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(21)Application Number: KE/P/201!1 001326   
   
(22) Filing Date: 01112/2009   
   
(30) Priority data: 2764/DEU2008  05/12/2008  IN

(86)  PCT data PCTIEP09/066119    01112/2009 wo 2010/063700    10/0612010

(73)0wner: SYNGENTA PARTICIPATIONS AG of Schwarzwaldallee 215, CH-4058 Basel, Switzerland

(72) Inventors: WALTER, Harald, Syngenta Crop Protection MUnchwilen AG, Schaffhauserstrasse 4332 Stein, Switzerland; RAJ AN, Ramya, Syngenta Biosciences Private Limited, Santa Monica Works, Cor lim Ilhas Goa, Goa 403 110, India and STIERLI, Daniel, Syngenta Crop Protection MUnchwilen AG, Schaffhauserstrasse, 4332 Stein, Switzerland

(74) Agent/address for correspondence: MUR!U, MUNGA1 & COMPANY ADVOCATES, P. 0. BOX 75362-00200, NAIROBI

(54) Title: NOVEL PYRAZOLE-4 -N-ALKOXYCARBOXAMIDES AS MICROBIOCIDES

(57) Abstract: Compounds of formula (I) in which the substituents are as defined in claim l,are suitable for use as microbiocides.

Novel Microbiocides

The present invention relates to novel microbiocidally active, in particular fungicidally active,

carboxamides. It further relates to intermediates used in the preparation of these

5    compounds, to compositions which comprise these compounds and to their use in agriculture or horticulture for controlling or preventing infestation of plants by phytopathogenic microorganisms, preferably fungi.

Fungicidally active carboxamides are described in EP 1787981 and EP 1792901.

10

It has been found that novel carboxamides with a specific substitution pattern have

microbiocidal activity.

The present invention accordingly relates to N-alkoxycarboxamides of formula I

15

R    (1),
12


wherein

R1 is C1-C4alkyl or C1-C4haloalkyl;

R2 is C1-C4alkyl;

20    R3 is hydrogen or halogen;

R4 is hydrogen, C1-C4alkyl or C,-C4halogenalkyl;

R5 , R6 , R8 , R9 and R10 are, independently from each other, hydrogen, halogen, C,-C,alkyl or C1-C,haloalkyl;

R7 is hydrogen, halogen, C1-C,alkyl, C,-C,alkenyl or C,-C,alkinyl;

25    R" is hydrogen, halogen or C,-C6alkyl;

R12 is hydrogen, halogen, C,-C,alkyl, C2-C,alkenyl, C3-C6alkinyl, C3-C6cycloalkyi-C,-C6alkinyl, halophenoxy, halophenyi-C3-C,alkinyl, C(C,-C,alkyi)=NO-C1-C4alkyl, C1-Cahaloalkyl, C1-C.haloalkoxy, C2-C6haloalkenyl, or C2-C6haloalkenyloxy;
R13 is hydrogen, halogen, C1-Csalkyl;


X is oxygen, sulfur or absent; with the proviso that R7 is different from halogen if X is oxygen

or sulfur; and

n is 0 or 1; and agronomically acceptable salts/isomers/structural

isomers/stereoisomers/diastereoisomers/enantio~mers/tautomers and N-oxides of those compounds.

The alkyl groups occurring in the definitions of the substituents can be straight-chain or

branched and are, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-bulyl, sec-butyl, iso-butyl or lert-butyl. Alkoxy, alkenyl and alkynyl radicals are derived from

10    the alkyl radicals mentioned. The alkenyl and alkynyl groups can be mono- or di-unsaturated. The cycloa\kyl groups occuring in the definitions of the substituents are, for example, cyclopropYI, cyclobulyl, cyclopentyl or cyclohexyl. Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, bromine or chlorine. This also applies,

correspondingly, to halogen in combination with other meanings, such as halogenalkyl or

15    halogenalkoxy. Haloalkyl groups preferably have a chain length of from 1 to 4 carbon atoms. Halonalkyl is, for example, fluoromethyl, difiuoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,
pentafluoroethy/, 1, 1-dif/uoro-2,2,2-trich/oroethy/, 2,2,3,3-tetrafluoroethyl and 2,2,2-

trich/oroethy/; preferably trichloromethyl, difluorochloromethyl, difluoromethyl, trifluoromethyl

20    and dichlorofluoromethyl. Alkoxy is, for example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; preferably methoxy and e!hoxy.
Halogenalkoxy is, for example, fluoromethoxy, difluoromethox.y, trifluoromethox.y, 2,2,2-trifiuoroethoxy, 1,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy and 2,2,2-trichloroethoxy; preferably difluoromethoxy, 2-ch/oroethoxy and trifluoromethoxy.
25

