US3481946A - Certain 3-acylthioalkylenethio-5-alkylthio - 4-cyano-isothiazoles and 5-acylthioalkylenethio - 3 - alkylthio - 4-cyano-isothiazoles - Google Patents

Certain 3-acylthioalkylenethio-5-alkylthio - 4-cyano-isothiazoles and 5-acylthioalkylenethio - 3 - alkylthio - 4-cyano-isothiazoles Download PDF

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US3481946A
US3481946A US631577A US3481946DA US3481946A US 3481946 A US3481946 A US 3481946A US 631577 A US631577 A US 631577A US 3481946D A US3481946D A US 3481946DA US 3481946 A US3481946 A US 3481946A
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cyano
isothiazoles
methylthio
isothiazole
alkylthio
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US631577A
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Karl Gunther Schmidt
Gunther Mohr
Sigmund Lust
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Merck KGaA
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E Merck AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • An object of this invention is, therefore, to provide novel chemical compounds and, concomitantly, intermediates, by-products, and processes relating to the production of such compounds.
  • R represents alkyl of 1-4 carbon atoms; phenyl;
  • R represents alkyl of 1-4 carbon atoms.
  • fungicidal agents can be incorporated with conventional carriers and/or fillers, and, if desired, additional conventional fungicides.
  • the activity of the novel compounds was determined in the spore germination test and in the infection test.
  • the LD and LD were determined, i.e., that amount of active agent (measured in mg./ 100 cm?) which prevents, to an extent of 50% and 95%, respectively, the germination of the fungus spores in the spore germination test, and the growth of the fungus on the leaf surface in the infection test.
  • novel compounds were compared with the known highly effective fungicide N-trichloromethylthio-tetrahydrophthalimide, as a standard.
  • N-trichloromethylthio-tetrahydrophthalimide N-trichloromethylthio-tetrahydrophthalimide
  • the novel fungicides 3-acetylthio-methylthio-S-methylthio-4-cyano-isothiazole and S-acetylthiomethylthio-3-methylthio-4-cyano-isothiazole are two to three times more effective than the standard compound, whereas approximately the same activity is observed when using these agents in the spore germination test on Alternaria.
  • Another object is to provide novel compositions and methods for effecting fungicidal activity.
  • fungicidal agents will also exhibit a finite fungicidal activity with fungi of the following genus: Alternaria, Botrytis, Bremia, Cercospora, Cladosporium, Colletotrichum, Helminthosporium, Monilia, Peronospora, Piricularia, Phytophthora, Septoria, Sklerotinia, Venturia.
  • R represents methylene, ethylene, as Well as the straight-chain or branched propylene and butylene residues.
  • R is either an alkyl residue of l-4 carbon atoms, i.e.,
  • R can also be a phenyl residue Which is substituted, if desired.
  • Suitable substituted phenyl radicals include among others, for example, hydroxyphenyl such as m-, p-hydroxyphenyl, 2,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,4,6-trihydroxyphenyl, alkyl phenyl wherein alkyl is of l-4 carbon atoms, such as o-, m-, or p-tolyl, xylyl, and 2,4,6-trimethylphenyl; halogen-substituted phenyl residues, such as 2,4-dihalogenophenyl, 3,5-dihalogenophenyl, or 2,4,6-trihalogenophenyl residues, the halogen atoms being preferably chlorine, bromine, or iodine; and phenyl substituted by methylenedioxy, preferably 2,3-methylenedioxyphenyl.
  • R hal
  • R represents the same alkyl residues named as substituents in R above.
  • R represents CH or CH CH R represents alkyl of 1-4 carbon atoms or phenyl; and R represents alkyl of 1-4 carbon atoms;
  • R represents CH R represents CH C H or C H and R represents CH or C H
  • Single species preferred include the following 4-cyanoisothiazoles:
  • novel compounds can be produced, for example, by reacting 4-cyano-isothiazoles of Formulae Ila and/ R represents an alkali, ammonium, or amine salt cation,
  • R is R or R with an u-halogenoalkylacyl sulfide of Formula III R COSR Hal (III) wherein R and R have the above-indicated meanings; and Hal represents halogen, preferably C1 or Br.
