Composition containing isothiazolecarboxylates allowing to fight the moulds and the bacteria at the plants.

PATENT AS AFRICAN AND MALAGASY

INDUSTRIAL PROPERTY

P. 887

international Patent Classification yaoundê (Cameroon): 01 - c 07 no. 02235 has

the R~VBE1

O A>M-I-P

Request 8 June 1966 to 17 hr 30 min

to ro.A.M.p. 1. (g.P. no. 52,477) by

THE FMC CORP.

residing in the United States of America.

5 May 1970 delivered

Published at official ballot № 1 of 1970

PRIORITY:

Patent application filed in the United States of America

the 8 June 1965 sec./ no. 462,428; 11 May 1966 no. 549,152/sec.

trade name Jerold Wang BUSHONG, the Serb by Paul VOLPP.

"Composition isothiazolecarboxylates for combating mold and bacteria in plants".

The present invention relates to novel compositions for combating pathogenic organisms and to novel methods for combatting organisms molds and bacteria in plants, by applica-a 5 action of the novel compositions. The invention particularly relates to novel fungicidal compositions and bactericidal cohtenant some isothiazolecarboxÿlatescoEime active substances as well as novel methods of combating pathogenic organisms in plants by

10 application of such compositions where - grow these■plants; systemic protection is due to the shifting of the active agent in plants..

The protective compositions systemic plants are those which are intended to combat the attack by pathogenic organisms, by means of a delivery mechanism for the complete absorption of the active substance through the roots, seeds, leaves, stems or even the bark plants.

It was found that certain isothiazolecarboxylates constitute agents useful and effective for the systemic control of plant disease produced by mold and bacteria. It has been shown that these chemicals move within a plant upon their absorption and lead to long lasting protection for the seeds, the seedlings as well as the growing plants. Many products among these chemicals also enable effective control mold and bacteria by topical application, so that there can be obtained a wide spectrum of efficacy.

The isothiazolecarboxylates of the invention correspond to the formula:

wherein R is hydrogen or a straight aliphatic saturated or unsaturated, primary or secondary alcohol having 1 to about 14 atoms of carbon, a metal or an amine having attached a proton; X is oxygen or sulfur and is hydrogen, a methyl group or a derivative of a methyl group. the groups E ' (0) and the c - FXR can be each attached to the ring. zoliq.ueisothia to each of the available positions, the numbering of this cycle being indicated above. In some preferred compositions, - the R * is attached at position 3 or 4 and the c - (0) XR is fixed in position 4 or 5 *

LEB in substituents R represent the appropriate

butyl, methyl, ethyl, propyl, isopropyl, ybutyle - employing the same

daire, isobutyl, pentyl, 1 a-methylbutyl, 2 a-methylbutyl, hexyl, 2-chloroethyl, allyl, propynyl, 2-butylidene, an L-nitrate 2-propyl, 2 a-nitroéthyle, 2 a-ethoxyethyl, 2 a-ethylhexyl, octyl, and dodecyl; metals including sodium, lithium, potassium, calcium, strontium, manganese, cobalt, copper and zinc; and amines having attached a proton such as ammonium, triethylammonium, pyridinium, the trimethyl ammonium, butyl ammonium and morpholinium. Suitable derivatives of methyl group represented by R ' are the hydroxymethyl groups, acetoxymethyl, dimèthoxymethyle, carboxaldehyde and carbaidoxime.

the active chemical compounds described herein can be prepared by various methods of synthesis, including methods analogous to the methods already, known for the synthesis of cyclic system isothiazolic. These methods include oxidation of benzo (d-) isothiazole (Adam and Slack, Chem. & lind. 1936 , 1232);

the addition of thiosulfate or thiocyanic acid éthynylcétones on, followed by 1' removing sulfurous acid or hydrocyanic acid (Wille and ai, Angew. Qàem ., DE internship ., 1, 335 (1962)); as well as the vapor-phase reaction of olefins, of acéthylènes or alcohols with sulfur dioxide and ammonia (Hubenett and ai, Angew. Chem., DE. Internship. 1, 508 (1962)); the online. 2, 325>714 - 9 (1963)). The processes for preparing the desired isothiazolecarboxyliques acids useful for forming esters, salts and ammoniates of the invention include treatment of lithium isothiazole derivatives or 3 - or 4 a-allcylisothiazoles to produce the corresponding compound comprising a lithium 5 -? compound is reacted with carbon dioxide to provide 5 a-isothiazolecarboxylic acid (Cato and ai, J mal. Share. 1964, 446); the bromination of 3 a-m.éthylisothiazole with " obtaining 3 a-dibro~mométhylisothiazole is hydrolyzed in and this compound 3 a-formylisothiazoleeèt oxidized with silver oxide to give 3 a-isothiazolecarboxylic acid (by Jones and ai, J mal. Share. 1964, 3114); the isothiazole derivatives and 4.5-dicarboxylic acid prepared by oxidation with permanganate of 5 - aminobenzo (D.) isothiazole derivatives is decarboxylated to give acid 4-isothiazol carboxylic (Adam and Slack, the j.

Mal. Plow 1959, 3061); the 4 a-bromo 3 a-méthylisothiazole reacts with cyanide to give the ctiivreux 4-cyano 3méthylisothiazole which is hydrolyzed to 3 methyl 4-isothiazole derivatives corresponding carboxylic (Belgian Patent 632,394 of 18 November 1963). An EAR selection of suitable starting materials, easily produced the desired acid according to known methods.

isothiazolecarboxyliques acids readily form the corresponding esters, metal salts and amine salts. Methods can be used types for conducting such reactions. Thus the esterification can be carried out by reaction of the acid, acid anhydride, acid halide or salt with the appropriate alcohol or another alkylating agent such as an aliphatic halide or sulfate, usually in the presence of a catalyst. The ammonium salts are readily formed by reacting the acid with the desired amine rigor metal salts are produced by reaction of the acid with the appropriate base. Drifts thiolo can be prepared from the corresponding acid halides of mercaptans and appropriate by methods kinds. A process suitable for the preparation of j-alkyl ee-to-isothiazolecarboxylates is described by Buttimoré and ai, j mal. Share. 1963, 20J2 AND 2039. Another method usable developed by bb.w. Woodward and G.P.Volpp, involves the addition of thiophosgene on the beta-aminocrotonates methyl (Woodward's, tea Dr. Harvey readings, pocketed 59? Academy press assembly, the New York and London, 1965? 3 ^ - 37) · it is evident that the ' reagents and synthetic routes are determined by the chosen désiras end products.

By applying an effective amount and concentration of the active agents described herein where the plants grow, one can then control useful and economically important plant disease produced by many pathogenic organisms infesting plants. Among the agents Pal>ù° Peppers^, ®^{the R>AE} infesting plants include species of bacteria and fungi following: The Corynebacterium, In Erwinia, Xanthcmonas, The Pseudomonas, The Agrobacterium, Rhizobia, and The Streptomyces; and ïïromyces, Venturies, Colletotrichum lindemuthianum, The Fusarium, Yerticillium, Of Alternaria, Cercospora diseases, and Diplodia.

The preparation and properties of representative compounds of the invention are décritesdans following non-limiting examples. All temperatures are expressed in degrees centigrade.

