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Publication numberUS3369046 A
Publication typeGrant
Publication dateFeb 13, 1968
Filing dateDec 2, 1965
Priority dateDec 2, 1965
Also published asDE1274281B
Publication numberUS 3369046 A, US 3369046A, US-A-3369046, US3369046 A, US3369046A
InventorsArno Cahn, John Kaniecki Thaddeus
Original AssigneeLever Brothers Ltd
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
2-hydroxy-alkyl-benzyl quaternary ammonium compounds
US 3369046 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent 3,369,046 Z-HYDROXY-ALKYL-BENZYL QUATERNARY AMMONIUM COMPOUNDS Thaddeus John Kaniecki, Brooklyn, and Arno Calm, Pearl River, N.Y., assignors to Lever Brothers Company, New

York, N.Y., a corporation of Maine No Drawing. Filed Dec. 2, 1965, Ser. No. 511,247 Claims. (Cl. 260-567.6)

This invention relates to quaternary ammonium compounds and, more particularly, to 2-hydroxyalkyl quaternary ammonium compounds having a pronounced antiseptic character. The term antiseptic is used in its broad sense and is intended to include all bacteriological activity, including bacteriostatic and bactericidal activity.

Quaternary ammonium compounds are Widely employed as germicidal agents due to their recognized microbial activity. They have been found to exhibit both bacteriostatic and bactericidal properties, as well as significant surface active properties. In view of these characteristics quaternary ammonium compounds have gained wide acceptance as effective agents for the sterilization of surgical and dental instruments, eating utensils, and food processing machinery and equipment.

In addition to the foregoing, the-compatibility of quaternary ammonium compounds with water, alcohol and other polar solvents, their freedom from disagreeable odors and their non-irritating character have made these compounds very desirable for use as antiseptics in the treatment of minor wounds, post-operative sterilization of human tissue, and for use as an antiseptic ingredient in mouthwashes, and other products contributing to personal hygiene. Quaternary ammonium compounds have been found to be particularly suited for such personal use in that they are eifective when used in solutions of moderate strength and also exhibit a prolonged bacteriostatic activity.

It is an object of this invention to provide novel quaternary ammonium compounds as hereinafter described.

It is a further object of the invention to provide quaternary ammonium compounds which are bacteriostatic, substantive, and bactericidal.

It is a still further object to provide quaternary ammonium compounds which are suitable for incorporation in various antiseptic preparations.

Quaternary ammonium compounds may be characterized as nitrogen compounds in which four carbon atoms are directly linked to the nitrogen atom through covalent bonds and in which an anion is linked to the nitrogen atom through an electrovalent bond. Compounds which are illustrative of the general class of quaternary ammonium compounds include the alkenyldimethylethylammonium halides, alkenyltrimethylammonium halides, alkyldimethylbenzylamrnonium halides, alkyltrimethylammonium halides, dialkyldimethylammonium halides, and the like.

The particular group of quaternary ammonium compounds contemplated by this invention are characterized by the general formula:

wherein R and R are the same or different groups such 3,369,046 Patented Feb. 13, 1968 ice as C to C alkyl groups, for example, methyl, ethyl, npropyl, isopropyl and the like, or a C to C alkanol group, such as ethanol, n-propanol, isopropanol and the like; R is an alkyl radical having from 6 to 18 carbon atoms, preferably from 6 to 16 carbon atoms, e.g., hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl, heptadecyl, and nonadecyl; X is hydrogen or a halogen, such as chlorine, iodine or bromine; and Y is a halogen, such as chlorine, iodine or bromine. These compounds are distinguishable from the previously known quaternary ammonium compounds by the presence of a Z-hydroxy substituent in the longest alkyl chain present on the nitrogen atom.

