JPS6045175B2 - Novel hydroxybenzoic acid ester and antiseptic agent for industrial products containing it as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an excellent static compound represented by the general formula (I) 15\(OH)-n, --, --(I) (wherein n represents an integer of 1 or 2). Bacteria,
The present invention relates to a novel 20 hydroxybenzoic acid ester having a dispersing action and a preservative and anti-bacterial agent for industrial products containing the hydroxybenzoic acid ester as an active ingredient.

Currently, alkyl esters of parahydroxybenzoic acid have strong growth-inhibiting or sterilizing power against bacteria, fungi, yeasts, and molds, and have low toxicity and irritation to the human body, so they are used in pharmaceuticals, quasi-drugs, cosmetics, etc. It is widely used as a preservative for industrial products.

Also lower alkyl esters of rose hydroxybenzoic acid,
For example, ethyl, propyl, butyl, isopropyl, and isobutyl esters are permitted to be used as food additives due to their high safety as preservatives, and are actually used as preservatives in foods such as soy sauce and sauces. has been done. The present inventors synthesized various hydroxybenzoic acid esters and investigated their physiological activities. As a result, the novel hydroxybenzoic acid esters represented by the above general formula (1) were found to be useful as conventional commercially available preservatives and anti-bacterial agents. It has more pronounced bacteriostatic and bactericidal effects against microorganisms, especially gram-positive bacteria and gram-negative bacteria, than the rose hydroxybenzoic acid alkyl ester used, and is non-toxic or extremely low-toxic to the human body, and is safe for the skin. Found that it is not irritating,
The present invention has now been completed.

Representative examples of the hydroxybenzoic acid ester represented by the general formula (1) in the present invention are shown below.

Compound number Structural formula A υ ′! The hydroxybenzoic acid ester represented by the general formula (1) of the present invention is, for example, the hydroxybenzoic acid ester represented by the general formula (■) (wherein, M represents an alkali metal, and n represents the general formula (1)). It is obtained by reacting an alkali metal salt of hydroxybenzoic acid represented by (having the same meaning as in ) with 3-halogeno-4-vinyl-1●8-nonadiene.

This reaction) is preferably carried out in a solvent such as benzene, acetone, dimethylformamide, etc. by heating at a temperature ranging from about 50° C. to the boiling point of the solvent used. General formula (■)
Examples of alkali salts of hydroxybenzoic acid represented by hydroxybenzoic acid include hydroxybenzoic acid, metahydroxybenzoic acid, orthohydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, and 2,5-dihydroxybenzoic acid. Examples of 3-halogeno-4a-vinyl-1,8-nonadiene include potassium salt and sodium salt of benzoic acid; 3-chloro-4-vinyl-1,8-nonadiene, 3-bromo4
-Vinyl-1●8-nonadiene, etc. can be used. The hydroxybenzoic acid ester represented by the general formula (1) can be used as a preservative and a binder for industrial products as one type or a mixture of two or more thereof. Two or more types can be mixed with various appropriate dilution aids, such as solvents and surfactants, to formulate emulsions, wettable powders, etc., and used as preservatives and antibacterial agents for industrial products.

When using the antiseptic agent for industrial products containing the hydroxybenzoic acid ester represented by the general formula (1) of the present invention as an active ingredient, examples of targets to be protected from damage caused by the action of microorganisms include pharmaceuticals, The preservative is applied to industrial products such as quasi-drugs, cosmetics, textiles and paper products, leather products, wood products, paints, plastic materials, metals, electronic equipment, and optical machinery, depending on the shape of these products. It can be mixed, applied or sprayed. In addition, when mixed with cosmetics such as medicated soaps, cosmetic soaps, lotions, lotions, and creams, they may be used to disinfect the skin or cause impetigo, hair follicles caused by shaving, folliculitis, acne, acne, and eczema. It is effective in preventing skin diseases such as. Moreover, by mixing it with the preservative and antibacterial detergent of the present invention, its cleaning action can be improved. The amount of the preservative and antibacterial agent of the present invention to be used is, for example, according to the general formula (1) included in quasi-drugs, cosmetics, paints, etc.
The appropriate amount of the hydroxybenzoic acid ester expressed as the active ingredient is usually about 50 to 2000 ppm. Synthesis examples of the hydroxybenzoic acid ester represented by the general formula (1) will be shown below, as well as test examples and effect examples to clarify the effects of the hydroxybenzoic acid ester on microorganisms.