EXAMPLE 1 -

Synthesis of 3'-methyl 4 a-isothiazolecarboxylate of methyl

Has an agitated solution of 57.5 beta-aminocrotonate methyl and 126 g of triethylamine in 3 liters of absolute ether, is added gradually 57.5 s

- thio-phosgene while the solution was cooled in an ice bath. The addition is complete, the reaction mixture was maintained in the cold state for another 1 hour to 2 hours, and then left off gradually assume the ambient temperature. It has adjusted the pH to 5~6 by adding 225 ml D.¹ hydrochloric acid 21t and has been effected the mixture

to that by water vapor. Is removed from the removal of the ether

i * aqueous distillate in ether/hprès drying has provided

40.5 g of 3-methyl 4 a-isothiazolecarboxylate methyl, identical to the product described by Buttimore and ai, j mal.

Share. 1963, 2038.

EXAMPLE 2 -

Systemic bactericidal activity of 3 a-méthyl~4 -methyl isothiazolecarboxylate

Shown to be bactericidal activity systemic as follows: we prepared a composition of wettable powder of 3 a-méthyl~4-to-isothiazolecarboxylateaébhyle of 25% by mixing in weight of chemical substance with 72% attapulgite clay, 1.5% sodium lignosulfonate and 1.5% of naphthalen ^ éulfonate'd ' allcyle. Is prepared suspensions of 3-methyl 4 a-isothiazolecarboxylate methyl in water, containing 600, jog and 150 parts per million active substances, by adding the appropriate amount of the powder composition was poured mouillafhle and 35 ml of each hanging on the plant s of tomato variety by Bonnie brepresents, in individual pots, to obtain equivalent doses. to 21.0 mg, 10.5 mg and 5.25 RAGs D.¹ isothiazole derivatives by the plant. after 2 days jtu inoculated with the foliage of the plants the pathogen Xanthomonas, it is the agent providing the üaches ' Victorian on tomatoes. Were left for about greenhouse plants 10 days and determined the degro disease control by comparing the plants treated with untreated plants. The results are shown in table 1. The number of lesions counted by sheet corresponds to the average of 2 tests by sheet and the numbers for the untreated plants correspond to the average of 4 trials per sheet.

TABLE 1

Systemic control against bacterial spot tomatoes

63

87

91.

Λ

0 EXAMPLE 3 -

Systemic fungicidal activity of the 3-methyl - methyl>4 a-isothiazolecarboxylate

The fungicidal activity of the systemic 3-methyl 4 a-isothiazolecarboxylate methyl was demonstrated corm follows: prepared suspensions of 3 a-Eæthyl-a 4 a-a-isothiazolecarboxylate methyl in water as in the example 2 and were found to be poured on the ground comprising of bean plants in amounts equivalent to 7.5 mg 15.0 and isothiazole by seedling. After 2 days, inoculated leaves to the pathogen rust D bean (Uromyces koae phaseoli the VAR. typica). Inoculated plants were left in a humidity chamber 18 °c during 48 hours to and then put in a greenhouse. The degree of combating this disease has been determined about 10 days after ' inoculation of sheets, by comparison plants treated with untreated plants. The results are shown in table 2 and represent the average of 2 tests for each treatment dose and 4 trials for untreated plants the systemic fungicidal activity of 1' order indicated in table 2 represents a degree important control and extremely useful against the pathogen bean rust, obtained for relatively very low concentrations aa.ctif agent applied to the soil.

Table 2

Systemic rust D bean

Systemic disease

Prepared suspensions of 3-methyl 4 a-isothiazolecarboxylate 1200 ppm methyl containing toxic agent as in the example 2, and were found to be poured on the ground tobacco plants located at individual despots in growing stage to twelve sheets, in an amount equivalent to 42.0 mg isothiazole per plant. After three days, was inoculated with to: sheets the pathogen The Pseudomonas tabaci, agent that produces disease (the Wild on Fire RJ) tobacco. Plants were left in a humidity chamber 18 to 48 hours °ç $uring of the transferred in a greenhouse. It determines the degree of control of 7 to 10 days after inoculation.

The treated plants have an average degree of control of 60%, in. comparing a degree of control of zero for the untreated control.

EXAMPLE 5

We prepared a composition to 5? " âe 3-methyl 4 a-isothiazolecarboxylr.te methyl as granules by mixing 5>05 wt. /® 1' isothiazole derivatives in 7, 5s % aromatic naphthas lousfe with 87.37% clay D.¹ in the form of granules of attapulgite. has been applied the granules on the surface of the sol containing the tomato plants because of 70.0 mg, 52.5 mg, 35.0 mg, 17.5 mg and 8.75&g of active ingredient per seedling.

4 Trials were made for each concentration. Four days after the treatment, inoculated with the leaves of plants to pathogen resulting bacterial stains on tomatoes. The treated plants and control plants were maintained in a greenhouse for approximately '] days and then after the period of time is determined.. with the efficacy of the treatment.

For the entire range of concentrations, a degree of control of 82 to 89% bacterial stains as compared with a degree of control of zero in the case of untreated plants. This has resulted in efficiency results by incorporating the active compound in the soil and by the treatment of the surface portion of the ground described above.

6 LXEhPLE -

Systemic activity obtained by

50% Mixed GN wt. 3-methyl-4isothiazolecarboxylate methyl in 5.0% of "I-to-.arcol 90", aliphatic petroleum liquid distillate, with 45.0% of talc. Is coated seeds of tomato plants by stirring with the above composition, in an amount of 2.0 kg of active substance for 100 kg of seeds. One day after coating, the seed was planted. Twenty - six days later *, was inoculated to the sheets 1' pathogen resulting bacterial stains on tomatoes. Were left greenhouse plants during 8 days was then compared plants grown from seed treated with the untreated control plants. The average number of lesions per leaf obtained for 8 tests was of 60 for the treated plants and 109 for the untreated plants, which represents a degree of control of 45% bacterial stains using this seed treatment -

EXAMPLE 7 -

Fungicidal activity by contacting the 3-methyl 4 a-isothiazolecarboxyla.te methyl The fungicidal activity by contacting the 3-methyl 4~isOthiazolecarboxylete m-thyle was demonstrated using a modification of the technique in cylindrical vessel used to assay the antibiotics, as follows ii

Individual batches have been seeded agar malt molten with back spore aspergillus niger, of Pullularia Aureobasidium pullulans, oD Penicillium expansum and d¹Of Alternaria solani or" Was poured 1' of agar seeded on a PLA is-ue of testing and has been allowed to set. It has a plastic ring or glass with a diameter of 10 to 12 mm at the center of the plate and it has been seeded about 0.25 g of 3-methyl 4 a-isothiazolecarboxylate-methyl. in 1' ring. Was incubated the plates during 72 hours to 2s °C. Has been recorded the distance (in mm) between the growth zone through the proximate the ring as zone of inhibition. The results are shown in the

table 3"

TABLE 3

TOTFMFT yew. R _

We prepared the 5 Me polyethylene resins and 4 a-isothiazo1ecarboxÿlate ethyl from chloride 3-methyl 4 a-Si-O thiazolecarhonyle which itself has éto prepared from the corresponding methyl ester as follows: was stirred suspension of 6s g of 3 a-iaethyl~4-to-isothiazolecarboxylate methyl in 600 ml of sodium hydroxide 2n 2 days at room temperature. The aqueous phase was extracted 3 times with clear an equal volume of ether, then it was cooled in an " ice bath and it was acidified with concentrated hydrochloric acid. The precipitate was isolated by filtration and dried under vacuum over the phosphorus pentoxide with attention of 42.3 acid amides 3-methyl 4 a-isothiazolecarboxylic, melting point 219 and 222°c.par recrystallization in 1' ethanol, the melting point was raised to 230 and 232 degrees Celsius.

