Bromate stabilizers for 3-isothiazolones

Abstract: A composition comprising (a) a 3-isothiazolone compound of the formula wherein R and R¹ are independently selected from hydrogen, halogen or R is a (C₁-C₄) alkyl group and R¹ is a halogen or R and R¹ may be joined to form an unsaturated 5- or 6-membered carbocyclic ring; Y is hydrogen, a (C₁-C₁₈) alkyl group, an unsubstitued or halo-substituted alkenyl or alkynyl of 2 to 8 carbon atoms, a cycloalkyl or substituted cycloalkyl of 3 to 12 carbon atoms, an aralkyl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aralkyl of to 10 carbon atoms, or an aryl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aryl group of up to 10 carbon atoms; and (b) an amount of a metal bromate salt sufficient to stabilize said composition; wherein said composition is free of metal nitrate salt is disclosed. Methods of use of the above compositions are also disclosed.

Description: This invention relates to bromate stabilized compositions of 3-isothiazolones, their preparation, and their use in controlling living organisms. 3-isothiazolones have generated high commercial interest as microbicides to prevent spoilage caused by microorganisms of a large number of aqueous and non-aqueous products subject to such spoilage. They are highly effective microbicides (as used herein, "microbicides" includes bactericides, fungicides and algaecides and microbicidal activity is intended to include both the elimination of and inhibition or prevention of growth of microbial organisms such as bacteria, fungi and algae); by suitable choice of functional groups, they are useful in a broad range of applications. However, it was early recognized that either in storage prior to addition to the matrix to be stabilized or after addition, their efficacy was decreased because the isothiazolone was not stable under practical conditions of long-term storage. Means have thus been sought from the beginning of research with such compounds to improve their stability. U.S.-A-3,870,795 and 4,067,878 teach the stabilization of 3-isothiazolones against chemical decomposition by addition of a metal nitrite or metal nitrate, preferably a di- or trivalent metal ion nitrate. The use of said metal nitrates has become conventional in commercial 3-isothiazolone products. These patents also disclose that other common metal salts, including carbonates, sulfates, chlorates, perchlorates and chlorides are ineffective in stabilizing solutions of isothiazolones, such solutions usually being in water or in an hydroxylic solvent. Bromate salts are not taught nor considered in these patents. Metal nitrates are known to cause problems in some 3-isothiazolone systems, the major problem being conversion of secondary or tertiary amine impurities to nitrosamines under certain conditions. As a group, nitroso compounds are generally suspected to be possible carcinogens. Alternatives have been developed to overcome the problems of metal nitrates; however, these alternatives have other disadvantages. For example, it is known to use certain organic stabilizers for 3-isothiazolones, generally for use situations where metal salts may create problems, such as corrosion, coagulation of latices, insolubility in non-aqueous media, interaction with the substrate to be stabilized, and the like. Formaldehyde or formaldehyde-releasing chemicals are known as stabilizers, (see U.S.-A-4,165,318 and 4,129,448), as are certain organic chemicals such as orthoesters (U.S.-A-4,906,274) and epoxides (U.S. SN 194,234). In certain applications, however, it is desirable to avoid addition of organic stabilizers by virtue of their volatility, decomposition in the presence of water or under high heat, higher cost, potential toxicity, and the like. Formaldehyde is a suspected carcinogen, and it is desirable not to use formaldehyde in applications where contact with human skin or lungs may occur. US 4975109 discloses the use of certain oxidants such as hydrogen peroxide to enhance the biocidal activity of isothlazolones. However there is no mention of whether or not the oxidants act as stabilizers. EP-A-436744 discloses the use of oxidants such as hydrogen peroxide and sodium perborate as stabilizers for isothiazolones however. Vogel's textbook of macro and semi micro qualitative analysis, 15th Edition, 1979, pgs 119-127, discloses that bromates are known as oxidants. It is also known to use sodium bromate and potassium bromate in the baking industry as bread and flour improving agents (see Merck Index, 11th ed.). Thus it is has become desirable to provide a stabilization system for 3-isothiazolones which avoids metal nitrates and organic stabilizers. It is also desirable to provide a stabilized 3-isothiazolone which uses low levels of stabilizer