JPS59161373A - Dicarboxylic acid diester and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or alkyl; R<2> is R<1>, alkoxy or together with R<1> form CH=CH-CH=CH; R<4> is H or protecting group; A is S, CH2S, S-S, CH2S-SCH2, SCH2S, or CH2SCH2SCH2]. EXAMPLE:Di[2-( 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl )-ethyl] thiodiacetate. USE:An antioxidant or its precursor. It has higher antioxidation activity than vitamine E. PREPARATION:The compound of formula I is prepared by reacting the 2-substituted ethyl alcohol of formula II (R is H or protecting group) with the dicarboxylic acid of formula IIIin an inert solvent in the presence of a dehydrative condensation agent or under azeotropic dehydration condition. The starting compound of formula II can be obtained easily by reacting hydroquinone of formula IV with 4-methyl-5,6-dihydro-2H-pyrane in the presence of a Lewis acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a dicarboxylic acid diester represented by the general formula (1) and a method for producing the same.

In the above formula, R1 does not represent a hydrogen atom or a lower alkyl group such as a methyl group, ethyl group, propyl group, or butyl group. R
2 and R3 are the same or different; a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group; or a lower alkoxy group such as a methquine group, an ethyl group, a propoxy group, a butquine group; or 1 and R together form -C1-1=Cfi-CH=CH
- form a group. R is hydrogen R does not like protecting groups, and as long as the protecting group has the purpose of protecting a hydroxyl group, any commonly used protecting group may be removed, such as an acetyl group, a glopionyl group, a butyryl group, Acyl groups such as benzoyl group, methyl group, L-butyl group, to1nophenylmethyl group, hensyl group, trimethylsilyl group, etc.
Shigerasu 1. Ru. A1-1 knee S-1-C) lI2S-
1-, S-5-1-C) hb 5C) i2-1-8CH
Represents a group consisting of 2S- and -Cii2SCHzSCH2-.

The dicarboxylic acid diester 6″ represented by the general formula (J) provided by the present invention is a new compound not described in known literature. Among these dicarboxylic diesters, R4 of the general formula (, I,) A is Hydrogen atoms have excellent r
- It has the effect of preventing the formation of silica, and prevents the formation of oxygen-sensitive materials such as oils and fats, rubber products, and plastics.
When R4 in the general formula (1) is a protecting group, the protecting group can be replaced with a hydrogen atom by a conventional method to obtain a compound having the above-mentioned antioxidant effect. be able to.

Recently, vitamin E has attracted attention as a highly safe antioxidant1, but it has a relatively low value and is easily oxidized and colored, so it has not yet become a general-purpose antioxidant. .

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 (2) has a superior antioxidant effect to vitamin E. The present inventors have discovered that these dicarboxylic diesters can be produced easily and inexpensively as precursors for compounds having antioxidant properties, leading to the present invention.

According to the present invention, general formula (n) 1 [wherein R1, R2 and R3 have the same meanings as in general formula (1,), and R is the same as R4 in general formula (1) or Unlike the hydrogen atom or the hydrogen atom. 2 indicated by ]
-Substituted ethyl alcohol or its reactive derivative and general formula (1) % formula % ( ) [wherein A has the same meaning as in general formula (I). ] The dicarboxylic acid diester represented by the general formula (I) can be produced by reacting the dicarboxylic acid represented by the above or its NOS-responsive derivative. Here, 2
-Reactive derivatives of substituted ethyl alcohols include halides, alkylsulfonates, arylsulfonates, and carboxylates. - Reactive derivatives of dicarboxylic acids include lower alkyl esters, acid halides, mixed acid anhydrides, alkali gold salts, silver salts, or salts of organic tertiary or quaternary bases. Shown by general formula (n)? The reaction between the 2-substituted ethyl alcohol or its reactive derivative represented by the general formula (II) and the dicarboxylic acid represented by the general formula (II) or its reactive derivative can be carried out under conventionally known fE-type ester synthesis reaction conditions. However, a narrow example of the ester synthesis reaction is shown below.

(Reaction example A) Reaction of alcohol and dicarboxylic acid civalide γ alcohol (II, l halide of dicarboxylic acid (river), preferably dicarboxylic acid dichloridetrabenzene,
The desired dicarboxylic acid diester ( 1) Get it.

