Diamine derivatives

Patented May 15, 1945

2,375,853

UNITED STATES PATENT OFFICE

2,375,853

DIAMINE DERIVATIVES

James E. Kirby, Wilmington, Del., and John F. Lontz, Gadsden, Ala., assignors to E. I. du Pont de Nemours & Company, Wilmington, Del., a corporation of Delaware

No Drawing. Application October 7,1942, Serial No. 461,166

Claims. (Cl. 260—583)

This invention relates to new compounds containing at least two nitrogen atoms and more particularly refers to long chain bis-quaternary ammonium compounds and processes for their production and use.

Numerous disinfectant compositions have been described in the scientific literature. As is well known many of these compositions lose a portion or all of their activity in the presence of blood, blood serum and other protein materials. Likewise, a large number of these compounds contain mercury or other heavy metals to which many individuals are sensitive.' The foregoing disadvantages in prior art compositions of this type restrict greatly their fields of use.

It is an object of the present invention to produce compounds which overcome the previously mentioned disadvantages and numerous other disadvantages which directly or indirectly result therefrom. A further object is to produce disinfectant compositions which are highly effective in destroying or preventing the growth of bacteria, molds, fungi and related organisms. A still further object is to produce a class of new chemical compounds which in addition to their disinfectant properties are of use for many other purposes in the chemical arts. Additional objects will become apparent from a consideration of the following description and claims.

These objects are attained in accordance with the present invention wherein compounds are produced which conform to the following general formula:

R’ R' R’ R' \ / \ / R—N—(CH,)to—N—R I I

X X wherein R is a monovalent straight chain alkyl group containing at least ten carbon atoms; R' is a lower molecular weight alkyl group; and X is an anion.

In a more restricted sense this invention is concerned with the production of compounds conforming to the foregoing general formula wherein R is a straight chain alkyl group containing from 10-18 carbon atoms; R' is a methyl or ethyl group; and X is an anion of an acid having a dissociation constant greater than 1 x 10-¹¹. In a still more restricted sense this invention is concerned with compounds conforming to the foregoing general formula wherein R is a straight chain alkyl group containing from 10-18 carbon 5 atoms; R' is in each case a methyl group; and

X is an anion of an acid having a dissociation constant greater than 1 χ 10-*. In a still more restricted sense this invention pertains to compounds of the immediately preceding type where10 in X is chlorine or bromine and R is a decyl or dodecyl group. In its preferred embodiment this invention pertains to compounds such as decamethylene - bis - (dimethyldecylammonium bromide), decamethylene-bis-(dimethyldecylam15 monium chloride), and decamethylene-bis-(dimethyldodecylammonium chloride). In another preferred embodiment this invention pertains to the use of the foregoing compounds in disinfectant compositions.

The compounds embraced herein are bisquaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two alkyl groups having not more than two car²⁵ bon atoms, one straight chain higher alkyl group of 10-18 carbon atoms, and an anion of an acid having a dissociation constant greater than 1 χ 10-¹¹. Compounds of this type may in accordance with this invention be produced by sev³⁰ eral methods.

In accordance with one of these methods these compounds may be produced by reacting, for example, one mole of an Ν,Ν,Ν',N'-tetraalkyldecamethylenediamine as Ν,Ν,Ν’ ,N'- tertame thyl35 decamethylenediamine with two moles of a higher alkyl halide such as dodecyl chloride for a period of 24 hours in methanol at 100° C. At the end of this time the methanol is removed by evaporation in the absence of moisture yielding the de⁴⁰ sired product.

In accordance with a second method these compounds are made by reacting, for example, a decamethylene dihalide such as 1,10-decamethylene dibromide with a tertiary amine such ⁴⁵ as N-dodecyldimethylamlne.

