US3270023A - Quaternary ammonium salts of indole derived acids - Google Patents

Description

United States Patent 3,270,023 QUATERNARY AMMONIUM SALTS 0F INDOLE DERIVED ACIDS Edward Griflin Shay, Belle Mead, N.J., and Reginald L.

Wakeman, Philadelphia, Pa., assignors to Millmaster Onyx Corporation, New York, N.Y., a corporation of New York No Drawing. Filed Aug. 12, 1965, Ser. No. 479,274

18 Claims. (Cl. 260-286) This invention has for its object the preparation of relatively water-insoluble, microbiologically active quaternary ammonium compounds obtained by the reaction of water-soluble, bacteriologically active quaternary ammonium compounds with water-soluble salts of aromatic acids derived from indole.

This application is a continuation-in-part of Serial No. 359,500, filed April 13, 1964.

The indole-derived acids which may be used in this invention correspond to the following formula:

in which X may be 0 o 0 I lOH, l( lOH 0r (IJOH (wherein the double bond is linked to a carbon of Y); Y may be or H; and Z may be H, Cl, Br, F, N0 OH or low molecular weight alkyl or aryl. Examples of suitable acids include isatin or isatic acid, isatoic acid, indoxylic acid, 7-chloro isatic acid, -chloro isatoic acid, isatin-3- (pnitrophenyl hydrazine), S-nitro isatic acid, S-nitro isatoic acid and the like.

The compounds of this invention can be prepared by mixing an aqueous solution of a water-soluble salt of the aromatic acid with an aqueous solution of a quaternary ammonium salt having microbiologically active properties. The two solutions are thoroughly mixed and are then allowed to stand until they separate into two distinct layers. The upper layer will normally contain the compound of the present invention. Layer separation is conveniently effected by conducting the reaction in a separatory funnel and drawing oh the desired layer. The product usually contains some water which can be removed by distillation or drying in a vacuum oven. The aqueous product layer can, however, be used in any process where the entrapped water would not be harmful.

Typical examples of the quaternary ammonium compounds which may be used in this invention are the alkyl trimethyl ammonium chlorides, alkyl-benzyl trimethyl ammonium chlorides, alkyl dirnethylbenzyl ammonium chlorides, alkyl dimethyl menaphthyl ammonium chlorides, alkyl dimethyl substituted-benzyl ammonium chlorides in which the benzyl radical is substituted with one or more side chains containing from 1 to 5 carbon atoms such, for example, as methyl, dimethyl, ethyl and the like and in which the carbon atoms may all be in the same or different side chains or in which the benzyl radical bears one, two or more halogen atoms such as chlorine or bromine, alkyl pyridinum chlorides, alkyl isoquinolinium chlorides and bromides, alkyl lower-alkyl pyrrolidinium chlorides, alkyl lower-alkyl morpholinium chlorides in all of which the alkyl group may have from 8 to 22 carbon atoms and the lower alkyl group may have from 1 to 5 carbon atoms and alkyl phenoxy ethoxy ethyl dimethylbenzyl ammonium chloride in which the alkyl radical may be iso-octyl or nonyl and in which the benzyl radical may, if desired, be substituted by a methyl radical. Various other analogs of these quaternaries may also be employed such, for example, as cetyl dimethyl ethyl ammonium bromide or oleyl dimethyl ethyl ammonium bromide.

In general, the quaternary ammonium compounds useful in this invention are the higher alkyl quaternary ammonium hydroxides, halides (chlorides and bromides), sulfates, methosulfates and the like possessing the following formula:

where R is an alkyl or alkaralkyl radical containing from 8 to 22 carbon atoms or an alkyl phenoxy ethoxy ethyl radical in which R is an alkyl radical containing from 8 to 9 carbon atoms and in which the phenyl radical may be substituted by a methyl group; R and R" are methyl or ethyl radicals or members of a heterocyclic ring system such as pyridine, isoquinoline, pyrrolidine and morpholine; R is a methyl radical or a benzyl group or a substituted-benzyl group such, for example, as a monochlorobenzyl radical or a dichlorobenzyl radical or mixture thereof or a methyl benzyl, dimethyl benzyl, ethyl benzyl, diethyl benzyl, isopropyl benzyl, tertiary butyl benzyl, isoamyl benzyl or another benzyl radical containing from 1 to 5 carbon atoms as side chains, either as a single side chain or a multiplicity of side chains including mixtures thereof or a menaphthyl group or hydrogenated menaphthyl group. When R or R" are members of a morpholine or pyrrolidine ring, R' is a methyl, ethyl, propyl or butyl group. When R and R" are members of an unsaturated heterocyclic ring such as pyridine or isoquinoline, R is the same radical as R". X in the above formula corresponds to a halide radical such as chloride, bromide or iodide, or to any other water-soluble anion such as methosulfate.