(Reaction side port) Reaction of alcohol and mixed acid anhydride Alcohol (11) and mixed acid anhydride of dicarboxylic acid (Il!) and pivalic acid, p-toluenesulfonic acid, etc. are reacted with benzene, toluene, xycin, -1) in the presence of an acid such as toluenesulfonic acid or a tertiary amine such as pyridine, triethylamine, etc. at room temperature or The desired dicarboxylic acid diester (I) is obtained by reacting at a temperature of 51.

(Reaction example) - Reaction of a small alcohol and a dicarboxylic acid Alcohol (■) and dicarboxylic acid (■) are reacted with benzene,
in an inert solvent such as toluene, xycin, e.g. dicyclohexylcarbodiimide, or 2-chloro-1 iodide.
- The desired diester dicarboxylic acid (1) is obtained by reacting methylpyridinium with a dehydration condensation agent such as triethylamine at room temperature or under heating, or under azeotropic dehydration conditions.

(Reaction Example 2) Reaction of alcohol and lower alkyl ester of dicarboxylic acid Alcohol (n) and lower alkyl ester of dicarboxylic acid (■) are reacted with a suitable ester base, such as p-toluenesulfonic acid, or The desired dicarboxylic acid diester ( 1) is obtained.

(Reaction example) Reaction of halide, alkyl sulfonate or aryl sulfonate of alcohol with alkali metal salt, silver salt or salt of organic tertiary or quaternary base of dicarboxylic acid Halide, alkyl sulfonate or haaryl of alcohol (n) Sulfonate dicarboxylic acid (110) is reacted 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. The desired dicarboxylic acid diester (1) is obtained.

The 14 dicarboxylic acid diesters produced 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 then subjected to P+ crystallization. Or, by purification by column chromatography, the general formula (1
) can be obtained.

Most of the 2-M:converted ethyl alcohol represented by the general formula (II) used as a raw material are compounds known per se (Japanese Patent Laid-Open Nos. 49-88876 and 1988-56).
According to the method previously discovered by the present inventors, the general formula (■) H [wherein R, R'', R2 and R3 have the same meanings as in the general formula (If) ] It can be easily obtained by reacting hydroquinone or its derivative represented by the formula with 4-methyl-5,6-dihydro-2H-pyran in the presence of a Lewis acid (Japanese Patent Application No. 83,654/1989). (See specification) Examples of Lewis acids used in this combination reaction include boron trifluoride ether complex, aluminum chloride, aluminum bromide, ferrous chloride, ferric chloride, stannous chloride, and stannic chloride. , zinc chloride, sulfuric acid, p-toluenesulfonic acid, etc., but preferably aluminum chloride, boron trifluoride/ether complex.The amount of Lewis acid used is shown by the general formula (IV). 01 to 2 times the mole of hydro-r-non or its derivative;
5 to 1.0 times the mole. This condensation reaction is preferably carried out in a 7'd medium, such as 1:2-dichloroethane, dichloromethano, dichloroform, 1,1,2-trichloroethene, carbon tetrachloride, chlorobenzene, etc.
, digenated carbon water cord; benzene, toluene, quince,
Hydrocarbons such as nitromethane, nitrobenzene, benzonitrile, and acetonitrile; nitrogen compounds such as methyl ethyl ketone, ethyl acetate, and butyl chloride, or a mixture thereof as a solvent. 2-dichloroethane is particularly preferred.The solvent used is hydroquinone or its derivative represented by the general formula 0. The condensation reaction is carried out at about 5 to 20 times the pressure (G-).This condensation reaction is usually carried out at -40
°C ~ 150° (°1, preferably 0°C ~] -00°C
Let's do it.

-4#; Reactive derivatives of 2jq heptanoleic ethyl alcohols represented by the formula (previously) are produced by halogenating, alkanesulfonylating, arenesulfolating or unarylating the 2-substituted ethyl alcohols in a conventional manner. be able to.

In addition, dicarboxylic acid, which is one of the raw materials, is a known compound, and can be prepared by conventional methods such as reactive derivatives of dicarboxylic acid such as lower alkyl esters, acid) rides, mixed acid anhydrides, alkali metal salts, silver salts, or organic tertiary Alternatively, it can be easily derived into a salt of a quaternary base.

