JPS5846518B2 - Production method of new dioxane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides 5-bromo-2-methyl-5-nitro 1,
5-Bromo-5-nitro-2-al-cow-1,3-dioxane such as 3-dioxen and its preparation and uses, especially suitable aldehydes and 2-bromo-2-nitropropane The present invention relates to the above-mentioned novel compound useful as an antibacterial agent having activity against both bacteria and fungi, which is obtained by reacting 1,3-')ol.

Conventionally, many types of antibacterial agents have been known, and a large number of antibiotics and synthetic organic compounds are useful as bacterial growth inhibitors, bactericidal agents, fungal growth inhibitors, mold killers, and the like.

Many of these effective antimicrobial agents have an important role in controlling microorganisms that infect humans.

Some antimicrobial agents have a narrow scope or only a single use, while others have a wide range of uses.

Antimicrobial preservatives are important ingredients in cosmetic creams used as cosmetic bases.

These creams are generally formulated as oil-in-water emulsions, the ingredients of which can serve as nutrient substrates for microorganisms such as bacteria and fungi, and because they contain water and oil, they require suitable preservatives. When selecting it, care must be taken that it must exhibit antibacterial activity in both water and oil systems.

Preservatives in such cosmetic creams should have sufficient solubility in water and in the paint system, since effective antimicrobial action is best achieved when the preservative is dissolved in the matrix to be protected. is important.

2-Bromo-2-nitropropane-1,3-';;ol shows some effectiveness as a preservative in cosmetic creams.

However, this compound has the disadvantage of being chemically unstable on the alkaline side.

Recently, 5-bromo-5-nitro-1,3-dioxane has been used, but this compound has chemical stability against alkalis.

Thus, although this compound has a relatively broad spectrum of activity, there are still important microorganisms for which it is ineffective or only active at relatively high concentrations.

Therefore, research has been continued to obtain alkali-stable compounds that have solubility in both oil and water systems and have a wide range of activity against microorganisms even at low concentrations.

It is an object of the present invention to provide alkaline stable compounds which have suitable solubility in oil and water and are effective against a wide range of both bacteria and fungi at relatively low concentrations.

As a result of the research conducted by the present inventors, a new compound 5-bromo-5-
It has been discovered that ditro-2-alkyl-1,3-dioxane is effective at low concentrations against a wide range of bacteria and fungi.

This compound exhibits excellent chemical stability in the pH range of 5 to 9 and is soluble in water and oil (mineral oil) to an extent of 1.1 to 1.5 degrees.

Cosmetic creams can be effectively preserved by incorporating the above-mentioned compounds in a small amount of about 0.01°C.

The object compound of the present invention can be represented by the following formula: [wherein R1 is methyl, ethyl, n-propyl or isopropyl].

] Useful compounds according to the invention can be prepared using 2-bromo-2-nitropropane-1,3-diol as a starting material.

2-Bromo-2-nitropropane-1,3-diol is available under the trade name Broch/L' (Bro-nopo I) and can be prepared by a variety of methods.

An example of the method uses nitromethane as a reaction reagent, which is reacted with formaldehyde to produce 2-nitropropane-1,3-diol, which is converted to the sodium salt and then brominated to produce 2-bromo. -2-nitropropane-1,3-diol is produced, and Production Example 1 below is an example of a specific embodiment thereof.

Production Example 1 A solution obtained by dissolving 20F (0.5 mol) of sodium hydroxide in 400M of water was cooled to 10°C, and 76ml of this solution was
35 polyformaldehyde (1.0 mol) 7411Ll
Add to.

Subsequently, 27 ml (0.5 mol) of nitromethane was added to this formaldehyde-sodium hydroxide mixed solution.

During that time, the reaction vessel was immersed in an ice water bath, and the reaction temperature was adjusted to 25-3.
Keep at 0℃.

The reaction between nitromethane and formaldehyde is catalyzed by sodium hydroxide, resulting in 2-nitropropane-1
, 3-diol (not isolated) is formed.

Next, add the remainder of the sodium hydroxide solution prepared earlier to 20°C.
The diol compound is converted to the sodium salt by adding it to the reaction vessel, and the mixture is stirred at room temperature and atmospheric pressure for 1/2 hour.