There is a mixture of 62.5 chaufé acid amides 3-methyl 4 a-isothiazolecarboxylic and 270 g of thionyl chloride at reflux: during 3 hours. Was the excess thionyl chloride at normal pressure and has been distilled off the crude acid chloride under reduced pressure to give 87 g of chloride 3 a-msthyl-a 4 a-isothiazolcarbonyle, boiling point 95 - 96 degrees/12 mm.

To a solution of 15.0 g of ice chloride 3-methyl 4 a-isothiazolcarhonyle in 75 ml of dichloromethane and 9? 4 g of triethylamine, is added dropwise 4.3 g of absolute ethanol. After half an hour, was removed from the ice bath and was allowed to stand for the reaction mixture 12 hours. The solution was then washed with dichloromethane to water, with a 5% solution of sodium bicarbonate and with a saturated solution of sodium chloride. After drying, the solvent is eliminated at reduced pressure and residuum to a vacuum distillation, boiling point 107 - 108 degrees/llivmi. The spectral results indicate that a mixture of ester and acid chloride was. feels. We therefore repeated the esterification with an additional amount of ethanol and of triethylamine. After the same treatment was

obtained 14.3 s of 3 a-metliyl-to-4-isothiazol-to-carbo2cylate ethyl 24.3

pure, boiling point 91.5 - 93 degrees/3 mm,^I 1.5139 * magnetic nuclear resonance spectra and infrared spectra are consistent with the formula.

Analysis : Calculated for c ^ ^ OAAs ands : C., 49.12; HR, 5.30; '

Found: C., 49.18; hr, 5.26.

By following the OED PO ratoiro.. in the example 2, 1 'systenic activity of 3-methyl 4 a-isothiazolecarboxylate ethyl against bacterial spot tomatoes has been evaluated using doses equivalent to 21.0 mg, 10.3 mg and 3.23 mg C.' isothiazole derivatives by the tomato plant. variety by Bonnie brepresents. We have made degrees OD combating 83%, 84% and 77%, respectively for these doses compared to the degro control zero with respect to the untreated plants.

9 EIEüPLJ -

Synthesis and systemic activity.... the 3-methyl 4 a-isothiazolecarboxythiol£te s-ethyl

To a solution of 9.3 g of ice of ethane-to-thiol and 15.2 g of triethyl amine in 100 ml of dichloromcthane added 20.0 g of chloride 3-methyl 4 a-isothiazolecarbonyle in solution in 25 ml of dichloronéthane. After termination 1^: the addition, the mixture is A maintained at ambient temperature for 14 hours " NC has washed the organic phase

to dilute hydrochloric acid, and dry over anhydrous calcium chloride. The solvent is eliminated in vacuo and the residue was distilled under reduced pressure to give - 16.5 s of 3-methyl 4 a-isothiazolecarboxythiolate s-ethyl, boiling point 77 degrees/0, 1 mm, melting point 35 to 37°•the nuclear magnetic resonance spectrum of a chloroform solution has vertices for 9) 25 ppm, 3) 06 ppm (quartet); 2.70 ppm (triplet energy) and 1.35 ppm

with field decreasing from the tétrsméthylsilane as internal standard, which is in accord with the above formula.

Analysis calculated for c ^ ^ ^ ^ I bone c, 44.92; hr, 4.85;

Found: C., 45.25; hr, 4.92.

The systemic activity was estimated by following

the modus operandi of the example 2 and using doses equivalent to 21.0 10.5 and 5.25 mg of 3-methyl 4 a-isotiiiazolcarboxythiolate s-ethyl by tomato plant. We have made degrees of control of 74%, 65% and 26% as compared with a degree of control of zero for non-treated plants.

EXAMPLE 10 -

Synthesis and biological activity of

1' cLIA 3 a-Bi.éthyl-a 5 a-igothiazolecarboxylique

It has cooled a solution.de 15 g of 3 a-méthylisothiazole in 200 ml of dry tetrahydrofuran by applying a bath of solid carbon dioxide-acetone. Are decreased still con rara.ture the solution additionally to -78° by replacing the bath of carbon dioxide-acetone by a bath of liquid nitrogen. The cold solution was added during 10 minutes at 160 ml of a 15% solution of butyllithium in 1' normal hexane, the aclclition being as quick as possible and the temperature rising point above the-70 degrees, the mixture was stirred 10 minutes and -78° during "^! it was poured into a suspension of solid carbon dioxide in dry ethyl ether. The slurry was allowed to heat up in ether at room temperature, and then it was treated with dilute hydrochloric acid. The aqueous layer was extracted 2 times with ethyl ether and the combined ether solutions is extracted 3 times with a sodium hydroxide solution 2n. It was acidified the base solution having dissolved therein and the precipitate in ether.

The solution was added to 150 ml of water and étherée has been distilled off the mixture. All of the ether and about 1/3 water were distilled to remove valeric acid. When the residue, étq.it cold, isolated crude product by filtration 17.7 sec., FARs recristallisati ^ n in boiling water was thus obtained. 17.0 g of product melts at 202 - 203 degrees.

When tested according to method of the example 2, acid 3 a-néthyl-a 5 a-isotliiazolecarboxyli that has provided a degree of combating bacterial stain of 97%, 97% and 91% for 21.0 mg, 5.3 mg and 10.5 mg /' per plant respectively. When its activity against Phase I-ïïromyces! has been examined in accordance with the procedure of the example 3, L-ascorbic acid has delayed substantially spores development and has provided finally a decrease 80% as to the infection with the disease.

eielpl:

Was a solution of diazomethane property requirements - ether from "Diaznld" (hence he-methyl-ii? - nitroso-P-toluènesulfamide) and ' methanolic potassium hydroxide. The solution was added dropwise to a cold solution

of 8.0 g acid 3-methyl 5 a-isothiazolecarboxylic in

150 ml of meth-to-mole, mowed or ' is 5 - tert hand it-it-the temperature of the. solution to 0°

persistence of the hue the j

1¹ the addition was completed,

iron at room temperature

. It has continued adding up to yellow during 2 min. When

or. left the réchaufet mixture is freed of the excess diazomethane and solvents by distillation. The c-n has distilled the residue to obtain 7_S 5 g of 3 a-sôthyl-a 5 a-isothiazolecarbo -

O

xylc Te which has distilled to 100 - 101/15 mm; melting point 30 - 31 degrees "

Analysis; calculated for CgEL ^ σ2/Tc is the c, 4 - 5 * 90; hr, 4.46;

found e grams, 45.90; hr, 4.35.

When it examines the activity center SAL bacterial stain tomatoes in accordance with the procedure of the example 2, it was found for the 3 a-mëthyl-a 5 a-isothiazolecarboxylate methyl a degree of control of 98 - 99% at concentrations of 2 ^, 0 milligrams, 10.5 mg and 5 * 3 mg per plant.

12 EIEtëFLE

We prepared the 3-methyl 5 a-isothiazolecarhoxythiolate s-ethyl acid from 3-methyl 5 a-isothiazolecarbcxylique via the acid chloride as follows: was mildly heated under reflux for 3 hours a year mixture of 20 g acid 3-methyl 5 a-isotliiazolecar'boxylique and 4 - 0 ml of thionyl chloride. Freed of the excess of thionyl chloride was distilled off by distillation and the product under vacuum by means of the horn to water to obtain 21 g of chloride 3-methyl 3 a-isothiazolecarbonyle, boiling point 86 - 87 degrees/15 millimeters.

Analysis: calculated for c ^ ^ H-CINOS: C., 37" 10; hr, 2.48;

found: C., 37? 17; hr, 2.27.

