Title of Invention

FUNGICIDAL TRIFLUOROMETHYLALKYLAMINO-TRIAZOLOPYRIMIDINES.

Abstract The novel optically active compounds of formula I: (R1 Hal and L1 through L5 are defined in the specification) wherein the enantiomenc excess of the (S)-enantiomer is at least 70 % show enhanced selective fungicidal activity The new compounds are processed with earners, and optionally with adjuvants, to form fungicidal compositions.
Full Text BACKGROUND OF THE INVENTION
This invention relates to certain tnazolopynmidine compounds, a process for their preparation, compositions containing such compounds, a method for combating a fungus at a locus compnsing treating the locus with such compounds and their use as fungicides
EP-A-0 071 792 claims compounds of the general formula

in which R1 represents alkyl, halogen, alkoxy, cyano, cycloalkyi, aryl, aryloxy, aryithio, aralkyi, arylthio, arylalkyl, arylalkyloxy or arylalkyithio each optionally substituted by halogen or alkoxy; or (R1)n, represents a benzene, indane or tetrahydronaphthalene ring fused with the phenyl nng, aromatic moieties in the above groups being optionally substituted by alkyl, alkoxy, halogen or cyano; n is 1 or 2, R2 and R3 are each hydrogen, aikyi or aryl, A represents a nitrogen atom or a CR4 group, and R4 is as R2 but can also be halogen, cyano or alkoxycarbonyf or together with R3 can form an aikylene chain containing up to two double bonds The compounds are said to be active against vanous phytopathogenic fungi, especially those of the phycomycete class. However evidence of fungicidal activity is only provided for these compounds against Piasmopara viticola, a member of the oomycete class of fungi. EP 0 550 113-A2 claims compounds of the general formula

2

in which R1 represents an optionally substituted alkyl, alkenyl, alkadienyl, cycloalkyi, bicycloalkyl or heterocycly! group; R2 represents a hydrogen atom or an alkyl group; or R1 and R2 together with the interjacent nitrogen atom represent an optionally substituted heterocyclic nng, R3 represents an optionally substituted aryl group, and R6 represents a hydrogen or halogen atom or a group -NR5R6 where R5 represents a hydrogen atom or an ammo, alkyl, cycloalkyi or bicycloalkyl group and R6 represents a hydrogen atom or an alkyl group Thus, compounds in which R1 is a tnfluoromethylalkyl group are generally embraced by this patent application However, there is no single compound disclosed in which R1 is an optically ennched tnfluoromethylalkyl group


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SUMMARY OF THE INVENTION
The present invention provides a compound of formula
in which
R1 represents a C1-4 alkyl group,
CH* indicates a chiral carbon atom,
Hal represents a halogen atom,
L1 through L5 each independently represent an hydrogen or halogen atom or an
alkyl, alkoxy or nitro group,
characterized in that the enantiomenc excess (ee) of the (S)-enantiomer is at least
70%
The new compounds show excellent selective fungicidal activity in vanous crops
It IS an object of the present invention to provide novel, selective fungicidal compounds.
It IS another object of the present invention to provide a method for the preparation of the fungicidal compounds of formula I and a method for the resolution of 1,1,1-trifluoroalkyi-2-amines
It IS also an object of the invention to provide methods for controlling undesired fungus by contacting said plants with a fungicidally effective amount of the new compounds
It IS another object of the invention to provide selective fungicidal compositions containing the new compounds as active ingredients
These and other objects and features of the invention will be more apparent from the detailed description set forth hereinbelow, and from the appended claims.

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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has surprisingly been found that the novel optically enriched compounds of
formula

in which R1 Hal and L1 through L5 have the meaning given above having an entantiomenc excess of at least 70 % show an excellent fungicidal activity against a broad range of fungi
In general terms, unless otherwise stated, as used herein the term halogen atom may denote a bromine, iodine, chlorine or fluonne atom, and is especially a bromine, chlonne or fluonne atom.
Hal represents preferably fluonne, chlonne, bromine or iodine, in particular chlonne.
In general terms, unless otherwise stated herein, the terms aikyt, alkoxy as used herein with respect to a radical or moiety refer to a straight or branched chain radical or moiety. As a rule, such radicals have up to 10, in particular up to 6 carbon atoms Suitably an alkyl moiety has from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms A preferred alkyl moiety is an ethyl or especially a methyl group Suitably an alkoxy moiety has from 1 to 6 carbon atoms A preferred alkoxy moiety IS a methoxy or ethoxy group
The invention especially relates to compounds of the general formula I in which any alkyl part of the group R1 which may be straight chained or branched contains up to 6 carbon atoms, preferably up to 4 carbon atoms, more preferably up to 2 carbon atoms, in particular a methyl group
Included in the scope of the present invention are the diastereomers caused by atropisomerism of compounds of general formula I, in which the substituents L1

5
or L1 and L2 are different fronn L5 or L5 and L4, and the racemates thereof, and salts, N-oxides and acid addition compounds"
The enantiomenc excess of the (S)-enantiomer is at least 70 %, preferably more than 75 %, in particular at least 80 %
Preferred are compounds of formula I. in which the phenyl group

The 2,6-difluorophenyl and the 2,4,6-trifluorophenyl group are particularly preferred.
The compounds according to general formula I are oils, gums, or, predominantly crystalline solid matenals They are supenor through their valuable fungicidal properties, in particular their enhanced systemicity and enhanced fungicitoxity against rice diseases and powdery mildews For example, they can be used-in agriculture or related fields for the control of phytopathogenic fungi such as Altemana solani Blumena graminis Botrytis cinerea. Cercospora beticola. Cladosponum herbarum. Corticium rolfsit, Guignardia bidwellii, Helminthosponum tritici repentis, Leptosphaeria nodorum, Magnaporthe gnsea f. sp. oryzae, Micro-nectriella nivalis, Monilinia fructigena, Mycosphaerella fijiensis, Mycosphaerella musicola, Mycosphaerella ligulicola, Mycosphaerella pinodes, Phomopsis viticola, Plasmopara viticola, Podosphaera leucotricha, Pseudopeziza tracheiphila,