Ethyl acetate 3 cooled to -5°C in an ice-acetone bath
25.5 d (0.5 mol) of bromine is slowly and constantly poured into 0.00 ml while keeping the temperature below 5°C.

Subsequently, the above 2-nitropropane-1,3-diol sodium salt reaction mixture is slowly added to the ethyl acetate-bromine mixture maintained at a temperature in the range of 5 to 10°C.

The reaction mixture was stirred at room temperature and atmospheric pressure for 5 minutes, then the pH was adjusted to 2.0 with 6N HCl, 200 g of sodium chloride was added, and 2-bromo-2-nitropropane-1,3- ,;'ol is taken up in the ethyl acetate layer.

Separate the ethyl acetate layer from the aqueous layer, dry over magnesium sulfate and filter.

Ethyl acetate was removed from the solution under reduced pressure, and the resulting dry solid was washed with methylcyclohydrochloride, beef sanitation, and dried again to give 83.1 g of 2-bromo-2-nitropropane-1,3-diol. (yield: 83.1 excellent).

Melting point: 108-114°C.

The object compound of the present invention is 2-bromo-2, which is obtained by preparing a suitable aldehyde compound as in Production Example 1 under acidic conditions.
It can be produced by reacting with -nitropropane-1,3-sil.

A specific embodiment of the production of 5-bromo-2-methyl-5-nitro-1,3-dioxane is shown in Example 1.

Example 1 2-furomo 2-nitropropane-1,3-diol 4
0 g (0.2 mol) are suspended in 200 TrLl of benzene and about 0.3 g of P-toluenesulfonic acid are added.

Attach a condenser to the reaction vessel and cool the mixture in an ice-water bath.

Approximately 13.5 g (0.3 mol) of acetaldehyde are added slowly through the condenser and the reaction mixture is stirred for 30 minutes.

A Dean-Stoke trap is connected and the mixture is gradually warmed and then heated to reflux until no more water evaporates (4 ml of fishing rod evaporates in 1.5 hours).

The solution is filtered and evaporated at about 45° C. in a rotary evaporator.

The dark oily residue is distilled under reduced pressure at 0.25 mmHg.

5-Bromo-2-methyl-5-nitro-1,3-dioxane 36.5. ii' (yield: 85 yen).

Boiling point 72-74°C (0,25mmH,!i').

The structure of this compound is consistent with nuclear magnetic resonance (NMR) analysis and infrared absorption spectrum (IR) analysis.

Elemental analysis, calculated value: C, 26,57φ; H, 3,57
%; N, 6.20%; Br, 35.35%.

Actual value: C226, 85%; H, 3, 85%; N, 6.
04%: Br.

35.21 excellent.

The resulting compound 5-bromo-2-methyl-5-nitro-
1,3-dioxane is a clear, water-like, colorless liquid at room temperature and does not solidify at -10°C.

It is also chemically stable at pH 5.0 to 9.0 and has a strong pungent odor somewhat similar to bromine.

Example 2 5-bromo-2-
Ethyl-5-nitro-1,3-dioxane is obtained.

The structure of this compound is consistent with the NMR analysis results.

Elemental analysis, calculated value: C, 30.02%; H, 4.20%
;N, 5. s3%; Br, 33.29%.

Actual measurements: C, 30,24%; H, 4,24%; N, 5.
92%: Br, 32.99%.

Melting point of the obtained white crystalline substance: 58-59°C, 0 pH: 5-
9 is chemically stable, and as in the case of methyl derivatives,
It has a strong pungent odor, somewhat similar to bromine.

Example 3 5-bromo-5-
Ditro-2-n-propyl-1,3-dioxane is obtained.

The structure of this compound is consistent with NMR and IR analysis results.

Elemental analysis, calculated value: C, 33,09%; H, 4,76%
;N, 5.51%;Br, 31.45%.

Actual values: C, 33,32%; H, 4,63%; N, 5.
66%; Br, 31.64%.

A colorless oily compound is obtained as a fraction at 73-75°C (0,005 Hg).

When this oil is left at room temperature, it becomes a waxy solid.

Has a strong pungent bromine odor.

