JPH0326188B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () The present invention relates to a dicarboxylic acid diester represented by the formula 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 -S-,-
CH ₂ S−, −S−S−, −CH ₂ S−SCH ₂ −, −
Represents a group selected from the group consisting of SCH ₂ S- and -CH ₂ SCH ₂ SCH ₂ -. The dicarboxylic acid diester 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 dicarboxylic acid diesters, those in which R ⁴ in the general formula () is a hydrogen atom have an excellent antioxidant effect, and are effective against oxidation of oxygen-sensitive organic materials such as oils and fats, rubber products, and plastics. Useful as an inhibitor. In addition, R ⁴ in the general formula () is an acyl group, a methyl group,
When a t-butyl group, a triphenylmethyl group, a benzyl group, or a trimethylsilyl group is substituted with a hydrogen atom by a conventional method, a compound having the above-mentioned antioxidant effect can be obtained. 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 dicarboxylic acid diester represented by the general formula () has a superior antioxidant effect than vitamin E, or its oxidation It was discovered that these dicarboxylic acid diesters can be produced easily and at low cost, and that they serve as precursors for compounds having a preventive effect, 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 () HO ₂ CCH ₂ -A-CH ₂ CO ₂ H ... () [wherein A has the same meaning as in the general formula () have ] The dicarboxylic acid diester represented by the general formula () can be produced by reacting the dicarboxylic acid represented by the formula () or a reactive derivative thereof. Here, examples of reactive derivatives of 2-substituted ethyl alcohol include halides, alkylsulfonates, arylsulfonates, and carboxylates. Examples of reactive derivatives of dicarboxylic acids include lower alkyl esters, acid halides, mixed acid anhydrides, alkali metal salts, silver salts, and salts of organic tertiary or quaternary bases. The reaction between the 2-substituted ethyl alcohol represented by the general formula () or its reactive derivative and the dicarboxylic acid represented by the general formula () or its reactive derivative is carried out under conventionally known general ester synthesis reaction conditions. Typical 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 dicarboxylic acid diester (2) is obtained by reacting at room temperature in the presence of a grade amine. (Reaction example 2) Reaction between alcohol and mixed acid anhydride Alcohol () and mixed acid anhydride of dicarboxylic acid (), pivalic acid, p-toluenesulfonic acid, etc. are reacted in benzene, toluene, xylene, hexane, etc. in an inert solvent, preferably sulfuric acid, p
- in the presence of an acid such as toluenesulfonic acid or a tertiary amine such as pyridine, triethylamine,
The desired dicarboxylic acid diester () is obtained by reacting at room temperature or under heating. (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 dicarboxylic acid diester () is obtained by reacting at room temperature or under heating, or by reacting under azeotropic dehydration conditions. (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, by performing a heating reaction in an inert solvent such as toluene or xylene in the presence of a titanium compound such as p-toluenesulfonic acid or tetramethyl titanate, and removing the generated low-boiling alcohol from the reaction system. The desired dicarboxylic acid diester () is obtained. (Reaction example e) Reaction of alcohol halide, alkyl sulfonate or aryl sulfonate with an alkali metal salt, silver salt or organic tertiary or quaternary base salt of dicarboxylic acid Halide, alkyl sulfonate or aryl sulfonate 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. Dicarboxylic acid diester () is obtained. The dicarboxylic acid diester obtained by the above ester synthesis reaction 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 dicarboxylic acid diester 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-
Halogenated hydrocarbons 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 reactive derivative of 2-substituted ethyl alcohol represented by the general formula () can be produced by halogenating, alkanesulfonylating, arenesulfonylating or acylating the 2-substituted ethyl alcohol in a conventional manner. Dicarboxylic acid, which is one of the raw materials, is a known compound, and reactive derivatives of dicarboxylic acid such as lower alkyl esters, acid halides, mixed acid anhydrides, alkali metal salts, silver salts, or organic tertiary
or quaternary base salts. Further, according to the present invention, hydroquinone or a derivative thereof represented by the general formula () and the general formula () [In the formula, X represents a halogen atom, and A has the same meaning as in the general formula (). ] The dicarboxylic acid diester represented by the general formula () can also be produced by reacting the dicarboxylic acid disubstituted pentenyl ester represented by the following in the presence of a Lewis acid. 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, and zinc chloride. Zinc chloride is preferred. The amount of Lewis acid used is based on the hydroquinone or its derivative represented by the general formula ().
The amount is 0.0001 to 1 times the molar amount, preferably 0.001 to 0.1 times the molar amount. This condensation reaction is preferably carried out in a solvent, in which hydroquinone or its derivative represented by the general formula () and 4-methyl-5,6-
