DE1695669C3 - 3-hydroxy isothiazoles - Google Patents

Description

where X and Z 'can be hydrogen atoms. X is also an alkyl group having 1 to 4 carbon atoms can be and Y represents a hydrogen atom.

This cyclization takes place by reacting the disulfide amide with a halogenating agent. Typical Haliding agents are chlorine. Bromine. Sulfuryl chloride. Sulfuryl bromide. N-chlorosuccinimide or N-bromosuccinimide. Are chlorine and sulfuryl chloride the preferred halogenating agents.

With an excess of halogenating agent, the isothiazolone in the 4- and or 5-position is the Formula 1 halogenated. When 5 molar equivalents of haloenating agent are available, a monohalogenation takes place. Are for dihalogenation 7 molar equivalents of halogenating agent required.

The preparation of isothiazolones with different halogen substituents in the 4- and 5-positions takes place by halogenation of an isothiazolone. which is already in one of the two in question Positions is halogenated. For example when a 4-bromo-5-chloro-3-isothiazolone is desired. so can this is done by bromination of a 5-chloro-3-isothiazolone ouer obtained by chlorination of a 4-bromo-3-isothiazolone. The starting isothiazolone is obtained by the cyclization of a disulfide amide, as described above. Methods or variants here, such as "secondary halogenation", are obvious to the person skilled in the art. the Temperature is not critical to the process, but generally and preferably it will be in the range carried out from 0 to 100 C.

The reaction is carried out in an inert non-aqueous solvent such as benzene. Toluene. Xylene. Ethyl acetate or ethylene dichloride. 4,5-dihalo-3-hydroxyisothiazole c can also be obtained by halogenation of an S-halo-.l-hydroxyisothiazole will.

The following examples serve to illustrate the invention.

example 1

5-chloro-3-hydroxyisothiazole

In a 1 liter three-necked flask with a mechanical stirrer, thermometer and dropping funnel. were 500 ml / \ ethylene dichloride and 20.3 g of dithiodipropionamide mixed together. This mixture was at K) bi; Stirred at 15 ° C. and 42.5 g of sulfuryl chloride were added added dropwise over 2 hours. After the addition was complete, the reaction slurry was left warm to 25 to 30 C, stirred overnight, un to ensure a complete response. The reaction lamb was then filtered, and the never the precipitate was dissolved in 150 liters of hot water. Tue aqueous solution was filtered to remove some insoluble material and then chilled in ice. Nacl Filtration and drying gave 4.0 g of 5 - ('chloro 3-hydroxyisothiazole as brown crystalline lest material. F. = 95 to% C.

Example 2

4-Bromo-5-chloro-3-hydroxyisothiazole

To a solution of 100 ml of ethyl acetate and 6.8 g of 5-chloro-3-hydroxyisothiazole, which according to Example Ϊ had been made. a solution of 8 g of bromine in 25 ml of ethyl acetate was added at 0 C. After After the addition, the red reaction solution was allowed to warm to room temperature, and after one hour the solvent was removed under reduced pressure and left 13.7 g of dark orange Solid treatment "of this solid with water was removed after drying 8.7 g of 4-bromo-5-chloro-3-hydroxyisothiazole. F. = 145 to 147 C (recrystallized from ethyl acetate).

In the same way, the ones in the table I also prepare compounds listed as examples no. 3 and 4.

Table I.

3 -H yrinm isothiazole Z OH

Z '

4 3! J

, N

\, 7

An; ily-ie * l

halogen

1 H Cl 95 to 96 26.20 (26.5! 1.22 (1.4) 10.11 (10.3) 23.39 (23.6)

2 Br Cl 145 to 147 17.43 (16.8) 0.61 (0.5) 6.65 (6.5) 15.17 (15.0)

3 Cl Cl 15! up to 154 21.61 (21.1) 0.61 (0.6) 7.86 (8.2) 18.58 (18.8)

4 CH, Cl 122 32.48 (32.2) 3.45 (2.7) 9.36 (9.4) 19.20 (21.5)

"The number in brackets is the theoretical value based on the empirical I-ormel leather connection.