Illustrative quaternary ammonium compounds include N-propyl-N- Z-hydroxyethyl) -N- (2hydroxyoctyl -N- benzyl ammonium chloride,

N-methyl-N- (2-hydroxyethyl -N- (Z-hydroxyundecyl) N-benzyl ammonium chloride,

N-ethyl-N- Z-hydroxyethyl) -N- (Z-hydroxydecyl) -N- (p-bromobenzyl) ammonium bromide,

N,N-bis 2-hydroxyethyl -N- (Z-hydroxydodecyl) -N- benzyl ammonium chloride,

N-methyl-N- (Z-hydroxyethyl) -N- (Z-hydroxydodecyl) N-benzyl ammonium chloride,

N-methyl-N- (2-hydroxyethyl -N- (Z-hydroxytridecyl) 'N-benzyl ammonium chloride,

N-methyl-N- Z-hydroxyethyl -N- (Z-hydroxytetradecyl N-benzyl ammonium chloride,

N,N-dimethyl-N- 2-hydroxytetradecyl -N-benzyl .ammonium chloride,

N,N-dimethyl-N- Z-hydroxytetradecyl -N-benzyl ammonium chloride,

N,N-bis (Z-hydroxyethyl) -N- (2-hydroxytetradecyl) -N- benzyl ammonium chloride,

N-methyl-N- (Z-hydroxyethyl) -N- (2-hy droxydodecyl) N-(p-bromobenzyl) ammonium chloride,

=N-methyl-N- (2hydroxyethyl) -N- (2-hydroxydecyl) -N- benzyl ammonium chloride,

N-rnethyl-N- (Z-hydroxyethyl) -N- (Z-hydroxyhexadecyl) N-benzyl ammonium chloride,

N-methyl-N-(Z-hydroxyethyl)-N-(2-hydroxydodecyl) N-(p-bromobenzyl) ammonium bromide, and the like.

The preferred quaternary ammonium compounds are N-rnethyl-N- Z-hydroxyethyl) -N- 2-hydroxydodecyl) N-benzyl ammonium chloride and N-methyl-N- Z-hydroxyethyl) -N- 2-hydroxydodecyl) N-(p-bromobenzyl) ammonium bromide.

The novel 2-hydroxyalkyl quaternary ammonium compounds are prepared by condensing an appropriate 1,2- epoxyalkane with an equimolar amount of a suitable secondary amine to provide a tertiary amine characterized by the presence of a 2-hydroxy group on the longest alkyl radical attached to the nitrogen atom. The corre sponding quaternary ammonium compound is then prepared by condensing the thus prepared tertiary amine with an equimolar amount of a suitable arylalkyl halide compound, such as a benzyl halide or a p-halobenzyl halide.

Illustrative 1,2-epoxyalkanes which can be used for the preparation of tertiary amines suitable for use in preparing the novel Z-hydroxyalkyl quaternary ammonium compounds include 1,2-epoxyoctane, l,2-epoxynonane, 1,2-epoxydecane, 1,2-epoxyundecane, 1,2-epoxydodecane, 1,2epoxytridecane, 1,2-epoxytetradecane, 1,2- epoxypentadecane, 1,2-epoxyhexadecane, and the like as well as mixtures of these compounds, e.g., mixture of epoxyalkanes containing both even and odd numbers of carbon atoms in the alkyl chain.

Illustrative secondary amine reactants include dimethylamine, diethylamine, methylethylamine, diethanolamine, dipropanolamine, methylmonoethanolamine and the like.

assume Organic halides suitable for condensation with the tertiary amines referred to above include arylalkyl halides, such as benzyl chloride, benzyl bromide, benzyl iodide; halobenzyl halides, such as p-bromobenzyl bromide, pchlorobenzyl chloride and the like.

The herein described compounds which may be conveniently referred to as antiseptic agents may be advantageously employed in bacteriologically active amounts in a wide variety of hygienic compositions such as mouthwashes and cleaning solutions for use in sterilization of surgical and dental instruments, food processing equipment and containers. The term bacteriologically active amounts represents that amount of the particular compound which will kill or inhibit the growth of microorganisms. Various factors such as possible contact time, the nature of the micro-organisms and the conditions under which the antiseptic composition is to be used determine what constitutes a bacteriologically active amount.

The following examples illustrate the principles and practice of the invention.

Example 1.Cndensati0n of LZ-epcrxyalkanes with merhyl-monoethanolamine N methyl N (2 hydroxyethyl) 2 hydroxyalkylamines were produced by heating a reaction mixture comprising 0.5 mole of a 1,2-epoxyalkane and 0.5 mole of methyl-monoethanolamine dissolved in about 75 milliliters of ethyl alcohol on a steam bath until a homogeneous solution was obtained. The temperature was then increased and the ethyl alcohol distilled oh; the final traces of ethyl alcohol were removed at reduced pressure.

