JPS59118781A - Thiodipropionic acid ester and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or lower alkyl; R<2> and R<3> are H, lower alkyl, lower alkoxy, or R<2> and R<3> are linked to form -CH=CH-CH=CH-; R<4> is H or protecting group). EXAMPLE:Di[ 2-( 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl- 2H-benzopyranyl ) ethyl]2,2-thiodipropionate. USE:An antioxidant. PROCESS:A compound shown by the formula II (R is H or protecting group) or its reactive derivative is reacted with thiodipropionic acid or its reactive derivative, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a thiodipropionic acid ester represented by the general formula (1) in Category 8A and a method for producing the same.

In the above formula, R1 represents a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group. R
2 and R3 are the same or different hydrogen atoms; lower alkyl groups such as methyl, ethyl, propyl, butyl; or lower alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, or R2 and R
3 together form -CH, =CI (-CH=CH- group. R4 represents a hydrogen atom or a protecting group. As a protecting group, any commonly used protecting group can be used as long as it achieves the purpose of protecting a hydroxyl group. groups may also be used, for example acetyl groups,
Examples include anlu groups such as a probionyl group, a butyryl group, and a benzoyl group, a methyl group, a t-butyl group, a triphenylmethyl group, a benzyl group, and a trimethylsilyl group.

The thiodipropionic acid ester represented by the general formula (I) provided by the present invention is a new compound that has not been described in any known literature. Among these thiodipropionate esters, those in general formula (I) A in which R4 is a hydrogen atom have excellent antioxidant effects and are suitable for use in oxygen-sensitive organic materials, such as oils and fats, rubber products, and plastics. It is useful as an antioxidant.

Further, when R4 in the general formula (1) is a protecting group, a compound having the above-mentioned antioxidant effect can be obtained by replacing this protecting group with a hydrogen atom by a conventional method.

Recently, vitamin E has been recognized as a highly safe antioxidant.
However, it is relatively expensive and is easily oxidized and colored, so it has not been used as a general-purpose antioxidant.

As a result of intensive research aimed at developing a new antioxidant that surpasses vitamin E, the present inventors found that the thiodipropionic acid ester represented by the general formula (I) has a superior antioxidant effect to that of vitamin E. The present inventors have discovered that these thiodipropionic acid esters can be produced easily and at low cost, and that these thiodipropionic acid esters can be produced easily and at low cost.The present invention has thus been completed.

According to the present invention, general formula (II) 1 is also 1 5 [Formula A, R1, R2 and R3 have the same meanings as in general formula (I), and R is the same as R4 in general formula (1). - or otherwise represents a hydrogen atom or a protective group. ] 2-
By reacting substituted ethyl alcohol or a reactive derivative thereof with thiodipropionic acid or a reactive derivative thereof, a thiodipropionic acid ester represented by the general formula (2) can be prepared. Reactive derivatives of iu-substituted ethyl alcohol include halides, alkyl sulfonates, aryl sulfonates, and carboxylates.Reactive derivatives of thiodipropionic acid include lower alkyl esters, acid halides, mixed acid anhydrides, alkali metal rings, and silver. Examples include salts and salts of tertiary or quaternary bases.The reaction between the 2-substituted ethyl alcohol represented by the general formula (n) or its reactive derivative and thiodipropionic acid or its reactive derivative The reaction 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 of alcohol and thiodipropionic acid halide Alcohol (II) and thiodipropionic acid halide,
A suitable solution of thiodipropionic acid tallolide is prepared in an inert solvent such as benzene, toluene, ether, or chloroform in the presence of a tertiary amine such as pyridine or triethylamine in an amount of 1 to 3 molar equivalents relative to the alcohol at room temperature. The desired thiodipropionic acid ester (I) is obtained by the reaction.

(Reaction side port) Reaction of alcohol and mixed acid anhydride Alcohol (■), thiodipropionic acid and pivalic acid, p-
Mixed acid anhydrides with toluenesulfonic acid, etc., in inert solvents such as toluene, xylene, hexane, etc.
Preferably, the desired thiodipropionic acid ester (I ) You can get it.

(Reaction Example C) Reaction of Alcohol and Thiodipropionic Acid The alcohol (It) and thiodipropionic acid are reacted in an inert solvent such as benzene, toluene, xylene, etc., for example, with dicyclohexanelupodiimide or 2-chloroiodide. −
The desired thiodiprobionic acid ester (x) .

