DE2316358A1 - Antimicrobial, N-monoalkyl-piperazine prepn. - by hydrogenative aminolysis of N-alkyl-diethanolamines - Google Patents

Abstract

N-monoalkylated piperazines (I) are prepd. by treating an N-alkylated diethanolamine (II) wth >=3 (esp. 5-20) moles NH3 at >150 degrees C (pref. 270-320 degrees C) in the presence of a Cr-Zn and/or Al-Zn hydrogenation catalyst, pref. at an H2 pressure of 50-400 (esp. 100-300) atm. The pref. prods. have a 10-16 C alkyl gp. They have antimicrobial activity, esp. in salt form, and can be used in disinfectants, etc.

Description

Process for the preparation of N-alkyl-piperazine It is known, M-alkyl-piperazines by aminolysis of N-alkyl-alkanolamines in the presence of Raney nickel and excess To produce hydrogen. However, this reaction is essential for the production of such N-alkyl-piperazines, which carry a longer alkyl radical or a cyclohexyl radical, not very suitable (cf. Chem. Abstracts Vol 53, Col. 7191 c).

The object of the present invention was to find a method that allows generally monoalkalized piperazines, especially those with a to produce longer alkyl radical in nitrogen.

According to the invention, N-alkylated diethanolamines are known per se Hydrogenation catalysts made from chromium-zinc and / or aluminum-zinc and excess hydrogen with at least 3 moles of ammonia per mole of alkyl diethanolamine at temperatures above Treated at 150 ° C.

Used as starting material for the process according to the invention one expediently N-alkyl-diethanolamines, which in a known manner from one mole of alkylamine have been prepared by reacting with 2 moles of ethylene oxide. This reaction is known and can be used at elevated temperatures and pressures with and without easily carried out by catalysts. One starts from alkylamines like they through z. B. pressure hydrogenation from the corresponding nitriles. Suitable Amines are, for example, laurylamine, tetradecylamine, stearylamine and cyclohexylamine. The carbon chain of the alkyl radical should have 1 to about 22 carbon atoms, in particular 6-18 carbon atoms. It can also have branches, should but do not contain any substituents which are not inert under the reaction conditions.

The manufacture of the chromium-zinc or aluminum-zinc catalysts to be used takes place in a manner known per se, pulverulent oxides of the metals mentioned be made into a paste in a suitable manner and optionally with the addition of wider ones Aids such as graphite or the like can be processed into tablets. These tablets are introduced into the reaction vessel before the reaction is carried out and reduced at elevated temperature in a hydrogen atmosphere.

The reaction according to the invention is carried out at a hydrogen pressure of carried out at least 50 atmospheres, the upper limit of the pressure is not limited, but is practically given by the known apparatus. Generally will work between 50 and 400 atm, especially 100-300 atm.

The reaction temperature is between 200 and 350 ° C, in particular 270 and 320 ° C. If hydrogen is replaced by nitrogen, the process according to the invention occurs Reaction does not occur and a large number of reaction products are obtained. N-alkyl-piperazines arise only as secondary products.

An excess of ammonia is essential for the reaction to proceed, which should be about 3 to 30 moles of ammonia per mole of N-alkyl diethanolamine. In general one becomes with an excess. from 5 to 20 moles of NH3 achieve good results, and it is true that a higher excess of N113 favors the yield.

To carry out the reaction, customary high-pressure hydrogenation is used common apparatus. The reaction product is worked up by Distillation expediently under reduced pressure. In particular, arise as by-products at higher temperatures piperazines and free underlying N-alkylamine. The latter can after reaction with 2 moles of ethylene oxide back into the reaction ground in place.

The N-mono-alkyl-piperazines, which were previously difficult to access, show in the form of their salts surface-active properties, in particular their antimicrobial properties Effectiveness to be emphasized, preferably in the form of their salts, are particularly suitable those alkylpiperazines in which the alkyl radical is an aliphatic chain with 10 to 16 carbon atoms.

EXAMPLE Preparation of the Catalyst a) Cr-Zn Catalyst 1 kilomole of powdery zinc oxide and 0> 6 kilomole of Ohrom trioxide were treated with this Mix a lot of water in a kneader to form a stiff paste. This was done at 800C dried; ground and after mixing with 3% graphite based on dry substance pressed into tablets with a diameter of 6mm.

b) Zn-Al catalyst 1 kilomole of powdery zinc oxide was used mixed with a suspension of freshly precipitated aluminum hydroxide, this suspension Contained 0.6 kilomoles of aluminum. The resulting paste was dried at 800C, then finely ground and after mixing in 3% graphite based on dry matter compressed into tablets.

Preparation of the n-alkyl-piperazine The reaction was carried out in a continuous manner working apparatus made as it is usually used for high pressure hydrogenation used. It consisted of a 14 liter furnace, hydrogen heater, heat exchanger, Separation bottles> Circulating pumps and metering pumps for the reactin participants.

12 liters each of the items described under a) and b) were put into the oven Filled hydrogenation catalyst. With a feed of 1/2 1 reaction mixture the reaction was carried out continuously. The reaction mixture obtained was worked up by distillation.

In the table below, the first column shows the catalyst used, the following are the molars based on 1 mole of N-alkyl diethanolamine Amount of ammonia as well as reaction temperature and hydrogen pressure in the reaction vessel. This is followed by the alkyl radical of the piperazine obtained on the nitrogen given as well as the yield and the boiling point of the N-alkyl-piperazine.