Table I presents data on a series of N-methyl-N-(2- hydroxyethyl)-2-hydroxyalkylamines prepared as described above. The alkyl groups shown in the first column of Table I represent R of Formula 1, above.

TABLE I Alkyl group (R Percent yield .10 C H 98.8 C H 95.8 C H 99 Example 2.-C0ndensati0n 0f 1,2-epoxyalkanes with Diethanolamine Table 11 below presents data on a series of N,N-(di- Z-hydroxyethyl)-2-hydroxyalkylamines prepared by condensing 1,2-epoxyalkanes, containing 12 to 18 carbon atoms with diethanolamine. In each instance 0.3 mole of diethanolamine and 0.3 mole of a 1,2-epoxyalkane were dissolved in to 100 milliliters of ethyl alcohol and the resulting admixture was heated on a steam bath with occasional stirring until a homogeneous solution was obtained. Heating was then continued until the ethyl alcohol was distilled off, the last traces being removed at 70 C. and a pressure of 30 millimeters of mercury. In each instance the product was cooled to room temperature and the melting point determined on a sample recrystallized from ethyl acetate. The alkyl groups shown in column 1 of Table II represent R of Formula 1, above.

TABLE II Alkyl Group (R Percent Yield Melting Point C.)

1 Deter-mined on recrystallized material.

Example 3 N methyl N (2 hydroxyethyl) (2-hydroxyalkyl)- N-benzyl ammonium chlorides were prepared by refluxing equimolar quantities (0.05 mole) of a tertiary amine prepared as described in Example 1, with benzyl chloride in 30 grams of ethanol. The reaction mixture was refluxed at 50 C. for 24 hours, after which it was cooled to room temperature and stored at room temperature for 10 days. At the end of this period, the ethanol was removed and the reaction product was stored over concentrated sulfuric acid at a pressure of 200 millimeters of mercury until the product crystallized.

Table III below presents data on the materials thus prepared. The alkyl groups shown in column 1 correspond to R of Formula I, above.

TABLE III Alkyl Group (R Percent Yield Percent Cationic Example 4 In the preparation of N-methyl-N-(2-hydroxyethyl)- N- (p-bromobenzyD-N (2 hydroxydodecyl) ammonium bromide, N (2 hydroxydodecyl) N methylethanolamine (0.05 mole) and p-bromobenzyl bromide (0.05 mole) dissolved in 30 grams of ethanol were refluxed together at 50 C. for a period of 24 hours. The resulting reaction product mixture was cooled and stored at room temperature for a period of 10 days after which the ethanol was removed and the product crystallized over concentrated sulfuric acid at a pressure of 200 millimeters of mercury.

Example 5 N,N-bis(2-hydroxyethyl) N (2 hydroxyalkyl) N- benzyl ammonium chlorides were prepared by refluxing together equimolar amounts (0.1 mole) of an N-(Z-hydroxyalkyl) diethanolamine prepared as described in Example 2 and benzyl chloride in 75 milliliters of npropyl alcohol for a period of 6 hours. The n-propyl alcohol was then removed by evaporation. The last traces of n-propyl alcohol were removed by heating the reaction product to 54 C. at a pressure of 30 millimeters of mercury. The resulting product was then dried over concentrated sulfuric acid at a pressure of 0.5 millimeters of mercury.

Table IV below presents data on the materials thus produced.

Quaternary ammonium compounds of the type described herein have been tested for germicidal activity and have been found to possess a significant degree of such activity.

The minimum effective concentration for representative quaternary ammonium compounds, shown in Table V below, was determined by means of a gradient plate tech nique in which agar plates having a gradual proportional increase in the concentration of antiseptic compound along the gradient axis were employed. Such plates are poured with two layers of nutrient, the bottom layer consisting of plain nutrient which is allowed to harden while the plate is slanted so that a wedge-shaped layer is formed. A second nutrient layer containing the antiseptic material is then poured while the plate is fiat. Downward diffusion of the antiseptic establishes a uniform linear concentration gradient during incubation. The plates are inoculated by streaking a bacterial culture suspension across the surface of the nutrient. The plates are incubated at 37 C. overnight and the extent of bacterial growth is measured.