Example 4 Using isobutyraldehyde instead of acetaldehyde, the same procedure as in Example 1 was carried out to obtain 5-bromoni-2-isopropyl-5-nitro-1,3-dioxane.

The structure of this compound is consistent with NMR and IR analysis results.

Elemental analysis, calculated value: C, 33,09 excellent; H, 4,76%
;N, 5.51%;Br, 31.45%.

Actual value: C, 33,3,3φ; H, 4,83%; N, 5
．． 33φ; Br, 31.241%.

The resulting compound is a colorless crystalline substance.

Improper tool: melting point 42-44°C after crystallization from water (1:1) solvent.

Actual examples 1, 2, 3 and 4 that handle strong irritating bromine odor
The novel object compounds according to the present invention, exemplified in , exist as cis and trans isomers.

The procedure described in Example 1 produces a ratio of about 9:1 isomers.

The present invention is intended to encompass geometric isomers and isomeric mixtures thereof as chemical entities.

In an antibacterial test of isomer mixtures of 5-bromo-2-methyl-5-nitro-1,3-dioxane, the one with more cis-type and the one with more trans-type were tested, and both showed equal activity. , and no significant difference was observed in terms of usefulness between the two geometric isomers.

The following utility test was conducted using the isomer mixture (approximately 9=1) prepared by the method of Example 1.

The compounds of the present invention exhibit significant antibacterial activity against a wide range of microorganisms, including both bacteria and fungi, in vitro.

For example, 5-bromo-2-methyl-5-nitro-1,3-
Dioxane (Compound A) was subjected to a conventional in vitro dilution test to detect Propionibacterium acnes (Propio
niba-cterium acnes) (formerly Corynebacterium.

The activity against acne (formerly known as acne) was investigated.

The same test was carried out with the antibacterial agent 2-bromo-2-nitropropane-
1,3-diol (compound C) and 5-bromo-5-
A study was also carried out on nitro-1,3-dioxane (compound B).

Minimum inhibition of each compound against tested microorganisms (
The inhibitory concentration (MIC) was 6.25 mcg/1 rLl.

Tests against Propionibacterium acnes were conducted under anaerobic conditions in the following media:

Pefton・・・・・・・・・・・・・・・・・・
...10.0g fermented yeast calf struct...
・・・・・・io, oy glucose・・・・・・・・・
・・・・・・・・・・・・・・・io, o, yCa C
132・・・・・・・・・・・・・・・・・・・・・
・・・・・・ 0.2!9Mg504・7H20・・・・・・
・・・・・・・・・・・・ 0. :IKHPO・・・・・・
・・・・・・・・・・・・・・・・・・ 1.0g2
4 KH2PO4・・・・・・・・・・・・・・・・・・
・・・・・・ i, o, pNaHC03・・・・・・・・・
・・・・・・・・・・・・・・・10.1Na CA
!・・・・・・・・・・・・・・・・・・・・・
・・・・・・ Add 2.0g distilled water ・・・・・・・・・
...1000TrLl (pH of medium = 6.9) At the same time, compounds A, B and C and 5-bromo-2-
Ethyl-5-nitro-1,3-dioxane (Compound D)
, 5-bromo-5-nitro-2-n-propyl-1,3
-dioxane (Compound E) and 5-bromo-2-isopropyl-5-nitro-1,3-dioxane (Compound F)
Pseudomonas aeruginosa
as aeruginosa).

Staphylococcus aureus (Staphylo-
coccus aureus)) Escherichia coli (
Escherichia coli) and Streptococcus faecalis
faeca-1is) was investigated by a conventional in vitro dilution test.

The medium used was Antibiotic/163 (CFR43
6,102 (3) ), and the microorganism concentration was 104 microorganisms/-(medium).

Each tube was inoculated with 0.1- inoculum.

mc the amount of active substance in the medium ITrLl such that microorganisms do not grow in the medium even after 2 days of incubation at 37°C.
, 9, the minimum concentration (minimum inhibitory concentration) is shown in Table I.
Listed below.

Furthermore, the antibacterial activity of compounds A, B, C, D, E, and F was measured by the agar plate method.

