DE1124048B - Process for the production of tertiary and quaternary diaethanolamines with bacteriostatic, bactericidal, fungistatic and fungicidal properties - Google Patents

Description

GERMAN

PATENT OFFICE

EXPLAINING EDITORIAL 1124 048

F 29746 IVb / 12 q

REGISTRATION DATE: OCTOBER 31, 1959

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: 22. FK B RU AR 1962

It is already known that one can use tertiary diethanolamines can produce by reacting primary amines with ethylene chlorohydrin or ethylene oxide. as well it is known that it is possible to convert tertiary amines into quaternary amines by the action of alkylating agents To transfer ammonium compounds.

It has now been found that tertiary diethanolamines and their quaternary ammonium salts can also be used excellent biological properties are obtained when using primary amines of the general formula

Method of manufacture

of tertiary and quaternary diethanol

amines with bacteriostatic, bactericidal,

fungistatic and fungicidal properties

■ ² >

-C CH ₂ -CH ₂ -NH ₂

A /

wherein R ₁ , R ₂ and R ₃ stand for hydrogen or halogen atoms, reacts with ethylene chlorohydrin or with ethylene oxide and on the amines of the general formula formed

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Manfred Schorr, Frankfurt / M.-Unterliederbach, Dr. Dr. Rudolf Pedestrian, Frankfurt / M.-Hoechst,

Dr. Fritz Bauer, Bad Soden,

and Dr. Georg Nesemann, Frankfurt / M.-Hoechst,

have been named as inventors

c-CH ₂ -CH ₂ -Nf

1 \

CH ₉ -CH ₃ OH

R ₃

in which R ₁ , R ₂ and R _{3 have} the meaning given, optionally a reactive ester of an alcohol of the general formula

R ₄ -OH

in which R _{4 is} an alkyl radical, a low molecular weight hydroxyalkyl radical, an alkenyl radical or an optionally halogen-substituted benzyl radical, allowed to act.

The following CH-CH OH ³⁵ primary amines are suitable as starting materials:

² y, ^, y-tri- (4'-chlorophenyl) propylamine,

y-phenyl-y, y-bis (4'-chlorophenyl) propylamine,
y- (3'-chlorophenyl) -y, y-bis- (4'-chlorophenyl) -

propylamine,
y- (3'-fluorophenyl) -y, y-bis- (4'-chlorophenyl) -

propylamine,
y, y-bis (4'-fluorophenyl) -y- (4'-chlorophenyl) -

propylamine,
y- (3 ', 4'-dichlorophenyl) -y, y-bis- (4'-chlorophenyl) -

propylamine.

These primary amines can e.g. B. in a simple manner from the corresponding triphenylcarbinols can be obtained by the process described in patent 1,088,972.

The method according to the invention is e.g. B. carried out in such a way that the primary amines with ethylene halohydrins, preferably ethylene

209 510/429

3 4

chlorohydrin, reacted at elevated temperature. The quaternary ammonium salts form in the The reaction mixture is partially heated to 100 to in most cases colorless crystals, which are in water 150 ° C. The use of a solvent depends on the type of substitution of the benzene nuclei and useful, but not absolutely necessary. the nature of the alkylating agent used On the other hand, it is advantageous to solve well for the formation of 5 or less. They are easily soluble for Reaction liberated hydrohalic acid for the most part in low aliphatic one or more inorganic or organic basic connective alcohols.

manure, for example an alkali carbonate, calcined die according to the method according to the invention or add dimethylaniline. To contain tertiary and quaternary amines or processing, the reaction mixture is treated with io whose salts are not very toxic and are valuable dilute aqueous alkalis and suitable therapeutic properties, of which in particular organic solvents such as ether or methylene bacteriostatic, bactericidal, fungistatic and funchlorid. After the solvent has evaporated, gicidal properties are in the foreground. Sample received the process products are in the form of the N- [y, y, y-tri- (4'-chlorophenyl) propyl] -free Bases, which if desired in the usual manner 15 N, N-bis (| 5-hydroxyethyl) -N-methyl-ammonium-medurch Treatment with inorganic or organic methyl sulfate or the N- [y, y, y-tri- (4'-chlorophenyl) acids, advantageous in the presence of an organic propyl] diethanolamine hydrochloride against gramposi solvent, into the corresponding acid addition germs such as Staphylococcus aureus, Streptococcus salts can be transferred. haemolyticus or Corynebacterium diphtheriae still