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Phytophthora infestans, Puccinia recondita, Pyrenophora teres, Rhizoctonia solani, Ventuna inaequalis, Uncinula necaforand Sclerotinia sclerotiorum, in particular for
the residual control of Blumena graminis, Plasmopara viticola, Puccinia recondita
and Pyrenophora teres, and for the curative control of Puccinia recondita The
compounds of general formula I according to the invention possess a high
fungicidal activity within a wide concentration range and may be used in agnculture
without any difficulties.
Moreover, the compounds according to the invention show enhanced
residual control of fungi, in particular of grape downy mildew compared with
conventional fungicides
Good results in terms of control of phytopathogenic fungi are obtained with a
compound as defined in formula I wherein
at least one of L1 and L5 represents a halogen atom, and/or
R1 represents a methyl group
Especially good results tn terms of control of phytopathogenic fungi are
obtained by using, for example, the following compounds of formula I, wherein the
e.e of the corresponding (S)-enantiomer is at least 80 %: 5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-(1,1,1-trifluoro)propyiamino]-[1,2,4]tnazolo[1,5-a]pynmidine, 5-chloro-6-(2,6-difluorophenyl)-7-[2-(1,1,1-trifluoro)propylamino]-[1,2,4]tnazolo[1,5-a]pyrimidine, 5-chtoro-6-(2,4,6-tnfluorophenyl)-7-[2-(1,1,1 -tr[fluoro)propylamino]-[1,2,4]triazolo[1,5-a]pynmidine, 5-chloro-6-(2-methylphenyl)-7-[2-(1.1,1-tnfluoro)propylamino]-[1,2,4]triazolo[1,5-a]pynmidine, 5-ch(oro-6-(2-fluorophenyl)-7-[2-(1,1,1-trifluoro)propylaminoH1,2,4]tnazolo[1,5-a]pyrimidine, 5-chloro-6-(2-chlorophenyl)-7-[2-(1,1,1 -tr[fluoro)propylamino]-[1,2,4]tnazolo[1,5-a]pynmidtne, 5-chloro-6-(2-bromo-5-chlorophenyl)-7-[2-(1,1,1 -trifluoro)propyiamino]-[1,2,4]tnazolo[1,5-a]pyrimidine, 5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-(1,1,1 -tnfiuoro)butylamino]-[1,2,4]triazoio[1,5-a]pynmidine, 5-chloro-6-(2-fluorophenyl)-7-[2-(1,1,1-tnfluoro)butylamino]-[1,2,4]tria2olo[1,5-a]pynmidine, 5-chloro-6-(2,4,6-trifluorophenyl)-7-[2-(1,1,14rifluoro)butyiamino]-[1,2,4]triazolo[1,5-a]pynmidine, 5-chloro-6-(2,6-difluorophenyl)-7-[2-(1,1,1 -trifluoro)butylamino]-[1,2.4]tria2olo[1,5-a]pynmidine, 5-chloro-6-(2-chlorophenyl)-7-[2-(1,1,1-

7
trifluoro)butylamino]-[1,2,4]triazolo[1,5-a]pynmidine, 5-chloro-6-(2,4,6-trifluoropheny!)-7-[2-( 1,1,1-trifIuoro)-3-methylbutyiamino]-
[1,2,4]triazolo[1,5-a]pynmidine, 5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-[2-(1,1,1-trifluoro)propylamino]-[1,2,4]tria2olo[1,5-a]pyrimidine, 5-chloro-6-(2,4-
difluorophenyl)-7-[2-(1,1,1-trifluoro)propylamino]-[1,2,4]triazolo[1,5-a]pyrimidine.

in which
L1 through L5 and Hal are as defined above, with an optically active amine of the formula III


The present invention further provides a process for the preparation of a compound of formula I as defined above which comprises treating a compound of the formula II
in which
R1 IS as defined above,
M represents a hydrogen atom or a free or complexed metal atom, and
the e e of the (S)-enantiomer is at least 70 %
The resulting 5,7-dihydroxy-6-phenyltriazolopyrimidines are subsequently treated with a halogenating agent, preferably with a brominating or chionnating agent, such as phosphorus oxybromide or phosphorus oxychloride, neat or in the presence of a solvent The reaction is suitably earned out at a temperature in the range from 0 °C to 150 'C, the preferred reaction temperature being from 80 'C to 125 °C
The reaction between the 5,7-dihalo-6-phenyltnazolopynmidines of formula l( and the amine or amide of formula III is conveniently earned out in the presence of

8
a solvent. Suitable solvents include ethers, such as dioxane, diethyl ether and, especially, tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and aromatic hydrocarbons, for example toluene The reaction is suitably earned out at a temperature in the range from 00C to 70 °C, the preferred reaction temperature being from 10 °C to 35 °C It is also preferred that the reaction is earned out in the presence of a base. Suitable bases include tertiary amines, such as triethylamine, and inorganic bases, such as potassium carbonate or sodium carbonate Alternatively, an excess of the compound of formula Ml may serve as a base
Compounds of formula II are known e g from EP 0 550 113 and are conventionally prepared by reacting 3-amino-1,2,4-tnazole wih 2-phenyl-substituted malonic acid ester of formula IV,

wherein R represents alkyl, under alkaline conditions, preferably using high boiling tertiary amines as for example tn-n-butylamine
The chirai amines of formula III, wherein M represents a hydrogen atom, are known in the literature or commercially available or may be prepared analogously to methods that are known per se. For example, they may be prepared from the corresponding chiral amino acids with fluonnation agents such as sulfurtetrafluonde/HF (eg EP 0 323 637).
Furthermore, they may be prepared from the corresponding tnfluoromethyl ketones by reaction with chiral a-phenylethylamine, treatment of the resulting chiral ketimines with a base, in particular DBU, and hydrolysis with mineral acid (e g V A-Soloshonok, T Ono, J Org. Chem. 1997, 62, 3030-3031)
In a preferred embodiment of the present invention the chiral amines of formula III are prepared from the corresponding racemic amines by conversion to diastereomenc salt with a chiral organic acid such as tartanc acid and fractional crystallisation of the diastereomeric salt.

