WO1984000159A1 - Ethylenglycol-(3-iodo-2-propynyl) ether, preparation and utilization thereof - Google Patents

Abstract

The ethers have the formula (I):$(1,)$I-C=CCH2O(CH2CH2O)n-R$(1,)wherein R is a straigth or branched alkyl rest from C1 to C4, or an optionally substituted aryl rest and n is 1, 2 or 3.

Description

 Mono-, di- and triethylene glycol alkyl / airyl (3-iodo-2-propynyl) ether, process for their preparation and their use as antimicrobial agents

The invention relates to mono-, di- and triethylene glycol alkyl / aryl (3-iodo-2-propynyl) ether of the general formula (I)

IC = CCH ₂ O (CH ₂ CH ₂ O) _n -R (I)

in which R is a linear or branched alkyl radical having 1 to 4 carbon atoms or an optionally substituted aryl radical and n is 1, 2 or 3.

The invention further relates to a process for the preparation of mono-, di- and triethylene glycol alkyl / aryl (3-iodo-2-propynyl) ethers of the general formula (I), in which mono-, di- or triethylene glycol monoethers of the general Formula (III)

HO (CH ₂ CH ₂ O) _n -R (III) is reacted with propargyl chloride and the propargyl ether obtained of the general formula (II)

HC = CCH ₂ O (CH ₂ CH ₂ O) _n -R (II) iodinated.

Finally, the invention relates to the use of the compounds of the formula (I) as antimicrobial substances.

Examples of linear or branched alkyl radicals with 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl. tert-butyl. Examples of aryl and substituted aryl are phenyl, naphthyl, tolyl and chlorophenyl.

Compounds in which R is methyl or ethyl and n is 1 are preferred.

The mono-, di- and triethylene glycol alkyl / aryl- (3-iodo-2-propynyl) ethers of the general formula (I) are prepared in the manner set out below

The mono-, di- and triethylene glycol alkyl / aryl (3-iodo-2-propynyl) ethers (I) are converted into the propargyl ether by reaction of the sodium alcoholates with corresponding ethylene glycol monoalkyl / aryl ethers (III) with propargyl chloride. Intermediate stages (II) in a first stage and by subsequent iodination in a second stage according to the following general reaction scheme:

R and n have the meanings given above The first reaction stage is carried out as follows: mono-, di- and triethylene glycol monoethers (III) are reacted with propargyl chloride to give the corresponding propargyl ethers (II). The reactions are carried out in analogy to the conditions of the ether synthesis according to Williamson. The commercially available mono-, di- and triethylene glycol monoalkyl / aryl ethers (III) are first converted into the corresponding sodium alcoholates by reaction with sodium (method A) or sodium hydride (method B). In method A, an excess of the ethylene glycol ether used serves as the solvent. Because of the insufficient dissolution rate of sodium, this method is only used for the two low molecular weight alcohols (III, n = 1, R ¹ = Me, Et). In method B, equimolar amounts of ethylene glycol ether and sodium hydride in absolute. Hexane implemented under N ₂ transfer.

The sodium alcoholates obtained in this way are then converted into the ethers (II) using equimolar amounts of propargyl chloride (addition of the propargyl chloride with cooling with ice; stirring: 2-16 h at 40-80 ° C., NaCl precipitation). The obtained after sucking off the salt precipitate formed and concentrating in vacuo, distillatively difficult to separate mixture of the desired propargyl ether (II) and excess or non-alkylated starting glycol ether (III) is used without separation directly in the second stage for iodination.

The second reaction stage is carried out as follows: The ethylene glycol propargyl ethers (II) are iodinated to give the end products (I).

The mixture of propargyl ether (II) and starting glycol ether (III) obtained in the 1st reaction stage is prepared by a known method (Methodicum Chimicum, Vol. 7, p. 295 (1976) and F. Kai and S. Seki, Chem. Pharm. Bull . Japan 13, 1374 (1965)) with I ₂ / NaOH in water / methanol to a mixture of the desired iodopropynyl ether (I) and unchanged starting glycol ether (III).

The amount of iodine to be used is determined after a gas chromatographic analysis of the respective mixture of (II) and (III). Due to the increased lipophilicity of iodopropynyl ether

(I) compared to the precursors (II) is a simple removal of the unreacted after the iodination

Starting glycol ether (III) by washing several times

Methylene chloride solution of (I / III) possible with water.

Due to their microbistatic and microbicidal activity, the compounds according to the invention are suitable, for example, as preservatives for cosmetics and for the preservation of technical products (for example lacquers, glues, cooling lubricants, dispersions, paints, leather, paper), for the antimicrobial finishing of joint sealants (for example silicone sealants) Control of mold (e.g. mold on damp walls, ceilings or floors) and to protect wood.