In preferred compounds of formula I, independently from each other,

a)    R1 is diftuoromethyl, trifluoromethyl or methyl,

b)    R2 is methyl;

c)    R, is hydrogen or fiuoro;

30    d) R., is hydrogen, methyl or ethyl;

e)    R, is methyl;

f)    R5 is hydrogen or methyl;

g)    n is 0;

h)    X is oxygen;


i)    Ra, Ro and R10 are hydrogen;

j)    R11. R12 and R13 is hydrogen or ch/oro;

k)    R1,  is chloro or C1-C,alkyl;

I)    R6 is hydrogen and
m)    R7 is methyl.

Especially preferred compounds of formula I are those, wherein

R1 is difluoromethyl or trifluoromethyl;

R, is methyl;

10    R3 is hydrogen;

R4 is methyl;
R11o R,2 and R13 are, independently from each other, hydrogen or halogen, preferably hydrogen or chlorine.

15    Further compounds of formula 1 are preferred, wherein

X is oxygen and simultaneously Rr is c,-C,alkyl, preferably methyl; or X is absent and R7 is hydrogen.

Compounds of formula J may be prepared by reacting a compound of formula II

20


R  (II),
12

wherein ~. Rs, R6, R7, X, Rs, Rs, R1oo n, R11o R12 and R13 are as defined under formula /;with

a compound of formula Ill





25    in which R1, R2 and R3 are as defined under formula I, and R"'is halogen, hydroxy or


c,~ alkoxy, preferably chloro.

The reactions to give compounds of formula I are advantageously carried out in aprotic inert organic solvents. Such solvents are hydrocarbons such as benzene, toluene, xylene or cyc\ohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane,

tetrachloromethane or chlorobenzene, ethers such as diethyl ether, ethylene glycol dimethyl

ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane, nitriles such as

acetonitrile or propionitrile, amides such as N,N-dimethylformamide, diethylformamide or N-methy/pyrrolidinone. The reaction temperatures are advantageously between -zooc and

10    +120°C. In general, the reactions are slightly exothermic and, as a rule, they can be carried out at ambient temperature. To shorten the reaction time, or else to start the reaction, the mixture may be heated briefly to the boiling point of the reaction mixture. The reaction times
can also be shortened by adding a few drops of base as reaction catalyst. Suitable bases

are, in particular, tertiary amines such as trimethylamine, triethylamine, quinuclidine,

15    1 ,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo{4.3.0]non-5•eneor 1,5-diazabicyclo-

{5.4.0]undec-7~ene. However, inorganic bases such as hydrides, e.g. sodium hydride or

calcium hydride, hydroxides, e.g. sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, or hydrogen carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate may also be used as bases.

20    The bases can be used as such or else with catalytic amounts of a phase-transfer catalyst, for example a crown ether, in particular 18-crown~6, or a tetraalkylammonium salt.

When R' is hydroxy, a coupling agent, such as benzotriazol-1-yloxylris(dimethylamino)

phosphoniumhexafluorophosphate, bis-(2-oxo-3-oxazolidiny/)-phosphinic acid chloride (BOP-

25    Cl), N,N'-dicyclohexylcarbodiimide(DCC) or 1,1 '-carbonyl-diimidazole(CD I), may be used. The intermediates of the formula II

0~•
H-NI---+---+--~~~•     R  (II),
12

wherein ~. Rs, Rs. R1, X, Ra, Rg, R,o, n, R11 , R,2 and ~3 are as defined under formula \,

30    preferably wherein R4 is C1-C,alkyl; are novel and were developed specifically for the


preparation of the compounds of the formula I. Accordingly, these intermediates of the formula fl also form a part of the subject-matter of the present invention.

The preferred substituent definitions for the compounds of formula I are also valid for the

5    compound of formula II. Thus, preferred compounds of formula I! are those, wherein, independently from each other,
a)    R• is hydrogen, methyl or ethyl; especially preferred methyl;

b)    R5 is hydrogen or methyl;

c)    n is 0;

10    d) X is oxygen;

e)    Ra, Rg and R10 are hydrogen;

f)    R,,, R12 and R13 is hydrogen or chloro;

g)    R12 is chloro or C,-C.alkyl;

h)    R6 is hydrogen and
15   i) R7 is methyl.                   
Intermediates of fo1111ula IIA                   
~•    ~'    R13           
H-~-++-X    j:>-sR  (IIA),   
H    H    ~    li    12   
                   
R,

wherein R4, Rs. X , R7,  R111  R12 and R13 are as defined under formula I may be prepared as

20    described in reaction scheme 1.
 