(Reaction example 2) Reaction of alcohol and thiodipropionic acid (D lower alkyl ester) Alcohol (II) and lower alkyl ester of thiodipropionic acid are transesterified using a suitable transesterification catalyst, such as p-toluenesulfonic acid or titanium The desired thiodipropionic acid is produced by heating the reaction in an inert solvent such as toluene or xylene in the presence of a titanium compound such as tetramethyl acid, and removing the generated low-boiling alcohol from the reaction system. Ester (1) is obtained.

(Reaction Example E) Reaction of alcohol halide, alkyl sulfonate or aryl sulfonate with alkali gold^ salt, silver salt or organic tertiary or quaternary base salt of thiodipropionic acid Halide of alcohol (II), alkyl A sulfonate or aryl sulfonate is reacted with an alkali metal salt, silver salt, or salt of an organic tertiary or quaternary base of thiodipropionic acid in a solvent such as dimethylformade, benzene, acetone, etc. at room temperature or under heating. By doing this, the desired thiodipropionic acid ester (1) was obtained.

The thiodipropionic acid ester 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 and dried, the solvent is distilled off, and the residue is recrystallized or purified by column chromatography to obtain the general formula A thiodipropionic acid ester represented by (1) can be obtained.

Most of the 2-substituted ethyl alcohols represented by the general formula (It) used as raw materials are compounds known per se (Japanese Patent Application Laid-Open Nos. 49-88876 and 56-1).
45282], according to the method previously discovered by the present inventors, the general formula (lit)H [wherein R, R, R and R have the same meanings as in the general formula (1). ] It can be easily obtained by reacting hydroquinone or its derivative represented by 4-methyl-5,6-sihydro-2H-bilane in the presence of a Lewis acid (see Japanese Patent Application No. 83654/1983). ).

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. , J)-) luenesulfonic acid, preferably aluminum chloride, boron trifluoride/ether complex. The amount of Lewis acid to be used is 0.1 to 2 times the molar amount, preferably 0.5 to 1.0 times the molar amount of hydroquinone or its derivative represented by the general formula (lit). This condensation reaction is preferably carried out in a solvent, such as 1,2-dichloroethane, dichloromethane, chloroform, 1,1.2
- Hydrocarbon halides such as trichloroethylene, carbon tetrachloride, and chlorobenzene; Hydrocarbons such as benzene, toluene, xylene, nclohexane, n-hexane, and ligroin; Nitrogen-containing compounds such as nitromethane, nitrobenzene, benzonitrile, and acetonitrile; Oxygenated compounds such as methyl ethyl ketone, ethyl acetate, butyl acetate or mixtures thereof can be used as solvents, but especially 1
, 2-dichloroethane are preferred. 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 (iff), preferably about 5 to 20 times the weight of the hydroquinone or its derivative.
It's twice as heavy. This condensation reaction is usually -40℃~150℃
, preferably at 0°C to 100°C.

The above-mentioned reactive derivative of 2-substituted ethyl alcohol can be obtained by halogenating, alkanesulfonylating, arenesulfonylating or acylating the 2-substituted ethyl alcohol represented by the general formula (n) by a conventional method.

Thiodipropionic acid, which is one of the raw materials, is a known compound, and reactive derivatives of thiodipropionic acid, such as lower alkyl esters, acid halides, mixed acid anhydrides, alkali metal salts, silver salts, or organic 3rd grade or 4th grade
easily derivatized into base salts.

Further, according to the present invention, hydroquinone or a derivative thereof represented by the general formula (1) and the general formula (IV) CHa
0 011]l X-CH2CH2C-CH2CH20-C-CH2CH
+5CH2CH2-C-CHa -OCH2CH2-C=CIICH2-X...(IV
) (wherein, X represents a halogen atom) can also be reacted with a thiodipropionic acid substituted pentenyl ester represented by the formula (1) in the presence of a Lewis acid.
A thiodipropionic acid ester represented by can be produced.

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 0.0001 to 1 times the molar amount, preferably 0.001 to 0.1 times the molar amount of hydroquinone or its derivative represented by the general formula (nl, l).

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 general formula (Ill) and 4-methyl-5,6-cyhydro-2H-pyran is the same. used for. The amount of solvent to be used is about 2 to 100 times the weight of hydroquinone or its derivative represented by general formula (1), preferably about 5 times
~20 times the weight. This condensation reaction is usually carried out at -40℃~1
5 (+'C, preferably 0 to 100C.