Further, according to the present invention, hydroquinone or a derivative thereof represented by the general formula (IV) and the general formula (V) CH300 111 X-CH2C)1=C-CH2CH20-C-CH2-
A -Cl-12-C-CH3 -OCH2CH2-C=CHCH2-X...(V) [
In the formula, X represents a halogen atom, and A has the same meaning as in general formula (1). The dicarboxylic acid diester represented by the general formula (1) can 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 combination with fluoride include boron fluoride/ether complex, aluminum chloride, aluminum bromide, ferrous chloride, ferric chloride, stannous chloride,
Examples include stannic chloride and substannic chloride, but
The amount of Lewis acid to be used, which is preferably zinc chloride, is shown by the general formula (IV).
Calculate from 1 to 0.1 times the mole ○ This condensation reaction is preferably carried out in a solvent, and the
The solvent used in the condensation reaction of idoguinone or its 4-isomer with 4-methyl-5,6-dihythro-2-1-pyran can be similarly used. Usability of the solvent: - is about 2 to 100 times heavier, preferably about 5 to 20 times heavier than other derivatives of hydroquinone or (l) represented by the general formula (heli).This condensation reaction is -40°C to L 50 'C1 Preferably carried out at 0°C to 100°C.

Dicarboxylic acid substituted pentenyl ester id, 4-methyl-5,6-dihydro-2H-pyran and di-ride of dicarboxylic acid are combined in the presence of a Lewis acid with the general formula (V, l) used as the original It. This condensation reaction (611,
It can be carried out in the presence of the same Lewis acid as used in the condensation reaction between the above-mentioned ino-idoquinone or its derivative represented by general formula (IV) and the dicarboxylic acid disubstituted pentenyl ester represented by general formula (V). can. The amount of Lewis acid used is 0001 to 05 times the molar amount of 4-methyl-5,6-sihydro-2H-pyran, preferably 0.01 to 0.5 times
○This condensation reaction is preferably carried out in a solvent, and is carried out in a solvent with the ido-guinone or its derivative represented by the general formula (IV) and the disubstituted pentenyl dicarboxylate represented by the general formula (V). The solvents used in the condensation reaction with the esters are likewise used. The amount of solvent used is approximately 2 to 1 to 4-methyl 15,6-cyhydro-2H-bilane.
It is about 5 to 20 times the weight of 00 times heavy weight. This condensation reaction is usually carried out at -5°C to 70°C, preferably at 0°C.
Perform at ~50°C. The general formula (V
The reaction mixture containing the dicarboxylic acid disubstituted pentenyl ester represented by
It can also be subjected to a reaction with a quinone or a derivative thereof.

Reaction of 4-methyl-5,6-sihydro-2H-pyran with civalide of a dicarboxylic acid yields a di-substituted pentenyl ester of lercicarboxylic acid represented by the general formula (■), and then a reaction with the di-substituted benzonyl ester of the dicarboxylic acid and a reaction of the general formula (■)
A preferred embodiment for producing the dicarboxylic acid diester represented by the general formula (1) by reacting the dicarboxylic acid diester represented by the general formula (1) with an idoguinoquinone (represented by R) or a derivative thereof is shown below. General formula (V) is obtained by dissolving or suspending 4-methyl-5,6-sihydro-2H-pyran and Lewis acid in a solvent, then adding civalide of dicarboxylic acid, and continuing stirring for about 0.5 to 4 hours. A reaction mixture containing a dicarboxylic acid disubstituted pentenyl ester represented by is obtained.

From this reaction mixture, for example, the general formula (V
) is isolated. Next, the compound represented by the general formula (■), . The dicarboxylic acid disubstituted benzonyl ester represented by the general formula (V,) in a molar amount of 0.5 to 0.6 times the general formula (indicated by the edge), idoguinone or its derivative (t), The dicarboxylic acid disubstituted pentenyl ester represented by the general formula (v) is cooled and stirred for an additional 0.5 to 4 hours to form a compound of the general formula (I). A mixture containing the dicarboxylic acid diester represented by the following formula was obtained. The dicarboxylic acid diester can be easily separated and recovered from this reaction mixture by the method described above.