The solvent used in the condensation reaction with dihydro-2H-pyran is used at the same time. The amount of the solvent to be used is about 2 to 100 times the weight of hydroquinone or its derivative represented by the general formula (), preferably about 5 to 100 times the weight.
It is 20 times heavier. This condensation reaction usually starts at -40℃
It is carried out at 150°C, preferably 0°C to 100°C. The dicarboxylic acid disubstituted pentenyl ester represented by the general formula () used as a raw material can be easily prepared by reacting 4-methyl-5,6-dihydro-2H-pyran with a dihalide of a dicarboxylic acid in the presence of a Lewis acid. Obtainable. This condensation reaction can be carried out in the presence of the same Lewis acid used in the condensation reaction between hydroquinone or its derivative represented by the above general formula () and the dicarboxylic acid disubstituted pentenyl ester represented by the general formula (). . The amount of Lewis acid used is 4-methyl-
0.001 to 5,6-dihydro-2H-pyran
The amount is 0.5 times the molar amount, preferably 0.01 to 0.5 times the molar amount. This condensation reaction is preferably carried out in a solvent, and the solvent used in the condensation reaction between hydroquinone or its derivative represented by the above general formula () and the dicarboxylic acid disubstituted pentenyl ester represented by the general formula () is the same. used for. The amount of solvent used is about 2 to 100 times the weight of 4-methyl-5,6-dihydro-2H-pyran, preferably about 5 times the weight of 4-methyl-5,6-dihydro-2H-pyran.
~20 times the weight. This condensation reaction usually starts at -5℃
It is carried out at 70°C, preferably 0°C to 50°C. The reaction mixture containing the dicarboxylic acid disubstituted pentenyl ester represented by the general formula () thus obtained can also be directly subjected to the reaction with the hydroquinone represented by the general formula () or a derivative thereof. A dicarboxylic acid disubstituted pentenyl ester represented by the general formula () is obtained by the reaction of 4-methyl-5,6-dihydro-2H-pyran and a dihalide of a dicarboxylic acid, and then the dicarboxylic acid disubstituted pentenyl ester and the general formula ( A preferred embodiment for producing the dicarboxylic acid diester represented by the general formula () by reacting it with hydroquinone or its derivative represented by the formula () is shown below. 4-Methyl-5,6-dihydro-2H-pyran and the Lewis acid are dissolved or suspended in a solvent, then the dihalide of the dicarboxylic acid is added,
By continuing stirring for 4 hours, a reaction mixture containing a dicarboxylic acid disubstituted pentenyl ester represented by the general formula () is obtained. From this reaction mixture, for example, a dicarboxylic acid disubstituted pentenyl ester represented by the general formula () is isolated by distillation. Next, hydroquinone or its derivative represented by general formula () and a Lewis acid are dissolved or suspended in a solvent, and while stirring and heating under an inert gas atmosphere such as nitrogen, hydroquinone or its derivative represented by general formula () is dissolved or suspended in a solvent. 0.5 to 0.6 times the molar amount of dicarboxylic acid disubstituted pentenyl ester represented by the general formula () is added over about 0.5 to 8 hours and allowed to react. After addition of the dicarboxylic acid disubstituted pentenyl ester represented by the general formula (), approximately 0.5
By continuing stirring for ~4 hours, a reaction mixture containing a dicarboxylic acid diester represented by the general formula () is obtained. The dicarboxylic diester can be easily separated and recovered from the reaction mixture by the method described above. 2-substituted ethyl alcohol represented by the general formula () or its reactive derivative used as a raw material in the production method of the 3,4-dihydro-2H-benzopyran derivative represented by the general formula () of the present invention and the general formula () The dicarboxylic acid disubstituted pentenyl ester represented by is easily derived from 4-methyl-5,6-dihydro-2H-pyran as described above;
-Dihydro-2H-pyran is produced in large amounts as a by-product during the production of 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 can be easily and inexpensively obtained. The present invention will be specifically described below with reference to Examples and Test Examples. Example 1 3,4-dihydro-2-(2-hydroxyethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-ol 2.5 g, thiodiglycolic acid 5 mmol, p-toluenesulfonic acid 0.1 g, While heating a solvent consisting of 100 ml of toluene under reflux, the water produced was distilled out of the system. After the resulting reaction solution was cooled, diethyl ether was added thereto, and the mixed solution was then washed with water, dried over anhydrous magnesium sulfate, and concentrated. By purifying the concentrated solution using silica gel column chromatography, di[2-(3,4-dihydro-6
-Hydroxy-2,5,7,8-tetramethyl-
1.79 g of 2H-benzopyran-2-yl)ethyl thiodiacetate was obtained (yield 58%). FD mass spectrum: [M] ⁺ 614 NMR spectrum (90MHz) δ ^CDCl3 _HMS : 1.22 (s, 6H); 1.55-2.2 (m, 26H); 2.56
(t, J=6Hz, 4H); 3.3 (s, 4H); 4.05
~4.53 (m, 6H) Examples 2 to 6 In Example 1, 5 mmol of thiodiglycolic acid
3-thia-1,6-hexanedioic acid, 3, instead of
4-dithia-1,6-hexanedioic acid, 4,5-dithia-1,8-octanedioic acid, 3,5-dithia-
1,7-heptanedioic acid, 4,6-dithia-1,9
The corresponding dicarboxylic acid diesters were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 1, except that 5 mmol of each nonanedioic acid was used. Respective yields and NMR spectra,
The FD mass spectra are shown in Table 1.