The solution was cooled mth, 4.3 g of ethanediol agitated and 7" 3 g of triethylamine in 75 ml of dichloromethane to 0° and added dropwise to solution of 9.0 g of the mth chloride 3-methyl 5 a-isoth.iazolecarbonyle. The mixture was stirred without additional cooling during 3 hours and then it was washed with hydrochloric acid in-, dried and distilled to give 8.0 g of 3-methyl 5-a-isothiazol carboxythidLate s-ethyl, boiling point 83 to-s3 degrees/0, 03 mm * analysis: calculated for c ^ ^ hr NOSgî C., 45.00 ;Η, 4.82;

found ii 0, 43.08 ;Η, 4.94.

When examined its activity against bacterial stains tomatoes according to the method of the example 2, it was found for the 3 * - Jnéthyl-a 5 a-isothiazolecarboxythiolate s-ethyl a degree of control of 96 - 98% against this disease, concentrations of 3? 3 to 21, 0 mg per plant.

EXAMPLE 13

Was added dropwise a solution of

10.0 g of chloride 3-methyl 5 a-isothiazolecarbonyle in 25 ml of dichlorornéthane at room temperature to an agitated solution of 7.9 g of ethanol and 7.6 g of triethylamine in 50 ml of dichloromethane. The mixture was allowed to dwell at room temperature for about 72 hours, then it was washed with hydrochloric acid to 5^C./ DEGREES and water.

The washed solution was dried over sodium sulfate and has been distilled to give 8.6 g of 3-methyl 5 a-isothiazolecarboxylate ethyl, boiling point 48 - 50 degrees/0, 15 mm. Analysis: ^ ^ CyE calculated for the m e: C., 49.11; hr, 5.30; 1, 8, 18;

found: C., 49.34; the H, 5.41; 1, 7, 92.

When examined its activity against bacterial stains tomatoes according to the procedure of the example 2, there was a degree of control for the exeellent 3-methyl 5 a-isothiazolecarboxylate.

EXAMPLE 14

Synthesis and systemic activity of the 5-methyl 5 a-isothiazolecarboxylate propyl

Which has been reacted with 10 ml of 1 propanol 10.0 g of chloride 3-methyl 5" isothiazolecarbonyle using the process of example 13 to give 9.65 g of 3 a-'méthyl-a 5 a-isothiazolecarboxylate propyl, boiling point 60 - 62 degrees/0, 13 mm.

Analysis: calculated for hCG ^ ^ e ïTC: - 0, 51, 82, hr, 5.99; the n, 7.56;

found: 0, 51, 95; hr, 6.29; e, 7.36 was obtained an excellent degree of combating bacterial stain tomatoes when examined the activity of the 3-methyl 5 a-isothiazolecarboxylate according to the procedure of the example 2.

EXAMPLE 13

Synthesis and systemic activity of the 5-methyl 5 a-isothiazolecarboxylate of 2 a-propynyl-L-reacted with 10 g of chloride 3-methyl 5 a-isothiazolecarbonyle with 4.3 g of propargyl alcohol using the procedure in example 13, but has not been distilled product. After drying the solution containing the crude product, the solvent is removed under reduced pressure A fact recrystallizing the residual solid in hexane to give of b, 5 g of 3-methyl 5 a-isothiazolecarboxyla.te of 2-propynyl-L-, melting point 72 - 74 degrees.

Analysis: calculations for CgHyï ^ e: grams, 55.02; hr, 3.90; Ε, 7.73 ;

found: C., 55.03; hr, 5.86; Ν, 7.47 when e examined its activity according to the method of the example 2, there was an excellent degree of control for the 3 "® - sthyl-a 5 a-isothiazolecarboxylate of 2-propynyl-L-, against bacterial stains tomatoes.

EXAMPLE 16

Synthesis and systemic activity of the 3 a-ffléthyl~5-to-isothiazolecarboxythiolate s-methyliyûne cold solution (ice bath) of

7.6 g of triethylamine in 50 ml of dichloromethane was added 7.9 g of methanethiol. during which maintained the temperature below 10 degrees, was added slowly a

10.0 g of chloride solution of 3-methyl 5-isothiazol -

25

in carbonyl/ml of dichloromethane. De-noised bath

of refroidissenent has been allowed and left for 20 hours méleange. Ε is lore the solution 2 times to hydrochloric acid in-, dry and distilled to give 9.0 g of 3-methyl 5 a-isotbiazolecarboxythiolate s-methyl boiling point 64 - 66 degrees/0, 04 mm.

Analysis: calculated for hCG ^ ïfOSg: C., 41.59; hr, 4.07; n, 8.09;

found: C., 41.76; hr, 3.95; u, 7.87.

When examined in accordance with the activity

the method of 1' example 2 has been found to degrees of control of 99/c, 99 c/o and 100% for the 3-methyl 5 a-isothiazolecarbo2cythiolate s-methyl against bacterial stains, for respective doses of 21.0 mg, 10, ^ mg and 5.5 mg per plant.

Synthesis and systemic activity of the 5-methyl 5" isothiazolecarboxyfchiolate of s-propyl

Have been reacted 5.5 g of propan-l-thiol with 10.0 g of chloride 5" ifté'tfoyl-a 5 a-isothiazoleearbonyle according to the method described in the example 16 to give 10.6 g of 5 a-mëtiiyl-a 5 a-isothiazolecarboxythiolate s-propyl which has distilled 7s above 80 degrees has 0 /, 1 mm.

Analysis: calculated GC hi ^ UOSg; grams, 47.75; ΰ, 5.51 ; h, 6.96;

found ii C., 48.02; hr, 5.55; n-, 7.05 in assays conforming to the procedure described in example 2, there was a degree of activity of the total 3-methyl-5isothiazolecarboxythiolate s-propyl already low spots' bacterial tomatoes for doses of 21, c-mg and 10.5 mg per plant and a degree of activity of 99% for a dose of 5j3 mg per plant.

EXAMPLE 18

Synthesis and systemic activity of the 3-methyl 5 a-isothi&zolocarboxylate triethylammonium NC has dissolved a mixture of 5) 0 g acid 3-methyl 5 a-isothiazolecarboxylic and 3" 5 g of tri-ethyl amine in 2.5 s by water. Brown solution was used for tests to the example 2 without performing purification or without preparing crumb another composition. The degrees of activity against bacterial stain tomatoes to doses of 21.0 mg, 10.5 mg and 5" 3 mg per plant were respectively of 99%) 98% and 99%•

EXAMPLE 19

Synthesis and systemic activity of

1¹ acid ~niéthyl 4 and 5 a-isothiazolecarboxylic

NC has cooled solution of 7) 5 s of 4~mcthylisothiazole in 130 ml of dry tetrahydrofuran in a bath of solid-acétcne COGs. There is instead the bath of COG acetone by a bath of liquid nitrogen and reduced the temperature of the solution to -78 degrees. Was slowly added to the solution cold for 4 - 5 min, a solution of 7) 2 g of butyl lithium in 78 ml of hexane. Resized the rate of addition so " seen the temperature of the reaction mixture does not exceed

- 75°•was poured the mixture immediately in a suspension of solid COGs. The slurry was stirred during commit échauffait 0° slowly. Was added diluted hydrochloric acid (ln), SAL layers were separated and the aqueous layer was extracted with ether. Have been combined organic extracts and were found to be extracted with 3 volumes of a solution of sodium hydroxide 211. Was acidified to alkaline aqueous solution, is resumed acid α - precipitated in ether, and incorporated with the ether solution in a vial will cost 150 ml i.e. ec.u. Has been distilled off the ether and about

50 ml of water to remove valeric acid. The LS residual solution was cooled water and the solid was isolated by filtration to give 6 g acid 4 a-méthylisothiazole-to-5-carboxylic, melting point 177 - 179 degrees "

Analysis: logarithms for: ^ ^ ^ C. hence he îs e: C., ^ 2, 10; hr, 5.50;

found: 0, 41.78; hr, 3.50.