TABLE V vial at room temperature. Aliquots (0.001 ml.) of the resulting mixture are taken at specific time intervals and mixed with milliliters of sterile liquid microinoculum agar at 45 C. After hardening, the resulting admixture is Minimum Emotive 5 incubated at 37 C. for colony development. Counts are Concentrat on in made in the same manner as standard plate counts. The Compound agamstinitial inoculum density is calculated from quadruplicate auteur wli loop samples taken from a control tube incubated as above which is prepared by admixing 1 milliliter of 0.1 percent gy i-( r y hy i; -lay y- 44 84 peptone water and 1 milliliter of a 10* dilution of the iii g i ffii gi gfigt itfihfiigagg r--- pooled saliva. The average colony count in the control ggg gzg g- -tr y ammonium 1 66 multiplied by the dilution factor represents the initial fi idl(ifini-bfiifig iji i liififi dgi inoculum density of the test mixture. Since the test mixdodecyll-N'bemyl ammonium chloride tures containing mouthwash employ undiluted saliva, any 15 count showing the same number of colonies as the con- A group of quaternary ammonium compounds containtrol represents 99.9% kill of the initial inoculum. The ing a 2-hydroxy substituent in the longest alkyl chain was time required to effect a 99.9% kill is recorded. tested for germicidal activity in a simulated mouthwash composition consisting of a 23% alcohol-in-water solu- TABLE VI tion by the following tests, the results of which are set ADC sDs BCT forthnn Table VI below. P arallel runs on a known an Compound Percent mm mm. mm tiseptic were made as a basis of comparison. S. aureus S. aureus Saliva Bacteriostatic activity was determined by an Agar Dilution Cup test (ADC) in which a standard Petri Dish NirInEethyl-N-(2-hylroxgeglyb- Z-hydroxydo ecy was filled w1th 40 milliliters of thioglycollate agar seeded 25 bemyl ammonium chloride M2 1p 4 3 at 1 percent with a culture of S. aureus. After hardening, 0. 05 3.5 2.7 M a cylnidrical plug is cut from the agar forming a cup into which is pipetted a 10 percent agar dilution of mouthbenzyl ammonium chloride. 0.01 4 1 2 wash containing the quaternary compound being eval- N methy1 N (2 hydroxyethyl) M uated, thus replacing the removed plug with an agar- N-(2 hydl'OXylTexadecyn N- mouthwash mixture. After the agar-mouthwash mixture benzylammmlum chlonde" 1 2 C 5 has hardened, the plate is incubated at 37 C. overnight. Cetylpyridinium chloride and 0. 05 1 o 3 Zones of inhibition which develop during incubation are 0'02 1 5 3 3 measured and recorded after subtractlng the dlameter of the plug- P reDresents partial inhibition of "seed with no clear zone of in- The substantlvity of these selected compounds in a P t 1 t b th th d. f mouthwash solution was determined by a Skin Disc Subifgf S Comp 6 e 1 1 1 men 6 W no Zone 0 stantivity test (SDS) in which a 10 milliliter seed layer of S. aureus is poured on a base of 40 milliliters of sterile N-methyl-N-(Z-hydroxyethyl)-N-(2 hydroxydodecyl)- thioglycollate agar in a Petri dish. Calf skin discs are then N-benzyl ammonium chloride in a mouthwash formulahydrated in distilled water, agitated in themouthwash sotion was compared to commercially available quaternary lution and thoroughly rinsed in water for 15 minutes. ammonium compounds at various concentration levels by Excess water is removed from the disc which is then the testing procedures described above. The results, placed on the surface of the prepared seed agar plate. tabulated in Table VII below, show that at all concentra- The plates are then incubated overnight at a temperature tion levels the 2-hydroxy-containing compound (comof 37 C. Inhibition zones which develop during incubapound 5) shows larger zones of growth inhibition than the tion are measured and recorded after subtracting the diother compounds tested. In addition, at the 0.04 percent ameter of the disc. If no inhibition Zones are evident, the level compound 5 shows superior activity in that a subdiscs are removed and inhibition in the contact area is stantially shorter period of time is required to achieve a rated. 99.9 percent kill of the saliva bacteria.