so as to avoid interference with other components in systems in which isothiazolones are used as microbicides. The present invention comprises in one aspect a composition comprising: (a) a 3-isothiazolone compound of the formula wherein R and R¹ are each independently hydrogen or halogen, or R is a (C₁-C₄) alkyl group and R¹ is a halogen, or R and R¹ may be joined to form an unsaturated 5- or 6-membered carbocyclic ring; Y is hydrogen, a (C₁ -C₁₈) alkyl group, an unsubstitued or halo-substituted alkenyl or alkynyl of 2 to 8 carbon atoms, a cycloalkyl or substituted cycloalkyl of 3 to 12 carbon atoms, an aralkyl or halo-, (C₁-C₄)alkyl-, or (C₁-C₄)alkoxy-substituted aralkyl of from 7 to 10 carbon atoms, or an aryl or halo-, (C₁-C₄)alkyl-, or (C₁-C₄) alkoxy-substituted aryl group of from 6 to 10 carbon atoms; and (b) an amount of a metal bromate salt effective to stabilize said composition; wherein said composition is free of metal nitrate salt. In another aspect, the invention comprises a method for inhibiting or preventing the growth of bacteria, fungi, yeast or algae in a locus subject or susceptibnle to contamination thereby, which comprises incorporating onto or into the locus, in an amount which is effective to adversely affect the growth of bacteria, fungi, yeast or algae, the aforementioned composition. The invention also comprises in a further aspect the use of said metal bromate salts as stabilizers for metal nitrate-free isothiazolones. The isothiazolones which are stabilized are of the formula wherein R and R¹ are independently selected from hydrogen, halogen or R is a (C₁-C₄) alkyl group and R¹ is a halogen or R and R¹ may be joined to form an unsaturated 5- or 6-membered carbocyclic ring; Y is hydrogen, a (C₁-C₁₈) alkyl group, an unsubstituted or halo-substituted alkenyl or alkynyl of 2 to 8 carbon atoms, a cycloalkyl or substituted cycloalkyl of 3 to 12 carbon atoms, an aralkyl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aralkyl of to 10 carbon atoms, or an aryl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aryl group of up to 10 carbon atoms. Representative Y substituents include methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, cyclohexyl, 4-methoxy phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenethyl, 2-(4-chlorophenyl)ethyl, 4-phenylbutyl, hydroxymethyl, chloromethyl, chloropropyl, hydrogen, and the like. By a substituted alkyl group is meant an alkyl group having one or more of its hydrogen atoms replaced by another substituted group. Examples of the substituted alkyl groups which characterize 3-isothiazolones of this invention include hydroxyalkyl, haloalkyl, cyanoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, carboxyalkyl, carbalkoxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, arylthioalkyl, haloalkoxyalkyl, cycloalkylaminoalkyl, such as morpholinoalkyl, piperidinoalkyl, pyrrolidonylalkyl, and the like, carbamoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, isothiazonylalkyl, and the like. By a substituted aralkyl group is meant an aralkyl group having one or more of the hydrogen atoms on either the aryl ring or the alkyl chain replaced by another substituent group. Examples of the substituent aralkyl groups which characterize 3-isothiazolones of this invention include halogen-, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy-substituted aralkyl groups, and the like. By a substituted aryl group is meant an aryl group, such as benzene, naphthalene, or pyridine, having one or more of the hydrogen atoms on the aryl ring replaced by another substituent group. Examples of such substituent groups include halogen, nitro, (C₁-C₄) alkyl, (C₁-C₄) alkyl-acylamino, (C₁-C₄) carbalkoxy, sulfamyl, and the like. Y is preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenethyl, 2-(4-chlorophenyl)ethyl, and cyclohexyl. The preferred 3-isothiazolones of this invention are 5-chloro-2-methyl-3-isothiazolone, and 4,5-dichloro-2-methyl-3-isothiazolone, 5-chloro-2- n -octyl-3-isothiazolone, 4,5-dichloro-2- n -octyl-3-isothiazolone, 5-chloro-2- p -chlorobenzyl-3-isothiazolone, 5-chloro-2-cyclohexyl-3-isothiazolone and 4,5-dichloro-2-cyclohexyl-3-isothiazolone. Especially preferred is 5-chloro-2-methyl-3-isothiazolone, either as a sole compound or in admixture with 2-methyl-3-isothiazolone. When in admixture, the preferred ratio of monochlorinated to unchlorinated 3-isothiazolone is from about 70:30 to 90:10. Preferred compositions comprise from about 0.5 to about 25 % by weight of one or more of the isothiazolones and a stabilizing amount of a metal bromate salt in the range of from about 0.1 to about 15 % by weight. Preferred ratios of isothiazolone to bromate are from 100:1 to 1:250, more preferably from 5:1 to 1:2. More