SYNTHESIS EXAMPLE 1.08 f of palladium acetate and 2.52 f of triphenylphosphine were dissolved in approximately 10 ml of dry tetrahydrofuran and charged to a stainless steel reactor under nitrogen atmosphere, cooled to -70°C and 160 ml of butadiene (
1.76 mol) and allyl alcohol 46.6 g (0
．． A mixed solution of 80 mol) was injected under pressure.

Thereafter, the temperature inside the reactor was gradually raised to 70° C., and the reaction was carried out by stirring for 8 hours while maintaining this temperature. By rectifying 169V of the resulting yellow-rimmed reaction solution, 130y of 2,7-octadienyl allyl ether having the following NMR spectrum was obtained as a fraction with a Bp of 80°C (15Tr0nHg). (95% yield from allyl alcohol). As a result of gas chromatography, the purity of this product was approximately 97%. NMR spectrum (10
0MHz) δCgl3l: 1.3-1.7(q)? ,1
．． 9~2.2 (Q,.J=4Hz)4H13.7~3.
9(m)4H14.7~5.3(m)4H15.3~6
．． 0(m)4H2.7-octadienyl allyl ether 29.9f(4). 18 mol) was dissolved in 300 ml of dry tetrahydrofuran, and the temperature was adjusted to -70°C in a nitrogen atmosphere.
Add 15% n-butyllithium under stirring while maintaining
- 100 ml of hexane solution (2 mmol/ml) about 3
It was added dropwise over 0 minutes.

The solution turned yellow and then deep red. After stirring at the same temperature for about 1 hour, the reaction solution was neutralized with dilute hydrochloric acid solution and extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate, and low-boiling substances were distilled off to obtain a pale yellow liquid. .
The resulting pale yellow liquid was distilled under reduced pressure to obtain a yield of 90~92°C (
8 wftHg), 29.39 4-vinyl-1,8-nonadien-3-ol having the following properties was obtained (98% yield). As a result of gas chromatography, the purity of this product was approximately 97%. 13CNMR spectrum (CDCl3) δ: 26.1 (C1), 30 (C2
), 33.5 (C3), 49.8 (C4), 75 (C,
), 113.1 (C6, CaIcll38), 115
(C7, CacI.ll5.7), 116.5 (C8,
CaIc. ll6.7), 138.1 (C9), 138
．． 7(ClO)IR spectrum (Rlert): 337
To a mixed solution of 0 cm-1 (0H) 4-vinyl-1,8-nonadien-3-ol 12.84y1 pyridine 0.8 ml and petroleum ether 20 ml was added phosphorus tribromide 8 while stirring while keeping the temperature between O and 10°C. A mixture of .38y and Petroleum Air (8 ml) was added dropwise.

The reaction was carried out by stirring at the same temperature for 5 hours. The resulting reaction solution was transferred to about three times the amount of ice water, extracted three times with water, and further extracted three times with a saturated aqueous solution of sodium bicarbonate. The ether layer was separated and the ether was removed using an evaporator to obtain a yellow liquid. Next, this yellow liquid was subjected to silica gel column chromatography (Wakogel C-2001n).
- Hexane developing solution) to separate and purify the 3-bromo-4
13.28y of -vinyl-1●8-nonadiene was obtained (yield 75%). Potassium rose hydroxybenzoate 6.7g
, 30ml of dimethylformamide and 0.5y of trimethylstearylammonium chloride were placed in a 100mt three-necked flask, and the temperature was raised to 80°C using an oil bath while stirring.
The temperature was maintained at ~90°C.

After making a homogeneous solution, 3-bromo-4 is added by dropwise loading.
-13.0 y of vinyl-1,8-nonadiene was added dropwise.
As the reaction progressed, the formation of potassium bromide was observed. After reacting for 5 hours, dimethylformamide was distilled off from the reaction solution under reduced pressure, and then 30 ml of benzene was added.

Materials insoluble in benzene were separated, and the oral fluid was neutralized with a 10% aqueous sodium bicarbonate solution and extracted three times with water. The benzene layer was taken and concentrated using an evaporator to obtain 6.5y of pale yellow crystal crude product. This crude product was then separated and purified by silica gel column chromatography (Wako Gel C-20, developed with benzene) to obtain 2.8 d of rose hydroxybenzoic acid 14I2-divinyl-6-heptenyl ester in the form of a pale yellow syrup. The nuclear magnetic resonance spectrum data of this product is shown below. NMR spectrum (
100MHz) δ crystal Gl3: 1.2-1.4 (m) 廿B
l. 8-2.1 (m) Sha B2.48-2.77 (m) 1
H; 4.2 (t) 1H; 4.6-5.0 (m); 5.4
6-5.70 (m) 3H; 6.77 (d), 7.81 (
d) 4H test example 1 The MIC (minimum inhibitory concentration) for various microorganisms was
Shown in the table.