TABLE VII ADC Zone BC'I 90.9% Size (mm.) Kill (min.) Active Ingredients Percent S. aureus Sir. Saliva faecalis Control (no quaternary compound) 0 0 30 Cetyl pyridiuium ch ride 0. 02 4. 2 3 2 0.03 3.9 3.2 5 0.04 4.7 3.4 V2 0. 02 3.3 1.9 2 0.03 3.9 2.6 0.04 3.8 2 pg 0.02 5.9 4.3 3 3 0.03 5.6 4 54 do 0.04 6.2 4.7 Alkyldimethyl naphthyl methyl ammonium chloride 1 0. 02 6.1 3 l 4 do. 0.03 7.7 3.1 }4 do. 0.04 7.6 3.4 4 N-methyl-N-(2-hydroxyethyD-N-(2-hydroxydodecyD-N-benzyl ammonium chloride 0. 02 11. 8 4 1 5 {undo .03 14.3 5 34 5seconds.

Bactericidal activity was determined by a Bactericidal Contact Time test (BCT) in which whole saliva from a group of donors is pooled and then 1 milliliter of pooled It will be understood by those skilled in the art that the embodiments described above are merely exemplary and that they are susceptible of modification without desaliva is mixed with 1 milliliter of mouthwash in a glass parting from the spirit and scope of the invention. Ac-

7 cordingly, all such variations and modifications are deemed included within the scope of the appended claims.

What is claimed is: 1. A quaternary ammonium halide having at least one 2-hydroxyalkyl substituent characterized by the formula wherein R and R are selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms and hydroxyalkyl groups having from 2 to 3 carbon atoms; R; is an alkyl radical having from 6 to 18 carbon atoms; X is selected from the group consisting of hydrogen and halogen; and Y is a halogen.

Z. The quaternary ammonium compound of claim 1 wherein R is methyl, R is Z-hydroxyethyl, R is decyl, X is hydrogen and Y is chloride.

3. The quaternary ammonium compound of claim 1 wherein R is methyl, R is 2-hydroxyethyl, R is decyl, X is bromide and Y is chloride.

4. The quaternary ammonium compound of claim 1 8 wherein R is methyl, R is Z-hydroxyethyl, R is octyl, X is hydrogen and Y is chloride.

5. The quaternary ammonium compound of claim 1 wherein R is methyl, R is Z-hydroxyethyl, R is dodecyl, X is hydrogen and Y is chloride.

6. The quaternary ammonium compound of claim 1 wherein R is methyl, R is 2-hydroxyethyl, R is tetradecyl, X is hydrogen and Y is chloride.

7. The quaternary ammonium compound of claim 1 wherein R and R are Z-hydroxyethyl, R is decyl, X is hydrogen and Y is chloride.

8. The quaternary ammonium compound of claim 1 wherein R and R are Z-hydroxyethyl, R is dodecyl, X is hydrogen and Y is chloride.

9. The quaternary ammonium compound of claim 1 wherein R is methyl, R is Z-hydroxyethyl, R is decyl, X is bromide and Y is bromide.

It). The quaternary ammonium compound of claim 1 wherein R is methyl, R is 2-hydroxyethyl, R is nonyl, X is hydrogen and Y is chloride.

References Cited UNITED STATES PATENTS 2,759,975 8/1956 Chiddix et al 260567.6

CHARLES B, PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2759975 *May 28, 1952Aug 21, 1956Gen Aniline & Film CorpMixed alkyl-benzyl-alkylol quaternary ammonium salts
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3928618 *Mar 21, 1974Dec 23, 1975Colgate Palmolive CoOral compositions
US3956479 *Apr 16, 1971May 11, 1976Colgate-Palmolive CompanyPharmaceutical composition containing novel quaternary ammonium compounds
US4042368 *Jun 27, 1975Aug 16, 1977Epic Chemical Inc.Additive for quaternary amine bactericides and algicides, compositions containing same and method of manufacture
US4820507 *Mar 2, 1987Apr 11, 1989Henkel Kommanditgesellschaft Auf AktienOral and dental hygiene preparations
US20050034651 *Aug 25, 2004Feb 17, 2005Ada Technologies, Inc.Apparatus and method for removing mercury and mercuric compounds from dental effluents
U.S. Classification564/285, 424/54, 549/512
International ClassificationA61Q11/00, A61K8/30, A61K8/41
Cooperative ClassificationA61K8/416, A61Q11/00
European ClassificationA61Q11/00, A61K8/41L