WO1984000162A1

WO1984000162A1 - Carbonic and sulphonic esters of 2-(3-iodo-2-propinyloxy)-ethanol, method for the preparation and utilization thereof as antimicrobial agent

Info

Publication number: WO1984000162A1
Application number: PCT/EP1983/000160
Authority: WO
Inventors: Werner Gerhardt; Rudolf Lehmann
Original assignee: Henkel Kgaa
Priority date: 1982-07-01
Filing date: 1983-06-23
Publication date: 1984-01-19
Also published as: DE3224504A1; IT1170158B; IT8321837A0

Abstract

The compounds have the formula (I);$(1,)$I-C=CCH2OCH2CH2-O-X-R$(1,)$wherein X is CO or SO2 and R is a straight or branched alkyl rest from C1 to C11, an optionally substituted aryl rest or an alkylaryl rest.

Description

Carboxylic acid and sulfonic acid esters of 2- (3-iodo-2-propynyloxy) ethanol, process for their preparation and their use as antimicrobial agents

The invention relates to carboxylic acid and sulfonic acid esters of 2- (3-iodo-2-propynyloxy) ethanol of the general formula (I)

IC = CCH ₂ -OCH ₂ CH ₂ -OXR (I)

in which X is CO or SO ₂ and R is a linear or branched alkyl radical having 1 to 11 carbon atoms, an optionally substituted aryl radical or an alkaryl radical.

The invention further relates to a process for the preparation of the carboxylic acid and sulfonic acid esters of 2- (3-iodo-2-propynyloxy) ethanol of the general formula (I), in which 2- (3-iodo-2-propynyloxy) ethanol with appropriate acid chlorides or acid anhydrides.

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

Examples of linear and branched alkyl radicals with 1 to 11 carbon atoms, for which R stands, are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, Nonyl, decyl, undecyl, dodecyl and the branched isomers of alkyls with 5 to 11 carbon atoms. Examples of aryl and optionally substituted aryl for which R is phenyl, naphthyl and chlorophenyl and an example of aralkyl is benzyl.

Compounds in which R is a lower alkyl radical having 1 to 4 carbon atoms and an aryl radical or benzyl radical are preferred.

The carboxylic acid and sulfonic acid esters of 2- (3-iodo-2-propynyloxy) ethanol of the general formula (I) are prepared in the manner described below in accordance with the following general reaction scheme

I-

The carboxylic acid esters (Ia) are prepared by customary methods by reacting 2- (3-iodo-2-propynyloxy) ethanol (II) with acid anhydrides (organic, basic organic chemistry internship, 9th edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1969, p. 443-5) or acid chlorides in the presence of pyridine as an acid-binding agent (unicorn variant, loc. Cit. P. 446). The yields are between 50 and 92% of theory.

The sulfonic acid esters (Ib) are synthesized in the usual way by reacting 2- (3-iodo-2-propynyloxy) ethanol (II) with sulfonic acid chlorides in the presence of pyridine (loc. Cit. P. 608). The yields are between 67% and 82% of theory.

Of the sulfonic acid esters (Ib), preference is given to those in which R is an alkyl radical of 1 to 4 carbon atoms or aryl.

Due to their microbistatic and microbicidal activity, the compounds according to the invention are suitable, for example, as preservatives, e.g. as technical preservatives for special areas such as Wood, leather, paper or lacquer.

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 it is not restricted to the examples. Production of carboxylic acid esters (Ia)

example 1

2- (3-iodo-2-propynyloxy) ethyl acetate

(Ia, R = CH ₃ ) - Method A. Compound A

A solution of 6.8 g (0.03 mol) of 2- (3-iodo-2-propynyloxy) ethanol (II) and 3.1 g (0.03 mol) of acetic anhydride was concentrated with a drop. Sulfuric acid added. After the highly exothermic reaction had subsided (temperature rose to 75 ° C.), the mixture was stirred at room temperature for 30 minutes and then poured into ice / water. After extraction twice with methylene chloride, drying and concentration of the solution was obtained

5.5 g (68% of theory) of acetic acid inyloxy) - ethyl ester as a yellowish oil

C ₇ H _g IO ₃ (268.05)

Analysis (%) CHI calculated 31.37 3.38 47.34 found 31.5 3.33 47.3

IR (film): 2185 (IC = C), 1739 (s, COOR) cm ^-1 1H-NMR (CDCl ₃ ): δ = 2.08 (s, 3H, CH ₃ ); 3.6 - 3.8 and 4.07 - 4.3 (m, 4H, OCH ₂ CH ₂ ); 4.33 (s, 2H, C = CCH ₂₎

Example 2

Cinnamic acid 2- (3-iodo-2-propynyloxy) ethyl ester (Ia, R = -CH = CHC ₆ H ₅ ) - Method B, Compound E

To a solution of 6.8 g (0.03 mol) of 2- (3-iodo-2-propynyloxy) ethanol (II) and 4.8 g (0.06 mol) of absolute cooled to 0 to 5 ° C. A solution of 6.7 g (0.04 mol) of cinnamic acid chloride in 20 ml of chloroform was added dropwise to the pyridine (exothermic reaction). After 16 h at room temperature, the reaction mixture was poured into 40 ml diluted hydrochloric acid entered. The organic phase was washed three times with water, twice with sodium hydrogen carbonate solution and again with water, dried and concentrated. After slurrying the solid obtained in cyclohexane and suction, 5.3 g (50% of theory) of ethyl cinnamate 2- (3-iodo-2-propynyloxy) were obtained in the form of yellowish crystals of melting p. 48 to 51 ° C.