Melt and cool the agar to 50°C and add 1.
Two-fold increasing concentrations of the above compounds were added from 56 mcJ to 50 mcg.

Pseudomonas aeruginosa, Staphylococcus
Antibiotic medium AI (for E. coli and Streptococcus faecalis)
CFR 436,102(1)) and antibiotic medium 22 (CFR436,102(22)) for Candida albicans and Aspergis niger.
It was used.

A microbial suspension containing 106 microorganisms per microorganism was used as the stock suspension.

A sterile cotton swab was dipped in the suspension and streaked onto the solidified agar.

Table 1 below lists the lowest concentration at which no growth is observed even after culturing at 30°C for 72 hours.

This value is considered the minimum inhibitory concentration (MIC).

Furthermore, compounds A, B, and C were examined for antifungal activity.

The test results for 10 types of fungi are shown in Table 2 below.

Compounds were added to the agar that had been melted and cooled to 50°C at concentrations of 100, 50°25, 2.5, 6.25, and 0.0 mci per mJ of agar.

After the agar has solidified, a sterile cotton swab is soaked in a microorganism preservation suspension (106 microorganisms per ml of physiological saline).
This agar was streaked.

The cells were cultured at 25° C. for 3 days, and the concentration that inhibited proliferation was recorded as the minimum inhibitory concentration.

The composition of the medium used in this test is as follows.

Mannit・・・・・・・・・・・・・・・・・・”・・
1.Q! li+ 5.0g 2.0g O,5,9 20,0,9 200,0m1 1000mA' Maltose・・・・・・・・・・・・・・・・・・
Yeast extract・・・・・・・・・ Calcium carbonate・・・・・・・・・・・・Mia (Me
er) Agar・・・・・・・・・VS juice tear fluid・・
・・・・・・ Add distilled water ・・・・・・・・・・・・(pH 5.
(adjusted to 7) From Tables 1 to 2 above, it can be seen that the compounds according to the present invention have antibacterial and antifungal effects, similar to the known compounds used for comparison.

An important property of the compounds according to the invention that distinguishes them from known compounds is their significantly lower irritation and subsequent sensitization, especially when applied to human skin in cosmetic creams.

In the present invention, the 2-methyl derivative of 5-bromo-5-nitro-1,3-diooxane is a particularly preferred compound because it has excellent solubility in water and oil.

Skin irritation and sensitivity can be reduced by conventional compounds viz.
-bromo-5-nitro-1,3-diothousane and particularly preferred compounds according to the invention, namely 5-bromo-2-methyl-
5-nitro and 1,3-diozensan were tested.

Each compound was tested according to the following treatment method.

200 subjects were selected for each test item, and a pasting test using the repeated injury method was conducted on different groups of subjects.

For each test substance, 9 injury-inducing patches were applied to each subject.
Do it twice.

After two weeks, each series of test subjects will be given a skin patch for each test substance to detect skin sensitivity.

■The injury-inducing patch was applied nine times per series on Mondays, Wednesdays, and Thursdays, and after contacting the skin for 24 hours, it was removed and the degree of irritation on the skin was evaluated.

After removing the sample pasted on Wednesday and evaluating the degree of injury induction, immediately apply it as the sample on Thursday.

After the ninth injury-inducing application, there is a 2-week non-application period before conducting an injury development test for susceptibility testing.

Apply the patch on another fresh skin surface for 24 hours.

This skin part is selected as the injury-inducing patch area, that is, the surface adjacent to the skin surface on which the injury-inducing patch has been applied nine times.

24 and 72 hours after applying the injury patch, the sensitivity of the skin surface to irritation is evaluated.

The skin patch for each test substance consists of an oval adhesive patch (1"Xl-1/4") with a central circular mesh.

Approximately 0.0 of each test substance is added to the center mesh area immediately before use.
It was applied to a thickness of 3 mm.

The skin irritation reactions that appeared in the injury development test and the scoring criteria for evaluating their sensitivity are shown below.

