula] [Formula] or [Formula]. Here, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group, or R ⁵ and R ⁶ together represent a -(CH ₂ ) ₄ - group. R ⁷ and R ⁸ together represent [Formula] [Formula] [Formula] [Formula] or [Formula], R ⁹ represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom. ] 3,4-dihydro-2H-benzopyran derivative 2 represented by the general formula (In the formula, R is a hydrogen atom, an acyl group, a methyl group,
It represents a t-butyl group, a triphenylmethyl group, a benzyl group or a trimethylsilyl group, and R ¹ represents a hydrogen atom or a lower alkyl group. R ² and R ³ are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, or R ² and R ³ together form a -CH=CH-CH=CH- group. ) 2-substituted ethyl alcohol or its reactive derivative represented by the general formula HOOC-A-COOH (wherein A represents [formula] [formula] or [formula]. Here, R ⁵ and R ⁶ are represent the same or different hydrogen atoms or lower alkyl groups, or
R ⁵ and R ⁶ together represent a -(CH ₂ ) ₄ - group.
R ⁷ and R ⁸ together represent [Formula] [Formula] [Formula] [Formula] or [Formula], R ⁹ represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom. ] A general formula characterized by reacting with a dicarboxylic acid represented by or a reactive derivative thereof (In the formula, R ¹ , R ² , R ³ and A are as defined above, and R ⁴ is the same as or different from R above, a hydrogen atom, an acyl group, a methyl group, a t-butyl group, a triphenylmethyl group) , a benzyl group or a trimethylsilyl group.) A method for producing a 3,4-dihydro-2H-benzopyran derivative represented by: