DE1005068B - Process for the preparation of quaternary ammonium salts of N- [p-methoxy-benzyl] -N- [pyrimidyl- (2)] ethylenediamine - Google Patents

Description

Process for the production of quaternary ammonium salts of N- [p-methoxybenzyl] -N- [pyrimidyl- (2) ] -äthylendiamins The invention relates to a process for the production of quaternary Ammonium salts of N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] ethylenediamine. This quaternary Ammonium salts have solubilizing and other technically useful properties. As solubilizers, they have proven to be valuable during manufacture of solutions of antibiotics, such as gramicidin, tyrothricin and subtilin.

The transfer of many therapeutically effective organic compounds in a soluble form often poses an important problem for practical use of these compounds, especially where the use of organic solvents, z. B. alcohol is disadvantageous. So is z. B. Gramicidin completely insoluble in water, and if the application in an aqueous medium is important, the only option is To use gramicidin in the form of a suspension. This, of course, is not the only thing set a practical limit for the concentration of the antibiotic to be used, but it also presents considerable difficulties in producing stable suspensions.

It has been found that quaternary ammonium salts of the general formula where R is an alkyl group with up to 20 carbon atoms and X is the anion of an acid, represent highly effective solubilizers, which are particularly valuable when it comes to dissolving antibiotics that are sparingly soluble in water. In addition, these salts have a bacteriostatic effect on various organisms, in particular Staphylococcus aureus, and as such are highly effective disinfectants. The anions of inorganic acids may be mentioned as an example of the acid constituents represented by the substituent X in the above formula such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid and various phosphoric acids. Such compounds, however, which have halogen as an inorganic anion in the quaternary ammonium salt, have the advantage that they can be produced industrially advantageously.

According to the quaternary salts by solutions of the N, N - dimethyl - N'- [p - methoxybenzyl] -N '- [pyrimidyl- (2)] - ethylenediamine in suitable organic solvents such as benzene, toluene or xylene, among the following Obtaining addition of an alkyl halide to the solution.

After a certain dwell time or after moderate heating arises the corresponding quaternary ammonium salt. However, the amine base can also be used directly with alkyl halide without the use of a solvent by mixing the reactants and heating at 40 to 100 ° for 8 to 72 hours. Preferably the reactants are used in a molar ratio. That way you can Compounds of the above general formula in which X is an iodine, bromine or chlorine atom means to be easily manufactured. If the iodized salt was first made, this can easily be converted into the corresponding bromine or chlorine salt by reacting the Iodized salt can be converted either with silver bromide or with silver chloride, whereby the iodine ions are exchanged for chlorine or bromine ions. Furthermore, the Chlorine, bromine or iodine salts also converted into the corresponding sulfuric acid salts are reacted by the halogen salts with silver sulfate will. In a corresponding manner, the halogen salt can also be used to produce the phosphate salt be reacted with silver phosphate.

In addition, the quaternary ammonium salts according to the invention can also be prepared in such a way that a 2 @ N- [p-methoxybenzyl] -N - [- pyrimidyl- (2)] @ - aminoethyl halide is reacted with a dimethylalkylamine. As already stated above, it can Halogen atom iodine, and the quaternary iodine compound can be converted into the corresponding Chlorine or bromine compound or that of another anion are converted.

The invention is illustrated by the following examples 1 2.86 parts by weight of N, N-dimethyl-N '- [p-methoxy -ben7-yl] -N' - [pyrimidyl- (2)] -ethylenediamine are dissolved in 22 parts by weight of benzene and add 1.42 parts by weight to this solution Methyl iodide added. The reaction mixture is stored at room temperature, where the @ N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} -trimethyl-axnmonium iodide separates from the solution. The new compound has a melting point of 168 to 169 °. Example 2 2.86 parts by weight of N, N-dimethyl-N'- [p-methoxy-benzyl] -N '- [pyrimidyl- (2)] -ethylenediamine and 1.8 parts by weight of n-amyl bromide are combined in a suitable vessel, and the reaction mixture is heated to about 100 ° for 48 hours. Then it will be the batch cooled and the residue from a mixture of ethyl ether and isopropanol recrystallized in a weight ratio of 3: 2, resulting in white crystals. That @ N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} -dimethyl-n-amylammonium bromide thus obtained melts at 127 to 128.5 ° and is in water and alcohols, such as methyl, ethyl and isopropyl alcohol, soluble.