For use in antimicrobial agents, the compounds according to the invention can be incorporated in a known manner into liquid, pasty or solid preparations which are present as solutions, suspensions or emulsions.

The invention is illustrated in the following examples, but the invention is not restricted to the examples. example 1

Ethylene glycol ethyl (3-iodo-2-propynyl) ether

(I, n = 1, R = Et) method A (Na), compound B

18.6 g (0.25 mol) of propargyl chloride in 5 were added to a cooled solution of 5.75 g (0.25 mol) of sodium in 90.1 g (1.0 mol) of ethylene glycol monoethyl ether (duration approx. 5-15 h) min added dropwise (exothermic reaction). After the reaction mixture had been stirred at 80 ° C. for 3 h, it was separated off from the precipitated sodium chloride. The mixture obtained from ethylene glycol ethyl propargyl ether and ethylene glycol monoethyl ether was used directly for iodination. About a third of a solution of 32.0 g (0.80 mol) of NaOH biscuits in 130 ml of water was added dropwise to a solution of the mixture in 200 ml of water. 56.0 g (0.22 mol) of iodine were added in portions in the course of 1 h, and at the same time the remaining amount of the NaOH solution. After stirring for 2 h at room temperature, the mixture was extracted twice with methylene chloride. The combined organic phases were washed neutral with water, dried over magnesium sulfate and concentrated in vacuo. 42.4 g (67% of theory) were obtained

Ethylene glycol ethyl (3-iodo-2-propynyl) ether as a yellow.

Analysis (%): C H I calculated 33.09 4.36 49.95 found 33.6 4.60 46.3

IR (film): 2183 (IC = C) cm ^-1

¹ H NMR (CDCl ₃ ): δ = 1.16 (t, 3H, J = 3.5 Hz, CH ₃ );

3.3 - 3.8 (q, 2H, J = 3.5 Hz, CH ₂ and m, 4H, OCH ₂ CH ₂ );

4.30 (s, 2H, C = CCH ₂ ) Example 2

Ethylene glycol methyl (3-iodo-2-propynyl) ether (I, n = 1, R = CH ₃ ) - method A (Na), compound A

Batch: 23.0 g (1.0 mol) sodium

300 ml of ethylene glycol monomethylethe

74.5 g (1.0 mol) propargyl chloride 400 ml methanol

96.0 g (2.4 mol) NaOH cookies in 400 ml

Water 152.3 g (0.6 mol) iodine (amount determined by GC analysis

The procedure was as in Example 1, but the iodination in methanol instead of in water and the extraction with ether instead of methylene chloride and the distillation of the end product (crude yield 100 g) were carried out in small quantities in the bulb tube. Yield: 26.7 g (11% of theory) of oil (n ²⁰ = 1.5248)

C ₆ H ₉ IO ₂ (240.04)

Analysis: (%) C H I calculated 30.02 3.78 52.87 found 30.5 3.65 52.9

IR (film): 2183 (IC = C) cm ^-1

¹ H NMR (CDCl ₃ ): δ = 3.35 (s, 3H, OCH ₃ ); 3.4 - 3.8 (m, 4H,

OCH ₂ CH ₂ ); 4.29 (s, 2H, C = CCH _2).

Example 3

General procedure for the synthesis of mono-, di- and tricthylene glycol alkyl / aryl (3-iodo-2-ρropinyl) ethers (I)

Method B (NaH)

To a solution prepared under N ₂ and Fcuchtigkeitsausschluß -Oberleitung dispersion of 0.14 mol of sodium hydride in 100 ml of anhydrous n-hexane was added dropwise at room temperature in 0.5 to 2 h, a solution of 0.14 mol of mono-, di- or triethylene glycol monoalkyl / aryl ether (III) in 40 ml of anhydrous n-hexane (exothermic reaction, temperature rise to 30 - 40 ° C).

After stirring for 2-6 h, a solution of 0.14 mol of propargyl chloride in 30 ml of anhydrous n-hexane was added dropwise in 15 min (exothermic reaction, temperature rise to 30 to 40 ° C.). After stirring for 2 to 16 hours at 40 to 80 ° C., the sodium chloride which had precipitated out was filtered off and the reaction solution was concentrated in vacuo. The mixture obtained from mono-, di- or triethylene glycol alkyl / aryl propynyl ether (II) and starting glycol ether (III) was used directly for iodination. About a third of a solution of 0.6 mol of NaOH biscuits in 95 ml of water was added dropwise to a solution of the mixture in 100 to 300 ml of methanol or methanol / water (2: 1 to 1: 1) while cooling. 0.14 mol of iodine was added in portions in the course of 1 h, and the remaining amount of the NaOH solution was simultaneously added. After stirring at room temperature for 2-16 h, the mixture was extracted twice with methylene chloride. The combined organic phases were washed neutral with water, dried over magnesium sulfate and concentrated in vacuo (after concentration of a methylene chloride solution of compound C on a rotary evaporator (bath temperature 70 ° C.), the substance rapidly decomposed when aerated). Residual amounts of (II, III) still present in the oil obtained were separated off as a preliminary distillation in a Kugelrohr: the desired mono-, di- or triethylene glycol alkyl / aryl- (3-iodo-2-propynyl) ether (I) was obtained. in the form of yellow oils with yields between 16 and 41% of theory. Compounds C, D, E, F, G and II were prepared according to this general procedure. The physical data are listed in Table I and the spectroscopic data in Table II.