  • the above salts of 3,S-dimercapto-4-cyano-isothiazoles employed as the starting material (11a and 11b) are produced in accordance with conventional methods, for example, by reacting malonic acid dinitrile with carbon disulfide in the presence of the corresponding salt-forming base; the solvent preferably used in this reaction is alcohol or acetonitrile.
  • Preferred salts of the 4-cyano-isothiazoles of Formulae Hz: or 1111 are particularly the alkali salts, such as sodium and potassium; the alkaline earth salts such as magnesium and calcium; ammonium and amine salts.
  • alkali salts such as sodium and potassium
  • alkaline earth salts such as magnesium and calcium
  • ammonium and amine salts With respect to amine salts, tertiary amine is preferred, but secondary and primary amines can also be employed. Since the cation does not directly participate in the reaction and does not appear in the final product, a wide variety of amine salts can be employed.
  • the substituted ammonium cations contain no more than 16 carbon atoms, specific examples of such amines being, for example: mono-, di-, and trimethylamine; mono-, di-, and triethylamine; mono-, di-, and tripropylamine; mono-, di-, and tributylamine, particularly N-tert.-butylamine and isobutylamine, nor tert.-octylamine, n-decylamine and isodecylamine, n-dodecylamine, and tert.-dodecylamine.
  • Straight or branched chain amines can be employed, it being preferred, of course, to use those readily available amines of commerce.
  • Novel intermediates are those of Formula IV as fol- R represents R -CO-SR or R and R to R have the above-indicated meanings.
  • Which of the two different isomers is formed is influenced by the selection of the starting material and the solvent.
  • one of the two isomeric 3(5)-acylthioalkylthio 5(3) alkylthio 4 cyano isothiazoles is produced when anhydrous solvents are employed in all instances.
  • the isomer of the product produced on an anhydrous basis is selectively obtained when the starting compound is one of Formula Ila or IIb wherein and if this substituent R, has previously been obtained by alkylation of the basic 4-cyano-isothiazole in the presence of water.
  • the resultant salt of the alkylthio-mercapto-4 cyano-isothiazole -(IIa or IIb) is preferably first isolated from the aqueous solution and then reacted with an ahalogenoalkylacyl sulfide, this later step being preferably conducted in an anhydrous organic solvent. It is apparent, therefore, that the solvent present during the introduction of the alkyl group R is an important factor in determining which one of the isomeric compounds is obtained.
  • reaction temperatures for these reactions generally range betwen 5 C. and the boiling point of the solvent employed. Normally, about /2 to 5 hours are required for conducting the reaction.
  • the isolation and the working up of the novel compounds are conducted in a conventional manner.
  • the isothiazoles of this invention can be beneficially combined with other fungicides, such as, among others:
  • Copper-containing fungicides e.g., cuprous oxide, cop per oxychloride, copper sulfate, basic copper carbonate, copper zinc chromate, boreaux mixture (mixture of copper sulfate and hydrated lime), copper naphthenate, copper 8 hydroxyquinolinate; sulfur-containing fungicides, e.g., wetting sulfur, polysulfides, lime-sulfur mixtures (aqeuous solutions of calcium polysulfides and calcium thiosulfate); mercury-containing fungicides, e.g., mercuric chloride, phenylmercuric acetate, benzoate and chloride, ethylmercuric acetate and chloride, Z-methoxyethylmercuric chloride, silicate and phosphate, (3-chloromethoxypropyl)-mercuric acetate, ethylmercuric-2,3-dihydroxypropyl mercaptide, N-(eth
  • the isothiazoles of this invention can be incorporated in all forms of compositions suitable for fungicidal applications, and contain generally about 1 to of the active agent. Adding conventional carriers and/or fillers, there can be produced, for example, sprayable or atomizable agents. Additives such as dressing agents for the preservation of seed; dispersing agents and/or wetting agents can be added. When using the appropriate additives, it is also possible to produce solutions or emulsions of the novel substances, which can, for example, be atomized as aerosols.