Instead of using ethylene halohydrins, ao can be bacteriostatic in a dilution of 1 to 4 y / ml. the primary amines for conversion into diethanoi- Compared to gram-negative germs such as E. Coli or amine in a particularly simple way with ethylene Pseudomonas aeruginosa is the lower limit of the convert oxide. It is advantageous to work in the bacteriostatic effectiveness of the N- [y, y, y-tri-presence of organic solvents in (4'-chlorophenyl) propyl] -N, N-bis - (^ - hydroxyethyl) closed Vials at elevated temperatures, 25 N-methyl-ammomum-methylsulfate at 15 y / ml. preferably between 80 and 160 ° C. As a solution What the bactericidal effectiveness of the process agents come z. B. alcohols and ethers, preferred products are concerned, z. B. the phenol but aromatic hydrocarbons such as benzene coefficient of N- [y, y, y-tri- (4'-chlorophenyl) propyl] - or toluene into consideration. N, N-bis - (/ S-hydroxyethyl) -N-methyl-ammonium-me-

The tertiary diethanolamines obtained in this way are thylsulphate, which is a measure of the bactericidal effect very viscous, yellow, only represents a substance with strong decomposition, compared to staphylococci lubricatable oils or crystalline substances. With about 400 and opposite E. Coli and Bacterium typhi organic or organic acids they form salts, 200. The phenol coefficient of N- [y, y, y-tri- (4'-chlorodie partly in crystallized form. As phenyl) propyl] diethanolamine hydrochloride against inorganic Acids are, for example, chlorinated water- 35 over staphylococci is between 400 and 800. chemical acid, hydrobromic acid, hydriodic acid, because of these properties the new ones are suitable Sulfuric acid, phosphoric acid or sulfamic acid compounds for example for use as called. As organic acids come z. B. vinegar disinfectants in various areas, acid, tartaric acid, malic acid or ethylenediamine- The fungistatic effect of the process produces tetraacetic acid into consideration. 40 nits is also excellent. For example be

The free tertiary diethanolamines can be converted into salts according to the invention, pathogenic yeasts such as Candida albicans or, according to apathodes, into corresponding quaternary ammonium molds such as Penicillium glaucum. For this purpose, concentrations of 50 μg / ml of the N- [y, y, Y-Tria on them alkylating agents such as reactive esters, (4'-chlorophenyl) -propyli-N, N-bis- (j5-hydroxyethyl) - advantageously act at elevated temperatures.45 N-methyl-ammomum-methylsulphate suitable for growth are for this, for example, the esters of inhibits. Compared to human pathogenic skin fungi alcohols of the formula R ₄ - OH with chlorine, bromine such as Microsporon gypseum, Epidermophyton and / or hydrogen iodide acid, sulfuric acid or a Trichophyton species is the fungistatic active aromatic or aliphatic sulfonic acid ability of the N- [y, y, y-tri- (4'-chlorophenyl) propyl] diet presence of a solvent is not necessary, 50 nolamine hydrochloride in the concentration between However, in most cases they are good for achieving good 8 and .16 y / ml, while the lower fungistatic yields are advantageous. In ^ rage are aromatic limits of action of N- [γ, γ , y-tri- (4'-chlorophenyl) - or aliphatic hydrocarbons, aliphatic propyl] -N, N-bis - (/ 5-hydroxyethyl) -N-methyl- ammo-esters, ethers, ketones or alcohols. For example, nium methyl sulfate is about 30 y / ml, the following may be mentioned: benzene, toluene, petroleum ether, ethyl acetate, 55 The bactericidal effectiveness of the new compounds diethyl ether, dioxane, tetrahydrofuran, acetone, gen was determined in the so-called Rideal Walker test, methanol or ethanol . Depending on the reactant. The determination of the bacteriostatic effectiveness of the alkylating agent used was carried out according to the known method of man at a slightly or greatly increased temperature. In Wright (The Lancet, year 1912) in general, the reaction in the boiling dilution test proceeds sufficiently quickly, depending on the type of germ temperature of the solvent used. In some cases in broth or in serum broth as a nutrient medium, however, it can be useful to use those with small seeds. The reading was after 18-reaction at temperatures between 100 and 200 ⁰ C, to 20 hours of incubation at 37 ° C at the boundary, where appropriate in an autoclave to carry out. The difference between clear and cloudy test solution of pre-process products fall after the end of the reaction.

tion either directly in crystalline form or testing for fungistatic effectiveness of the

can by treatment with a suitable compound was based on that of

Solvent are brought to crystallization. Schraufstätter, Richter and Dittscheid im