The thiodipropionic acid substituted pentenyl ester represented by the general formula (IV) used as a raw material is 4-methyl-5,
It can be easily obtained by reacting 6-sihydro-2H-pyran with a halide of thiodipropionic acid in the presence of a Lewis acid. This condensation reaction is carried out in the presence of the same Lewis acid used in the combination reaction of hydroquinone or its derivative represented by the general formula (IIl) and the thiodipropionic acid substituted pentenyl ester represented by the general formula (rv). can be done. The amount of Lewis acid used is 4
-0 for methyl-5,6-cyhydro-2H-pyran
．． 001 to 0.5 times the molar weight, preferably 0.01 to 0.0.
5 times the molar amount. This combination reaction is preferably carried out in a solvent, and is used in the condensation reaction between hydroquinone or its derivative represented by the general formula (Ill) and the thiodipropionic acid substituted pentenyl ester represented by the general formula (IV). Solvents are used as well. The amount of solvent used is 4
-Methyl-5,6-cyhydro-2M-pyran is about 2 to 100 times the weight, preferably about 5 to 20 times the weight. The condensation reaction with
Carry out at 50°C to 50°C.

The reaction mixture containing the thiodipropionic acid-substituted pentenyl ester represented by the general formula (IV) thus obtained is directly subjected to a reaction with hydroquinone or its derivative represented by the general formula (1!i). You can also do it.

The general formula (lν
) is obtained, and then the thiodipropionic acid-substituted pentenyl ester is reacted with hydroquinone or a derivative thereof represented by the general formula (1) to obtain the thiodipropionic acid-substituted pentenyl ester represented by the general formula (1). A preferred embodiment for producing thiodipropionic acid ester is shown below. By dissolving or suspending 4-methyl-5,6-sihydro-2H-pyran and Lewis acid in a solvent, then adding thiodipropionic acid halide and continuing stirring for about 0.5 to 4 hours, the general formula (IV)
A reaction mixture containing a thiodipropionic acid substituted pentenyl ester is obtained. From this reaction mixture, for example, a thiodipropionic acid substituted pentenyl ester represented by the general formula CJ) is isolated by distillation. Next, hydroquinone or its derivative represented by general formula (III) and Lewis acid are dissolved or suspended in a solvent, and while stirring and heating in an inert gas atmosphere such as nitrogen,・0.0 for hydroquinone or its derivatives.
About 0.5 to 0.6 times the molar amount of thiodipropionic acid substituted pentenyl ester represented by the general formula (IV)
Incubate and react for 8 hours. After adding the thiodipropionic acid substituted pentenyl ester represented by the general formula (edge), stirring is continued for about 0.5 to 4 hours to obtain a reaction mixture containing the thiodipropionic acid ester represented by the general formula (1). The separation and recovery of thiodipropionic acid ester from this reaction mixture can be easily carried out by the method described above.

Furthermore, according to the present invention, a compound of the general formula (V) 1 3 [wherein R, R1, R2 and R3 have the same meanings as in the general formula (1)]. ] The thiodipropionic acid ester represented by the general formula (1) can also be produced by reacting the 2-substituted ethyl acrylic acid ester represented by the following with hydrogen sulfide in the presence of a base catalyst.

Examples of the base catalyst used in this reaction include sodium acetate; alkaline hydroxides such as sodium hydroxide and potassium hydroxide; sodium methylate, sodium ethylate, potassium methylate, potassium ethylate,
Alkali metal alcoholades such as potassium t-butyradonat; tertiary amines such as pyridine and triethylamine;
Examples include basic ion exchangers. The amount of the base catalyst to be used is preferably 0.1 to 10% by weight relative to the 2-substituted acrylic acid ethyl ester represented by the general formula (V). This reaction is preferably carried out in a solvent, e.g.
．． 2-dichloroethane, methylene chloride, tetrahydrofuran, diethyl ether, toluene, quinolene, ethanol, impropatol, and the like can be used as the solvent.

The amount of solvent used is acrylic acid 2-
Approximately 2 to 100 times the weight of substituted ethyl ester, preferably 1
The structure is about 5 to 20 times N view. Although this reaction can be carried out at room temperature, it is preferably carried out at or under heating up to about 100'C.

It can be easily obtained by subjecting the 2-substituted ethyl alcohol represented by the general formula (II) and methyl acrylate to a transesterification reaction in a conventional manner.

The separation and recovery of the thiodipropionate ester represented by the general formula (2) obtained by the reaction of the acrylic acid 2-substituted ethyl ester represented by the general formula (V) of Uegobi with hydrogen sulfide is carried out as described above. This can be easily done by the following method.