After thorough mixing in the manner previously described, the organic product layer is separated from the aqueous layer (as with a separatory funnel) since two distinct phases are formed. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or unreacted materials. The solvent, if any, may be evaporated and the product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in which the starting materials are soluble will be satisfactory. Non-aqueous solvents facilitate the separation of by-product inorganic salt and reduce the need for vacuum drying to get an anhydrous product. When a non-aqueous medium is employed, it is usually necessary to add a small amount of water to facilitate ionic reaction.

An alternative method for the preparation of compounds especially applicable to the treatment of fabric, ropes, net, woven and non-woven fabric and reticulated or convoluted materials involves a two-step process. In the first step, the material is passed through a bath containing the anionic moiety. Excess solution is removed by methods well known to those skilled in the art. The treated material is then passed through a second bath wherein the concentration of quaternary ammonium compound is such that the material pickup will result in an equivalent amount of quaternary ammonium compound reacting with the anionic moiety, depositing the product be formulated as water dispersions by dissolving them in a Walter-miscible organic solvent such as acetone or methanol and diluting with water or by dissolving them in emulsifiable oils such as, for example, sulfonated castor oil or pine oil and diluting with water. In preparing aqueous dispersions, emulsifying agents such, for example, as ethylene oxide condensates of alkyl phenols may be used with or without organic solvents.

It is surprising that the compounds of this invention exhibit high microbiological activity despite their relative insolubility in water. Because of their unusual combination of physical and microbiological properties, they can be used to impart laundry-resistant anti-microbial characteristics to textiles. They can also be used as the active agent in anti-mildew finishes for textiles which are resistant to leaching with water.

Although the compounds have low water solubility, they are compatible with various organic solvents, plasticizers and high molecular weight compounds. Consequently, they may be incorporated as anti-microbial agents in synthetic resins and plastics. The compounds are compatible with natural and synthetic rubber latices. Therefore, they may be used to prepare bacteriostatic films and molded objects deposited from such latices.

The compounds can be incorporated into cutting and grinding fluids without precipitation. Also, they blend well with non-ionic and anionic surface-active agents. In such compositions they retain their microbiological activity.

It will be understood that the properties of the products described herein will vary depending upon the nature of the cationic quaternary ammonium compound used in their preparation as well as the anionic compound reacted therewith.

The chemical, physical and biological properties of the products of our invention make them especially appropriate for the following applications when suitably incorporated in active amounts in an appropriate vehicle, binder, medium or substrate:

(1) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails, tenting and other woven and non-woven reticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of microor' ganisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppressant for shoes and other leather products.

(6) Topical antiseptics.

(7) Antidandrutf agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement, brick and other inorganic building materials to retard growth of microorganisms, fungi, mold and algae.

(11) Wool perservative.

( 12) Plant and tree spray to combat fungi.

(13) Antimycotic agents for soap wrappers.

(l4) Self-sanitizing brushes.

(15) Mildewproofing agent in and on plastic and film.

(16) Mildewproofing of cellulosics, cardboard, fibreboard,

paper and cordage.

(17) Contact biostat for application to film, waxes and cloth to preserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where low foaming is desirable.

(19) Paper pulp slime control.

( 20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metal-working compounds.

(25) Additives for soap and for both anionic and nonionic deter-gents in liquid, bar,.powder, bead, solution and other forms to impart bacteriostatic and fungistatic properties thereto.

(26) Ba'cteriostats, fungistats and algistats for the treatment of industrial cooling waters as in cooling towers, air conditioners and humidifiers and for use in secondary oil recovery.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard Tube Dilution Test, the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This test is used to determine the lowest concentration of microibiologically active compounds which will inhibit the growth of the organism in question. For a wide range of applications, the inhibition of growth rather than outright kill is satisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the microbiologically active compound at an appropriate concentration is added to the test tube which is then inoculated with 0.1 cc. of a twenty-four hour old culture of the organism under study. The test tube is then incubated at 37 C. for fortyeight hours and observed for bacterial growth.

The same procedure is followed for fungi. In such tests, however, the tubes are incubated for fourteen days at a temperature suitable for optimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the following examples:

Example I A 10% aqueous solution of the sodium salt of isatin (2,3 indolinedione) was prepared. 222 grams of this solution was charged into a separatory funnel and to it was added 410 grams of a 10% solution of alkyl dimethyl ethyl-benzyl ammonium chloride =(BTC471Onyx Chemical Company, alkyl distribution being 50% C 30% C 17% C 3% C and a little benzene to facilitate phase separation, and the funnel was well shaken. The product layer was separated and dried in a vacuum oven to yield alkyl dimethyl ethyl-benzyl ammonium isatate in 98% of the theoretical yield as a red paste.

Example II Using equimolar quantities of the solution of sodium isatate of Example I and of a solution of alkyl dimethyl benzyl ammonium chloride (BTC824-Onyx Chemical Company, alkyl distribution being 60% C 30% C 5% C 5% C and following the same procedure, 98% of the calculated yield of alkyl dimethyl benzyl ammonium isatate was recovered as an orange paste.