Cl 26.26

(26.201
Cl 16.67

(16.5)
Br 33.81

(37.2)
Cl 40.35

(41.7)
Cl 22.58

123.8)

The new 3-hydroxyisothiazoles according to the invention are biocidal compounds and as such are suitable for the control of microorganisms. Out for this reason they are particularly effective bactericides. algaecide. fungicides and pesticides. Also, these new compounds have the unexpected Property against inhibition by the usual additions of impurities such as lecithin, normal Horse serum. Alkyl benzene sulfonates. water soluble lanolin. Sodium chromate. Sodium nitrite. Glycerin or propylene glycol. to be consistent.

The fungicidal assessment of these compounds was carried out according to the standard slide germ development test [Phytopathology. 33, p. 627, 1943 using germs from Alternaria solani (Alt.). Sclerotinia fructicola (Sci.) And Stemphylium sarcinaforma (Stem.) Or Botrytis cinerea (Bot.)]. The values obtained for the concentration in

Table Il

Parts per million (ppm) that effectively inhibited 50% of the germs are listed in Table II.

The antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were determined using the serial dilution test, wherein a series of broths containing varying dilutions of a test compound and one of contains both microorganisms, starting with I: 1000 is halved with respect to the concentration. The values obtained, also in tables are shown represent the maximum dilution at which the tested compound is complete Inhibition of the microorganism causes. In the tests were known reference substances 6 - ethoxy - 2,4 - dimethyl - m - dioxane and hexahydro - 1.3.5 - tris- (2 - hydroxyäthyll-s - triazine included.

Hek.inutc comparison links

.tatic Aknwlal ηIlIis niger Baklcriosiatische Akin Hat

S aureus l \. ctli

6-acetoxy-2.4-dimeth \ l-m-dioxane I:!

lle \ ahvdro-1.3.5-tris- (2-hydrox \ ethyl) - 1: 2

2 (KK)
4 (KK)

I: 2,000
I: 2 (K) O

Ll

continuation

Bckanme V'er ^ ieichäverbintjungcn

Fungi <r .-. I. «: He Akliviiät Bakleriostaiische Akiiviiiit
Aspergillus niger S. aureus E. coli

Compounds according to the invention

Example 1

I: 16000

Example 2
Example 3
Example 4

With regard to the acute oral toxicity was for the compound according to Example 1 be ^; Rats had an LD ₅₀ -VV'ert of 52 mg / kg and for the compound according to Example 3 of the invention in mice an LD ₅₀ -WeM of 538 mg / kg.

Certain isothiazoles were also called algaecides according to the Fitzgerald test (Applied Microbiology, 7, Pp. 205 to 211, No. 4, 1959), and it was found that they are extraordinarily effective.

Furthermore, the fungicidal activity of some of the hydroxyisothiazoles was increased by using of seed treatment shown. "Seed treatment" means the distribution of an ice biocidal Material above a seed to attack microorganisms and especially fungi, being such an amount of the biocidal material is used that it is effective. such microorganisms without harmful To inhibit the influence of the seeds or to bring them under control. In most cases it will biocidal material, in this case the hydroxyisothiazoles or compositions thereof, on the Surface of the seed to be treated applied. This can vary according to technology known methods, such as slurrying, dipping, dusting, spraying, etc.

The amount of hydroxyisothiazole required to be effective in seed treatment will vary depending on the conditions, such as the type of seed, the method of application, the soil and the atmospheric Conditions. Generally, an application in the range of about 70 to 370 grams is more active Components, namely the hydroxyisothiazole, per 45 kg of seeds effective to avoid any undesirable Bringing microorganisms under control and protecting the seeds. An application of active agent in the range of about 28 to 285 g per 45 kg of seed is preferred.

An experimental method was used to determine the effectiveness of these compounds for the To demonstrate seed treatment. This consists in that you have two portions of 100 corn kernels slurried with the hydroxyisothiazole to determine an amount of 2X to 57 g per 36 l of seed. For comparison purposes, an untreated control sample was also included in the experiment. After drying, the Saatgui was planted in a manure soil that was littered with pythium and had a high moisture content. The corn kernels were in this soil for a week at 10 ° C held to allow infection. After completion During this period the temperature was raised and maintained to about 21 to 27 ("to allow germination of the Do not use internal grains to ucslatten. The number of 64 (X) O

12s 000

32,000 1: 32,000 32,000 1: 32,000 2 0 (X) ! : 32,000

germinating grains were counted after the emergence of the plant, and these values are in the Table III listed.