9
The invention relates to an improved process for the preparation of (S)-1,1,1-trifIuoroalkyl-2-amine of formula IllA

wherein R1 has the meaning given, by resolution of the corresponding racemic mixture of 1,1,1-trifluoroaikyl-2-amine with optically active tartaric acid, wherein 1 mole of the racemic mixture of 1,1,1-trifiuoroalkyl-2-amine is treated with 0.3 to 0.7 mole of D-(-)-tartanc acid in the presence of an inert solvent.
Further preferred embodiments of the process according to the present invention is a process wherein:
• diastereomenc salt formed from the (S)-1,1,1-tnfluoroalkyl-2-amine and D-(-)-tartanc acid precipitates from the solution;
• 1 mole of the racemic mixture of 1,1,1-trifluoroalkyl-2-amine is treated with about 0 5 mole of D-(-)-tartaric acid;
• the diastereomenc salt is separated by filtration techniques,
• the diastereomenc salt is treated with a strong base to liberate the optically active amine from the tartanc acid,
• the inert solvent is water or an alcohol or a mixture thereof,
• the 1,1,1-trifluoroalkyl-2-amine is 1,1,1-trif!uoropropyl-2-amine
• (S)-1,1,1-trifluoropropyl-2-amine obtained is treated with hydrochlonc acid and the resulting the hydrochlonde has a specific rotation [a] of -4 26 at a wavelength of 589 nm at 27°C.
the resulting (S)-1,1,1 -trifluoroalkyl-2-amine has an enantiomenc excess of at least 70 %, preferably at least 80 %

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The obtained (R)-1,1,1-trifluoroalkyl-2-amine can be easily recycled for example according to one of the following reaction sequences Racemization 1

Due to excellent activity, the compounds of formula I may be used in cultivation of all plants where infection by phytopathogenic fungi is not desired, e.g cereals, solanaceous crops, vegetables, legumes, apples, vine.
The invention further provides a fungicidal composition which comprises an active ingredient, which is at least one compound of formula I as defined above, and one or more earners. A method of making such a composition is also provided which comprises bringing a compound of formula I as defined above into association with the camer(s). Such a composition may contain a single active ingredient or a mixture of several active ingredients of the present invention it is also envisaged that different isomers or mixtures of isomers may have different levels or spectra of

11
activity and thus compositions may comprise individual isomers or mixtures of isomers
A composition according to the invention preferably contains from 0 5% to 95% by weight (w/w) of active ingredient(s)
A earner in a composition according to the invention is any matenal with which the active ingredient is formulated to facilitate application to the locus to be treated (which locus may be. for example, a plant, seed, soil, or water in which a plant grows), or to facilitate storage, transport or handling. A carrier may be a solid or a liquid, including material which is normally a gas but which has been compressed to form a liquid
The compositions may be manufactured into e.g. emulsion oremulsifiable concentrates, solutions, oil in water emulsions, wettable powders, soluble powders, suspension concentrates, dusts, granules, water dispersible granules, aerosols, micro-capsules, gels, tablets and other formulation types by well-established procedures These procedures include intensive mixing and/or milling of the active ingredients with other substances, such as fillers, solvents, solid earners, surface active compounds (surfactants), and optionally solid and/or liquid auxiiianes and/or adjuvants. The form of application such as spraying, atomizing, dispersing or pounng may be chosen like the compositions according to the desired objectives and the given circumstances
Solvents may be aromatic hydrocarbons, e.g. Solvesso® 200, substituted naphthalenes, phthalic acid esters, such as dibutyl or dioctyl phthalate, aliphatic hydrocarbons, e.g cyciohexane or paraffins, alcohols and glycols as well as their ethers and esters, e g. ethanol, ethyleneglycol mono- and dimethyl ether, ketones such as cyclohexanone, strongly polar solvents such as N-methyI-2-pyrrolidone, ory-butyrolactone, higher aikyi pyrrolidones, e g. n-octylpyrrolidone or cyclohexylpyrrolidone, epoxidized plant oil esters, e.g methylated coconut or soybean oil ester and water Mixtures of different liquids are often suitable
Solid earners, which may be used for dusts, wettable powders, water dispersibie granules, or granules,.may be mineral fillers, such as calcite, tale, kaolin, montmorillonite or attapulgite. The physical properties may be improved by addition of highly dispersed silica gel or polymers Carriers for granules may be porous