Example 3 2.86 parts by weight of N, N-dimethyl-N'- [p-methoxybenzyl] -N '- [pyrimidyl- (2)] - ethylenediamine and 2.5 parts by weight of n-decyl bromide are mixed together at about 100 ° for 48 hours heated, whereupon the batch is cooled to about 20 ° and then the ether extract is decanted. The residue, which is insoluble in ether, solidifies on standing and, after recrystallization from a mixture of ether and isopropanol in a weight ratio of 3: 2, gives white crystals of {N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl -dimethyl-n-decyl-ammonium-brornides. This compound has a melting point of 105 to 107 ° and is soluble in water and in the alcohols mentioned in Example 2. Example 4 2.86 parts by weight of N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and 5 parts by weight of lauryl bromide are combined and heated at about 100 ° for 48 hours, whereupon the batch is cooled to about 20 ° and the ether extract is decanted. The ether-insoluble residue solidifies on standing. After recrystallization of this residue from a mixture of ether and isopropanol in a weight ratio of 3: 2 , 5 parts by weight of N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} -dimethyl-iauryl-ammonium are obtained -bromide in the form of white crystals. The compound has a melting point of 107.5 to 108 ° and is soluble in ethyl alcohol; it is somewhat soluble in water.

Example 5 By reacting 2.86 parts by weight of N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and 10 parts by weight of n-decyl iodide in the manner described in Example 3 arise 8.5 parts by weight of fN- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl J-dimethyl-n-decyl-ammonium-j odid in the form of light yellow crystals with a melting point of 96 to 97 °. This connection is somewhat soluble in water and readily soluble in ethyl alcohol.

Example 6 By reacting 2.86 parts by weight of N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and 10 parts by weight of cetyl iodide in the manner described in Example 3 arise 8.3 parts by weight of fN- [p-methoxybenzyl] -N- [pyrim.idyl- (2)] - ß-aminoethyl @ -dimethyl-cetylammonium iodide in the form of light yellow crystals with a melting point of 92 to 94 °. This connection is soluble in ethyl alcohol. Example 7 By reacting 2.86 parts by weight N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and 10 parts by weight Dodecyl iodide in the manner described in Example 3 gives 8 parts by weight @ N- [p-Methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl @ -dimethyl-n-dodecylmonium iodide, in the form of light yellow crystals with a melting point of 96 to 98 °. These Compound is soluble in ethyl alcohol.

Example 8 5.8 parts by weight of N, N-dimethyl-N'- [p-methoxybenzyl] -N '- [pyrimidyl- (2)] -ethylenediamine are heated with 10 parts by weight of cetyl bromide for 48 hours at about 100 °. The batch is then cooled to 20 ° and extracted with ether. When cooling the Crude product purified in this way, a solid precipitate separates out, which is obtained by recrystallization from ether - isopropanol 5.5 parts by weight white crystals of tN- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} -dimethylcetylammonium bromide results. These Compound has a melting point of 91-92 °, it is good in alcohol and in Slightly soluble in water. Example 9 1.18 parts by weight of one prepared according to Example 8 quaternary ammonium salt from N, N - dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediaxn.in and cetyl bromide are dissolved in 75 parts by weight of water at 80 °, whereupon a solution of 0.312 parts by weight of silver sulfate in 100 parts by weight of water at 80 ° will. The mixed solution is then heated to 100 ° until the precipitate forms is coagulated by silver bromide. The silver bromide is filtered off and the filtrate evaporated. The @ N- [p-methoxybenzyl] -N - [pyrimidyl- (2)] -ß-aminoethyl} - obtained dimethylcetyl ammonium sulfate is a yellow C51.

Example 10 1.1 parts by weight of one prepared according to Example 5 quaternary ammonium salt from N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and n-decyl iodide are dissolved in 50 parts by weight of ethanol, and to this solution becomes a solution of 0.34 parts by weight of silver nitrate in 50 parts by weight of ethanol admitted. The precipitate of silver iodide that forms will filtered off. The filtrate is evaporated to dryness and then isopropanol from ether recrystallized to white crystals. The resulting (N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} dimethyl decylammonium nitrate melts at 101 to 102 ° and is readily soluble in alcohol and slightly soluble in water.

Example 11 1.16 parts by weight of one prepared according to Example 7 quaternary ammonium salt from N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine and n-dodecyl iodide are stirred into 1000 parts by weight of water at 80 °, whereupon 1.14 parts by weight of silver chloride are added. The mixture is then reduced to about 100 ° heated and kept at this temperature for 48 hours with stirring. The precipitate of silver iodide formed is filtered off, and that after evaporation the residue obtained from the filtrate to dryness is recrystallized from ether-isopropanol. The obtained white crystals of @ N- [p-methoxybenzyl] -N - [pyrimidyl - (2)] - ß - aminoethyl} - dimethyl - dodecyl ammonium chloride have a melting point from 75 to 78 ° and are soluble in water and alcohol.