In accordance with a third method these compounds are made by the methylation or ethylation with the corresponding alkyl halide or dialkyl sul2

2,875,853 fate of a disecondary amine of the following type:

RNH(CHa) 10NHR wherein R is a straight chain higher alkyl group of 10-18 carbon atoms. ,Intermediates used in producing the products of this invention may be prepared readily by any of the conventional methods of organic chemistry for the synthesis of such products. For example, Ν.Ν,Ν',Ν'-tetraalkyldecamethylenediamines, the preferred starting materials, are readily prepared from decamethylene dibromide by reaction with an excess of dimethylamine or diethylamine.

The invention may be more readily understood by a consideration of the following illustrative examples wherein the quantities are stated in parts by weight:

Example 1

Decamethylene -bis - (dimethyldecylammonium bromide')

A mixture of 11.4 parts of Ν,Ν,Ν',Ν’-tetramethyldecamethylenediamine and 22.1 parts of n-decyl bromide in 50 parts of methanol is heated in a closed vessel for 24 hours at 100° C. The reaction mixture is cooled and the methanol is removed by evaporation under reduced pressure. The residue is treated with 500 parts of dry ether and is then allowed to stand several days. The solid is removed by filtration, washed with ether and dried in vacuo over phosphorus pentoxide. A quantitative yield of an exceedingly hygroscopic white crystalline solid is obtained. Analysis calc’d for CnHnNaBra, Br 23.84; found, Br 23.83.

The above compound when tested by the . standard F. D. A. (Food & Drug Administration) method for bactericidal activity at dilutions of 1:100,000 kills Staphylococcus aureus in 5 minutes. When the above test is carried out In the presence of whole blood, the killing dilution is found to be 1:5,000 in 5 minutes. This compound shows high bactericidal activity against other organisms; e. g„ B. coli and B. typhosis are killed at dilutions of 1:200,000 in 5 minutes. The compound shows bacteriostatic activity against Staphylococcus aureus at dilutions of 1:1,000,000 when tested in broth by the well known standard method. When tested for bacteriostatic action in broth containing 10% blood, the compound is active at dilutions of 1:330,000.

The compound when tested against Staphylococcus aureus by the well known agar cup plate method gives the following results:

Zones of growth inhibition in mm. after 2 days incubation at room temperature

<td></td><td> 1-100</td><td> 1-1,000</td><td> 1-5,000</td><td> 1-10,000</td>

<td> In plain agar............</td><td> 5.0</td><td> 2.0</td><td> 1.5</td><td> 1.5</td>

<td> 10% horse serum.........</td><td> 5.0</td><td> 2.0</td><td> 1.0</td><td> 1.0</td>

<td> 50% horse serum.........</td><td> 5.0</td><td> 2.0</td><td> 1.0</td><td> 1.0</td>

<td> 10% human blood........</td><td> 6.0</td><td> 2.0</td><td> 1.5</td><td> 1.0</td>

<td> 50% human blood........</td><td rowspan="2"> 5.0</td><td rowspan="2"> 2.0</td><td> 1.0</td><td> 0.5</td>

<td></td><td></td><td></td>

co

Fungicidal tests carried out by the agar cup plate method using Trichophyton as the test organism yielded the following results:

<td rowspan="2"></td><td colspan="3"> Zones of growth inhibition in mm. after 1 week incubation at room temperature</td>

<td> 1-100</td><td> 1-1,000</td><td> 1-5,000</td>

<td> Tn plain agar_______________________</td><td> 11.0</td><td> 7.0</td><td> 6.0</td>

<td> ' +10% horse serum..............</td><td> 8.0</td><td> 4.0</td><td> 2.5</td>

After two weeks’ incubation at room temperature

<td> In plain agar.......................</td><td> 10.0</td><td> 4.6</td><td> 3.5</td>

<td> +10% horse sorum..............</td><td> 7.0</td><td> 3.0</td><td> 1.0</td>

The compound shows some protective action for mice against Pneumococcus Type I. Seven mice were given 0.1 cc. of a 1:200 solution of decamethylene - bis - (dimethyldecylammonium bromide), by subcutaneous injection following an intraperitoneal injection of Type I Pneumococcus. Of this group, three mice were dead in 24 hours, two died in 30 hours, one died in 48 hours, and one died after 14 days. Control mice given similar injections of Pneumococcus all died within 24 hours.