12
material, e g. pumice, kaolin, sepiolite, bentonite, non-sorptive earners may be calcite or sand Additionally, a multitude of pre-granulated inorganic or organic matenals may be used, such as dolomite or crushed plant residues
Pesticidal compositions are often formulated and transported in a concentrated form which is subsequently diluted by the user before application The presence of small amounts of a carrier which is a surfactant facilitates this process of dilution Thus, preferably at least one carrier in a composition according to the invention is a surfactant For example, the composition may contain at two or more earners, at least one of which is a surfactant
Surfactants may be nonionic, anionic, cationic or zwitterionic substances with good dispersing, emulsifying and wetting properties depending on the nature of the compound according to general formula I to be formulated Surfactants may also mean mixtures of individual surfactants
Wettable powders of this invention suitably contain 5 to 90% w/w of active ingredient, and in addition to solid inert carrier, 3 to10% w/w of dispersing and wetting agents and, where necessary, 0 to 10% w/w of stabilizer(s) and/or other additives such as penetrants or stickers Dusts may be formulated as a dust concentrate ' having a similar composition to that of a wettable powder but without a dispersant, and may be diluted in the field with further solid earner to give a composition usually containing 0.5 to 10% w/w of active ingredient Water dispersible granules and granules of this invention typically have a size between 0 15 mm and 2 0 mm and may be manufactured by a variety of techniques Generally, these types of granules will contain 0 5 to 90% w/w active ingredient and 0 to 20% w/w of additives such as stabilizer, surfactants, slow release modifiers and binding agents Emuisifiable concentrates may contain, in addition to a solvent or a mixture of solvents, 1 to 80% w/v active ingredient, 2 to 20% w/v emulsifiers and 0 to 20% w/v of other additives such as stabilizers, penetrants and corrosion inhibitors. Suspension concentrates are suitably milled so as to obtain a stable, non-sedimenting flowable product and preferably contain 5 to 75% w/v active ingredient, 0.5 to 15% w/v of dispersing agents, 0.1 to 10% w/v of suspending agents such as protective colloids and thixotropic agents, 0 to 10% w/v of other additives such as defoamers, corrosion inhibitors, stabilizers, penetrants and stickers, and water or an organic liquid in which

13
the active ingredient is substantially insoluble, certain organic solids or inorganic salts may be present dissolved in the formulation to assist in preventing sedimentation and crystalization, or as antifreeze agents.
Aqueous dispersions and emulsions, for example compositions obtained by diluting the formulated product according to the invention with water, also lie within the scope of the invention
Of particular interest in enhancing the duration of the protective activity of the compounds of this invention is the use of a earner which will provide slow release of the pesticidal compounds into the environment of a plant which is to be protected.
The biological activity of the active ingredient can also be increased by including an adjuvant in the spray dilution. An adjuvant is defined here as a substance which can increase the biological activity of an active ingredient but is not itself significantly biologically active The adjuvant can either be included in the formulation as a coformulant or carrier, or can be added to the spray tank together with the formulation containing the active ingredient
As a commodity, the compositions preferably may be in a concentrated form, whereas the end user generally employs diluted compositions The compositions may be diluted to a concentration down to 0.001% of active ingredient The doses usually are in the range from 0.01 to 10 kg a.i./ha
Examples of formulations according to the invention are
Emulsion Concentrate (EC)
Active Ingredient Compound of Example 2 30 % (w/v)
Emulsifier(s) Atlox®4856 B /Atlox®4858 B ' 5 % (w/v)
(mixture containing calcium alkyl aryl
•sulfonate, fatty alcohol ethoxylates and light
aromatics / mixture containing calcium alkyl
aryl sulfonate, fatty alcohol ethoxylates and
light aromatics)
Solvent Shelisol® A 2) to 1000 ml
(mixture of C9 - C10 aromatic hydrocarbons)

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Suspension Concentrate (SC)
Active ingredient Compound of Example 2 50 o/, (w/v)
Dispersing agent Soprophor® FL 3) 3 % (w/v)
(polyoxyethylene polyaryl phenyl ether
phosphate amine salt)
Antifoaming agent Rhodorsil® 422 3) 0.2 % (w/v)
(nonionic aqueous emulsion of
polydimethylsiloxanes)
Structure agent Kelzan® S 4) 0.2 % (w/v)
(Xanthan gum)
Antifreezing agent Propylene glycol 5 % (w/v)
Biocidal agent Proxel®5) 0.1 % (w/v)
(aqueous dipropylene glycol solution
containing 20% 1,2-benisothiazolin-3-one)
Water to 1000 ml
Wettable Powder (WP)
Active Ingredient Compound of Example 2 60 % (w/w)
Wetting agent Atlox® 4995 1) 2 % (w/w)
(polyoxyethylene alkyl ether)
Dispersing agent Witcosperse® D-60 6) 3 % (w/w)
(mixture of sodium salts of condensed
naphthalene sulfonic acid and
alkylarylpolyoxy acetates
Carner / Filler Kaolin 35 % (w/w)

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Water Dispersible Granules (WG)
Active Ingredient Compound of Example 2 50 % (W/W)
Dispersing / Witcosperse® D-450 6) 8 % (w/w)
Binding agent (mixture of sodium salts of condensed
naphthalene sulfonic acid and alkyl
sulfonates)
Wetting agent Morwet® EFW 6) 2 % (w/w)
(formaldehyde condensation product)
Antifoaming agent Rhodorsil® EP 6703 3) 1 % (w/w)
(encapsulated silicone)
Disintegrant Agnmer® ATF 7) 2 % (w/w)
(cross-linked homopolymer of N-vinyl-2-
pyrrolidone)
Carrier / Filler Kaolin 35 % (w/w)
commercially available from ICI Surfactants
2)
commercially available from Deutsche Shell AG 3) commercially available from Rhone-Poulenc 4) commercially available from Keico Go 5) commercially available from Zeneca 6) commercially available from Witco 7) commercially available from International Speciality Products
The compositions of this invention can also compnse other compounds having biological activity, e.g. compounds having similar or complementary pesticidal activity or compounds having plant growth regulating, fungicidal or insecticidal activity. These mixtures of pesticides can have a broader spectrum of activity than the compound of formula 1 alone Furthermore, the other pesticide can have a synergistic effect on the pesticidal activity of the compound of formula 1
The other fungicidal compound can be, for example, one which is also capable of combating diseases of cereals (e g wheat) such as those caused by Erysipha, Puccinia, Septoha, Gibberella and Helminthosporium spp., seed and soil borne diseases and downy and powdery mildews on vines, early and late blight on