preferably, the composition comprises at least one 3-isothiazolone wherein Y is (C₁-C₁₈) alkyl, (C₃-C₁₂) cycloalkyl or (C₇-C₁₂) aralkyl; R is hydrogen, methyl or chloro; and R₁ is chloro. Solvents may be used to dissolve the isothiazolones and may be water or any organic solvent which dissolves the isothiazolones, is compatible with the proposed end use, does not destabilize the 3-isothiazolone, dissolves the metal bromate salt and does not react with the metal bromate salt to eliminate its stabilizing action. Typical formulation ranges are illustrated in the following Table (all percentages are parts by weight) for both a concentrated solution of the 3-isothiazolone and a dilute solution. Formulations Table 3-isothiazolone Metal Bromate Salt Solvent 7 - 25 % (concentrated) 5 - 15 % 60 - 88 % 0.5 - 6.9 % (dilute) 0.1 - 5 % 88.1 - 99.4 % A wide variety of metal bromate salts are known to the art. The preferred metal bromates for this invention are lithium bromate, sodium bromate, potassium bromate, magnesium bromate, calcium bromate, strontium bromate, cobalt bromate and zinc bromate. Especially preferred for use in this invention are lithium bromate, magnesium bromate, potassium bromate and sodium bromate. Uses of these stabilized microbicides are typically at any locus subject to contamination by bacteria, fungi, yeast or algae. Typically, loci are in aqueous systems such as water cooling, laundry rinse water, oil systems such as cutting oils, oil fields and the like, where microorganisms need to be killed or where their growth needs to be controlled. However, these stabilized microbicides may also be used in all applications for which known microbicidal compositions are useful; preferred utilities of the compositions are to protect wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, caulking, feed and industrial cooling water from microorganisms. Because isothiazolones are so active as microbicides and only low levels of metal bromate salts are required to achieve stabilization, the amount of metal bromate salts in systems being treated will be vary small, and therefore it is not likely to interfere with other components in systems requiring protection or with systems to which protected systems will be applied. It is known in the art that the performance of microbicides may be enhanced by combination with one or more other microbicides. Thus, other known microbicides may be combined advantageously with the composition of this invention. The following specific examples are presented to illustrate the various aspects of the present invention. EXAMPLE 1 Two 14 % AI aqueous solutions of 5-chloro-2-methyl-3- isothiazolone ("CMI") and 2-methyl-3-isothiazolone ("MI') in an approximate ratio of 3:1 were prepared in deionized water, one at pH 2 and one at pH 7. To each sample was added 3 % magnesium bromate or sodium bromate. The samples were stored for two weeks at 55° C in a dri-bath with the initial samples stored in a freezer. The relative concentration of the active ingredient was determined by reverse phase high pressure liquid chromatography, utilizing an ultraviolet detector. The results are presented in Table 1. Stabilizer pH Weeks @ 55° C % CMI % CMI Loss None (Control) -- 0 10.7 -- 2 0 100 NaBrO₃ 2 0 11.3 -- 2 12.2 0 7 0 9.8 -- 2 9.4 5 Mg(BrO₃)₂ 2 0 10.9 -- 2 11.7 0 7 0 9.0 -- 2 9.6 0 EXAMPLE 2 Two 14 % AI aqueous solutions of 5-chloro-2-methyl-3- isothiazolone ("CMI") were prepared in deionized water. To each sample was added 3 % magnesium bromate or sodium bromate (pH 6 to 7). The samples were stored for two weeks at 55 °C in a dri-bath with the initial samples stored in a freezer. The relative concentration of the active ingredient was determined by reverse phase high pressure liquid chromatography, utilizing an ultraviolet detector. The results are presented in Table 2. Stabilizer Weeks @ 55° C % CMI % CMI Loss None (Control) 0 13.9 -- 2 0 100 NaBrO₃ 0 14.0 -- 2 12.6 10 Mg(BrO₃)₂ 0 14.7 -- 2 13.7 7 EXAMPLE 3 A 3 % solution of 5-chloro-2-methyl-3-isothiazolone ("CMI") and 2-methyl-3-isothiazolone in an approximate ratio of 3:1 was prepared by dissolving 4.7 g of the 3-isothiazolone mixture in 130 g deionized water. This 3 % 3-isothiazolone solution was combined 1:1 with a 2 % stabilizer solution, prepared by dissolving sodium bromate (0.4 g) in deionized water (20 g), yielding a single solution containing 1.5 % 3-isothiazolones and 1 % sodium bromate as stabilizer, the remaining amount being deionized water. A control consisting of a 1.5 % solution of the isothiazolones without any stabilizer was prepared. These solutions were stored at 55 °C. The solutions were analyzed for active ingredient by an ultraviolet spectrophotometer. These results are presented in Table 3. % CMI