Decamethylene-bis - (dimethyldecylammonium bromide) is active in the presence of saliva, as indicated by the abilty of the compound to kill Staphylococcus aureus at a dilution of 1:1,000 in the presence of saliva in one-half minute.

The compound was found to have a minimum lethal dose (the dose which kills one half of the animals) of 275 mg./kg. when administered subcutaneously to mice. By intraperitoneal injection, the minimum lethal dose was found to be 150 mg./kg.

Example II

Decamethylene-bis-(dimethyldecylammonium chloride)

A mixture consisting of 35.3 parts of decyl chloride, 22.8 parts of N,N,Ν',N' -tetramethyldecamethylenediamine and 75 parts of methanol is placed in a closed vessel and heated at 100° C. for 64 hours. The mixture is cooled and the methanol is removed by evaporation. The crystalline residue which remains is suspended in dry ether and filtered. The product is dried in vacuo, yielding 40 parts of a white hygroscopic crystalline solid.

The above compound was tested for bactericidal activity by the standard F. D. A. (Food &amp; Drug Administration Method) against Staphylococcus aureus at 37° C. in the presence of 10% horse serum. The results are given in the following table:

<td rowspan="2"></td><td colspan="3"> Dilution</td><td colspan="2"> Phenol control</td>

<td> 1-50,000</td><td> 1-75,000</td><td> 1-1,000,000</td><td> 1-80</td><td> 1-90</td>

<td> Cultures: 5 min...........</td><td></td><td> +</td><td> +</td><td rowspan="2"> +</td><td> +</td>

<td> 10 mln..........</td><td> —</td><td></td><td> +</td><td> +</td>

<td> 15 min..........</td><td></td><td></td><td> +</td><td></td><td> +</td>

+ indicates growth.

When tested against Staphylococcus aureus at 37° C. by the standard F. D. A. method without serum present, the results In the following table were obtained:

<td rowspan="2"></td><td colspan="5"> Dilution</td>

<td> 1-50,000</td><td> 1-75,000</td><td> 1-100,000</td><td> 1-150,000</td><td> 1-300,000</td>

<td> Cultures: 6 min.....</td><td></td><td></td><td></td><td></td><td> +</td>

<td> 10 min....</td><td></td><td> —</td><td> —</td><td> —</td><td></td>

<td> 15 min____</td><td> ~~</td><td></td><td></td><td> —</td><td></td>

+ indicates growth.

2,375,863

Bactericidal titers for this compound against other organisms are given in the following table:

Organism

E.coli............................

B. typhosus.......................

Staphylococcus albus...............

Proteus morganii..................

H. catarrhahs.....................

Pneumococcus Type I............

Hemolytic streptococcus..........

Viridans streptococcus............

Bovine streptococcus.............

Bovine hemolytic streptococcus.. Paradysentery....................

Dysentery........................

ΛΓ. albacans.......................

Trichophyton rosaceum............