16
soianaceous crops, and powdery mildew and scab on apples etc These mixtures of fungicides can have a broader spectrum of activity than the compound of formula I alone Furthermore, the other fungicide can have a synergistic effect on the fungicidal activities of the compound of formula I
Examples of the other fungicidal compounds are anilazine, azoxystrobin, benalaxyl, benomyl, bethoxazin, binapacryl, bitertanol, blasttcidin S, Bordeaux mixture, bromuconazote, bupinmate, captafol, captan, carbendazim, carboxin, carpropamid, chlorbenzthiazon, chlorothalonil, chlozolinate, copper-containing compounds such as copper oxychlonde, and copper sulfate, cycloheximide, cymoxanil, cypofuram, cyproconazole, cyprodinil, dichlofluanid, dichlone, dichloran, diclobutrazol, diclocymet, diclomezine, diethofencarb, difenoconazoie, diflumetonm, dimethinmol, dimethomorph, diniconazole, dinocap, ditalimfos, dithianon, dodemorph, dodine, edifenphos, epoxiconazole, etaconazole, ethinmot, etndiazole, famoxadone, fenapanil, fenanmol, fenbuconazole, fenfuram, fenhexamid, fenpiclonil, fenpropidin. fenpropimorph, fentm, fentin acetate, fentin hydroxide, ferimzone, fluazmam, fiudioxonil, flumetover, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutnafol, folpet, fosetyl-aluminium, fubendazole, furalaxyl, furametpyr, guazatine, hexaconazote, imazalil, immoctadine, ipconazote, iprodione, isoprothiolane, kasugamycin, kitazin P, kresoxim-methyl, mancozeb, maneb, mepanipynm, mepronil, metalaxyl, metconazole, methfuroxam, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothalisopropyl, nuanmol, ofurace, organo mercury compounds, oxadixyl, oxycarboxin penconazole, pencycuron, phenazineoxide, phthalide, polyoxin D, polyram, probenazole, prochloraz, procymidione, propamocarb, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, quinomethionate, quinoxyfen, quintozene, spiroxamine, SSF-126, SSF-129, streptomycin, sulfur, tebuconazole, tecloftatame, tecnazene, tetraconazole, thiabendazole, thifiuzamide, thiophanate-methyl, thiram, tolciofosmethyl, tolylfluanid, triadimefon, tnadimenol, triazbutii, triazoxide, thcyclazole, tridemorph, triflumizole, triforine, thticonazole, validamycin A, vinclozolin, XRD-563, zarilamid, zineb, and ziram.
In addition, the fomiulations according to the invention may contain at least one compound of fomnula I and any of the following classes of biological control

17
agents such as viruses, bacteria, nematodes, fungi and other microorganisms which are suitable to control insects, weeds or plant diseases or to induce host resistance in the plants Examples of such biological control agents are Bacillus thunngiensis, Verticillium lecann, Autographica californica NPV, Beauvana bassiana, Ampelomyces quisqualis, Bacilis subtilis. Pseudomonas chlororaphis, Pseudomonas fluorescens, Steptomyces gnseovindis and Tnchoderma harzianum
Moreover the formulations according to the invention may contain at least one compound of formula I and a chemical agent that induces the systemic acquired resistance in plants such as for example nicotinic acid or denvatives thereof, 2,2-dichloro-3,3-dimethylcyclopropylcarboxylic acid or BION.
The compounds of formula I can be mixed with soil, peat or other rooting media for the protection of the plants against seed-borne, soil-borne or foliar fungal diseases
The invention also includes the fungicidal use of a compound of formula I as defined above or a composition as defined above, and a method for combating fungus at a locus, which comprises treating the locus (which may be, for example, plants subject to or subjected to fungal attack, seeds of such plants or the medium in which such plants are growing or are to be grown), with such a compound or composition
The present invention is of wide applicability in the protection of crop and ornamental plants against fungal attack Typical crops which may be protected include vines, grain crops such as wheat and barley, rice, sugar beet, top fruit, peanuts, potatoes, vegetables and tomatoes The duration of the protection Is normally dependent on the individual compound selected, and also a vanety of external factors, such as climate, whose impact is normally mitigated by the use of a suitable formulation
The following examples further illustrate the present invention. It should be understood, however, that the invention is not limited solely to the particular examples given below.

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Example 1
Resolution of 1.1,1-trif!uoroprop-2-yiamine
To D(-)-tartanc acid ( 25 5 g, 0.17 mol) in methanol ( 250 ml) is added racemic tnflucroisopropyl amine ( 38 g, 0 34 mo!) as a methanolic solution ( 100 mi) After the addition of half of the amine a white precipitate forms After the addition is complete the mixture is bnefly heated to reflux It is then allowed to cool to ambient The mixture is cooled in an ice bath and the salt is isolated by filtration and dried in vacuo The obtained product (36 g) is then recrystallized from boiling methanol (170 ml) to yield 29 0 g of the salt which is finally recrystallized from 140 ml methanol to furnish a final yield of 25 5 g (S)-tnfluoroisopropyl amine D(-)-tartrate
For the preparation of the target compound the amine is then liberated from the salt by placing the salt in a distillation apparatus and carefully adding aqueous 50% sodium hydroxide with heating and stirring
Liberation of the D(-)-tartrate gives nse to an amine with a negative optical rotation [a]D27 -3 67 ( c = 10, methanol) It is noteworthy that the optical rotation inverts for the hydrochlorides [a]D27 +4.26 ( c= 10, methanol)
Determination of the enantomeric purity
In a small vial approx. 7 mg of the tartrate is dissolved in 0.6 ml CDCI3. Aqueous sodium hydroxide (50%, 3 drops) is added and the two phase mixture is shaken vigorously for 10 seconds. The organic layer is then separated via a pasteur pipette and filtered through a small plug of cotton directly into the NMR-tube. (S)-(+)-1-(9-anthryl)-2,2,2-trifluoro ethanol (21 mg) is added and the 1H-NMR spectrum (400 MHz ) is recorded . The ratio of the enantiomers is determined by integration of the signals of the methyl group at 1.20 ppm ( R-enantiomer) and 1.17ppm(S-enantiomer) The enantiomenc excess of the S-enantiomer is > 85 %
Example 2
5-Chloro-6-(2,4,6-trifluorophenyl)-7-N-[(S)-(1,1,1-trifluoroprop-2-yIamino)]-1,2,4-triazolo[1.5a]pyrimidine
A mixture of (S)-1,1,1-trifluoroprop-2-ylamine (4.2 mmoles) obtained according to example 1 and dtchloromethane (10 ml) is added to a mixture of 5,7-