When examined its activity in accordance with the procedure of the example 2, it was found for the acid 4-methyl 5 a-isothiazolecurboxylique degrees of activity of 95%, 95% and 92% against bacterial stains tomatoes to respective doses of 21.0 mg, 10.5 mg and 5.3 mg per plant.

EXAMPLE 20

The prepared 4-methyl 5 a-isothiazolecarboxylate acid from ethyl 4 a-mëthyl-a 5 a-isothiazolecarboxylic via the acid chloride as follows:

Was heated a mixture of 88 g acid 4-methyl 5 a-isothiazolecarboxylic and 118 g of thionyl chloride in 50 ml of benzene during 18 hours to about 80°. Having added a supplement of 82 g of chloride of thio ' nyle and heated the mixture at reflux for 3 hours.

Freed of the excess of thionyl chloride and benzene by distillation and 1 residue is distilled under reduced pressure ο. By re-distillation has been ettenu 59.2 g of chloride 4-methyl 5-to-a-isothiazolecarbonyledistillait to 90 - 93 degrees which/25 mm.

Has an agitated 7" 9 s by ethanol and 7.6 grams of triethylamine in 50 ml of dichloromé Thane was added slowly at room temperature a solution of 10.0 g of chloride 4-methyl 5 a-isothiazoleoarbonyle in 25 ml of dichloromethane. The mixture was allowed to stand for 20 hours, then it was washed 2 times with hydrochloric acid 1f and water. The washed solution was dried and has been distilled to give 6.0 g of 4-methyl 5 a-isothiazolecarboxylate ethyl, boiling point 113 - 115 degrees/mm 21.

Analysis: calculated for c ^ ^ H-FOgS: C., 49.11; hr, 5? 30; f, 8.18;

found: C., 49.3 ^; hr, 5, ^ e; F., 8.45.

By examining 1' activity of 4-methyl 5 a-isothiazo|ecarboxylate. ethyl in accordance with the method of the example 2, bacterial stains tomatoes to respective doses of 21.0 mg, 10.5 mg and 5.3 mg per plant, there were degrees of activity 98%, 97% and 95% "

21 EAFiâ-to-he and

^Û n has cooled an agitated solution of 9? 3 grams

of 1-propanol and 10.8 g of triethylamine in 75 ml of dichloromethane in an ice bath while added dropwise to a solution of 12.0 g of chloride 4-methyl "" 5 a-isotliiazolecarbonyle in 25 ml of dichloromethane.

Has been removed the ice bath and was allowed to stand for the reaction mixture 20 minutes at room temperature.

The reaction mixture is washed with A. to hydrochloric acid in vivo, was then volatiles are removed under reduced pressure and has been distilled off the product. îar re-distillation

10.3 g of the obtained 4 - * mëthyl-a 5 a-isothiazolocarboxylate propyl that boiled to 55 - 59 degrees/0, 75 mm.

Analysis: calculated for EMC ^ ^ e lo and: grams, 51.57; hr, 5.99; 1, 7, 55;

found: grams, 51.96; h, 5.93; 1, 7, 51.

In O: - s.is performed in accordance with the

procedure 1' example 1, it was found for the 4 a-CD the Thyl-a 5 a-iscthiasolocarbo: -: ylate propyl, back degrees of activity of 95%, 95% and g5% against the LOS bacterial stain to verbs: iites, at doses respective 21, O-RAGs, 10.5 mg and 5.3 mg per plant.

EXAMPLE 22

Synthesis and systemic activity of the 4 methyl-5 a-isothiazolecarboxythiola.te s-methyl

It has cooled solution of 7.9 g of methanethiol and 7.6 g of triéthylanire 5g of ns thx.nedichloromê ml to about 0° and was added slowly a solution of 10.0 g of chloride OD 4 a-néthyl-a 5 a-isoth±azolecarbonyledichlorométhanc 25 ml of donations. Has been removed the ice bath and the mixture was allowed to stand at room temperature for 20 hours. It was then washed 2 times with hydrochloric acid 11, it was dried and the dried solution with distilled." obtaining of 7.7 g of 4 a-meth.yl-a 5 a-isothiazolecarboxythiolato s-mcthyle, boiling point 76 - 74 degrees/0, the G2 millimeters.

Analysis: ^ ^ CTCL computes for CGH were: C., 41.55; hr, 4.07; n-, 8.09;

found: C., 41.85 "hr, 3" 99; the n? 7? 95.

In back tests performed confornement at

procedure 1' example 2, is determined for the formulae 4 a-méthméth.yl-a 5 a-isoth.iazoleca.rboxyth.iolate s-néthyle degrees of activity of 99%? 98%, and 99%, their interactions with bacterial stains tomatoes, for respective doses of 21.0 nanograms;

10.5 mg and 5j3 mg per plant.

3 ≤ Χΐ;νρΐ 25

the Mo -! - T-hly - 5 I-O O T of hi and has Z-O 1 I c has Rh-oxyth tee-OD-s-prooryl th

LC

/Is made according to the method of reacting 1' g.

22, 5.3 g of 1 a-propanethiol with 10.0 g of chloride 4-me-to-polyethylene resins and 5 a-isothiazolecarbonyle obtain 8.2 g of 4-methyl - 5 a-isothiazolecarhosythiolate s-propyl, boiling point ûg and 84 degrees/0, 07 mm.

Analysis: 0 Iculé for: ^ ^ our CGH were: C., 47.75; hr, 5" 51; ITs, 6.96 ' found: 0, 47.88; the H, 5.54, does, 7.21.

When it was examined conforiaément at procedure 1' example 2 was shown for the s-propyl isothiazolecarboxythiolate 4~methyl~5 degrees of activity of 99%, 98% and 97%, against bacterial stains tomatoes, for respective doses of 21.0 mg, 10.5 mg and 5.3 mg per seedling.

EXAMPLE 24

It is: rifié. 6.0 g acid 5 a-isothiazolocarboxylique by reaction with diazonéthane according to the method of 1' example 11 was obtained and 6.0 g of methyl 5 a-isothiazolecarboxylate, boiling point 68 degrees/15 mm;

melting point 40 - 42 degrees.

Analysis: calculated for c ^ ^ ^ hr IFO 8371 e: C., 42.0; hr, 3.5;

found: C., 41.9; e, 3.5 "

The degrees of activity against bacterial stain tonates found in tests made in accordance with the method of the example 2 were OD 95%, of 86% and 67% for respective doses of 21.0 mg, 10.5 mg and 5j3 mg per seedling.

EXAMPLE 25

The synthesis and activity systonique 3-methyl 4 a-a-isothiazolecarboxylate of 2-propynyl and 1

It has cooled a mixture of 3, 5g alcohol propargyligue and 15.0 g of triethylamine in 150 ml of OD ' ch-dichloromethane nsec. an ice bath while stirring vigorously. L this cold solution was added dropwise 10.0 g of chloride 3-methyl 4 a-isothiazolûce.rbonyle. The resultant solution was washed with water, baking soda in-, with sodium chloride to 5% and hydrochloric acid 1n " has dried the washed solution and ' it was distilled under reduced pressure. By crystallization of the distillate was obtained 7.1 g of 3-methyl 4 a-isothiazolecaboxylate of 2-propynyl and 1.

Analysis: calculated for: ^ ^ ggee LC-sii grams, 53.04; hr, 3.90;

found ii C., 53.34; hence he, 3.95.