The present invention will be specifically explained below with reference to Examples and Test Examples.

Example 1 3,4-dihydro-2-hydroquinethyl-2,5,7,8-tetramethyl-2H-benzopyran-6-ol5. under nitrogen atmosphere. Of, thiodipropionic acid 1.78
f, p-toluenesulfonic acid 0.3F and toluene 10
A mixed solution consisting of 0d was heated and allowed to flow for 20 hours while being azeotropically dehydrated. The reaction solution was concentrated and purified by gel force chromatography to obtain the following spectrum (2-(3,4-
Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-penthyranyl) ether) 2,2-thiodipropionate in 5.279 (yield: 82%) O HMS.

NMR spectrum (90MHz) δCDQ! a'1
．． 2 (s, 6M); 1.68-2.17 (m, 2
6H); 2.37-2.9 (m, 12M,); 3.7
~4.5 (rn, 6JFD-mass vector: CM)
+642 Example The reaction and separation and recovery were carried out in the same manner as in Example 1, except that 2.34 ykM of ethyl thiodipropionate was used instead of 1.78 F of thiodipropionic acid. 4-dihydro-6-hydroquine-2,5
,7,8-tetramethyl-2H-benzopyranyl)ethyl] 5.231 of 2,2-thiodipropionate was obtained (
yield 81%).

Example 3 3,4-dihydro-2-hydroxyethyl-2,5,7,8-tetramethyl-2H-benzopyran-6-ol5. under nitrogen atmosphere. Of, a solution of 1,67 grams of pyridine and 10 grams of methylene chloride was gradually added dropwise to a solution consisting of 221 grams of thiodipropionic acid chloride and 50 grams of methylene chloride. After the dropwise addition, the mixture was stirred at room temperature overnight, and the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid and then with saturated saline, dried over anhydrous magnesium sulfate, concentrated, and the resulting concentrated solution was purified by silica gel column chromatography to obtain 42-
(3゜4-dihydro-6-hydroxy-2,5,7,8
-tetramethyl-2H-benzopyranyl) ether) 2,
5.64.1 of 2-thiodipropionate was obtained (yield 8
Section 8).

Examples 4 to 11 In Example 1, 3,4-dihydro-2-hydroxyethyl-2,5,7,8-tetramethyl-2H-benzobyran-6-ol 5,Of was replaced with the following first coating. The corresponding thiodipropionate esters were obtained by performing the reaction and separation and recovery in the same manner as in Example 1 except that 20 mmol of the 2-substituted ethyl alcohol shown was used. The results are shown in Table 1.

Example 12 In Example 3, 2-(6-acedoquin-3, By carrying out the reaction and separation and recovery in the same manner as in Example 3 except that 5.02% of 4-dihydro-2-methyl-2H-benzopyranyl)ethanol was used, the following tiger 2-( 6-acedoquine-3,
5.81F of 4-dihydro-2-methyl-2H-benzopyranyl)ethyl)2.2-thiodipropionate was obtained (yield: 80%).

FD mass spectrum: [M] +642 Example 13 2-(6-Hydooxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl acrylate 6.08 under nitrogen atmosphere ? 10 mmol of hydrogen sulfide gas was blown into a solution consisting of 0.12 d of sodium ethylate and 50 d of tetrahydrofuran. The reaction solution was stirred at room temperature overnight, poured into water, and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated, and the resulting concentrated solution was subjected to lt'? By setting I M', [
:2-(6-hydroxy-3,4-dihydro-2,5
,7,8-tetramethyl-2H-penthyranyl)ethyl)2,2-thiodipropionate in 4. r2t? Example 14 The reaction and separation and recovery were carried out in the same manner as in Example 13, except that triethylamine Q and lme were used in place of 0.12% of sodium ethylate in Example 13. By cedar, (2-(6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-benzoviciel)ethyl)2.2-thiodipropionate 4.
28r was obtained (yield 67 items).

Examples 15 to 23 In Example 13, 24th F was used instead of 2-(6-hydroxy-3°4-dihydro-2,5,7,8-tetramethyl-2H-benzopyra,=)ethyl acrylate 6.0+3f. The corresponding thiodipropionate esters were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 13 and [4] except that 20 mmol of the 2-substituted acrylic acid ethyl ester shown above was used. Confirmation was performed in the same manner as in Examples 4 to 12, respectively.

Table 2 shows the yield of seven seeds.