19
dichloro-6-(2,4,6-trifluorophenyl}-1,2,4-triazolo[1.5a]pyrimidine (1 4 mmoles, obtained from diethyl 2,4,6-trifluorophenylmalonate and 3-amino-1,2,4-triazole as described rn EP 0 770 615) and dichloromethane (30 ml) under stirnng The reaction mixture is stirred 16 hours at room temperature subsequently washed two times with 1 N hydrochtonc acid and once with water The organic layer is separated, dned with anhydrous sodium sulfate and the solvent is evaporated under reduced pressure Treatment of the resulting light brown oil with tert -butyl methyl ether (50 ml) yields beige crystals having a melting point of 117-121 °C and an enantiomenc excess of > 98 %
Examples 3-18
The following examples (Table 1, structure and melting point) are synthesized analogously to Examples 1 and 2

(CH* indicates that the compound has an enantiomeric excess of at least 80 % with respect to the (S)-isomer)



Biological Investigations
A. Determination of Minimum Inhibitory Concentration by Test Compounds in the Serial Dilution Test with Vanous Phytopathogenic Fungi
The MIC (Minimum Inhibitory Concentration) value, which indicates the lowest concentration of the active ingredient in the growth medium which causes a total inhibition of myecelial growth, is determined by senal dilution tests using Microtiter plates with 24 or 48 wells per plate. The dilution of the test compounds in the nutrient solution and the distnbution to the wells is carned out by a TECAN RSP 5000 Robotic Sample Processor The following test compound concentrations are used. 0.05, 0.10, 0.20, 0.39, 0.78, 1 56, 3.13, 6.25, 12 50, 25 00, 50.00 and 100 00 mg/ml. For preparation of the nutrient solution, V8 vegetable jutce (333 ml) is mixed with calcium carbonate (4.95 g), centrifuged, the supernatant (200 ml) diluted with water (800 ml) and autoclaved at 121 0C for 30 min

21
The respective inocula (Altemaria solani, ALTESO, Botrytis cinerea, BOTRCI; Gurgnardia bidwellii, GUIGBI, Cochliobulus sattvus. COCHSA, Leptosphaena nodorum, LEPTNO, Phytophthora infestans, PHYTIN, Magnaporthe grisea f sp oryzae, PYRIOR, Pyrenophora teres, PYRNTE; Phomopsis viticola, PHOPVl, Pseudopeziza tracheiphila, PSEUTR, Rhizoctonia solani, RHIZSO,) are added into the wells as spore suspensions (50 ml, 5x105/ml) or agar slices (6 mm) of an agar culture of the fungus
After 6-12 days incubation at suitable temperatures (18-25°C), the MIC values are determined by visual inspection of the plates The results of these tests in comparison with the corresponding racemic compound are shown in tables il to IV
Table ll Minimum Inhibitory Concentration of Compound of Example 2 against
different pathogens

PATHOGEN Example 2 S-lsomer Companson
(R/S)-Racemate
ALTESO 0.39 1.56
BOTRCI 1 56 3 13
GUIGBI LEPTNO 0 1 0 78
PHYTIN 25 >100
PYRIOR 0.2 0 78
PYRNTE 313 6 25
PHOPVI 0.39 0 78
PSEUTR fs130 RHIZSO 1.56 3 13
Besides Botrytis cinerea the targets included 3 other grape pathogens which occur early in the grape growing season. Guignardia bidwellii (black rot), Phomopsis viticola (dead arm)and Pseudopeziza tracheiphila (Red fire disease) The results indicate that both the (R/S)-racemate and the (S)-enantiomer have

22
good to very good activity against these grape fungi. However, the activity of the (S)-isomer is more than twice as high against almost all pathogens
Table III Minimum Inhibitory Contentration of Compound of Example 13
against different pathogens

PATHOGEN Example 13 S-lsomer Companson (R/S)-Racemate
BOTRCI 0.2 0.2
ALTESO 0 1 0.2
RHIZSO 1 56 3 13
PHYTIN 25 50
COCHSA 1.56 1 56
PYRIOR LEPTNO 3 13 3 13
The results indicate that both the (R/S)-racemate and the (S)-enantiomer have good to very good activity against the tested fungi However, the activity of the (S)-isomer is about twice as high against three of the tested pathogens
Table IV Minimum Inhibitory Concentration of Compound of Example 18 against different pathogens

PATHOGEN Example 18 S-lsomer Companson (R/S)-Racemate
BOTRCI 0 78 > 100
ALTESO 0 78 > 100
RHIZSO 3 13 > 100
COCHSA 6 25 > 100
PYRIOR 0 05 0.2
LEPTNO 3.13 > 100
The results indicate that the (S)-enantiomer has very good activity against the tested fungi, whereas the (R/S) racemate is nearly inactive against almost all

23
fungi with the exception of Magnaporthe grisea f. sp. oryzae However, the activity of the (S)-isomer is four times as high against this pathogen
B. Determination of the efficacy of Test Compounds in greenhouse trials The efficacy of the (R/S)-racemate and the (S)-enantiomer was also
investigated in-vivo in greenhouse tnals against several cereal diseases and
diseases of dicotyledonous crops The curative and residual activity as well as the
systemicity of both the compounds was assessed
Both showed fungicidal activity against the diseases tested (Tables V to
VIII) In all tests, the (S)-enatiomer performed comparable to the racemate,
however in most tests it was even better
Table V- Efficacy (in % disease control) of Compound of Example 2 ((S)-
enantiomer) against wheat leaf rust (WLR), and wheat powdery mildew (WPM) (curatively (2 do) and residually (2dp) after foliar application) compared with the corresponding (R/S)-racemate

