JPS5943453B2 - Oxybenzoic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula 7□(OH)m(I) (wherein the dotted line represents the presence or absence of a double bond at the indicated position, and m represents an integer of 1 or 2, and n represents an integer of o or 1.

Currently, alkyl esters of paraoxybenzoic acid are
It is widely used as a preservative and anti-bacterial agent for pharmaceuticals, quasi-drugs, cosmetics, and other industrial chemicals because it has strong growth-inhibiting or bactericidal properties against fungi, yeast, and molds, and low toxicity and irritation to the human body. It is used.

In particular, lower alkyl esters of paraoxybenzoic acid, such as 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 in soy sauce. It is used as a preservative in foods such as Saka sauce. The present inventors synthesized various oxybenzoic acid esters and investigated their biological activities. As a result, the novel oxybenzoic acid esters represented by the above general formula (1) were found to be the above-mentioned conventional commercially available preservatives and anti-bacterial agents. The present inventors have discovered that it has a stronger bactericidal effect against microorganisms, particularly gram-positive bacteria, than the alkyl ester of paraoxybenzoic acid used as a paraoxybenzoic acid, and is not irritating to the skin, leading to the completion of the present invention.

Furthermore, in the present invention, among the oxybenzoic acid esters represented by the general formula (1), 3,7
- Dimethyloctyl ester, citronellyl ester or geranyl ester has a particularly remarkable bactericidal effect against Gram-positive bacteria and also has an excellent bacteriostatic effect, and paraoxybenzoic acid prenyl ester or 3,4-dioxy Benzoic acid prenyl ester also has remarkable bactericidal activity against Gram-negative bacteria, particularly Proteus bacterium and Aeruginosa bacterium.

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

The oxybenzoic acid ester represented by the general formula (1) of the present invention is, for example, the general formula () (in the formula, M represents an alkali metal, and m has the same meaning as in the general formula (1)).
The alkali metal salt of oxybenzoic acid and the general formula (
) (wherein, X represents a halogen atom, and n represents the general formula (1
) has the same meaning as in )).

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. Examples of the alkali metal salts of oxybenzoic acid represented by the general formula (1) include paraoxybenzoic acid, metaoxybenzoic acid, orthoxybenzoic acid, 2,4-dioxybenzoic acid, 3,4-dioxybenzoic acid, and 2,5-dioxybenzoic acid. Examples include potassium salts and sodium salts of oxybenzoic acid such as benzoic acid, and considering the strength of antibacterial activity of the target oxybenzoic acid ester represented by general formula (1), p-oxybenzoic acid, Or an alkali metal salt of 3,4-dioxybenzoic acid is preferred. Examples of alcohol halides represented by general formula (l) include prenol (3-methyl-2-buten-1-ol), 3,7-dimethyl-octan-1-ol, and citronellol (3,7-dimethyl-6-ol). Octene-1-ohnoly, geraniol (△2-trans, 3
,7-dimethyl-2,6-octadien-1-ol)
, nerol (Δ2-cis, 3,7-dimethyl-2,6-
Examples include chloride and bromide such as octadiene-1-ohno(c). The oxybenzoic acid ester represented by the general formula (1) may be one or two types thereof.
A mixture of more than one type of hydroxybenzoic acid ester can be used as it is as a preservative and sterilizer, or one or more of the hydroxybenzoic acid esters can be blended with various suitable dilution aids, such as Solutin L surfactant. It can also be used as a preservative and bactericide by formulating it in the form of a wettable powder.

When using a preservative disinfectant containing an oxybenzoic acid ester represented by the general formula (1) as an active ingredient, the preservative disinfectant should be used in quasi-drugs, cosmetics, textile/paper products, leather products, wood processing products, etc. products, paints, plastic materials, metals, electronic equipment,
It may be mixed, applied, or sprayed onto industrial products such as optical machines, depending on the shape of these products.

The amount of the preservative sterilizer used is usually 50 to 200 in terms of the amount of the active ingredient of the oxybenzoic acid ester represented by the general formula (1) contained in, for example, quasi-drugs, cosmetics, or paints.
Approximately 0PF1 is appropriate. Examples of the synthesis of the oxybenzoic acid ester represented by the general formula (1) are shown below, as well as test examples and effect examples to clarify the effects of the oxybenzoic acid ester on microorganisms.

Synthesis Example 67.57 g of potassium paraoxybenzoate, 200 d of dimethylformamide, and 1.98 t of trimethylstearylammonium chloride were placed in a 1000 d three-necked flask, and the temperature was maintained at 800 to 90° C. using an oil bath while stirring.

After making a homogeneous solution, 39.7v of prenyl chloride was added dropwise by dropwise loading. As the reaction progressed, potassium chloride was observed to be produced. After reacting for 5 hours, dimethylformamide was distilled off from the reaction solution under reduced pressure, and then a 200% hexane-benzene solution (mixing ratio 95:5) was added.
m1 was added.

Insoluble materials were separated from the hexane-benzene solution, and the mouth fluid was neutralized with a 1001) aqueous sodium bicarbonate solution and extracted three times with water. The hexane-benzene layer was taken and concentrated using an evaporator to obtain 45 tons of pale yellow crude product.
Next, this crude product was recrystallized using a solvent consisting of n-hexane and benzene (mixing ratio 95:5) to obtain pale cream-colored crystals 167 of prenyl paraoxybenzoate. NMR spectral data of this product is shown below.
．． -,,-The following oxybenzoic acid esters (2) to (6) were obtained by the same method as above.