Erythema and epilepsy No reaction: Oo Very slight erythema (hardly noticeable): 1o Mild, clearly visible erythema: 2° Moderate to severe erythema: 3° Severe erythema (beet-like redness) ~ Mild derma formation (severe injury): 4° Highest possible score for erythema: 4° No response to edema: Oo Very slight edema (hardly noticeable): 1° Mild edema (obviously raised) 2o Moderate edema (skin surface rises for about 1 inch): 3o Severe edema (skin surface rises for more than 1 inch and spreads beyond the application surface to the exposed surface): 4o Maximum score for edema: 4° Total possible primary irritation score:
The names of the target compound and control compound used in the 8° test and their concentrations in the cosmetic cream are shown in Table 3.

As is clear from Table ■, in the injury patch test, 5
-Bromo-5-nitro-1,3-dioxane o, 1%
Of the 200 subjects, 11 subjects showed significant sensitivity to the concentration, whereas those who showed sensitivity to 5-bromo-2-methyl-5-nitro-1,3-dioxane, which is the compound of interest of the present invention, Out of 200 people, there were none.

Out of a total of 8 points, a score of 5 or more indicates sensitivity to the active compound.

Moreover, the irritation test values of the conventional compound show that it has more severe irritation than its 2-methyl derivative in the present invention.

The novel compounds of this invention have the important property of having a solubility in water of up to about 1.5% and in mineral oil of up to about 1.1%.

This important property makes the compounds of the invention highly useful as antibacterial agents for preserving cosmetic creams.

Effective preservation of cosmetic creams is achieved by containing the compound of the present invention in an amount of about 0.01 to about 1.5%, preferably about 0.1φ to about 1.0%.
This can be achieved by containing %.

Reference Example 1 shows an example of a method for manufacturing a typical cosmetic base cream using 0.1% of 5-bromo-2-methyl-5-nitro-1,3-dioxane as a preservative.

Reference example 1 Cosmetic base cream with nonionic surface activity 7.5
kg is produced as follows.

Phase I: heavy mineral oil having the following composition in a suitable container:
1875g cetyl alcohol
300g white wax
450g lanolin (anhydrous) 225g
Sorbitan monostearate 300g polio 1,000'
1ch'7 (20) 45o.

sorbitan monosterate and heat to 80°C with continuous stirring.

Pour 3750ml of pure water into a second suitable container, and
Heat to 0°C.

Add phase (1) to phase (2) with continuous stirring and then cool to 45° C. with continuous stirring.

Furthermore, in a suitable container, a phase having the following composition: Polyethylene glycol 200 93.7i5-B-D-
E-2-, fflchitv-57, 5g nitro-1,3
- Add dioxane and heat to 45° C. with stirring to dissolve it, add this to the above mixture at 45° C. and mix thoroughly with constant stirring.

Add 2001 rLl of pure water to this to obtain a sufficient amount of mixture to prepare a total amount of 7.5 kg.
Cool to ℃.

Compounds of another embodiment of the invention, 5-bromo-2
, 2-dimethyl-5-nitro-1,3-dioxane is an effective antimicrobial agent suitable for inclusion as a preservative in compositions such as cosmetics and pharmaceuticals.

In addition, this useful compound is used in a wide variety of compositions, such as adhesives, aqueous and oil-based products, especially latex, toilet, wash, industrial soaps and cleaning products, shampoos, cutting oils, preservative and disinfectant chemicals. It can be mixed as an effective antibacterial agent.

This compound, 5-bromo-2,2-dimethyl-5nitro-1,3-dioxane, is similar to the already mentioned 2-bromo-2-nitropropane-1,3-'#-ruwo'j'7ton. It can be produced by contacting.

This manufacturing method is given in Example 5 below. Example 5 2-Bromo-2-nitro-propane 1,3-diol 20. ! ? (0.1 mol) and 30 ml of acetone (0.5 mol)
mol).

The temperature will be 15°C when it becomes a complete solution.

13 ml (0.1 mol) of boron trifluoride ether complex are then added in portions to the reaction mixture from the dropping funnel in about 2 minutes.

The temperature rises to 47°C and then falls to 35°C in 10 minutes.

The reaction mixture is poured into 150 ml of saturated sodium bicarbonate solution and stirred for 15 minutes.

The solid is filtered off, washed with 200 mJ of acetone and dried.

IR shows that the reaction has proceeded. The crude product (18.9%) was dissolved in 15011 liters of hot water and filtered.