  • the agents can be incorporated with pulverulent solids to form sprayable powders or dusting compositions. They also can be incorporated with surface active agents and thickening agents to form sprayable dispersions.
  • Additives and fillers used in this connection are the conventional ones, such as, for example, bole, kaolin, bentonite, ground shale, talc, chalk, dolomite, or kieselguhr, if solid preparations are concerned.
  • xylene, solvent naphtha, petroleum, acetone, cyclohexane, dimethyl formamide, or aliphatic alcohols are preferably used as solvents.
  • the emulsion concentrates thus prepared can be marketed as such.
  • the emulsion concentrates Prior to use, the emulsion concentrates are diluted with water in the usual manner. Due to the low solubility of the active agents in organic solvents, it is, however, preferable to formulate them as aqueous dispersions.
  • organic thickening agents for such dispersions the following can, e.g., be used: methyl, ethyl, carboxymethyl and hydroxyethyl cellulose, tragacanth, dextrines, alginic acids and their salts, polyvinyl alcohol.
  • Typical inorganic thickening agents are bentonite, attaclay and hectorite.
  • wetting and dispersing agents which are usually applied in pesticides, preferably in an amount of about 0.01 to 1% calculated on the basis of the preparation form for use.
  • Suitable wetting and/or dispersing agents are alkyl benzene sulfonates, alkyl naphthalene sulfonates, polyoxyethylene esters of fatty and resinic acids, alkyl phenol polyglycol ethers.
  • the compounds being employed as fungicides in a pest control program are generally applied to the locus subject to infestation in a quantity per hectare of about 1 to 50 kg.; preferably about 2.5 to 25 kg. More or less active ingredient can be used in dependence on the vegetation involved.
  • Example 2 Under stirring, 12.4 g. chloromethyl acetyl sulfide, dissolved in 10 ml. ethanol, are added dropwise to 21.8 g. of the disodium salt of 3,5-dimercapto-4-cyano-isothiazole, suspended in 300 ml. absolute ethanol. After two hours of agitation at 60 C., 12.6 g. dimethyl sulfate, dissolved in 20 ml. ethanol, are added dropwise. The reaction mixture is stirred for another two hours at 60 C., then cooled to 20 C., and vacuum-filtered. The residue is extracted with 150 ml. boiling ethanol and again vacuum-filtered. The ethanol solution is treated with activated charcoal and concentrated.
  • Example 3 11.3 g. of the potassium salt of 3-mercapto-5-methylthio-4-cyano-isothiazole are dissolved in 200 ml. ethanol and mixed, under stirring, with 6.2 g chloromethyl acetyl sulfide. Thereafter, the reaction mixture is heated for one hour to 60-70 C., then cooled to 20 C., and the reaction product is precipitated by the careful dropwise addition of Water. The 3-acetylthio-methylthio-5-methylthio-4-cyano-isothiazole is vacuum-filtered and recrystallized from ethanol.
  • Example 4 21.8 g. of the disodium salt of 3,5-dimercapto-4-cyanoisothiazole are dissolved in 300 ml. water and mixed, at 510 C. under stirring, within minutes, with 14.2 g. methyl iodide. The reaction mixture is then stirred for another 1% hours at 510 C. and vacuum-filtered from the precipitated 3,S-dimethylthio-4-cyano-isothiazole, the latter being obtained as a by-product. The filtrate is concentrated to dryness, the residue is suspended in 150 ml. ethanol, and within 10 minutes, at 60 C., 11.2 g. chloromethyl acetyl sulfide are added dropwise to the suspension.
  • reaction mixture is stirred for another hour at 60 C. Then, the inorganic residue is vacuum-filtered, and the mother liquor is concentrated to one-third its volume. The precipitated 5-acetylthio methylthio 3 methylthio 4 cyano isothiazole is vacuum-filtered and recrystallized from ethanol, with the addition of charcoal.
