JPS58116481A - Manufacture of novel dioxane derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides 5-bromo-2-methyl-5-nitro 1,
5-bromo-5-nitro-2-alkyl-1,3-dioxane such as 3-dioxane and its preparation and uses, especially suitable aldehydes and 2-bromo-2-nitropropane-1,3-diol. The present invention relates to the provision of the above-mentioned novel compound useful as an antibacterial agent having activity against both bacteria and fungi.

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, since they contain water and oil, require suitable preservatives. When selecting a compound, 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 both water and oil systems, 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-diol has shown 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. Research has therefore continued to obtain alkali-stable compounds with broad and sufficient activity against oil and water substances.

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. The compound exhibits excellent chemical stability in the pH range 5-9, and in water and oil (mineral oil) between 1.1 and 1.
Dissolve to the extent of 5%. Cosmetic creams can be effectively preserved by incorporating the above-mentioned compounds in small amounts of about 0.01%.

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-buqmo-2-nitropropane-1,3-diol as a starting material. 2-Bromo-2-nitropropane-1,3-
The diol is available under the trade name Bronopol and can be produced in a variety of ways. An example of the method uses nitromethane as a reaction reagent, which is reacted with formaldehyde to form 2-nitropropane-1,3-diol, which is converted to the sodium salt and then brominated to give 2-diol.
-Bromo-2-nitropropane-1,3-cit-ruo, and the following Production Example 1 is an example of a specific embodiment thereof.

Production Example 1 A solution obtained by dissolving 20 y (0.5 mol) of sodium hydroxide in 400 d of water was cooled to 10°C, and 76 tn of this solution was obtained.
1 to 74 d of 35% formaldehyde (1.0 mol). Subsequently, nitromethane 27,z (0.5 mol) was added dropwise to this formaldehyde-sodium hydroxide mixed solution. Meanwhile, the reaction vessel is immersed in an ice water bath to maintain the reaction temperature at 25-30'C.

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 previously prepared sulfur hydroxide solution 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 t (0.5 mol) of bromine was slowly and constantly poured into 00d while keeping the temperature below 5°C. The 2-nitropropane-1,3-di-luna) IJ salt reaction mixture is then slowly added to the ethyl acetate-bromine mixture maintained at 5-10'C. The reaction mixture was stirred at room temperature and atmospheric pressure for 5 minutes, then 6N-
Adjust the pH to 2.0 with HCj and add 200 ml of sodium chloride.
2-bromo-2-nitropropane-1,3-
The diol is taken up in the ethyl acetate layer.

The ethyl acetate layer is separated from the aqueous layer, dried over magnesium sulfate, and filtered. Ethyl acetate was removed from the Oki liquor under reduced pressure, and the resulting dry solid was washed with methylcyclohexane and dried again to give 83.1y of 2-bromo-2-nitropropane-1,3-diol (yield). Rate 83.
1%). Melting point: 108-114°C.

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

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

Example 1 40y (0.2 mol) of 2-bromo-2-nitropropane-1,3-')ol is suspended in 200 me of benzea and approximately 0.3y of P-toluenesulfonic acid is added. Attach a condenser to the reaction vessel and cool the mixture in an ice-water bath. Approximately 13.59 (0,3
mol) are added gradually 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 (aqueous layer 4d evaporates in 1.5 hours). Filter the solution,
Evaporate in a rotary evaporator at approximately 45°C. The dark oily residue is vacuum distilled at 0.25 tm H9. 5-bromo-
2-Methyl-5-nitro-1,3-dioxane 36.5
y (yield 85%) is obtained. Boiling point 72-74℃ (0,25
, Hg). The structure of this compound is determined by nuclear magnetic resonance absorption (NMR).
) analysis and infrared absorption spectrum (IR) analysis results.

Elemental analysis, calculated value: C, 26,57%; H, 3,57%
;N, 6.20%;Br, 35.35%. Actual value: C1
26,85%; H, 3,85%; N, 6.04%; B
r.

35.21%.

The resulting compound 5-bromo-2-methyl-5-nitro-
1,3-dioxane is a clear, water-like 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 NMR analysis.

Elemental analysis, calculated value: C, 30.02%; H, 4.20%
; N, 5.83%; Br, 33.29%. Actual value 2C, 30,24%; H, 4,24%; N, 5.92%;
Br, 32.99%.