3,4-dihydro-2 represented by general formula (I) of the present invention
2-substituted ethyl alcohol represented by the general formula (11) or its reactive derivative and a dicarboxylic acid disubstituted product represented by the general formula (V) The pentenyl ester is 4-methy/l/-5°0-dihydro-2H as described above.
The 4-methyl-5,6-sihydro-2n-bilane is produced as a by-product in the production of isoprene from isobutyne and formalin, and is also produced as a by-product of acid catalysts. It can also be synthesized by a reaction between tertiary butanol and an aqueous formaldehyde solution in the presence of hydrogen, and is easily and inexpensively available. Explain in detail.

Example 1 3.4-dihydro-2-(2-hydroxyethyl]-2
,5,7,8-tetramethyl-2H-benzobilane-6
-4- 2.5El, thiA-diglycylic acid 5mm
ol.

A solution consisting of 0.1 g of p-) toluene sulfonic acid and 100 d of toluene was heated under reflux, and 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 by silica gel column chromatography, diC2-<3.4-dihydro-6-deloxy-2,5,7,8-tetramethyl-2H-benzopyranyl) having the following physical properties was obtained. ethyl cothiodiacetate 1.79,
S? (yield 58%).

FD mass spectrum: [M]”614 NMRy, vector (90 MHz) δCDα3MS 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,
6) Examples 2 to 6 In Example 1, instead of 5 mmol of thiodiglycolic acid, 3-thia-1,6-hexanionic acid, 3,4-dithia-1,6-hexanionic acid, 4,5-dithia -1,8-octanedioic acid, 3,5-dithia-1,7-hebutanedioic acid,
5 mmol each of 4,6-cythia-1,9-nonannioic acid
By performing the reaction and separation and recovery in the same manner as in Example 1, the corresponding dicarboxylic acid diesters were obtained.The respective yields and NMR spectra,
The FD mass spectra are shown in Table 1.

Example 7 3,4-dihydro-2(2-hydroxyethyl)-2,
5,7,8-tetramethyl-2H-benzopyran-6-
All 2,5. 5 mmol of thiodiglycolic acid dichloride was added dropwise to a mixed solution consisting of y, 0.79 g of pyridine, and 10 ml of methylene chloride under water cooling, and the mixture was stirred 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 condensed.

The concentrated solution was purified by silica gel column chromatography to obtain di[2-(3,4-dihydro-6-hydroxyloxy)2.5, which has the following NMR spectrum.
．． 2.82.9 of 7.8-tetramethyl-2H-benzopyranyl)ethyl]thiodiacetate was obtained (yield 92%).
).

Examples 8 to 15 In Example 1, 3,4-dihydro-2-(2-hydroxyethyl)-2,5,7,8-tetramethyl-2H
- Reaction and separation and recovery were carried out in the same manner as in Example 1 except that 2.5 g of benzobylan-6-ol was used as flK of 2-substituted ethyl alcohol l Q mmol shown in Table 2. The corresponding thiodiglycolic acid diester was obtained. The results are shown in Table 2.

Example 16 In Example 7, 3,4-dihydro-2-(27hydroxyethyl)-2,5,7,8-tetramethyl-2H
-benzobilan-6-ol 2.5.9 substituted 2-(
6-acedoquine-3,4-dihydro-2-methyl-2H
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 (2-(6-benzopyranyl)),
2.8I of acetoxy-3,4-dihydro-2-methyl-2H-benzopyranyl)ethyl]thiodiacetate was obtained (yield 91%)O FD texture spectrum [M″]”614 Example 17 5.6 -Sihydro-4-methyl-2H-pyran 1.96
is], 1.87.9 g of thiodiglycolic acid dichloride was added dropwise to a mixed solution of 10 ml of 2-dichloroethane and anhydrous zinc chloride o, os, y, and the mixture was stirred at room temperature for 1 hour. The resulting reaction solution was diluted with 3.04 g of trimethylhydroquinone.
．． ! i', was added dropwise to a mixed solution of 0.05p of anhydrous zinc chloride and 18rrtl of 1,2-dichloroethane while heating under reflux. After the dropwise addition, the reaction solution was heated under reflux for 2 hours, and then cooled.
It was poured into water and then extracted with diethyl gothyl. 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, 4.33 g of 5,7,8-tetramethyl-2H-benzopyranyl)ethyl thiodiacetate (yield 71%) Examples 18-20 In Example 17, trimethylhydroquinone 3,04
．． Hydroquinone derivative 20r shown in Table 3 in the place of 9
The corresponding thiodiglycolic acid diesters were isolated by carrying out the reaction and separation and recovery in the same manner as in Example 17, except that nmol was used. These products were confirmed in the same manner as in Examples 12, 13, and 16, respectively. The respective yields are shown in Table 53.