tab

Antimicrobial activity of the compounds of the general formula (I)

The microbistatic activity of the compounds A to H was determined against the following test germ suspensions:

1. Staphylococcus aureus 2 x 10 ⁹ germs / ml

2. Escherichia coli 2 x 10 ⁹ germs / ml

3. Pseudomonas aeruginosa 5 x 10 ⁸ germs / ml

4. Candida albicans 2 x 10 ⁸ germs / ml 5. Aspergillus niger 5 x 10 ⁷ germs / ml

6. Penicillium camerunense 5 x 10 ⁷ germs / ml

7. Trichophyton mentagrophytes 2 x 10 ⁷ germs / ml

8. Penicillium funiculosum 5 x 10 germs / ml

The inhibitory concentrations of the compounds to be examined were determined using the dilution test according to the guidelines for testing chemical disinfectants of the German Society for Hygiene and Microbiology (1972). The experiments were carried out in sterile test tubes containing standard I broth (pH 7.5 Merck) or wort broth (pH 5.5, Merck, 8 ° BG). After the addition of the active ingredients, the volume of nutrient solution in the tubes was 10 ml in each case. Then 0.1 ml of the test microbial suspension of the stated concentration was introduced into the tubes. The nutrient solution samples inoculated with bacteria were stored in the incubator at 37 ° C. for 3 days. The inoculated samples were incubated at 30 ° C for 3 to 4 days. Then it was determined which active substance concentration supplied to the nutrient medium had just just inhibited the growth of none. The value found in this way was called the approach concentration. The following active ingredient concentrations in ppm were tested: 1,000, 500, 250, 100, 50, 10, 25, 10, 5, 2.5 and 1 for mushrooms.

The inhibitory concentrations listed in Table III below were determined for the compounds A to H:

The microbicidal activity of the compounds A to H was determined compared to the following test germ suspensions:

1. Staphylococcus aureus 2 x 10 ⁹ germs / ml

2. Escherichia coli 2 x 10 ⁹ germs / ml

3. Pseudomonas aeruginosa 5 x 10 ⁸ germs / ml

4. Candida albicans 2 x 10 ⁸ germs / ml

5. Aspergillus niger 5 x 10 ⁷ germs / ml

6. Penicillium camerunense 5 x 10 ⁷ germs / ml

The killing times of the products to be examined were determined using the suspension test according to the guidelines for the testing of chemical disinfectants of the German Society for Hygiene and Microbiology (1972). The substances to be tested were first dissolved in a little alcohol. Test solutions containing 3000 ppm and 500 ppm active ingredient and a maximum of 1% by weight ethanol were prepared from the ethanoic solutions by dilution with hard water with a hardness of 17 ° dH. 0.1 ml of the test microbial suspension was pipetted into test tubes at room temperature. For this, 10 ml of the test solution described above were added. After an exposure time of 15, 60 and 120 minutes at room temperature, a drop of material was removed from the test tubes with the aid of an eyelet and inoculated in 10 ml of nutrient solution containing 3% Tween 80 and 0.3% lecithin as a stripper. The nutrient medium consisted of 1% by weight standard I broth (Merck). The samples were incubated at 30 ° C. After 5 days at the earliest, the cultures were macroscopically assessed for growth and in this way the kill times determined, which are given in Table IV below.

Claims

Patent claims 1. Mono-, di- and triethylene glycol alkyl / aryl (3-iodo-2-propynyl) ether of the general formula (I) IC≡CCH ₂ O (CH ₂ CH ₂ O) _n -R (I) in which R is a linear or branched alkyl radical having 1 to 4 carbon atoms or an optionally substituted aryl radical and n is 1, 2 or 3. 2. A process for the preparation of compounds according to claim 1, characterized in that mono-, di- or triethylene glycol monoalkyl / aryl ether of the general formula (III) HO (CH ₂ CH ₂ O) _n -R (III) reacted with propargyl chloride and the ethylene glycol propargyl ethers of the general formula (II) obtained HC = CCH ₂ O (CH ₂ CH ₂ O) _n -R (II) iodinated, where R and n have the meanings given in claim 1. 3. Antimicrobial agents containing at least one compound according to claim 1 together with conventional formulation substances. 4. Use of the compounds according to claim 1 as antimicrobial substances.