2nd Example 24 5.6-hydro-4-methyl-2H-bilane 1.96
F, 1,2-diq O/L/ :I-ta:/l Q H
2.15 F of thiodipropionic acid chloride was added dropwise to a mixed solution of 0.08 F of anhydrous zinc chloride and the mixture was stirred at room temperature for 1 hour. The resulting reaction solution was mixed with 3.04y of trimethylhydroquinone, 0.05F of anhydrous zinc chloride, and 18m of 1,2-dichloroethane. The mixture was added dropwise to a mixed solution of 7+ under 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, the low-spot content was removed, and the resulting concentrated solution was purified by silica gel column chromatography to obtain di[2-(3,4-dihydro-6-hydroxy-2 , 5,7,8-tetramethyl-2H-benzopyranyl)ethyl]2.2-thiodipropionate to 4.5
1? (yield 70%).

Examples 25-27 In Example 24, trimethylhydroquinone 3,04
Hydroquinone derivative 201 shown in Table 3 in place of f and p
The corresponding thiodipropionate esters were prepared by carrying out the reaction and recovery of the additive in the same manner as in Example 24, except that T111101 was used. Confirmation of these products is provided in Examples 8.9 and 12 and l"J 45 ft.
, I did it. The respective yields are shown in Table 3.

Table 3 Examples Hydroquinone Derivative Product Yield (Decoration Test Examples 1 to 9 The test compounds shown in Table 4 were mixed with ethyl linoleate by adding 0.02 (H') to 100F of the ethyl linoleate. A sample solution was prepared.

20rrtl of these samples were added to AOM (Antioxygen
<97.gen method) test equipment under AOM conditions. s℃, ventilation 2.33 cc/5ec)? Abuse 1. , "o" (A oxide value) is 100 meq/kg
The time it took to reach was measured. The results are shown in Table 4.

Table 4 1 No additives 0.22
BHT 3. .

3 α-Tocopherol 3.2 Procedural amendment (voluntary) Kazuo Wakasugi, Commissioner of the Japan Patent Office 1. Indication of the case, Patent Application No. 229693 filed in 1982. 2. Title of the invention: Thiodipropion dragon ester and its manufacturing method 3. Amendment. Relationship with the patent applicant Kurashikifu/i! ! Itsu 1621 (108) RiRashi Co., Ltd. Representative Director Iya Ueno -4, Agent Telephone: Tokyo 03 (277) 3182 5, Column 6 for detailed explanation of the invention in the specification to be amended, Contents of the amendment (1) Lines 4-5 of page 22, lines 1-2 of page 23, bottom line of page 23 to line 1 of page 24, lines 6-5 from the bottom of page 26, page 27 “2,2-thiodipropionate” in lines 12-13, line 1 on page 28 and line 2 on page 31
is corrected to 1-3°3'-thiodipropionate.

(2) EA Specifications, page 31, No. 3,
”

Claims (1)

[Claims] 1. General formula (wherein 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 form a -CH=CH-C)I=CH- group. R4 represents a hydrogen atom or a protective group. ) Thiodipropionic acid ester 02 represented by the general formula (wherein R represents a hydrogen atom or a protecting group, R1 represents a hydrogen atom or a lower alkyl group, R2 and R3 are the same -
or differently represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, or R2 and R3 together represent -C
It is characterized by reacting 2-substituted ethyl alcohol or a reactive derivative thereof represented by I-1=cf (0 forming a -CH==CH- group) with thiodipropionic acid or a reactive derivative thereof. Production of thiodipropionic acid ester represented by the general formula (wherein Hl, R2 and R3 are as defined above, and R4 represents a hydrogen atom or a protective group, which is the same as or different from R above) Method. 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 -
or differently represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, or R2 and R3 together represent -C
Forms a H-CH-CH=CH- group. ) Reacting hydroquinone or a derivative thereof with a thiodipropionic acid substituted pentenyl ester represented by the general formula % (wherein, X represents a halogen atom) in the presence of a Lewis acid. A thiodipropionic acid ester represented by the general formula characterized by Production method. 4. General formula (in the formula, R represents a hydrogen atom or a reserved group, R1 represents a hydrogen atom or a lower alkyl group, R2 and R3 are 4-
or differently represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, or R2R3 together represent -CH
The general formula (in the formula, R1, R2 and R3 are as defined above, and R4 is the same as or different from R and represents a hydrogen atom or a protective group.) A method for producing a thiodipropionic acid ester.