Test Example 1 MIC (minimum inhibitory concentration D) for various microorganisms is shown in Table 1.

Test method: Dilute the test solution with a concentration of 10Tf19/ml in 10 steps, put 1ml of each concentration into a Petri dish, add 9ml of Nutriendo agar medium, mix and dilute well before solidifying, and prepare a flat plate. .

On the other hand, about 1 platinum loopful of bacteria was transplanted into a test tube containing 10 ml of peptone water, and statically cultured at 37°C for 24 hours. Apply one platinum loopful of this culture solution to a previously prepared flat plate, and
Incubate at ℃ for 48 hours. Then, determine the minimum concentration that inhibits the growth of the applied bacteria. The bacterial strains used in the test are shown below. Test example 2 The phenol coefficient (bactericidal effect) against various microorganisms was
Shown in the table.

Test method: Each test strain is cultured with shaking for 24 hours using Nutriendo liquid medium.

On the other hand, the test drug solution was appropriately diluted with sterile distilled water, 10 ml of the solution was prepared in a large test tube, 1 Tn1 of the above bacterial solution was added thereto, and the mixture was heated at 20°C for 2.5 minutes and then for 5 minutes until VlO. ,
After contacting for 15 minutes, mix about 1 platinum loopful of the mixture into a new Nutriendo liquid medium, immediately apply this portion to Nutriendo agar medium, incubate at 37°C for 24 hours, and determine if the bacteria have died. *Kushita. The phenol coefficient was defined as the ratio between the maximum dilution ratio of the test drug solution at which bacteria were not killed in 5 minutes of action and killed in 10 minutes, and the maximum dilution ratio of phenol that yielded the same result. In addition, strain NQl6-1
8 represents the following bacteria. f compound (1) at 4γ/7,
20γ/Y, lOOγ/7 added, compound (4)
10γ/7,50γ/7,100γ/f, and n-butyl paraoxybenzoate at 50γ/F7
, lOOγ/y and those without additives were prepared, and each was incubated at 32°C using a broth liquid medium.
1 ml of culture solution of Staphylococcus aureus FDA2O9P bacteria cultured for 24 hours with shaking (number of bacteria: approximately 109 to 1
010 cells/ml) was inoculated, stirred well, and then placed in a glass container filled with water, and cultured at 27°C.

After culturing for a certain period of time, a loopful of each base was taken, spread on a bouillon plate, and cultured for 24 hours.The number of growing bacteria (number of colonies) was determined and the mortality rate was calculated.
The results are shown in Table 3. In addition, the mortality rate ((7) = 100 - (number of viable bacteria / number of viable bacteria without additives)
OO effect example 2 Stearic acid 12(f), liquid paraffin 6.07, white beeswax 4.0%, surfactant (Span2O) 4
．． 0%, glycerin 5.0%, purified lanolin 1.0%,
A cosmetic cream base consisting of 0.3% triethanolamine and 67.7% distilled water was prepared.

0.07 of each of compound (1), compound (2) or n-butyl paraoxybenzoate was added to base 12.57.
%, 0.2% added, and no additives were prepared, and each was incubated at 32°C with broth liquid medium.
Staphylococcus aureus F cultured with shaking for 4 hours
I) Culture solution of A2O9P bacteria 17111 (bacteria number approximately 109 ~
After inoculating at 1010 cells/MO and stirring well, the cells were placed in a glass container filled with water and cultured in a constant temperature bath at 27°C. After culturing for a certain period of time, one platinum loopful of each base was applied to a bouillon plate and cultured for 24 hours.The number of growing bacteria (number of colonies) was determined and the mortality rate was calculated.

The results are shown in Table 4. Effect example 3 Add distilled water to 20ml of squeezed orange juice passed through gauze and 207ml of sugar to make 200ml of orange juice (PH2 4.2)
was prepared and subjected to an intermittent heat treatment at 80°C for 15 hours.

Prepared mandarin orange juice 25? Add compound (1) to 10γ
/Ml, lOOγ/ml, compound starch 6) was added at 10γ/D, lOOγ/Ml, lO
OOγ/ml, and n-butyl paraoxybenzoate at 100γ/ml.
, lOOOOγ/ml, and those without additives were prepared in sterilized 100 mJ Erlenmeyer flasks, and each was cultured for one week at 27°C using a potato slant medium. After adding 1.5a of bacterial suspension of FO464O bacteria and stirring well, culture was performed in a constant temperature bath at 27°C.
The growth rate of the bacteria was observed. The results are shown in Table 5. However, - indicates that no growth of bacteria was observed.

+ indicates slight bacterial growth. Considerable bacterial growth is observed in the ridges.

Significant bacterial growth is observed in the squares.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, the dotted line represents the presence or absence of a double bond at the indicated position, m is 1 or an integer of 2, and n represents an integer of 0 or 1). 2 Claim 1 represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, m' represents an integer of 0 or 1, and n' represents an integer of 1 or 2)
Oxybenzoic acid esters described in Section. 3. The oxybenzoic acid ester according to claim 2, which is prenyl paraoxybenzoate. 4. The oxybenzoic acid ester according to claim 2, which is prenyl 3,4-dioxybenzoate. 5. The oxybenzoic acid ester according to claim 2, which is geranyl 3,4-dioxybenzoate.