TABLE 1 Mol Reak. H2 pressure alkyl exert. boiling point Cat. NH3 temp. Rest in% a 8 300 ° C 250 Lauryl 70 115-117 ° C / 0.3 a 16 295 ° C 250 lauryl 81 115-117 ° C / 0.3 a 20 300 ° C 250 tetra- 79 141-144 ° C / 0.03 decyl a, 15 2850C 250 Cycclo- 82 122-124 ° C / 11 Hexyl a 15 3000C 250 ethyl 73 136-137 ° C / 760 b 15 280 ° C 200 Lauryl 70 110-112 ° C / 0.2 w Testing of the antimicrobial effectiveness 1) Plate test Mono-N-Laurylpiperazine and its dichloride were investigated on the following germs: 1) Staphylococcus aureus 2) Escherichia coli 3) Pseudomonas aeruginosa 4) Candida albicans The so-called plate test is a modified embodiment of the guidelines for the testing of chemical disinfectants of the German Society for Hygiene and Microbiology under the methods for preliminary testing of such agents described dilution test to determine the microbistatic effect and can be used with advantage in various tests instead of the use of liquid nutrient media specified there.

The desired test concentrations were measured by mixing Liquefied quantities of substance solutions of suitable concentrations with measured quantities Broth or beer-wort agars produced in sterile Petri dishes, which were pipetted in Quantities of the substance solutions were 0.1 to a maximum of 1 ml, the total volume in the Petri dishes after mixing with the nutrient media 10 ml. After the solidification of the The surface with the test germ suspension in broth or wort became the nutrient medium inoculates. Incubation took place at 37 ° C for bacteria and 30 ° C for fungi and lasted 8 days. It was then determined which one added to the nutrient medium Substance concentration was just able to completely prevent the growth of germs, The value determined in this way was referred to as the inhibitory concentration. The investigations were carried out in the following concentration intervals: 2500 ppm, 1000 ppm, 750 ppm, 500 ppm, 25Q ppm, 100 ppm, 50 ppm, 25 ppm and 10 ppm.

In this plate test, those listed in Table 2 below were used Inhibitory concentrations for the individual products determined for the aforementioned germs.

TABLE 2 Microbistatic effect in the plate test Numbers: Inhibitory concentrations in ppm Staph. E. Ps.aeru-Candida aureus coli ginosa albicans mono-N-laurylpiperazine 10 10 100 50 mono II laurylpiperazine 10 10 100 75 dichloride .2) Suspension test The antimicrobial effectiveness of the mono-N-alkylpiperazines was carried out according to the method described in the guidelines for testing chemical disinfectants, published by the German Society for Hygiene and Microbiology. 0.1 ml of germ suspensions were used in accordance with these guidelines of the bacteria and fungi listed below are piped into test tubes at a temperature of 18-21 ° C.

1) Staphylococcus aureus 2) Escherichia coli 3) Pseudomonas aeruginosa 4) Candida albicans For this purpose 10 ml of each of the different dilution amounts were added of the substances to be tested. The concentration was 100, 250, 500 ppm. After exposure times of 1, 2 1/2, 5, 10, 20, 30, 60 and 120 minutes, the Each loop material is removed from test tubes and 10 ml of nutrient solution is inoculated. the Inoculated with bacteria, nutrient solutions were inoculated with Candida albicans at 37 ° C incubated at 300C. After 6 days, the cultures were assessed macroscopically for growth and on this ee the killing times are determined, as shown in the table below 3 are compiled, In the following table 3 mean the numbers are the killing times in minutes.

TABLE 3 (testing in unbuffered aqueous solution) Staph. Esch. Ps. Cand. concentration aureus coli aerugin. silly 100 ppm lauryl-5 10 10 2.5 250 ppm # pipera- <2.5 5 10 2.5 500 ppm interest <2.5 5 10 2.5 100 ppm lauryl-2.5 2.5 2.5 5 250 ppm # piperaz. 2.5 2.5 2.5 5 500 ppm 2HCl 2.5 2.5 2.5 5 100 ppm tetra- <2.5 120 40 5 # decyl- 250 ppm <2.5 120 20 2.5 pipera- interest

Claims (5)

Claims: Process for the production of a nitrogen monoalkylated piperazines by catalytic aminolysis of N-alkylated diethanolamines characterized in that N-alkylated diethanolamines in the presence of an known hydrogenation catalysts made of chromium-zinc and / or aluminum-zinc with at least Treated 3 moles of ammonia per mole of alkyl-0 diethanolamine at temperatures above 150 C. 2) Method according to claim 1, characterized in that one is the Reaction at a hydrogen pressure of 50-400, in particular 100-300 atmospheres and a temperature of 200-350 ° C, in particular 270-320 ° C. 3) Method according to claim 1 and 2, characterized in that one the reaction with an excess of 3-30, in particular 5-20 mol of NH3 per mole tJ-alkyl diethanolamine. 4) Use of N-nono-alkylpiperazines, preferably in the form of their Ointment as an antimicrobial agent. 5) Use of-N-mono-alkylpiperazines according to claim 4, wherein the alkyl radical is an aliphatic chain with 10 to 16 carbon atoms.