The resulting white crystalline material had a melting point of 58-59°C.

It is chemically stable at pH 5 to 9 and, like the methyl derivative, exhibits a strong pungent odor somewhat similar to bromine.

Example 3 In place of acetaldehyde, n-butyraldehyde-bromo-5-nitro-2-n-propyl-1,3-dioxane is obtained. . The structure of this compound was determined by NMR and I
Consistent with R analysis results.

Elemental analysis, calculated value: C, 33.09%; H, 4.76%
; N, 5.51%; Br, 31.45%. Actual value: C,
33, 32%; H, 4.63%; N, 5.66%; Br
, 3 1.6 4%.

A colorless oily compound is obtained as a fraction at 73-75°C (0.005 mHy). When this oil is left at room temperature, it becomes a waxy solid. Has a strong pungent bromine odor.

Example 4 5-Furomo 2-
Isopropyl-5-nitro-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 value: C,
33,33%; H, 4,83%; N, 5.33%; Br
, 31.24%.

The resulting compound is a colorless crystalline substance. Improper Tool: Melting point 42-4 after crystallization from water (1:1) solvent
4℃. Has a strong pungent bromine odor.

The novel object compounds according to the invention, exemplified in Examples 1.2.3 and 4, 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.

It exhibits significant antibacterial activity against a wide range of microorganisms, including both species and fungi. For example, 5-bromo-2-methyl-
5-Nitro-1,3-dioxane (Compound A) was subjected to a conventional in vitro dilution test and tested against Propionibacterium acnes (Propionibacterium acnes).
Cnes) (previously called Corynebacterium acnes).

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). The minimum inhibitory concentration (MIC) of each compound against the microorganisms tested was 6.25 mcg/d.
Te Atsuta.

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

Hefton・・・・・・・・・・・・・・・・・・・・・
・・・・・・・・・10.0y yeast extract・・
・・・・・・10. OF glucose・・・・・・・・・
・・・・・・・・・・・・・・・ 10.0gCa C
12・・・・・・・・・・・・・・・・・・・・・・・・
・・・・・・・・・ 0.2 no MgSO4・7H20・・
・・・・・・・・・・・・ 0.2yK2HPO4・・
・・・・・・・・・・・・・・・・・・・・・・・・
1,0yKH2PO4・・・・・・・・・・・・・・・
・・・・・・・・・・・・ 1. OfN a HCO
3・・・・・・・・・・・・・・・・・・・・・・・・
・・・ 10.0yNaCz ・・・・・・・・・・・・
・・・・・・・・・・・・・・・・・・・・・ 2.02
Add distilled water ・・・・・・・・・・・・10
00- (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)
) of Pseudomonas aeruginosa (Pseudomonas aeruginosa)
naSaeruginosa), Staphylococcus aureus (5taphylococcus au)
reus), Escherichia coli (Escheri-
chia coli) and Streptococcus faecalis (5.
is) was investigated by a conventional in vitro dilution test. The medium used was antibiotic inhibitor 3 (CFR4).
36,102 (3)), and the concentration of microorganisms was 10 microorganisms/dC medium). Inoculum 0 in each tube
．． 1 wet was inoculated. A medium that does not allow microorganisms to grow even if incubated at 37°C for 2 days.
The minimum concentration (mC9) of the active substance in
(minimum inhibitory concentration) is listed as a surface technique.

Furthermore, the antibacterial activity of compounds A, B, C%D, E and F was measured by the agar plate method. To the agar that had been melted and cooled to 50° C., the above compound was added in an amount increasing in concentration by a factor of 2 from 1.56 mcy to 50 mcp per d of agar. 11 hl of antibiotic medium for Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Streptococcus faecalis
(CFR436,102+11) and antibiotic medium 22 (CFR436,102 (Foundation)) for Candida albicans and Aspergillus niger.
)It was used. A microbial suspension containing 10 6 microorganisms per 1 d 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 the minimum inhibitory concentration (MIC
).