"Archive for Dermatology and Syphilis", Vol. 188 (1949), p. 259, method described in the serial dilution test performed.

example 1

N- [y, y,> '- tri- (4'-chlorophenyl) propyl] -N, N-bis (iö-hydroxyethyl) amine

Γ 203 g ^, γ, y-tri (4'-chlorophenyl) propylamine and 65 cc of ethylene oxide are dissolved in 600 cc of benzene and the mixture is heated in an autoclave for 5 hours at 120 ⁰ C. After distilling off the solvent, one obtains 250 g crude N- [y, y, y-tri- (4'-chlorophenyl) - propyl] - N ₅ N - bis - (ß - hydroxyethyl) - amine in the form of a yellow, very viscous oil, which is used for the production of salts or for quaternization can be used directly. If the crude amine is dissolved in about twice the amount of diisopropyl ether and the batch is left to stand for a long time or is seeded, crystallization takes place and the N - [γ, γ, γ -Tri - (A'- chlorophenyl) - propyl is obtained ] -N, N-bis (j3-hydroxyethyl) amine as a colorless crystal powder with a melting point of 109 to 110 ° C.

By adding a small excess of alcoholic hydrochloric acid to an ethereal solution of the amine, the corresponding hydrochloride of the compound is obtained, which melts ^{at 208 to 211 ° C. after recrystallization from alcohol diisopropyl ether.}

Example 2

N- [y, y, y-tri- (4'chlorophenyl) propyl] -N, N-bis (/? - hydroxyethyl) amine

A mixture of 78 g of γ, γ, γ-Τά- (4'-chlorophenyl) propylamine, 40 g of ethylene chlorohydrin and 12 g of quicklime is heated to 110 ° C. for 20 hours while stirring. After cooling, the viscous mass obtained is treated with chloroform and dilute sodium hydroxide solution, the chloroform layer is separated off, washed with water, dried over magnesium sulfate and finally the solvent is distilled off. The residue is dissolved in 100 ecm diisopropyl ether and inoculated. The N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis- (β-hydroxyethyl) amine slowly crystallizes out and is filtered off with suction. The process product melts at 108 to 110 ° C, the yield is 70 g.

35

Example 3

N- [y- (3'-fluorophenyl) -y, y-bis- (4 "-chlorophenyl) propyl] -N, N-bis (β-hydroxyethyl) amine

Dissolve 109 g of y- (3'-fluorophenyl) -y, y-bis- (4 "-chlorophenyl) - γ, γ - bis - (4" - chlorophenyl) -propylamine and 41 ecm of ethylene oxide in 300 ecm of benzene and heat the mixture in the autoclave to 120 ° C. for 5 hours. After the solvent has been distilled off, the N- [y- (3'-fluorophenyl) -y, y-bis- (4 "- chlorophenyl) - propyl] - N ₅ N remains - bis - (ß - hydroxyethyl) - amine in the form of a light brown, very viscous oil. The yield is 130 g.

Example 4

N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis - (/ J-hydroxyethyl) -N-methyl-ammonium methyl sulfate

19 g of N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis (/ 3-hydroxyethyl) amine and 5.5 g of dimethyl sulfate are dissolved in 60 ecm of benzene and reflux the mixture on the steam bath for 15 minutes. Then 60 ecm of diisopropyl ether is added, an oil precipitating which solidifies slowly when standing and quickly when inoculated. After suctioning off, 20 g of N - [γ, γ, γ- tri- (4'-chlorophenyl) propyl] -N, N-bis (| iS-hydroxyethyl) -N-methylammonium methyl sulfate with a melting point are obtained 110 to 113 ° C (with weak decomposition). For purification, the crude product can be recrystallized by dissolving it in 80 ecm warm ethyl acetate, adding 100 ecm ether and inoculating it. The colorless crystals obtained melt at 111 to 113 ° C. with weak decomposition.

Example 5

N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis (/ 3-hydroxyethyl) -N-allyl-ammonium bromide

A solution of 24 g of N- [y, y, y-tri- (4 '- chlorophenyl) - propyl] - N ₅ N - bis (β - hydroxyethyl) amine and 7.2 g of allyl bromide in 50 ecm is heated Alcohol reflux for 8 hours. After adding 200 ecm of diisopropyl ether, crystallization takes place and 17 g of N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis - (/ S-hydroxyethyl) -N are obtained -allyl-ammonium-bromide, which can be recrystallized from alcohol-diisopropyl ether. The product of the process forms colorless crystals with a melting point of 210 to 211 ° C (with decomposition).