Examining the j-mcthyl - ^ - isothiazolecarboxylate of 2-propynyl-L-according to the method of the example 2 showed degrees of activity against bacterial stain tomatoes of 86%, 87% and 94% "for respective doses of 21.0 mg, 10.5 mg and 5" 3 mg per plant.

EXEULE - 26

Preparation of bis (3 ~méthyl-a 4 a-isothiazolecarboxylate) The Ag 2 a-butynylene

5.3 Grams AEs AEs by reacting 2 a-butyn L, 4 diol and Ae 10.0 grams AEs AEs chloride 3-methyl 4 a-isothia.zolecarbonyle according to the method of 1' example 25, this has resulted in a solution of a product by evaporation gave a crude solid. FARs recrystallization in dichloromethane was obtained 5.5 g of the bis - (3 methyl 4 a-isothiazolecarboxylate) AEs 2 a-butynylene, melting point 114 - 115 degrees.

Analysis: calculated for 0, 50, 00 h, 3.60

Found: 0, 49, 49; h, 3.88

When " 'a examined bis (3 methyl 4 a-isothiazo~lecarboxylate) AEs 2 a-butynylene AEs procedure in accordance with the example 2, was conste, tee degrees of activity of 92%, 94% and 92/3 against bacterial stains tomatoes to respective 21.0 mg doses, 10.5 mg and 5.3 mg per plant.

EXELPLE - 27

Bynthèse and systemic activity of the ' 3 a-methy1-a 4 a-1sothiazo1ecarboxy1ate L-nitrate 2 a-propythe

We prepared the 3-methyl 4 a-isothiazolecarboxylate L-nitrate 2-propyl by esterification of L-nitrate 2 propanol using anhydride 3 a-mm.é polyethylene resins and 4 a-Si othiaz goose ARB with c-oxylic obtained as follows:

It was heated to reflux a mixture of 40.0 g of diacid 3-methyl 4 a-isothiazolecarboxyliç [UE and 310 ml of acetic anhydride for 15 hours. The reaction mixture was allowed to cool to temperature aiabiante and eliminated a small amount of white solid by filtration. Eliminated the acetic anhydride and the unreacted acetic acid by distillation at 30 mm. The residue is solidified by cooling. The solid residue was dissolved in 300 ml of toluene and poured the solution into 375 ml of hexane. The resultant solution was treated with activated carbon and to the clear solution was added 200 ml of pentane. The mixture was cooled to allow complete separation of the crystalline solid. The solid was isolated by filtration to give 11.6 g of acid anhydride 3-methyl 4 a-isothiazolecarboxylic desired, melting point 129 and 130 degrees Celsius.

WITH 4.8 g of L-nitrate 2-propanol containing 1 drop of concentrated sulfuric acid was added by small portions 11.6 g of anhydride in 3 a-métîiyl-a 4 a-isotliiazolecarboxylique. The mélarg ^ has solidified after addition of about 1/3 of 1' the anhydride. The mixture was heated to 60 degrees for 4 hours /. Was added 3 volumes of benzene and suspended solid isolated by filtration and is identified as being acid 3-methyl 4 a-isothiazolecarboxylic. Benzene has been distilled off the solution and after removal of low boiling materials was obtained 5 "9 s 3-methyl 4 a-isothiazolecarboxylate L-nitrate 2-propyl, boiling point 125° / 10"^mm.

Analysis: calculated for hCG ^ ^ ^ 9.ï O-O: C., 41.73; h, 4.38; ITs, 12.17;

Found: C., 42.20; Η, 4.34 ; n, 11.24.

When examined the 5-methyl 4 a-isothiazolccarboxylate L-nitrate 2-propyl in conformity ' centeredly at procedure the example 2 found degrees of activity of 97%, 98-and 96% against bacterial stains tomatoes_F. for respective doses of 21.0 mg, 10.5 mg and 5.5 mg per plant.

EXAMPLE 28 -

synthesis and systemic activity of the 5-methyl 4 a-isothiazolecarboxylate methyl

It has cooled solution of 9.0 g acid in 250 ml of 4 a-i3othiazolecarboxyliquetétrehydrofuranre dry -75° by using a bath of liquid nitrogen. Was added dropwise a solution of butyllithium in 1' normal hexane (120 ml containing 15% of butyl lithium) for 50 min. Temperature was maintained lower compound to -70 degrees making the addition.

When the addition was completed, the reaction mixture is left confectioneries heat up slightly but by holding it between -65 70° during 15 min - and. It has cooled fresh * therein, the mixture -75 degrees and has been treated with 28 g of sulfate dinéthyle again by maintaining a temperature of less than -70 degrees through during the addition. When the addition was completed OD dimethyl sulfate, the mixture was allowed to warm slowly to room temperature. The solution was extracted with 5 times. 50 ml portions of sodium aydroxyde OD 2nd.

Have been combined aqueous extracts and were found to be acidified by addition of concentrated sulfuric acid. Has been extracted the aqueous solution continuously with ethyl ether during 24 hours. The extract was dried ethereal and has been distilled to give 5.5 g of a yellow solid that was used without further purification*

Was treated a solution of 15 g of acid 5 a-méthylisothiazole-to-4-carboxylic acid in 200 ml of methanol with diazomethane in ether to 0°. Eliminated the ether and methanol by distillation has been distilled off and the residue, under the pressure of the tromp.. e with water to give 8.5 g of 5-methyl 4-isothiazol-a 4 a-carbodiimide: xylate methyl, boiling point 100⁰/15min; melting point 42 above 45 degrees Celsius.

Analysis: calculated for hCG ^ NOgS: C., 45.90; hr, 4.46;

Found: C., 45.82; hr, 4.74.

In experiments on the 5-methyl 4-isothiazol-carboxylate methyl according to the method of the example 2 are found degrees of activity of 88%, 87%, and 77% against bacterial stains tomatoes to respective doses of 21.0 mg, 10.5 mg and 5.3 mg per plant.

EXEhPLF - 29

Synthesis and properties of systemic

1¹ acid 5 bishydroxymethyl-4 a-isothiazolecarboxvlique

To a solution of 100 g of 3-methyl 4 a-isothiazolecarboxylate in 1 liter of methyl carbon tetrachloride was added 114 grams of f-bromosuccinimide are. The slurry was heated to reflux and has been agitated. The agitated mixture is irradiated with a sun lamp during 2 hours 1/2. At the end of this period only saw more of f-bromosuccinimide are. The suspension was cooled and has been filtered.•

The precipitate was washed with 250 ml of carbon tetrachloride■chilled and have been combined filtrates and were found to be concentrated under pressure

dthyliqu "

reduced

Recrystallizing the residue was, in 1

T tLLs

. S

obtaining a j-bror.onéthyl 72.6-to-'de - ^ - - isothiazole derivatives methyl cerboxylate, melting point 80 - 82 degrees - the ethereal solution wherein the compound nonobroué - has crystallized contains a mixture OD section: about sgaiscle concerns-nctliyl-a 4 a-isotliiazolecarboxylate OD OD and methyl 3 a-dibro£ioiaéthyl-a 4 a-isothiazolecurboxylate of néthyle.

nalyso.: calculated for c ^ ^ e BgBrïTO; C., 52.52; hr, 2.56;

3, 15.58; Brr, 33.85;

Found: C., 30.77; hr, 2.76;

O, 13.73; brr, 34 -, 11.