WLR WLR WPM WPM
2d c 2d p 2d c 2dp
rate (ppm) 100 25 6.3 1 6 200 25 12 5 25 6 3 1 6 25 6 3 1.6
Compound
Example 2 100 100 100 95 100 100 96 97 79 49 100 97 92
(S)-
enantiomer
Comparison 100 100 97 13 100 100 21 92 0 0 100 97 0
(R/S)-
racemate
Table VI: Efficacy (in % disease control) of Compound of Example 2 ((S)-enantiomer), against apple scab (AS) (after foliar application curatively two days

24
after the inoculation (2 d c) or prophylactically two days before the inoculation (2 d p)) compared with the corresponding (R/S)-racemate

AS AS
2dc 2d p
rate (ppm) 25 6 3 16 25 6.3 16
Compound
Example 2 100 94 63 100 100 98
{S)-Enantiomer
Companson 98 71 23 99 90 38
(R/S)-Racemate
Table VIl Efficacy (in % disease control) of Compound of Example 2 ((S)-enantiomer) against grape downy mildew (GDM) and barley net blotch (BNB) (residually (2 d p) after foliar application) compared with the corresponding (R/S)-racemate

GDM BNB
rate (ppm) 100 25 6 3 1 6 200 50 12 5
Compound
Example 2 100 100 77 17 100 90 74
(S)-enantiomer
Comparison 100 93 17 0 100 72 0
(R/S)-racemate
Table VIII Efficacy (in % disease control) of Compound of Example 2 ((S)-enantiomer) against barley powdery mildew (BPM) (curatively (2d c) and residuatiy (2d p) after foliar application) compared with the corresponding (R/S)-racemate

25

BPM BPM
2dc 2dp
rate (ppm) Compound 25 6.3 1 6 25 6 3 16
Example 2 100 100 100 100 100 83
(S)-Enantiomer
Comparison 100 86 42 100 0 0
(R/S)-Racemate
Tabie IX: Efficacy (in % disease control) of Compound of Example 5 {(S)-enantiomer) against grape downy mildew (GDM), wheat leaf rust (WLR), wheat powdery mildew (WPM) and barley net blotch (BNB) (residually (1 d p) after folor application) compared with the corresponding (R/S)-racemate

GDM WLR WPM BNB
rate (ppm) Compound 200 50 12.5 20 4 0.8 20 4 0.8 20 4 0.8
Example 5 87 10 0 100 99 91 100 68 14 85 17 23
(S)-
enantiomer
Companson 20 0 0 100 87 68 98 27 7 58 0 1
(R/S)-
racemate
_ . J
Table X Efficacy (in % disease control) of Compound of Example 5 ((S)-
enanttomer) against wheat leaf rust (WLR), apple scab (AS) (curativeiy (2 d c) after foliar application) and broad bean Botrytis (SB) (residuaiiy (2 d p) after foliar application) compared with the corresponding (R/S)-racemate

26

BB
rate (ppm) Compound 100 25 63
Example 5 88 73 5
(S)-enantiomer
Comparison 40 5 0
(R/S)-racemate

WLR AS
rate (ppm) 25 63 1.6 25 63 1.6
Compound
Example 5 100 100 38 99 99 78
(S)-enantiomer
Comparison 88 33 0 70 38 0
(R/S)-racemate


27
WE CLAIM:
1 An optically active 7-(1,1,1 -trifluoroalk-2-ylamino)-triazolopynmidine of formula I
in which
R1 represents a C1-6 alkyl group,
CH* indicates a chirai carbon atom,
Hal represents a halogen atom,
L1 through L5 each independently represent an hydrogen or halogen atom
or an alkyl, alkoxy or nitro group, characterized in that the enantiomeric
excess of the (S)-enantiomer is at least 70%
2. A compound according to Claim 1 in which at least one of L' and L5 represents a halogen atom
3 A compound according to Claim 1 or 2 consisting essentially of the (S)-enantiomer
4 A compound according to any of the preceding claims in which R1 represents a methyl group
5 A compound according to any of the preceding claims in
which L1 and L5 represent a fluoro atom and L3 represents a hydrogen or fluoro atom or a methoxy group

28
6 A compound according to claim 1, selected from the
group consisting of
5-chloro-6-(2-Chloro-6-fluorophenyl)-7-[2-( 1,1,1 -tnfluoro)propylamino]-[1,2,4]triazolo[1,5-a]pyrimidme,
5-chloro-6-(2,6-difluorophenyi)-7-[2-(1,1,1 -trifluoro)propytamino]-[1,2,4]triazolo[1,5-a]pyrimidine,
5-chloro-6-(2,4,6-trlfluorophenyI)-7-[2-(1,1,1-tnfluoro)propylamino]-[1,2,4]triazolo[1,5-a]pyrimidine,
5-chloro-6-(2-methylphenyI)-7-[2-(1,1,1-trifiuoro)propylamino]-[1 ,2,4]triazolo[1,5-a]pyrimidine,
5-chloro-6-(2-ftuorophenyl)-7-[2-(1,1,1 -trifluoro)propylamino]-[1,2,4]triazolo[1,5-a]pynmidine, 5-chioro-6-(2-chlorophenyl)-7-[2-(1,1.1-tnfluoro)propyiamino]-
[1,2,4]tnazolo[1,5-a]pyrimidine,
5-chloro-6-(2-bromo-5-chloropheny l)-7-[2-( 1,1,1 -trifluoro)propylamino]-
[1,2,4]triazolo[1,5-a]pynmidine,
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-( 1,1,1-trifluoro)butylamino]-
[1,2,4]triazolo[1,5-a]pyrimidine,
5-chloro-6-(2-fluorophenyl)-7-[2-(1,1,1-trifluoro)butylamino]-
[1,2,4]triazolo[1,5-alpynmidine,
5-chloro-6-(2,4,6-tnfiuorophenyl)-7-[2-( 1,1,1-trtfluoro)butylamino]-
[1,2,4]triazolo[1,5-a]pynmidine,
5-chloro-6-(2,6-difluorophenyl)-7-[2-(1,1,1-tnfluoro)butyiamino]-
[1,2,4]triazolo[1,5-a]pyrimidine,
5-chloro-6-(2-chlorophenyl)-7-[2-(1,1,1 -trifluoro)butylamino]-
[1,2,4]tnazolo[1,5-a]pyrimidine,
5-chloro-6-(2,4,6-trifluorophenyl)-7-[2-(1,1,1-trifluoro)-3-methylbutylamino]-
[1,2,4]triazolo[1,5-a]pyrimidine, 5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-[2-(1,1,1 -trifluoro)propylamino]-[1,2,4]triazoto[1,5-a]pyrimid)ne, and