Upon cooling and standing overnight, 5-bromo-2,2-dimethyl-5-nitro-1,3-dioxane is obtained as white needles.

Yield: 9.09 (yield: 40%).

The structure was confirmed by IR2 and NMR.

The results of elemental analysis are as follows. CHN B
r Theoretical value: 30.024.205.8333.29 Actual value: 29.944.266.0533.505-bromo-
2-Methyl-5-nitro-1,3-dioxane (Compound A) and 5-bromo-5-nitro-1,3-dioxane (Compound B) simultaneously with 5-nitro-2,2-dimethyl-5-nitro The antibacterial activity of -1,3 Geogyu San (Kakanmono G) against the same six types of microorganisms shown in Table 2 was investigated.

Compounds A, B and G showed similar effects.

This test contains 10.2 liters of active substance per 111 liters of agar.
In vitro experiments were performed using agar plates containing 5 and 50 mcg.

Microorganisms were streaked onto solidified agar at a concentration of 10' microorganisms per cell.

Plates were incubated for 24 hours and the presence or absence of growth was recorded.

The lowest concentration of active substance at which no growth was observed in the agar was recorded as the minimum inhibitory concentration (MIC).

The test results are shown in Table ■ below.

The compound of the present invention is useful and effective as an antibacterial agent for inhibiting the growth of microorganisms such as Durham-positive and Durham-negative bacteria and fungi, and has the structure shown in the following formula.

[In the formula, R1 represents methyl, ethyl, n-propyl or iso-propyl.

The growth of microorganisms can be inhibited by bringing them into contact with an amount of the target compound sufficient to inhibit the growth of microorganisms.

The effective amount of the present invention to be incorporated into the composition is about 0.01~
2.0%, preferably in the range of about 0.1 to 1.0% (by weight).

Typical examples of such compositions and the concentrations of the target compounds that should be contained therein are shown in Reference Examples 2 to 8.

Reference examples 2 to 8 antibacterial solution 951% 5D3A alcohol: 50 parts.

Deionized water: 49.5 parts.

0.5 parts of 5-bromo-2-methyl-5-nitro-1,3-dione.

antibacterial ointment Polyethylene glycol 300: 49.5 parts.

49.5 parts of polyethylene glycol 1500.

5-bromo-5-nitro-2-n-propyl-1,3-
Geo Sun: 10 parts Antibacterial powder talc (U, S, P,): 99 parts.

5-Bromo-2-methyl-5-nitro-1,3-diosan: 1 part.

shampoo Sodium lauryl sulfate: 40 parts.

Coconut fatty acid jetanolamide: 6 parts.

Deionized water: 53 parts.

721 parts of 5-bromo-2-ethyl-5-nitro-1,3-diothousand.

antibacterial soap Coconut oil glyceride sodium salt 260s.

Tallow glyceride sodium salt: 39 parts.

5-Bromo-2-methyl-5-nitro-1,3-diogynosan: 1 part.

antibacterial detergent Fatty alcohol sulfate (sodium sulfate): 25 parts.

Sodium carbonate near part. Sodium sulfate: 15 parts.

Trisodium phosphate: 40 parts. Amino-trimethylene pentasodium phosphate: 10 parts.

Carbo-thousand dimethylcellulose = 1 part.

722 parts of 5-bromo-2-methyl-5-nitro-1,3-diothousand.

Antibacterial emulsion coating agent 20 parts of polyvinyl acetate (emulsified).

8 parts of deionized water.

5-Bromo-2-ethyl-5-nitro-1,3-dioxane: 2 parts.

As is clear from the above description, the method and application of the novel object compound of the present invention as an antibacterial agent can be readily recognized in the art.

The above examples are intended to explain specific embodiments of the present invention, and are not intended to limit the gist of the invention or the scope of the claims in any way.

Claims (1)

[Claims] 12-bromo-2-diol and tropropane [wherein R1 represents lower alkyl]. By reacting an aldehyde represented by the formula [wherein, R1 has the same meaning as above]. ] 5-Bromo-5-nitro-2-a) Li-gyoku-1,3-dio-gyosan derivatives are obtained.