Loss Stabilizer Weeks Stored at 55 °C 1 2 3 4 8 NaBrO₃ 9 16 10 4 24 None (control) 82 100 -- -- -- EXAMPLE 4 (Comparative) This example illustrates the stabilizing effect of bromate salts. A solution containing 1.5 % 5-chloro-2-methyl-3-isothiazolone ("CMI") and 2-methyl-3-isothiazolone in an approximate ratio of 3:1 and 1.0 % stabilizer was prepared by combining 0.32 g of the 3-isothiazolone mixture with 0.20 g of the stabilizer in 19.48 g deionized water. A control consisting of a 1.5 % solution of the 3-isothiazolones without any stabilizer was prepared. These solutions were stored at 55 °C. The relative concentration of the active ingredient was determined by reverse phase high pressure liquid chromatography, utilizing an ultraviolet detector. The results presented in Table 4 show that the bromate salt is an effective stabilizer for 3-isothiazolones but not the chlorate or perchlorate salts. % CMI Loss Stabilizer Weeks Stored at 55° C 1 2 5 6 NaBrO₃ 0 0 35 41 NaClO₃ 100 100 -- -- KClO₄ 100 100 -- -- None (control) 100 -- -- -- EXAMPLE 5 To a 14 % aqueous solution of 5-chloro-2-methyl-3-isothiazolone ("CMI") and 2-methyl-3-isothiazolone in an approximate ratio of 3:1 which was obtained from the magnesium oxide neutralization of the HCl salts of the 3-isothlazolones, 0 to 15 % of potassium bromate as a stabilizer was added. The samples were stored at 50° C for a period of time. The solutions were analyzed for active ingredient by an ultraviolet spectrophotometer. These results are presented in Table 5. % CMI Loss Stabilizer Storage Time at 50° C 5Days 2 WKS 4WKS None (control) 29 96 1% KBrO₃ 2 98 -- 5% KBrO₃ 0 7 19 10% KBrO₃ 12 11 29 15% KBrO₃ 0 1 16

Claims: Composition comprising (a) a 3-isothiazolone compound of the formula wherein R and R¹ are each independently hydrogen or halogen, or R is (C₁-C₄) alkyl and R¹ is halogen, or R and R¹ are joined to form an unsaturated 5- or 6-membered carbocyclic ring; Y is hydrogen, a (C₁-C₁₈) alkyl group, an unsubstituted or halo-substituted alkenyl or alkynyl of 2 to 8 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an aralkyl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aralkyl of from 7 to 10 carbon atoms, or an aryl or halo-, (C₁-C₄) alkyl-, or (C₁-C₄) alkoxy-substituted aryl group of from 6 to 10 carbon atoms; and (b) a metal bromate salt in a ratio to isothiazolone of from 1:100 to 250:1; wherein said composition is free of metal nitrate salt. Composition according to claim 1 wherein the ratio of isothiazolone to bromate salt is from 5:1 to 1:2. Composition according to claim 1 or 2 wherein said metal bromate salt is a salt of lithium, sodium, potassium, magnesium, calcium, strontium, cobalt or zinc. Composition according to any preceding claim which comprises from 0.5 to 25 parts by weight of one or more 3-isothiazolones, and from 0.1 to 15 parts by weight of said metal bromate salt. Composition according to any preceding claim which comprises from 1 to 15 parts by weight of one or more 3-isothiazolone, and from 1 to 10 parts by weight of said metal bromate salt. Composition according to any preceding claim which comprises from 1 to 2 parts by weight of one or more said 3-isothiazolone, and from 1 to 2 parts by weight said metal bromate salt. Composition according to any preceding claim wherein said 3-isothiazolone is 5-chloro-2-methyl-3-isothiazolone, 4,5-dichloro-2-methyl-3-isothiazolone, 5-chioro-2- n -octyl-3-isothiazolone, 4,5-dichloro-2- n -octyl-3-isothiazolone, 5-dichioro-2- p -chlorobenzyl-3-isothiazolone, 5-chloro-2-cyclohexyl-3-isothiazolone or 4,5-dichioro-2-cyclohexyl-3-isothiazolone, or a mixture thereof. Composition according to any preceding claim comprising 14 parts by weight of an aqueous solution of 5-chloro-2-methyl-3- isothiazolone and 2-methyl-3-isothiazolone in a ratio of 3 to 1 and 5 parts by weight of potassium bromate; or 1.5 parts by weight of said aqueous solution and 1 part by weight of potasium bromate. Method for inhibiting or preventing the growth of bacteria, fungi, or algae in a locus subject or susceptible to contamination thereby, which comprises incorporating into or onto said locus, in an amount effective to adversely affect said growth a composition as defined in any preceding claim. Method according to claim 9 wherein said locus is an aqueous medium, a cosmetic formulation, fabric, leather, paper or wood, or a solid protective or decorative film. Use of a metal bromate salt as a stabilizer for a metal nitrate-free 3-isothiazolone.

Inventors: LASHEN EDWARD SAMUEL, PETIGARA RAMESH BALUBHAI, LASHEN, EDWARD SAMUEL, PETIGARA, RAMESH BALUBHAI
Applicants: ROHM & HAAS, ROHM AND HAAS COMPANY
Application year: 1992
Main classification: A01N43
IPC codes: A61K8, C01B11, A61L2, A01N25, A01N43, C07D275