29
5-chloro-6-(2,4-difluorophenyl)-7-[2-(1,1,1 -trifluoro)propylamino]-
[1.2,4]triazolo[1,5-a]pyrimidine.
wherein the enantomenc excess of the (S)-enantiomer ts at least 80 %
7 A compound according to claim 1, selected from the
group consisting of,
5-chloro-6-(3,4,6-trifluorophenyl)-7-[2-(1,1,1-trifluoro)propyIamino]-[1,2,4]triazolo[1,5-a]pynmidine, and
5-chloro-6-(2-Chloro-4,6-difluorophenyl)-7-[2-(1,1,1-trifIuoro)propylamino]-[1,2,4]tnazolo[l ,5-a]pyrimidine
characterized in that the enantiomeric excess of the corresponding (S)-enantiomer is at least 80 %.
8 A process for the preparation of an optically active
compound of formula I as defined in any of the preceding claims which
comprises treating a compound of formula

in which
L1 through L5 and Hal are as defined in claim 1, and
with an optically active amine of formula Hi

in which
R1 and R2 are as defined in claim 1,
M represents a hydrogen atom or a free or complexed metal atom, and
the enantiomeric excess of the (S)-enantiomer is at least 70%

30
9 A fungicidal composition which comprises a carrier,
and as active agent, at least one compound of formula I as
defined in any one of clailms 1-6.
10 Fungicidal trifluoromethylalkylamino
triazolopyrimidines, substantially as herein described,
particularly with reference to the foregoing examples.
11. A fungicidal composition, substantially as herein described, particularly with reference to the foregoing examples.
The novel optically active compounds of formula I:
(R1 Hal and L1 through L5 are defined in the specification)
wherein the enantiomenc excess of the (S)-enantiomer is at least 70 %
show enhanced selective fungicidal activity The new compounds are
processed with earners, and optionally with adjuvants, to form fungicidal
compositions.


Documents:

00806-cal-1999 abstract.pdf

00806-cal-1999 assignment.pdf

00806-cal-1999 claims.pdf

00806-cal-1999 correspondence.pdf

00806-cal-1999 description(complete).pdf

00806-cal-1999 form-1.pdf

00806-cal-1999 form-13.pdf

00806-cal-1999 form-18.pdf

00806-cal-1999 form-2.pdf

00806-cal-1999 form-3.pdf

00806-cal-1999 form-5.pdf

00806-cal-1999 g.p.a.pdf

00806-cal-1999 latters patent.pdf

00806-cal-1999 priority document.pdf

00806-cal-1999 reply f.e.r.pdf

806-cal-1999-granted-abstract.pdf

806-cal-1999-granted-claims.pdf

806-cal-1999-granted-correspondence.pdf

806-cal-1999-granted-description (complete).pdf

806-cal-1999-granted-form 1.pdf

806-cal-1999-granted-form 13.pdf

806-cal-1999-granted-form 18.pdf

806-cal-1999-granted-form 2.pdf

806-cal-1999-granted-form 3.pdf

806-cal-1999-granted-form 5.pdf

806-cal-1999-granted-gpa.pdf

806-cal-1999-granted-letter patent.pdf

806-cal-1999-granted-reply to examination report.pdf

806-cal-1999-granted-specification.pdf

806-cal-1999-granted-translated copy of priority document.pdf

806-CAL-1999-OTHER PATENT DOCUMENT.pdf


Patent Number 212277
Indian Patent Application Number 806/CAL/1999
PG Journal Number 48/2007
Publication Date 30-Nov-2007
Grant Date 28-Nov-2007
Date of Filing 21-Sep-1999
Name of Patentee AMERICAN CYANAMID COMPANY.
Applicant Address FIVE GIRALDA FARMS,MADISON,NEW JERSEY 07940-0874,
Inventors:
# Inventor's Name Inventor's Address
1 PFRENGLE, WALDEMAR JUNKERMUEHLE 1 D-55444, SEIBERSBACH
2 PEES, KLAUS-JUERGEN SOONWALDSTRASSE 9 D-55129, MAINZ
3 ALBERT GUIDO VOLXHEIMER STRASSE 4 D-55546, HACKENHEIM
4 CARTER,PAUL SCHUBERTSTRASSE 29 D-55578, WOLFSHEIM
5 REHNIG, ANNEROSE RATHENAUSTRASSE 11, D-55218, INGELHEIM
6 COTTER, HENRY VAN TUYL 34, CHELMSFORD COURT TRENTON, NEW JERSEY 08618
PCT International Classification Number A61K 5/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/160,894 1998-09-25 U.S.A.