Weakest dilution lethal in water

<td></td><td colspan="2"> solution</td><td> 5</td>

<td> 5 min.</td><td> 10 min.</td><td> IS min.</td><td></td>

<td> 1-100,000</td><td> 1-100,000</td><td> 1-100,000'</td><td></td>

<td> 1-100,000</td><td> 1-100,000</td><td> 1-100,000</td><td> Ί0</td>

<td> 1-50,000</td><td> 1-100,000</td><td> 1-100,000</td><td></td>

<td> 1-lOOiOOO</td><td> 1-100,000</td><td> 1-100,000</td><td></td>

<td> 1-200,000</td><td> 1-300,000</td><td> 1-300,000</td><td></td>

<td> 1-100,000</td><td> 1-100,000</td><td> 1-100,000</td><td></td>

<td> 1-200,000</td><td> 1-200,000</td><td> 1-200,000</td><td></td>

<td> ι-ιοάοοο</td><td> 1-100,000</td><td> 1-200,000</td><td></td>

<td> 1-100,000</td><td> 1-200,000</td><td> 1-200,000</td><td></td>

<td> 1-30,000</td><td> 1-50,000</td><td> 1-50,000</td><td> 15</td>

<td> 1-50,000</td><td> 1-50,000</td><td> 1-50,000</td><td></td>

<td> 1-100,000</td><td> 1-100,000</td><td> 1-100,000</td><td></td>

<td> 1-100,000</td><td> 1-100.000</td><td> 1-300,000</td><td></td>

<td> 1-30,000</td><td> 1-30,000</td><td> ι-δάοοο</td><td></td>

Bacteriostatic titers for this compound were determined for other organisms in broth. This test consists in adding to broth a given amount of the test compound followed by inoculation of the broth with the organism. The growth of the bacteria i‘s then observed for a period of 5 days at 37° C. The highest dilution at which no growth takes place is considered the maximum effective bacteriostatic dilution. The results obtained are included in the following table:

Organism

Weakest dilution bacteriostatic

Staphylococcus aureus...............................

Staphylococcus albus................................

B. typhosus........................................

E. ewi..............................................

Pneumococcus Type I.............................

Hemolytic streptococcus.. -.......................

Viridans streptococcus............................

Bovine streptococcus................................

Bovine hemolytic streptococcus....................

N. catarrhalis.......................................

Proteus morganii...................................

Paradysentery.....................................

Dysentery.........................................

Λ1. albacans........................................

1-500,000 M-t

1-500,000 ’ '

1-367,000 • 1-367,000

1-667,000 1-5,000,000 1-1,330,000 1-1,330,000 1-1,000,000 40 1-5,000,000

1-250,000 1-2,500,000 1-1,330,000 1-1,330,000

This compound was tested for fungistatic properties by the agar plate cup method against Trichophyton rosaceum. In this method which indicates the penetrating power of the antiseptic agent, the chemical as a dilute water solution is ₅₍₎placed in a small depression in agar containing the organism. The diameter of the area of growth inhibition is then measured in millimeters. The results of these tests are given in the following table. 55

<td rowspan="2"> Medium</td><td colspan="2"> Zone of growth inhibition in mm. after 14 days incubation at room temperature, dilution</td>

<td> 1-100</td><td> 1-1,000</td>

<td> Plflin agar .___--..___...........___..</td><td> 6.0</td><td> 3.0</td>

<td> +10¾ horse gemm........ ...._____</td><td> 6.0</td><td> 2.0</td>

<td> +50% horse serum..... ...^</td><td> 5.0</td><td> 3.0</td>

Example ΠΙ

Decamethylene-bis - (dimethyldodecylammonium chloride)

A mixture consisting of 40.8 parts of dodecyl chloride, 22.8 parts of Ν,Ν,Ν· ,N'-tetramethyldecamethylenediamine and 100, parts of methanol is heated in a closed vessel at 100° for 64 hours. The 75 mixture is cooled and the methanol removed by evaporation. The crystalline residue is suspended in dry ether and Altered. The product is dried in vacuo, yielding 43 parts of a white hygroscopic crystalline solid. It has excellent disinfectant properties. Analysis calc’d for CseHeaNaCb; Cl 11.14; found: Cl 11.00.

This compound was tested for bactericidal activity by the standard F. D. A. method against Staphylococcus aureus at 37° C. The results are given in the following table;

<td rowspan="2"></td><td colspan="3"> Dilution</td><td colspan="2"> Phenol control</td>

<td> 1-20,000</td><td> 1-30,000</td><td> 1-50,000</td><td> 1-80</td><td> 1-90</td>

<td> Cultures: 5 min.............</td><td></td><td> +-</td><td> +-</td><td> +</td><td> +</td>

<td> 10 min...........</td><td> —</td><td> —.</td><td> +-</td><td></td><td> +</td>

<td> 15 min............</td><td> — —</td><td></td><td> -i—</td><td></td><td> +</td>

When this compound was tested for bacteriostatic action against Staphylococcus aureus by the agar cup plate method, the following results were obtained as shown in the table below:

<td rowspan="2"> Medium</td><td colspan="3"> Zone of growth inhibition in mm. after 14 days incubation at room temperature, dilution</td>

<td> 1-100</td><td> 1-1,000</td><td> 1-5,000</td>

<td> Plain agar.......................</td><td> 6.0</td><td> 4.0</td><td> 1.0</td>

<td> +10% horse serum . ..........</td><td> 5.0</td><td> 4.0</td><td> 1.5</td>

<td> +10% human blood.............</td><td> 4.0</td><td> 2.5</td><td> 0.5</td>

<td> +50% human blood.............</td><td> 2.0</td><td> 1.0</td><td> Trace</td>

When this compound was tested for bacteriostatic action against Staphylococcus aureus in broth the highest dilution in which no growth took place was 1-260,000.

Example IV

Decamethylene-bis-(dimethyl “Lorol” ammonium chloride)

A mixture consisting of 6.8 parts of Ν,Ν,Ν',Ν'tetramethyldecamethylenediamine, 13.0 parts of “Lorol” chloride (the term “Lorol” refers to the alkyl radicals derived from the fatty acids of coconut oil, containing from 8 to 18 carbon atoms) and 25 parts of methanol is heated in a closed vessel at 100° C. for 64 hours. The mixture is then cooled and the methanol removed by evaporation. The residue is suspended in dry ether and filtered. The product is dried in vacuo, yielding 5.1 parts of a white, hygroscopic crystalline solid. It, likewise, has excellent disinfectant properties. Analysis found: Cl 11.43.

This compound was tested for bactericidal, activity by the standard F. D. A. method against Staphylococcus aureus at 37° C. The results are given in the following table:

<td rowspan="2"></td><td colspan="3"> Dilution</td><td colspan="2"> Phenol control</td>

<td> 1-20,000</td><td> 1-30,000</td><td> 1-50,000</td><td> 1-80.</td><td> 1-90</td>

<td> Cultures: 5 min........ ... .</td><td></td><td>^! + -·'</td><td>^!+-</td><td> +</td><td> +</td>

<td> 10 min.-----------</td><td> —</td><td> — — ·</td><td> +-</td><td> — </td><td> +</td>

<td> 15 min.............</td><td></td><td></td><td></td><td></td><td> +</td>

When this compound was tested for bacteriostatic action against Staphylococcus aureus by

2,376,863 the agar cup plate method the results in the following table were obtained:

Medium

Zones of growth Inhibition in mm. after days incubation at room tempera- J ture, dilution

<td></td><td> 1-100</td><td> 1-1,000</td><td> 1-5,000</td><td> 1-10,000</td>

<td> Plain acar...............</td><td> 6.0</td><td> 5.0</td><td> 2.0</td><td> 1.0</td>

<td rowspan="2"> +10% horse serum.-. +10% human serum.</td><td> 4.5</td><td> 4.0</td><td> 2.0</td><td> 1.0</td>

<td> 5.0</td><td> 3.0</td><td> Trace</td><td> Trace</td>

<td> +50% blood serum...</td><td> 3.0</td><td> 1.5</td><td> Trace</td><td> Trace</td>

When tested for bacteriostatic action the highest dilution in which no growth was obtained ₁₈was 1-260,000.

It is to be understood that the foregoing examples are illustrative merely of a few of the many modifications to which the present invention is susceptible. They may be varied widely ₂₀with respect to the individual reactants, the amounts thereof and the conditions of reaction without departing from the scope hereof.

As previously mentioned, compounds coming within the scope of this invention may be repre- ₂₅sen ted by the following general formula:

R' R' R' R' R—N—(CHiiuX-R x i .

wherein R is a monovalent straight chain alkyl group containing at least ten carbon atoms; R' is a lower molecular weight alkyl group; and X is an anion.

In the above formula R is preferably a higher 35 straight chain alkyl group of 10-18 carbon atoms; R' is a methyl or ethyl group; and X is an anion of an acid having a dissociation constant greater thanlX10-H.