Test method: Dilute the test solution with a concentration of 10 mg/ml in 10 steps, put 1 ml of each concentration into a Petri dish, add 9 ml of nutrient agar medium, mix well before solidifying, and prepare a flat plate.

- On the other hand, transplant about 1 platinum loop of bacteria into a test tube containing 10 ml of peptone water, and perform static culture at 37°C for 2 hours. One platinum loopful of this culture solution is applied to the above-mentioned plate, and after culturing for 14 hours at 3TC, the minimum concentration that inhibits the growth of the applied bacteria is determined. The two strains used in the test are shown below. Vermilion No.
．． l Staphylococcus ◆Aureus FDA2O9
PNO. 2 Staphylococcus aureus New
nlan NO. 3 Bacillus Subtilis IAMlO69NO. 4
Bacillus ●Cereus NO. 5 Sarcina Lutea IFO3
232 NO. 6 Corynebacteum equi IAMlO3
8NO. 7 Mycobacterium avium IFO3l54
No. 8 Mycobacterium Frey 1F03158N0
．． 9 No Chaldea Asteroides IF'0342
4 N0.10 Aerobacter Aerogenes C- 12
No.11 Ethelicia coli AMl239NO. l2 Serratia●Marsetsu sense IFO3736NO. l3 Salmonella ● Teifu Murium IF'012529 N0.14 Sieudomonas ● Aeruginosa AKU8
23 NO. l5 Penicillium notatum IFO464O The numbers in the table indicate the concentration of the compound that inhibits the growth of the fungus.
Indicated by

Test Example 2 The phenol coefficient (bactericidal effect) against various microorganisms was
Shown in the table.

Test method: Staphylococcus aureus FDA2O9
Culture P. in a nutrient liquid medium with shaking between two cells.

The test drug solution was appropriately diluted with sterile distilled water, 1 ml of the above bacterial solution was added to 10 ml of the solution, kept at 20°C, and 2. After the conflict, after 5 minutes, after 1 conflict, and after 1 conflict, 1 of them
A platinum loopful was taken and mixed into a new nutrient liquid medium. Immediately, a portion of this was applied to a nutrient agar medium and cultured on a 3TC12 bridge, after which the viability of the bacteria was determined. The phenol coefficient was defined as the ratio of the maximum dilution of the test drug solution at which bacteria were not killed within 5 minutes of action and killed after one application to the maximum dilution of phenol that yielded the same result. Effect Example 1 A base was prepared by adding 10 f of glycerin to a white ointment consisting of 10 y of purified lanolin, 10 y of white beeswax, and 80 y of white petrolatum.

Base 12.5f! compound (1) to 4γ1f120, respectively.
Prepare yIf1100γIy-added and non-additive-added ones, and incubate each with bouillon liquid medium for 3
1 ml of culture solution of Staphylococcus aureus FDA2O9P bacteria cultured with shaking for 2 hours at 7fC (number of bacteria approximately 1 (P
~1010 pieces/Mt) was inoculated, stirred well, and then
The cells were placed in a glass container filled with water and cultured at 2TC. After culturing for 2 and 3 days, one platinum loopful of each base was taken, spread on a bouillon plate, and cultured for 24 TI1f. The number of growing bacteria (number of colonies) was determined and the mortality rate was calculated.

Note that the mortality rate (%) = 100 - (number of viable bacteria/number of viable bacteria without additives) x 100. The results are shown in Table 3. Effect Example 2 Stearic acid 12%, liquid paraffin 6.0%, white beeswax 4.0%, surfactant (Span2O) 4.0
%, glycerin 5.0%, purified lanolin 1.0%, triethanolamine 0.3%, and distilled water 67.7%.

Claims (1)

[Scope of Claims] 1. A hydroxybenzoic acid ester represented by the general formula (numerical formula, chemical formula, table, etc.) (in the formula, n represents an integer of 1 or 2). 2. The hydroxybenzoic acid ester according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 3. A preservative for industrial products containing a hydroxybenzoic acid ester represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, n represents an integer of 1 or 2) as an active ingredient. 4. The antiseptic agent for industrial products according to claim 3, wherein the hydroxybenzoic acid ester is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.