[Table] Example 7 A mixture of 2.5 g of 3,4-dihydro-2-(2-hydroxyethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-ol, 0.79 g of pyridine, and 10 ml of methylene chloride was cooled on ice. Below, 5 mmol of thiodiglycolic acid dichloride was added dropwise.
Stir overnight at room temperature. Water was added to the resulting reaction solution, which was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. By purifying the concentrated solution by silica gel column chromatography, di[2-(3,4-dihydro-6-
Hydroxy-2,5,7,8-tetramethyl-
2.82 g of 2H-benzopyran-2-yl)ethyl thiodiacetate was obtained (yield 92%). Examples 8 to 15 In Example 1, 3,4-dihydro-2-(2
2-substituted ethyl alcohol shown in Table 2 instead of 2.5 g of -hydroxyethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-ol
The corresponding thiodiglycolic acid diesters were obtained by performing the reaction and separation and recovery in the same manner as in Example 1 except that 10 mmol was used. The results are shown in Table 2.

【table】

[Table] Example 16 In Example 7, 3,4-dihydro-2-(2
2-(6-acetoxy-3,4-dihydro-2-methyl-2H-benzopyran-2 −il)
By carrying out the reaction and separation and recovery in the same manner as in Example 7 except for using 2.5 g of ethanol, the following was obtained.
2.8 g of di[2-(6-acetoxy-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)ethyl]thiodiacetate having an FD mass spectrum was obtained (yield 91%). FD mass spectrum: [M] ⁺ 614 Example 17 5,6-dihydro-4-methyl-2H-pyran
1.87 g of thiodiglycolic acid dichloride was added dropwise to a mixed solution of 1.96 g, 10 ml of 1,2-dichloroethane, and 0.08 g of anhydrous zinc chloride, and the mixture was stirred at room temperature for 1 hour. Add trimethylhydroquinone to the resulting reaction solution.
It was added dropwise to a mixed solution of 3.04 g of anhydrous zinc chloride, 0.05 g of anhydrous zinc chloride, and 18 ml of 1,2-dichloroethane while heating under reflux.
After the dropwise addition, the reaction solution was heated under reflux for 2 hours, cooled, poured into water, and then extracted with diethyl ether. After washing the extract with water and drying, low-boiling substances were distilled off, and the resulting concentrated liquid was purified by silica gel column chromatography to obtain di[2-(3,
4-dihydro-6-hydroxy-2,5,7,8
-tetramethyl-2H-benzopyran-2-yl)
4.33g of ethyl]thiodiacetate was obtained (yield: 71
%). Examples 18-20 In Example 17, trimethylhydroquinone
The corresponding thiodiglycolic acid diesters were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 17, except that 20 mmol of the hydroquinone derivative shown in Table 3 was used instead of 3.04 g. These products were confirmed in the same manner as in Examples 12, 13, and 16, respectively. The respective yields are shown in Table 3.

[Table] Examples 21 to 24 In Example 17, 3-thia-1,6-hexanedioic acid dichloride, 3,4-dithia-1,6-hexanedioic acid dichloride, 4,5-dithia-1,
8-octanedioic acid dipromide and 3,5-dithia-1,7-heptanedioic acid dichloride, respectively.
The corresponding dicarboxylic acid diesters were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 17, except that 10 mmol was used. These products were confirmed in the same manner as in Examples 2, 3, 4, and 5, respectively. The respective yields are shown in Table 4.

[Table] Test Examples 1 to 13 The test compounds shown in Table 5 were added to ethyl linoleate at 0.020 g per 100 g of the ethyl linoleate.
g was added and mixed to prepare a sample. These samples were tested using AOM (Antioxygen method) test equipment.
The material was abused under AOM conditions (97.8°C, aeration 2.33cc/sec), and the time required for POV (peroxide value) to reach 100meq/Kg was measured. The results are shown in Table 5.

【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 -S-, -CH ₂ S-, -S-S-, -CH _2S
−SCH ₂ −, −SCH ₂ S− and −CH ₂ SCH ₂ SCH ₂ −
represents a group selected from the group consisting of ) A dicarboxylic acid diester represented by 2 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 HO ₂ CCH ₂ -A-CH ₂ CO ₂ H (wherein A is -S-, -CH ₂ S-, -S-S- ，
−CH ₂ S−SCH ₂ −, −SCH ₂ S− and −
Represents a group selected from the group consisting of CH ₂ SCH ₂ SCH ₂ -. ) A general formula characterized by reacting with a dicarboxylic acid or its reactive derivative represented by (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) , representing a benzyl group or a trimethylsilyl group. 3 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. ) Hydroquinone or its derivatives and general formula (In the formula, X represents a halogen atom, and A is -S
−, −CH ₂ S−, −S−S−, −CH ₂ S−SCH ₂ −, −
Represents a group selected from the group consisting of SCH ₂ S- and -CH ₂ SCH ₂ SCH ₂ -. ) A general formula characterized by reacting a dicarboxylic acid disubstituted pentenyl ester represented by the following in the presence of a Lewis acid: (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) , representing a benzyl group or a trimethylsilyl group.