NC-refluxed 6 hours making a mixture of 25.6 g of 3 - b - 1 thy a renewed 4 I-O-O ethi o.z the O C. 1 C. HRO oxy1ate of néthyle and 250 2ît nor sodium hydroxide. Has cooled the solution at room temperature and it was acidified by

•OD 20 nor the addition of concentrated hydrochloric acid. The LS was allowed. acidified solution dwell while auo the solid cristalli knows. gold has isolated the crystalline solid by filtntion and 3.' has dried under vacuum and then sublimated 100 °c to 160 °c to obtain 10.0 g acid 3 a-hyclroxynéthyl-a 4 a-icothiasolecarboxylique, melting point 197 - 202 °0.

analysis:

Calculated for CrLL-to-an HO ^ e:

found:

0, 37, 74 -;

GM, 38.30;

HR, 5.17;

^T 9.ï, 3.51.

EXAMPLE 30 - - - 55

Was treated a solution of 34 - 0 mg acid 3 hydroxy-methyl-4 a-isothiazolecarboxylic in 20 ml of methanol with diazomethane in accordance with the method of the example 11. This solution having dissolved in an equal volume of ether and carbon tetrachloride and the solution was washed with a 5% solution of sodium carbonate, with a saturated solution of sodium chloride and 5% with a solution to he and sodium sulfate. The elinination solvents by distillation and recrystallization of the residue in carbon tetrachloride gave 270 mg of 3 bishydroxymethyl-4 a-isothiazolecarboxylate methyl, melting point 77 - 78 degrees.

Analysis: calculated for hCG ^ ^ e ïîo: C., 41.62; hr, 4.08;

found: C., 42.62; hr, 4.56 when examined the 3 hydroxymethyl-to-4 a-isothiazolecarboxylate methyl according to the method of the example 2, it was found a degree of activity of 97% against bacterial stains for a dose of 21.0 mg per plant.

31 EXEî&CLP -

Synthesis and activity of languageQ.the UEs 3-methyl 4 a-isothiazolecarboxythiolate s-methyl

By reaction of 8.5 g of meth ^ el 15.0 g of chloride and of 3-methyl 4 a-isothiazolec3rbonyle according to the method of example 16, was obtained 5? 0 g of 3-methyl 4 a-isothiazolecarboxythiolate s-methyl, boiling point 70 degrees/0, 1 mm; melting point 61 - 63 degrees.

Analysis: calculated for: C., 41.60; hr, 4.05;

found: C., 42.01; hr, 4.21 when examined the 3-methyl 4 a-isothiazolecarboxythiolate s-methyl according to the inode. operation of the example 2, it was found the degrees d'act5.vité of 96%, 83% and 67% against bacterial stains, for doses of 21.0 mg, 10.5 mg and 5.3 mg per plant.

ixZEjX_il Tm - PI-p2

We prepared the 3-formyl 4 - isothiazolecarboxylate by hydrolysis of methyl 3 - (dibromomethyl) - 4 a-isothiazolecarboxylate methyl, obtained as follows:

Has an agitated solution of 4 - 3, 9 grams 3rd 3-methyl 4 diiminoisoindolene ΐΜ3ζο1℮οβΛοχ··-to-ΐ3ΐ ℮ methyl in 450 ml of carbon tetrachloride, was added 100 g of VI-bromosuccinimide are heated the mixture. NC at reflux temperature and has been irradiated with a sun lamp piendant 31 hours while maintaining a gentle reflux flow. The solution was cooled to brown 4° and eliminated the succinimide by filtration. The filtrate was concentrated by distilling the carbon tetrachloride and residuum to the distillation

1 rOMs. It has been shown by nuclear magnetic resonance applications that the first fraction of 3.4 grams contained the monobromo compounds and dibromométhyles in a ratio of about

4 to 3•part has 77.6 grams contained 38.5% of 3 a-Cbnomométhyl) - 4 a-isothiazolecarboxylate 61.5% of methyl 3 - (dibromomethyl) - 4 a-isothiazolecarboxylate methyl.

FARs recrystallization in a minimum of ethyl ether boiling was obtained 42.8 g of 3 - (<iibromométhyl) - 4 a-isothiazolecarboxylate pure methyl; melting point 61 - 62 degrees.

Analysis

calculated for DC-a HT-brr ^ Teilhard•C., 6, 5 2, 2 ^ 22.87; 10.19; hr, brr, 50.72 1.61

found: C., 23.08; hr, 1.85

O, 10.04; brr, 50.37

Has a hot solution of 3.2 g of 3 - (dibromomethyl) - 4 a-isothiazolecarboxylate in 23 ml of methanol methyl, we aiouté a solution of 4.6 g of silver nitrate in 6.0 ml of hot water. The mixture was heated at reflux for

5 min. A yellow precipitate appeared immediately. Has cooled the solution and the precipitated excess silver ion solution is added to 5% of sodium chloride.

Eliminated the silver salt precipitate by filtration and the solid was washed with water and chloroform. Have been combined filtrates were extracted with aqueous and an equal volume of chloroform. We washed the combined chloroform extracts with a saturated solution of sodium chloride and dried the chloroform solution was washed over sodium sulfate. It has removed the solvent and the residue was collected 1.14 gm, melting point 92 - 96 degrees. By recrystallization in the étheréther petroleum followed by sublimation 80° under 0.5 mm, the melting point of the 3-formyl 4 a-isothiazolecarboxylste methyl was raised to 98 - 99 degrees•

Analysis: calculated for hCG ^ îto s: C., 42.11; hr, 2.95; n-, 8.19

found: C., 42.39; hr, 3.21; F., 7.83 when examined the 3-formyl 4 a-isothiazoicarboxylate methyl AIs in accordance with procedure described in example 2, there was a degree of activity of 77% against bacterial stains tomatoes for a dose of 21.0 mg per plant.

33 EUSUPLE -

Synthesis and systemic activity of the

3 - 00" (hydroxyimino) methyl - 4 a-isothiazolecarboxylat ^I methyl -

It was heated to reflux a mixture of 800 mg of 3-formyl H isothiazolecarboxylate methyl, of 1.0 g of hydroxylamine hydrochloride in 5 ml of pyridine and

10 ml of methanol under reflux for 3 hours sounds. The solvent is eliminated at reduced pressure and the residue was triturated with a mixture of 5 ml of chloroform and 3 ml of hydrochloric acid 1f. n has washed the layer. chloroformic with

5 ml of hydrochloric acid 2! 9.ï and with 5 ml of a saturated solution of sodium chloride, was then dried. It has removed the solvent and the residue was sublimated 125° under 0.5 mm to obtain 200 mg of 3 - [(hydroxylmino) methyl a j-4 - methyl isothiazolecarboxylate, point fusion' 167 and 169 degrees■

Analysis: calculated for FMB ^ ^ ^ O-it-e: C., 30.72; hr, 3.25

found: C., 39₅ OA; hr, 3, ' + 2 when attempts are the 3 -) _ (hydroxyimini) methyl } methyl - 4 a-isothiazolecarboxylatevaode according to the procedure in example 2, it was found according to the degrees of activity of 98%, 91% and 96% against bacterial stain ôes tomatoes to respective doses of 21.0 mg, 10.5 mg and 5 * 3 mg per plant.

5 Hr ELSiéPLl -

Sthe systéraigueynthèse and activity 3 - (dimethoxymethyl) - " I isothiazolecarboxylate - methyl

Was heated nearly to reflux a solution of 20.0 g of 3 - (dibromomethyl) - methyl-isothiazolecarbox.ylate in 150 ml of methanol and to this solution is added a warm solution of (70°) 29.0 g of silver nitrate in 36 ml of water. Was heated m " at reflux for 5 hours diaper.