Example 6

N- [y- (3'-fluorophenyl) -y, y-bis-

(4 "-chlorphe * nyl) -propyl] -N, N-bis- ( _l 8-hydroxyethyl) -

N-allyl ammonium bromide

■ A solution of 23.1 g of N- [y- (3'-fluorophenyl) -γ, γ - bis - (4 "- chlorophenyl) - propyl] - N ₅ N - bis-

40- (/ Miydroxyäthyl) -amine and 7.2 g of allyl bromide in 50 ecm alcohol for 7 hours under reflux. The solvent is then distilled off completely and the residue is dissolved in 50 ecm of ethyl acetate. Crystallization slowly takes place on standing, which can be accelerated by inoculation. After adding 50 ecm of diisopropyl ether, the product is filtered off with suction and 10 g of N- [y- (3'-fluorophenyl) -y, y-bis- (4 "-chlorophenyl) propyl] -N, N-bis - (/? -hydroxyäthyl) -N-allyl-bromide of melting point 190-193 ⁰ C. by recrystallization from isopropanol-diisopropyl ether can be further purify the salt, it then melts at 193-194 ° C.

55

Example 7

N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis (/ 5-hydroxyethyl) -N-ethyl-ammonium-p-toluenesulfonate

Dissolve 24 g of N- [γ, γ, γ -tri- (4'-chlorophenyl) propyl] -N, N-bis (ß-hydroxyethyl) amine and 12 g of ethyl p-toluenesulfonate in 50 ecm of alcohol and heat the solution under reflux for 6 hours. After adding 100 ecm of diisopropyl ether and suction, 26 g of colorless N- [γ, γ, γ -tri- (4'-chlorophenyl) propyl] -N, N-bis - ((S-hydroxyethyl) -N-ethyl are obtained ammonium p-toluenesulfonate with a melting point of 157 to 158 ° C. The process product can be recrystallized from isopropanol, the melting point no longer changing.

Example 8

N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis (/ 3-hydroxyethyl) -N- (p-chlorobenzyl) ammonium chloride

19 g of N- [y, y, y-tri- (4'-chlorophenyl) propyl] -N, N-bis- (jS-hydroxyethyl) amine and 7 g of p-chlorobenzyl chloride are mixed and the mixture is heated in the open Flask on the steam bath for 8 hours. The mixture slowly becomes thick and finally solidifies into a hard crystal mass. The product is dissolved in 450 ecm of boiling alcohol, filtered, 500 ecm of petroleum ether is added and inoculated. The next day it is suctioned off and 10gN- [γ, γ, γ-Ίή- (4 '- chlorophenyl) - propyl] - N ₅ N - bis - (ß - hydroxyethyl) -N- (p-chlorobenzyl) ammonium is obtained chloride with a melting point of 208 to 210 ° C.

Example 9

N- [y, y, y-tri- (4-chlorophenyl) propyl] -N, N, N-tri-

(ß-hydroxyethyl) ammonium chloride ^ao

24 g of N- [y, y, y-tri- (4-chlorophenyl) propyl] -N, N-bis (/? - hydroxyethyl) amine and 4.8 g of ethylene chlorohydrin are heated to 120 to 130 for 15 hours ⁰ C heated. The melt is then treated with about 50 ecm of ethyl acetate, during which crystallization takes place. After suctioning off 10 g of N- [y, y, y-tri- (4-chlorophenyl) propyl] - N ₅ N ₅ N - tri - (ß - hydroxyethyl) - ammonium chloride with a melting point of 233 to 235 ° C ( with decomposition). The salt can be recrystallized from alcohol-diisopropyl ether without changing the decomposition point.

Claims (1)

Claim: 35 Process for the preparation of tertiary and quaternary diethanolamines with bacteriostatic, bactericidal, fungistatic and fungicidal properties, characterized in that one primary amines of the general formula yx ^Rl f '. -C _{-CH 2 -CH 2} -NH ₂ - INi-I ₂ wherein R ₁ , R ₂ and R _{3 represent} hydrogen or halogen atoms, reacts with ethylene chlorohydrin or with ethylene oxide and optionally on the amines of the general formula formed C-CH ₂ -CH ₂ -N CH ₂ -CH ₂ OH CH ₂ -CH ₂ OH in which R _15, R ₂ and R _{3 have} the meaning given, a reactive ester of an alcohol of the general formula R ₄ -OH in which R _{4 is} an alkyl radical, a low molecular weight hydroxyalkyl radical, an alkenyl radical or an optionally halogen-substituted benzyl radical, allowed to act. © 209 510/429 2.62