For optimum results over a wide range of con- 40 ditions the monovalent straight chain alkyl group (R) attached to each nitrogen atom in these compounds contains from 10-18 carbon atoms. Radicals conforming to this requirement are decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 46 hexadecyl, heptadecyl or octadecyl groups. Of these groups, decyl and dodecyl represent the preferred types. The mixture obtained when R represents the alkyl groups of “Lorol” is also a preferred type. “Lorol” Is the mixture of long chain go alcohols formed by the carboxylic reduction of coconut oil fatty acids.

The group previously represented by R' is advisably methyl or ethyl, but is preferably the former. 55

The anion previously represented by X may be the anion of any acid of dissociation constant greater than lx IO^-11, such as carbonic, acetic, citric, tartaric, lactic, boric or propionic acid. However, the preferred anions are those of the co strong mineral acids, having a dissociation constant greater than lx 10~⁴. such as sulfuric, phosphoric, hydrochloric, hydriodic or hydrobromic. Of this group of strong acids, hydrochloric and hydrobromic represent the preferred members. _β5

As stated previously, these products may be prepared by any of several methods. For example, a decamethylene dihallde such as decamethylene dichloride or decamethylene dibromide may be reacted with a tertiary amine of the fol- 70 lowing general formula:

where R and R' have the same significance as R and R' in the preceding general formula.

The reaction may be formulated as follows:

R' R' R' R' R'

Cl (CHi) i.Cl+2i-R=R-N-(C Hi) ir^N-R k’ ii ii

The preferred method of preparation Involves the reaction of an alkyl halide such as, for example, decyl chloride decyl bromide, dodecyl chloride or dodecyl bromide with an Ν,Ν,Ν'Ν'-tetramethyl- or an Ν,Ν,Ν',Ν'-tetraethyldecamethylene diamine. This reaction proceeds as follows:

R' R' R' R' R' R' ^ΝίΟΗιΙ,οΖ +2RC1=R-N—(CH,)i^N- R

A third method of preparation involves the methylation or ethylation of a disecondary amine of the following type:

RNH(CHa) 10NHR where R is a straight chain higher alkyl group of 10-18 carbon atoms. Dialkyl sulfates (dimethyl sulfate or diethyl sulfate) or alkyl halides (methyl chloride) are employed as the alkylating agent. The reaction may be formulated as follows:

R' R' R' R' R—-NH- (CHi)ie—NH-R+4R'X=R-Yt-(CH,)ZN-R

The reactions involved in these methods of preparation are very similar in that they are all reactions of a hydrocarbon halide with an amine. They may be carried out either in the presence or in the absence of a solvent at temperatures between 75’ and 150’ C. The reaction may take place at atmospheric, superatmospheric or subatmospheric pressure. The preferred conditions for carrying out the reaction are those using methanol as a solvent at a temperature of 100-120° C. and sufficient pressure above atmospheric to prevent the loss of methanol by evaporation

The products of this Invention may be employed as bactericides or fungicides or as bacteriostatic agents. They are most advantageously used in solution in water or in alcohol. The compounds may be mixed with other bactericidally active ingredients such as phenolic bactericides of the type of phenol, cresol and hexylresorcinol, or with mercurial bactericides such as Metaphen. The bis-quatemary compounds may also be diluted with inert solid ingredients such as talc. The products are useful in the control of harmful bacteria such as Staphylococcus, Pneumococcus, Streptococcus, Bacillus typhosis, and the like. The compounds are also useful as agents for the control of other harmful single celled organisms such as amoeba. Fungi and molds such as the various lumber molds are likewise controlled by these products.

In addition to the foregoing uses these products are also capable of use as surface-active agents either alone, in admixture with one another and/or in admixture with the numerous prior art agents which possess surface activity. Likewise, they may be employed as intermediates in the synthesis of many other organic chemical compounds.

As many widely different embodiment of this invention may be made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited to the

2,3' specific embodiments thereof except as defined in the appended claims.