The quaternary ammonium salts of N, which can be prepared according to the invention, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine, as already said above, disinfectant effect against various bacteria. Investigations in Vitro showed that the quaternary salts of N, N-dimethyl-N '- [p-methoxyben7, yl] -N' - [pyrimidyl- (2)] - ethylenediamine and n-decyl bromide, lauryl bromide, cetyl bromide and n-decyl iodide against Staphylococcus aureus bacteriostatic in concentrations of less than 0.25 mg / 100 g nutrient medium are effective. The tests were carried out as follows: 10 cc each of a suitable one Nutrient medium were placed in ten test tubes. Then the to be examined Compound in one of the nutrient media at a concentration of 128 mg / 100 g nutrient medium dissolved or dispersed. 10 ccm of the solution prepared in this way were then poured into the Second test glass introduced and the mixture mixed thoroughly. Thereupon were 10 ccm removed from the second test tube and transferred to the third test tube, mixed and the dilution then continued up to the tenth test glass. 10 cc from the last test jar were set aside. The first test glass to which nothing was added served as a control. The concentration of The compound to be investigated was between 64 in the various test glasses mg and 0.25 mg / 100 g nutrient medium. Each test glass with 0.1 ccm was then a 1 to 500 fold dilution of an 18 hour old culture of Staphylococcus aureus inoculated and the test tubes kept for 72 hours. The bacteriostatic The endpoint was from the lowest concentration of the test compound, at which was not observed to grow.

In this way, the bacteriostatic effectiveness of the @ N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ß-aminoethyl} -dimethyl-cetylammonium bromide (II) obtained according to the method was compared with that of the from the USA. Patent specification 2,465,865 compared the known N, N-dimethyl-N '- [p-methoxybenzyl] -N'- [pyrimidyl - (2)] - ethylenediamine - hydrochloride (I) and found the following result Bacteriostatic Concentration in Organisms mg1100 g Nutrient medium Substance II Substance II Clostridium welchii. . . . . . . . > 128 0.04 Escherichia coli. . . . . . . . . . . . > 128 25.0 Streptococcus haemolyticus. . > 128 34.0 Vibrio metchnikovi ......... > 128 2.5 The tests reveal the superiority of the compound obtained according to the invention.

A particularly valuable property of those that can be produced according to the invention quaternary ammonium salts of N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine consists in their ability to use antibacterial agents, e.g. B. gramicidin to disperse or put into solution. It is thus possible to obtain a clear aqueous dispersion from the following Ingredients to produce: 1 percent by weight N, N - dimethyl - N'- [p - methoxy -benzyl] -N '- [pyrimidyl- (2)] ethylenediwnine hydrochloride, 0.25 percent by weight (p-phenylephedrine hydrochloride, 0.005 percent by weight gramicidin, 2 percent by weight a mixture of monobasic sodium phosphate and dibasic sodium phosphate and 0.001 percent by weight of a preservative (a mixture of methyl and Propyl esters of p-oxybenzoic acid) and 0.1 percent by weight of a quaternary ammonium salt of N, N-dimethyl-N '- [p-methoxybenzyl] -N' - [pyrimidyl- (2)] - ethylenediamine with z. B. cetyl bromide or lauryl bromide. This solution remains clear and stable.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of quaternary ammonium salts of N- [p-methoxybenzyl] -N- [pyrimidyl- (2)] - ethylenediamine, characterized in that N, N-dimethyl-N'- [p-methoxybenzyl] - N '- [pyrimidyl- (2)] - ethylene diamine with an alkyl halide containing up to 20 carbon atoms in the alkyl radical, or a 2- {N- [p-methoxybenzyl] -N- [pyrimidyl- (2)]} -amino-ethyl halide is reacted with a dimethylalkylamine which contains up to 20 carbon atoms in the alkyl radical and, if necessary, the halogen ion of the quaternary ammonium salt thus obtained is replaced by the anion of another acid. 2. The method according to claim 1, characterized in that that the replacement of the halogen ion by the anion of another acid by means of a Silver salt is made. 3. The method according to claim 1, characterized in that that the reaction at temperatures of 40 to 100 ° and for a period of Runs for 8 to 72 hours. References Considered: U.S. Patents No. 2,465,865, 2,534,246.