Example III Using equimolar quantities of the solution of the sodium salt of isatin of Example I and of a 10% aqueousalcoholic solution of lauryl isoquinoliniurn bromide (Isothan QOnyx Chemical Company), and following the procedure described in Example I, a dark red paste was obtained in 100% yield of lauryl isoquinolinium isatate.

Example IV A 0.1 molar solution of the mono-potassium salt of isatoic anhydride was prepared in water. An aliquot of this solution was treated as in Example I with an equimolar amount of a solution of the alkyl dimethyl ethylbenzyl ammonium chloride of Example I. Alkyl dimethyl ethyl-benzyl ammonium isatoate was recovered in substantially the theoretical yield as a brown paste.

Example V An aliquot of the mono-potassium isatoate of Example IV was treated in the same manner with an equimolar amount of the lauryl isoquinolinium bromide of Example III. The product, lauryl isoquinolinium isatoate was recovered as a dark red paste in the theoretical yield.

Example VI A 0.254 normal solution of alkyl dimethyl benzyl ammonium chloride of Example H was reacted in stoichiometric proportions with the mono-potassium isatoate of Example IV and in the same manner. Alkyl dimethyl benzyl ammonium isatoate was obtained in substantially the theoretical yield as a brown paste.

Example VII Using the Standard Tube Dilution Test described above, the following bacteriostatic levels were determined (S.a.=Staphylcoccus aureus; S.t.=Salmonella typhosa; A.n=Aspergillus niger):

Baeteriostatic Dilution Level vs.- Product from Example No.

8.11. Si. A.n

Example VIII Example IX In the same manner as in Example V, mono(1auryl isoquinolinium) S-chloroisato'ate and mono(lauryl isoquinolinium) S-nitroisatoate were prepared from the respective 5-chloroisatoic land S-nitroisatoic acids. Similarly, the alkyl dimethyl ethyl-benzyl ammonium and alkyl dimethyl benzyl ammonium salts of 5-chloroisatoic acid and 5-nitroisatoic acid may be prepared by the respective procedures of Examples IV and VI.

We claim:

1. The quaternary ammonium salt of an indole derived acid selected from the group of isatic acid, isatoic acid, the 5- and 7-chloro isatic and isatoic acids and the S-nitroisatic and isatoic acids, the quaternary cation thereof being derived from a quaternary ammonium compound having a phenol coefiicient of at least with respect to both Staphylococcus aureus and Salmonella typhosa at 20 C. and having an alkyl of from 8 to 22 carbon atoms.

2. Alkyl dimethyl ethyl-benzyl ammonium isatate, the alkyl having 12 to 18 carbon atoms.

3. Alkyl dimethyl benzyl ammonium isatate, the alkyl having 12 to 18 carbon atoms.

4. Lauryl isoquinolinium isatate.

5. Alkyl dimethyl ethyl-benzyl ammonium 7-chloroisatate.

6. Alkyl dimethyl ethyl-benzyl ammonium S-nitroisatate.

7. Alkyl dimethyl ethyl-benzyl ammonium 7-chloroisatate.

8. Alkyl dimethyl benzyl ammonium 7-chloroisatate.

9. Lauryl isoquinolinium S-chloroisatate.

10. Lauryl isoquinolinium 7-chloroisatate.

11. Lauryl isoquinolinium S-nitroisatate.

12. Mono(lauryl isoquinolinium) S-chloroisatate.

13. Mono(laury1isoquinolinium) S-nitroisatate.

14. Alkyl dimethyl ethyl-benzyl ammonium S-chloroisatate.

15. Alkyl dimethyl benzyl ammonium S-chloroisatate.

16. Lauryl isoquinolinium isatoate.

17. Alkyl dimethyl ethyl-benzyl ammonium isatoate.

18. Alkyl dimethyl benzyl ammonium isatoate.

OTHER REFERENCES Elderfield, Heterocyclic Chemistry, vol. III, Wiley, 1952, pp. 63 and 215.

Hope et al., abstracted in Chem. Abstr., vol. 7, col. 2217-8.

Schwartz et al., Surface Active Agents and Detergents, vol. II, Intersciences, 1958, pp. 211 and 222.

ALEX MAZEL, Primary Examiner. HENRY R. JILES, Examiner.

DONALD G. DAUS, Assistant Examiner.

Claims (2)

1. THE QUATERNARY AMMONIUM SALT OF AN INDOLE DERIVED ACID SELECTED FROM THE GROUP OF ISATIC ACID, ISATOIC ACID, THE 5- AND 7-CHLORO ISATIC AND ISATOIC ACIDS AND THE 5-NITROISATIC AND ISATOIC ACIDS, THE QUATERNARY CATION THEREOF BEING DERIVED FROM A QUATERNARY AMMONIUM COMPOUND HAVING A PHENOL COEFFICIENT OF AT LEAST 100 WITH RESPECT TO BOTH STAPHYLOCOCCUS AUREUS AND SALMONELLA TYPHOSA AT 20*C. AND HAVING AN ALKYL OF FROM 8 TO 22 CARBON ATOMS.

9. LAURYL ISOQUINOLINIUM 5-CHLOROISATATE.