/ aiii the
germinating
I'flan / en ie
20 (1 pp. Aikorner

10

104

Table III
Seed treatment

Trial connection

Unbchandclt

S-chloro ^ -hydroxyisothia / oi

4-Bromo-5-chloro-3-hydroxyi.MUhiazole

4,5-dichloro-3-hydroxyisothiazole

4-methyl-5-chloro-3-hydroxyisothiazole

The value of the hydroxyisothiazoles as agents with synthetic activity shows that numerous round worms, Mites, insects such as beetles and aphids. be brought under control exceptionally well. Some typical roundworms. Insects and mites after treatment with the compounds of the invention have been killed are the following: The northern root nematode (Meloidogyne hapla), the Mexican ladybird (F.pilachna varivesta), the black carpet beetle (Attagenus pieeus). the black beetle (Tribolium confusum). the grain beetle (Sitophilus granarius), the two-spotted mite (Tetranychus urticasc), the house fly (Musea domestica), the southern army worm (prodenia cridania). the German cockroach (Blattclla germania) and the green peach aphid (Myzus persicac).

The compounds according to the invention can be used as Slimicidc, Algaecide, Bakterieide, Fungicide or Combinations thereof in any medium, especially in aqueous medium, for example for water cooling systems, Swimming pool or paper pulp methods. They also serve Compounds and / or compositions thereof, for example, as protective agents, especially as Fabric protectants, soap additives, as sanitary preparations and preservatives for metalworking compounds.

In general, it can be attacked by microorganisms exposed media according to this invention are protected by giving them a hydroxyisothiazole in a meme bucket body. the for

Killing or controlling this microorganism sufficient. The exact amount of hydroxyisothiazole that is required. of course varies depending depending on the medium to be protected, depending on the microorganism to be controlled, depending on the specie'il used hydroxyisolhiazoles or compositions thereof, etc. Typically, excellent control is obtained in a liquid Medium when the Hydroxyisothiazolc in one area from 0.1 to 10,000 parts per million (ppm) or 0.00001 to 1% based on the weight of the media, be incorporated. A range of 1 to 2000 ppm is preferred.

The term "control" is used here to mean some means that is existence or adversely affects the growth of a microorganism. This influence can be in a complete mortification. Extermination, in a growth stoppage, in an inhibition, in a diminution consist in the number or a combination of these effects.

Outstanding fungistatic activity due to the Isothiazoles were obtained when these were used as color protectants. Microbial activity Acrylic compound-based paint emulsions are effectively inhibited when these compounds are used in an amount of about 900 to 9000 g or more per 378 liters of paint.

The hydroxyisothiazoles of the invention are particularly useful as agriculturally used ones Fungicide. As such, they are particularly valuable when incorporated into a fungicidal composition are. Such compositions comprise an agriculturally acceptable carrier and the compounds described herein as active or active agents. Where necessary or desired, Surfactants or other additives can also be incorporated to make uniform To give mixtures. One understands by "a carrier material that is compatible in agriculture" any substance that can be used to get the inside incorporated chemical to dissolve, disperse or finely distribute without compromising the effectiveness of the toxic By means of »to affect, and the one environment, such as soil, a plant or agricultural products, does not permanently damage it.

For use as pesticides, the compounds according to the invention are usually in an in agriculturally compatible carrier material added or finely divided to make them door a subsequent one To make scattering suitable. For example, the hydroxyisothiazoles can be used as wettable powders. Emulsion concentrates, as dust. Granules. Aerosols or distributed as flowable emulsifiable concentrates. Hydroxyisothiazoles are used in such preparations diluted with a liquid or solid carrier material, and. if desired, will also suitable surfactants incorporated.

The compounds according to the invention can be in a water-miscible liquid, such as ethanol. Isopropanol or acetone. Such solutions can easily be diluted with water.

The isothiazoles can also be treated with a delicate, solid carrier material or mixed with it, such as with clays, inorganic Silicates. Carbonates or silicas. Organic carrier materials can also be used will. Siauhkon / entrate iiewinni one usually with a content of Hydroxyisolhiazolcn in the range of 20 to 80%. Be for final use these concentrates normally diluted to about 1 to 20% with additional solids.