  • Example 6 Sprayable powder: Percent Copper oxychloride 7O 3 benzoylthio methylthio 5 methylthio 4- cyano-isothiazole (or the corresponding 5-, 3-
  • R represents alkylene of 1-4 carbon atoms
  • R represents alkyl of 1-4 carbon atoms, or X -phenyl wherein n is an integer of 13 and X is hydrogen, hydroxyl, alkyl of 1-4 carbon atoms, or halogen, or 2X represents methylenedioxy;
  • R represents alkyl of 1-4 carbon atoms.
  • a compound as defined by claim 1 wherein the compound is 3-acetylthiomethylthio. 5 methylthio-4- cyano-isothiazole.
  • a compound as definedby claim 1 wherein the compound is S-acetylthiomethylthio 3 methylthio-4- cyano-isothiazole.
  • a compound as defined by claim. 1 wherein the compound is 3-benzoylthiomethylthio 5 methylthio-4- cyano-isothiazole.
  • a compound as defined by claim 1 wherein the and 9 10 compound is S-benzoylthiomethylthio 3 methy1thio-4- ALEX MAZEL, Primary Examiner cyano-isothiazole- R. J. GALLAGHER, Assistant Examiner References Cited US Cl X,-R.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US631577A 1966-04-23 1967-04-18 Certain 3-acylthioalkylenethio-5-alkylthio - 4-cyano-isothiazoles and 5-acylthioalkylenethio - 3 - alkylthio - 4-cyano-isothiazoles Expired - Lifetime US3481946A (en)

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DEM0069263 1966-04-23

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US (1) US3481946A (ref)
BE (1) BE697389A (ref)
CH (1) CH482711A (ref)
DE (1) DE1595995A1 (ref)
ES (1) ES339659A1 (ref)
GB (1) GB1124545A (ref)
IL (1) IL27732A (ref)
NL (1) NL6703832A (ref)
SE (1) SE325886B (ref)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989710A (en) * 1973-09-01 1976-11-02 Bayer Aktiengesellschaft Certain 2-mercapto-4,5-dichloro-thiazole compounds
US5352792A (en) * 1990-07-19 1994-10-04 Shionogi & Co., Ltd. Thioalkylthio cephalosporin derivatives
EP0697409A1 (en) * 1994-06-30 1996-02-21 Nihon Nohyaku Co., Ltd. Isothiazole derivatives containing (an) iodoalkylnyl group(s), their preparation and their use as fungicide and/or bactericide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155678A (en) * 1961-11-14 1964-11-03 Du Pont Certain isothiazole compounds and their production
US3341518A (en) * 1965-06-23 1967-09-12 Bristol Banyu Res Inst Ltd 6-[5'-loweralkyl-3'-phenylisothiazole-4'-carboxamido]penicillanic acids and salts thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155678A (en) * 1961-11-14 1964-11-03 Du Pont Certain isothiazole compounds and their production
US3341518A (en) * 1965-06-23 1967-09-12 Bristol Banyu Res Inst Ltd 6-[5'-loweralkyl-3'-phenylisothiazole-4'-carboxamido]penicillanic acids and salts thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989710A (en) * 1973-09-01 1976-11-02 Bayer Aktiengesellschaft Certain 2-mercapto-4,5-dichloro-thiazole compounds
US5352792A (en) * 1990-07-19 1994-10-04 Shionogi & Co., Ltd. Thioalkylthio cephalosporin derivatives
EP0697409A1 (en) * 1994-06-30 1996-02-21 Nihon Nohyaku Co., Ltd. Isothiazole derivatives containing (an) iodoalkylnyl group(s), their preparation and their use as fungicide and/or bactericide
US5578622A (en) * 1994-06-30 1996-11-26 Asamura Patent Office Isothiazole derivatives and their uses

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SE325886B (ref) 1970-07-13
IL27732A (en) 1971-03-24
NL6703832A (ref) 1967-10-24
CH482711A (de) 1969-12-15
GB1124545A (en) 1968-08-21
DE1595995A1 (de) 1970-02-12
BE697389A (ref) 1967-10-23
ES339659A1 (es) 1968-07-16

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