Table 3 Examples 21-24 Thiodiglycolic acid dichloride 1 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 dibromide, 3,5 instead of 87 g -Dithia-1,7-hebutanedioic acid dichloride was used in an amount of 10 mmol (Example 1)
The reaction and separation and recovery were carried out in the same manner as in 7 to obtain the corresponding dicarboxylic N-diesters. 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 4 11 (1 21αCCH25CH2CH2Cα 720 II lI 22 αCCH25SCH2Cα 650 II 11 23 BrCCH2CH25SCH2CH2CBr
630 111 24 αCCH25CH2SC)I2Cα 74 Test Examples 1 to 13 Samples were prepared by adding and mixing 0.020 g of each of the test compounds shown in Table 5 to 100 g of ethyl linoleate. These samples are AOM
(Antioxygen method) Using a test device, A 01Vi (under Jz conditions (97.8°C, ventilation 2
．． 33 cc/sec), and the time required for the pov (peroxide value) to reach 4 to 100 meq/sec was measured. The results are shown in Table 5.

5 Table 1 Additive-free 02 2 BHT Note (1)
1.03 Irganox]010
Note f21 0. B4 α-Tocopherol 1.2 N(r)7 City R5 product 3-(3
,5-tertiary phthyl-4-hydroxyphenyl) propionic acid tetraester Patent applicant: RiRa Co., Ltd. Representative patent attorney: Ken Honda

Claims (1)

[Claims] 1. General formula (wherein R represents a hydrogen atom or a lower alkyl group.
and R are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, and 1 or R and R together form a -CH=CH-1=CH- group. R+d hydrogen atom or protecting group, A is -S-1-CH2S-
1-3-8-1-CH, 2S-8C Month 2-1-SC
Dicarboxylic acids and diesters represented by R2S- and -(J12S (J (represents the first group selected from where R1 represents a hydrogen atom or a lower alkyl group; R2 and R3 are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, or R2 and R3 together represent -
2-substituted ethyl alcohol or its reactive derivative represented by CH=, -C1 (-CH=CH- forms. -1-8-3-1-
C locus S-8CH2-1-8C, H2S - and 0: -C
H2SCH2SCH2-represents a group selected from the group consisting of Kara. ) or a reactive derivative thereof (wherein R1, R'4. B3 and A are as defined above, and R4 is the same as R above) or (represents a hydrogen atom or a protective group). 3. General formula (wherein R represents a hydrogen atom or a protective group, R1 represents a hydrogen atom or a lower alkyl group R2 and R3 are the same.
Alternatively, a hydrogen atom, a lower alkyl group or a lower ψ alkoxy group, or 1t2 and 1co3, together form a -CH-CI-CH-Chi- group. Indicated by... Hydroquinone or its derivatives and general CH3
0,0 111 X-CI-bc)i=C-CM2C month, 2O-C-CH
2-A-CH2-C-Ha -OCR2CH2-C=CHCH,2-X (wherein, X represents a halogen atom, and A is -8-1-CH2S-1-
Represents a group selected from the group consisting of 8-8-1-CH2S-8CH2-1-SCH2S- and -CH2SCI-12SCH2-. ) is reacted with a dicarboxylic acid disubstituted pentenyl ester in the presence of a Lewis acid to form a general formula (wherein R1, B2. R3 and A are as defined above, and R4 is the same as or different from the above R and represents a hydrogen atom or a protective group. 9. A method for producing a dicarboxylic acid diester represented by.