It is a yellow precipitate formed immediately. Has cooled the suspension and added an excess of a solution to

10? e of sodium chloride. The mixture was filtered and the solution was concentrated by distillation of 1' eauméthanol azeotrope. The aqueous suspension was cooled residual and it was extracted with an equal volume of chloroform. The chloroform layers were washed with a saturated solution of sodium chloride and was dried over sodium sulfate.

By removal of the solvent, was obtained 15.6 g of a 3-formyl 4 a-isothiazolecarboxylate methyl 3 - (dimethoxymethyl) - 4 a-isothiazolecarboxylate methyl. The mixture was dissolved in 100 ml of methanol and the solution was saturated hydrochloric gas dry. While hydrochloric acid continued to sparging the mixture, subsequent increase at reflux temperature that was maintained for 1 hour. The mixture was cooled and then poured into an excess of sodium hydroxide 2f chilled and have been extracted from the mixture basic aqueous with an equal volume of chloroform.

The chloroform extracts were dried and was concentrated to give a residue by distillation 2.7 g of giving 3 - (dimethoxymethyl) - 4 a-isothiazolecarboxylate methyl, boiling point 119 - 120 degrees/1, 8 mm.

Analysis: calculated for OgH ^ ^ e POs: C., 44.24; hr, 5>11

found: C., 43.93; hr, 5j21 when examined 3 - (dimethoxymethyl) the - 4 a-isothiazolecarboxylete methyl according to the procedure of the example 2, there was a degree of activity of 69% against bacterial stains tomatoes for a dose of 21.0 mg per plant.

Other examples of compounds covered by general formulae in the present specification,

which may be crumb as compositions fungicides and bactericides and be applied as described, include:

the 5-M 3thyl-to-a-isothiazolecarboxylate propyl

the 4 a-n4th.yl-a 5 a-isothiazolecarbo:; cyl.? Te of methyl

the 4 m; the Thyl-a 5 a-isothiazolecarboxyl3te of 2-propynyl and 1 the has - methyl-5 a-isothiazolecarboxythiolate s-ethyl

the 3 a-isothiazolecarboxythiolate'e S-ethyl

1¹ 5 a-isothiazolecarboxylic acid

the 5 a-isothiazolecarboxythiolate s-ethyl

the 3-methyl - ' isothiazolecarboxythiolete. + - s-propyl 1¹ 3 - (3cétoxyméthyl) acid - tert-isothiazolecarborylique

the 3 methyl-has - isothiazoleearboxylate sodium.

The isothiazolecarboxylates compositions according to the invention form systémioues effective when mixed with any adjuvants related; the ent inert carriers normally used to facilitate the dispersion of the active agents for agricultural applications, considering unterstanding the composition and mode of application of a toxicant may affect the activity of the material for a given application. Thus, these compounds fungicides and bactericides assets can be formed into granules having dimensions relatively high particle in the form of dust, powder form mouillsble, as dd.e product emulsifiable concentrate, solution form or in any form among the various other types of known shape, according to the desired application.^{the U} in ES compositions may contain an amount of between 0.5% and 95% or more by weight of the active substance.

The dusts or powders are dd.es mixtures of the substance® discitive with finely divided solids such as talc, natural clays, soil leaf brewer, powders such as powdered walnut shell flour and oil and other organic or inorganic solids which act as dispersants and carriers for the toxicant, which are flowing freely;

these finely divided solids have particle sizes of less than about average ?0 micron.

A typical powder composition, that can be used according the present invention is a composition containing 1.0 part isothiazole and 99.0 parts of talc.

Wettable powders are also useful compositions and are in the form of finely divided particles that disperse readily in water or other dispersant. The wettable powder is ultimately applied either as a dry powder, or as a suspension in water or another liquid.

Vehicles toab ' spikes for wettable powders include Fuller's earth, kaolin clays, silicas and other organic or inorganic diluents readily wettable. Wettable powders normally are prepared to contain about 5 to 95% of active substances, according to the absorption capacity of the vehicle or carrier and they usually also contain a small amount of a wetting agent, dispersant or emulsifier imposition to aid wetting or dispersion. For example, a wettable powder composition usable contains ^ 5, O-parts isothiazole, 72.0 parts clay attapulgite and 1.5 part, sodium lignosulfonate and 1.5 part of sodium alkyl as wetting agents.

Other compositions that can be used are the products that are emulsifiable concentrates as liquid compositions homogeneous or paste, can be dispersed in water or other dispersant and may be formed entirely of 1' isothiazole derivatives with a liquid or solid emulsifying agent or may also contain a liquid carrier such as xylene, heavy aromatic naphthas are, dimethyl sulfoxide, isophorone and other non-volatile organic solvents ;. For the application, these concentrated products are dispersed in water or another liquid carrier and are normally applied by spraying onto the area to be treated. The weight percent of

the essential active ingredient may vary in accordance with the composition

how to apply - does/but in general it comprises 0.5% to

95% active ingredient by weight based on the bactericidal or fungicidal composition.

The compositions in the form of granules, in which the active substance is supported by relatively coarse particles, are usually applied to the soil in which plants grow or in which native plants or plants to be protected. Of sunports are typical for compositions in the form of granules comprise attaprlgite of clays, kaolin clays, fuller's earth soil, sand, i3 vermiculûte, perlite and other organic or inorganic materials, which absorb or which may be coated with the active substance. The compositions in the form of granules are normally prepared to contain about 2 to 25% of active substances and may also contain small amounts of other substances such as agents surfactants (wetting agents, dispersing agents, emulsifiers), oils (kerosene, naphthas heavy aromatics, vegetable oils) and tackifiers (dextrinesj glues or synthetic resins). The mean particle size of the granules are traditionally included between 2400 and 150 microns thick. A composition usable, as granules contains for example 10.1 parts by weight of isôthiazolecarboxylate, 15₅ 2 parts of aromatic naphthas (boiling range 177 à252 °C) and 74.7 parts clay D.^F. attapulgite clay (particle size of 0.7 mm/0, 50 mm)/

Wetting agents, dispersants or emulsifiers used in the compositions typical agricultural comprise for example alkyls and the alkylaryl sulfonates and sulfates and their sodium salts; polyalcohols and other types of agents surfactants; numerous products of these agents are commercially.

The surfactant, whem ' it IXC■used, 1 to 15% of normally represents by weight of the composition.

Other compositions useful for applications on the ground include simple solutions of the active substance in a dispersant in which it is completely insoluble to the desired concentration, such as acetone, alkylated naphthalenes, xylene or other organic solvents. Pressurized sprays, aerosols typical in which the active substance is dispersed in finely divided form as a result of vaporization of the medium dispersion solvent low boiling point, such as freons, may also be used.

One can then control useful against bacteria and molds infesting plants by applying an amount and a concentration of effective active izothiaaola seeds, ground, before confirms, at the time of plant or during the growth of the plant, or by incorporation into the ground or applying to the soil suriace; and on increasing the plant itself either directly to the foliage or even by injection into the green rod the trunk of the plant or of the shaft.

In deùors of their systemic activity and topical, these novel bactericides and fungicides also provide excellent residual activity in the soil and in the plant by providing long lasting protection against plant pathogens.

The active compounds of the invention may be in the form of compositions and/or applied with other active compounds such as insecticides, nematocides, agents for regulating plant growth, fertilizers, other fungicides or bactericides and similar products. They also have utility as regards the effect on the growth of bacteria and molds in the varieties of cut plants, for the use in combination with detergents and washing liquors antiseptics, for the preservation of the leather, the preservation of wood and for other applications where control against pathogenic microorganisms is important.