C ₁₄ H ₁₃ IO ₃ (356'16)

Analysis (%) C H I calculated 47.21 3.68 35.63 found 47.7 3.67 35.6

IR (KBr): 2171 (IC = C), 1700 (s, COOR) cm ^-1

¹ H-NMR (CDCl ₃ ): δ = 3.65 - 3.9 and 4.2 - 4.5 (m, 4H,

OCH ₂ -CH ₂ ); 4.36 (s, 2H, C = CCH _2); 6.43 (d, 1H, J = 8 Hz, CH = C); 7.2 7.65 (m, 5H, C ₆ H ₅ ); 7.7 (d, 1H, J = 8 Hz, C = CH).

The remaining esters (Ia) listed in Table I were prepared by the same synthetic method. The spectroscopic data of the carboxylic acid esters (Ia) are listed in Table II.

Production of sulfonic acid esters (Ib)

Example 3 p-Toluenesulfonic acid 2- (3-iodo-2-propynyloxy) ethyl ester

(Ib, R = 4-C ₆ H ₄ -CH ₃ , compound H)

To a solution of 62.9 g (0.33 mol) of p-toluenesulfonic acid chloride and 67.8 g (0.30 mol) of 2- (3-iodo-2-propynyloxy) ethanol (II ) in 250 ml. Chloroform were absolute with stirring in 1 h 47.5 g (0.60 mol). Dropped pyridine (exothermic reaction, temperature rise to 15 ° C).

After 3 h at 5 - 10 ° C and 20 h at room temperature, the reaction mixture was concentrated in 200 g ice / 70 ml. Hydrochloric acid entered and the chloroform phase separated. The aqueous phase was extracted twice with chloroform. The organic phases were combined, washed twice with water until neutral. dried over magnesium sulfate and evaporated. After recrystallization of the crude product (97.2 g) from 150 ml of isopropanol, 76.3 g (67% of theory) of p-toluenesulfonic acid 2- (3-iodo-2-propynyloxy) ethyl ester were obtained in the weak form yellowish crystals with a melting point of 68 to 70 ° C.

C ₁₂ H ₁₃ IO ₄ S (380 _'20)

Analysis (%) C H I calculated 37.91 3.45 33.38 found 37.9 3.41 33.4

IR (KBr): 2192 (IC = C), 1348 (SO ₂ -O) cm ^-1

¹ H NMR (CDCl ₃ ): δ = 2.39 (s, 3H, CH ₃ ); 3.51 - 3.78 and

3.96 - 4.2 (m, 4H, OCH ₂ CH ₂ ); 4.20 (s, 2H, C = CCH _2); 7.2 to 7.8 (m, 4H, pC ₆ H ₄ ). The remaining sulfonic acid esters (Ib) listed in Table III were prepared by the same synthetic method. The spectroscopic data of the sulfonic acid esters (Ib) are listed in Table IV.

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

The microbistatic activity of the compounds A to J 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 χ 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 ⁷ 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 kept in an incubator at 37 ° C. for 3 days. The inoculated samples were incubated at 30 ° C for 3 to 4 days. It was then determined which concentration of active ingredient added to the nutrient medium had just inhibited the growth of the germs. The value found in this way was called the inhibitory concentration. The following active ingredient concentrations in ppm were tested: 1,000, 500, 250, 100, 50, 10, in some cases additionally 25, 10, 5, 2.5 and 1 for fungi. The inhibitory concentrations listed in Table V below were determined for the compounds A to J:

The killing times of the products to be examined were determined using the suspension test according to the guidelines for testing 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 were prepared from the ethanolic solutions by dilution with hard water with a hardness of 17 ° dH, which contained 3000 ppm and 500 ppm of active ingredient and a maximum of 1% by weight of ethanol. 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 VI below.

Claims

1. Carboxylic acid and sulfonic acid esters of 2- (3-iodo-2-propynyloxy) ethanol of the general formula (I)

IC = CCH ₂ OCH ₂ CH ₂ -OXR (I)

2. Process for the preparation of compounds according to

Claim 1, characterized in that 2- (3-iodo-2-propynyloxy) ethanol is reacted in a manner known per se with corresponding acid chlorides or acid anhydrides.

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.