Table ■ In vitro antibacterial activity In addition, compounds A, B, and C were examined for antifungal activity. The test results for 10 types of fungi are shown in Table ■ below. Compounds were added to the agar that had been melted and cooled to 50° C. so that the concentration per 1 d of agar was 100.50.25.12.5.6.25 and Q, Qmcy. After the agar had solidified, the agar was streaked with a sterile cotton swab immersed in a stock suspension of microorganisms (10' microorganisms per 1-1 saline solution). 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 ・・・・・・・・・・・・・・・・・・
・ 1.02 Maltose・・・・・・・・・・・・
・・・・・・・・・・・・ 5.02 Yeast extract・・・・・・ 2.0g calcium carbonate・・
・・・・・・・・・・・・・・・ 0.52 Meer
) Agar・・・・・・・・・・・・ 20.09V-8 Youth Oki liquid・・・・・・・・・200. Add Oare distilled water and make 1000 d(
Adjustment of pH to 5.7) 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-dioxane is a particularly preferred compound because of its excellent solubility in water and oil.

Skin irritation and sensitivity can be reduced by conventional compounds viz.
-bromo-5-nitro-1,3-dioxane and particularly preferred compounds according to the invention, namely 5-bromo-2-methyl-
5-nitro-1,3-dioxane was 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 being in contact with the skin for 24 hours, it was removed and the degree of irritation on the skin surface was evaluated. After removing the sample applied on Wednesday and evaluating the degree of injury induction, immediately apply it as the sample applied 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. After applying the injury patch, 24
and evaluate skin surface irritation sensitivity 72 hours later.

The skin patch for each test substance is an oval adhesive patch (1" x 1-1/4") with a central circular mesh. Each test substance was applied to a thickness of about 0.03 m on the central mesh area immediately before use.

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

Table ■ Repeated application test of injury to the human body: No reaction: 0° Very slight erythema (almost unnoticeable): 1° Mild, clearly visible erythema: 2° Moderate to severe erythema: 3° Severe erythema (Beet-like redness) to mild demarcation (severe injury): 4° Highest possible score for erythema: 4° No response to edema: Oo Very slight edema (almost not noticeable) = 1° Mild edema ( 2° Moderate edema (skin surface rises by approximately 1 fi): 3° Severe edema (skin surface rises more than (Spreads over exposed surface): 4° Maximum score for edema - 4° Total possible primary irritation evaluation score -
The target compounds and control compounds used in the 8° test and their concentrations in cosmetic creams are shown in Table 3.

Table ■ The test results are summarized and shown in Table ■.

Table ■ 5 in repeated application tests for detecting injuries to the human body
- Comparison of skin irritation and sensitivity of bromo-5-nitro-1,3-dioxane and 5-bromo-2-methyl-1,3-dioxane 5-bromo-5-nitro-1,
3-Dioxane Injury Induction Patch Test 5-Bromo-5-nitro-1,3-dioxane Injury Induction Patch Test * indicates skin sensitivity.

Injury induction patch test of 5-bromo-2-methyl-5-nitro-1,3-dioxane 5-bromo-2-methyl-5-nitro-1,3-As is clear from Table 2, injury induction patch test In 5-bromo-5-nitro-1,3-dioxane at a concentration of 0.1%, 11 out of 200 subjects showed significant sensitivity, whereas the compound of the present invention, 5-bromo-2-methyl- 5
-None of the 200 subjects showed sensitivity to nitro-1,3-dioxane. Out of a total score of 8, 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 compounds of the present invention in an amount of about 0.01 to about 1.5%, preferably about 0.
．． This can be achieved by containing 1% to about 1.0%.

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 IJ-me with nonionic surface activity7.
5Kf is manufactured as follows.

Phase I: heavy mineral oil having the following composition in a suitable container:
1875y heptyl alcohol
300y white wax 450
Add y lanolin (anhydrous), 225y sorbitan monostearate, 300y sorbitan monostearate and heat to 80"C while stirring continuously.

Pour into a second suitable container: 3750 ml of pure water. Enter r, 8
Heat to 0°C. Add the continuously stirred wet phase (2) to the phase (2) and then cool to 45° C. with continuous stirring. Further, phase (1) having the following composition was placed in a suitable container: Polyethylene glycol 200 93.7f5-bromo-2-methyl-5- was heated to 45°C with stirring to dissolve it, and this was added to the above mixture at 45°C. Add and stir constantly to mix thoroughly. Add 200 m of pure water to this to obtain a sufficient amount of mixture.
Prepare a total amount of 7.5KF and heat to 37℃ with continuous stirring.
Cool.