Wettable powder preparations are obtained by incorporating the compounds according to the invention into an inert, finely divided, solid carrier material, together with a surface-active agent that consists of one or more emulsifiers, wetting agents, dispersants or distribution media or mixtures can consist of this. The hydroxyisothiazoles are usually in the range of 10 to 80 percent by weight and the surfactants contain in the range of 0.5 to 10 percent by weight. Usually emulsifiers and wetting agents used are, for example, polyoxyethylene derivatives of alkylphenols, Fatty alcohols. Fatty acids and alkylamines. Alkylarenesulfonals and Dialkylsulfosuccinatc. Distribution agent are for example materials such as glycine mannitol laurate and a condensate of polyglycerine and oleic acid modified with phthalic anhydride. Dispersants are, for example, materials such as the sodium salt of the mixed polymer of maleic anhydride and an olefin such as diisobutylene. Sodium lignosulfonate and sodium formaldehyde naphthalene sulfonate c.

A convenient method of making a solid preparation is to. the isolhiazole on the solid support material with the aid of a volatile solvent such as acetone. This way you can too Additives such as activators. Adhesives. Plant nutrients and various surface-active substances, be incorporated.

Emulsifiable concentrate preparations can be obtained in such a way that the isothiazoles after Invention dissolves in an agriculturally acceptable organic solvent and one in the Solvent soluble emulsifier added. Suitable solvents are usually with water immiscible and for example hydrocarbons, chlorinated hydrocarbons. Ketones. Ester. Alcohols and amides. Mixtures of these solvents are usually used. As emulsifiers Useful surfactants can be from about 0.5 to 10 percent by weight of the emulsifiable concentrate and be anionic, cationic or nonionic in character. Anionic Surfactants are, for example, alcohol sulfates or sulfonates, alkyl arene sulfonates and sulfosuccinates. Examples of cationic surfactants are fatty acid alkylamine salts and quaternary fatty acid alkyl compounds. Nonionic emulsifiers are, for example, ethylene oxide adducts of Alkyl phenols. Fatty alcohols. Mercaptans and fatty acids. The concentration of the active ingredients can vary between 10 and 80% and is preferably in the range of 25 to 50%.

For use as phytopathogenic food these compounds should be applied in an effective amount by methods known per se sufficient to achieve the desired biocidal activity to surrender. Usually you bring the Hydroxyisothiazole on the areas to be protected in one Agriculture compatible carrier material incorporated in an effective amount. In particular In situations, however, it may be desirable and advantageous to place the compounds on the / u protective sites directly and without an essential mcnuc of Triiner

509 684/91

to apply material. This is particularly effective Method if the nature of Mydroxyisothiazole is such. that they stole a so-called "low volume deposition". d. h .. if the connections are essentially soluble in liquid form or in higher-boiling solvents.

The application ratios vary, of course depending on the purpose of application, the hydroxyisothiazoles used and the frequency of Application.

For use as used in agriculture Bacterial and fungicides can be diluted spray liquids with concentrations of

23 to 9000 g of active hydroxyl solhiazole besides 37 <1/2 liters of the spray liquid can be applied. You will usually be having a focus from 45 to 45 (X) g per 378 liters and preferably with a concentration of 57 to 2270 μ each 378 liters applied. With more concentrated spray liquids the active ingredient is increased by a factor of 2 to 12. Diluted spray liquids are usually used on plants until a drain is achieved. while with more Concentrated or lower volume spray liquids apply the materials as a mist will.

Claims (1)

my formula Patent claims:
3-H \ drox;> isothiazole of the general formula Z OH Z ' wherein Z is a hydrogen atom, a chlorine atom Bromine atom or an alkyl group having 1 to 4 carbon atoms and Z 'represents a chlorine atom or a bromine atom. .1 Use of the 3-hydroxyisothiazoles according to claim I for the commercial control of Bacteria and fungi. The invention relates to substituted 3-hydroxyiso-ihiazoles the common formula OH (1) 30th 35 wherein Z is a hydrogen atom. an alkyl group having 1 to 4 carbon atoms, a chlorine or bromine atom and Z 'denotes a chlorine or bromine atom, as well as the use of the 3-Hydroxyisothiazolc of the general Formula I for the commercial control of bacteria and fungi. It should be noted at this point that the mass of physical values available indicates that the general formula I correctly designates the isothiazoles according to the invention. However, these compounds are tautomeric with their keto tons. which by the following general form
besides can be: wiciierüe- N ¹ H 55 /. S. For this reason, the isothiazoles can be in either configuration or as a mixture in any mixing ratio of the two forms may occur, and therefore any reference to one of the both forms here at the same time include the other form. Compounds of the general formula I can be prepared by Zvkiisierunü a disulfidamide of the alliie- 60 50 / XO \ Ij - SCH -CHC-NHY
Z