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, water-based and oil-based paints, especially latex, toilet, wash and industrial soaps and cleaning agents, shampoos, cutting oils, preservative and disinfectant chemicals, etc. It can be mixed as an effective antibacterial agent.

This compound, 5-bromo-2,2-dimethyl-5-nitro-1,3-dioxane, is the 2-bromo-2-dioxane mentioned above.
It can be produced by contacting nitropropane-1,3-diol with acetone. This manufacturing method is given in Example 5 below.

Example 5 20 p (0.1 mol) of 1,3-diol containing 2-bromo-2-nitropropane and 30 sIl (0.5
mol). When it becomes a complete solution, the temperature is 15
℃. Next, boron trifluoride ether complex compound 13m (
0.1 mol) is added dropwise from the addition funnel to the reaction mixture 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 d of saturated sodium bicarbonate solution and stirred for 15 minutes. The solids are filtered, washed with 200ml of acetone and dried. IR shows that the reaction has proceeded. Approximately 182 mL of the crude product was dissolved in 1 mL of hot hexane.
50- and filter. Cool and set up at night.
-Bromo-2,2-dimethyl-5-nitro-1,3-dioxane is obtained as white needles. Yield 9.0 IC
yield 40%).

The structure was confirmed by IR and NMR. The results of elemental analysis are as follows.

Theoretical value: 30.02 4.20 5.83 3
3.29 Actual value: 29.94 4.26 6.
05 33.505-bromo-2-methyl-5-nitro-1,3-dioxane (compound A) and 5-bromo-
5-nitro-1,3-dioxane (compound B) and simultaneously 5-nitro-2,2-dimethyl-5-nitro-1,3
- Same 6 as shown in Table 2 for dioxane (compound G)
The antibacterial activity of the seeds against microorganisms was investigated. Compounds A, B and G showed similar effects. This test consists of agar 1-
In vitro experiments were carried out using agar plates containing 10.25 and 50 mcy of active substance per sample. IIa1
The solidified agar was streaked with microorganisms at a concentration of 10 6 microorganisms per sample. 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.

Table ■ In vitro antibacterial activity The compound of the present invention is useful and effective as an antibacterial agent for inhibiting the growth of microorganisms such as Durum-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 0.1-1.0% (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 95% 5D3A/alcohol = 50 parts. Deionized water: 4
9.5 parts. 5-bromo-2-methyl-5-nitro 1,
3-dioxane: 0.5 part.

Antibacterial ointment polyethylene glycol 300: 49.5 parts. Polyethylene glycol 1500: 49.5 parts. 5-Bromo-5
-nitro-2-n-propyl-1,3-dioxane=1
．． 0 parts Antibacterial powder talc (U, S, P,): 99 parts. 5-bromo-2
- 240 parts of shampoo sodium lauryl sulfate. Coconut fatty acid jetanolamide: 6 parts. Deionized water = 53 parts. 5-bromo-2-ethyl-5-nitro-1,3-dioxane = 1
Department.

antibacterial soap Coconut oil glyceride sodium salt: 60 parts.

Tallow glyceride sodium salt = 39 parts. 5-bromo-
2-Methyl-5-nitro-1,3-dioxane = 1 part.

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

Sodium carbonate near part. Sodium sulfate: 15 parts. Trisodium phosphate = 40 parts. Trisodium amino-trimethylene phosphate: 10 parts. Carboxymethyl cellulose = 1 part. 5-buo-2-methyl-5-nitro-1,3-dioxane: 2 parts.

20 parts of antibacterial emulsion coating agent polyvinyl acetate (emulsified). 8 parts of deionized water. S--/lomo 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 easily 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.

Patent applicant: Eli Lilly & Kannoguni, patent attorney, Hajime Aoyama, and 1 other person

Claims (1)

[Claims] 1.2-Bromo-2-nitropropane-1,3-diol and the formula O 1 1-C-H [wherein Ro represents lower alkyl]. ] is reacted with the aldehyde represented by the formula [wherein K□ has the same meaning as above. ] 5-bromo-5-nitro-2-alkyl-1 represented by
, 3-dioxane. , 3-dioxane.