Nitroa\kenes of formula VI, in which and Rs, R11 , R12 and R13are as defined under formula

II A, can be prepared by a Henry-reaction (nitroaldol-reaction) of a nitroalkane of formula V, in which R5 is as defined under formula IIA, with a carbonyl compound of formula (IV), in
which R1,, R12and  R,3 are as defined under formula 1\A, in the presence of acetic acid and

ammonium acetate at temperatures between ambient temperature and reflux temperature.

Michael addition of a compound of formula VIla, in which R7 and X are as defined under

10    formula I and M is Li, Na, K or hydrogen, to the nitroalkenes of formula VI may be accomplished using earth alkali a\coholates preferred sodium, potassium and lithium salts in the corresponding alcohol, thiol, toluene or an ether solvent such as dlethy\ ether, ethylene


glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane to form the nitroalkanes of forrnufa Vff/, in which R5 , R7, R11 , R12 and R13 are as defined under formula
II A.

Nitroalkenes of formula VI, in which and R5, R111 R12 and R13 are as defined under formula JJA, may be reduced with iron and hydrochloric acid to give oximes of formula IX, in which

Rs. R11 , R12 and R,3are as defined under formula IIA. Said oximes can be hydrolyzed to ketones of formula Xa, in which and R5, R11 , R12 and R13 are as defined under formula IIA, as it is described, for example, in M. Kulka and H. Hibbert J. Am. Chern. Soc. 65, 1180 (1943)

10    and in Prasun K. Pradhan et al. Synthetic Commun., 35, 913-922, 2005. The reaction is carried out at temperatures of between 40 -1 00°C in a convenient organic solvent such as methanol, ethanol, tert-butanol, trif/uoroethanol or dioxane.

Alkylation of ketones of formula Xa with a compound R7~Y, in which R7 is as defined under

15    formula HA andY represents a leaving group, such as halogen, mesylate or tosylate, in the

presence of a base yields an a~alkylated ketone of formula Xb, wherein Rs, R1, R11 , R,2 and R13 are as defined under formula IlA. The alkylation reaction is advantageously carried out in aprotic inert organic solvents. Such solvents are hydrocarbons such as benzene,_ toluene,

xylene or cyclohexane, ethers such as diethyl ether, ethylene glycol dimethyl ether,

20    diethylene glycol dimethyl ether, tetrahydrofuran or dioxane, amides such as N,N-dimethylformamide, diethylformamide or N~mefhyfpyrrofidinone. The reaction temperatures are between -20°C and +120°C. Suitable bases are inorganic bases such as hydrides, e.g. sodium hydride or calcium hydride, hydroxides, e.g. sodium hydroxide or potassium

hydroxide, carbonates such as sodium carbonate and potassium carbonate, or hydrogen

25    carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate may also be used as bases. The bases can be used as such or else with catalytic amounts of a phase-transfer catalyst, for example crown ether, in particular 18-crown-6, or a tetraa/kylammonium salt.

30    0-alkoxy oxime derivatives of formula Xlla, Xllb may be prepared by oximation of ketones of formula Xa and Xb with 0-alkyl hydroxylamine derivatives of formula XI or a salt thereof. Suitable solvents carrying out the oximation step are hydrocarbons such as benzene, toluene, xylene or cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane, tetrachforomethane or chlorobenzene, ethers such as diethyl ether,


ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane,

nitriles such as acetonitrile or propionitrile, amides such as N,N-dimethylformamide, diethylformamide, N-methylpyrrolidinone water or mixtures. The reaction temperatures are a'dvantageouslybetween -zooc and +120°C. In general, the reactions can be carried out at ambient temperature. Suitable bases are, in particular pyridine, tertiary amines such as
trimethylamine, triethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane,

1 ,5-diazabicyclo[4.3.0]non-5-ene or 1,5-diazabicyclo[5.4.0]undec-7-ene. However, inorganic

bases such as hydrides, e.g. sodium hydride or calcium hydride, hydroxides, e.g. sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate and potassium

10    carbonate, or hydrogen carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate may also be used as bases.

Oxime derivatives of formula XIII may be prepared by selective reduction of nitroalkenes of

formula VI in an alcohol or thiol of formula Vllb using SnCI,.2H20 according the procedure

15    reported by R.S. Varma and G.W. Kabalka Chern. Lett., 243-244 (1985).

Oxime ether derivatives of formula Xllc may be prepared by O~alkylation of oxime derivatives of formula XIII with a compound R,-Y, in which R. is as defined under formula IIA andY represents a leaving group, such as halogen, mesylate or tosylate, in the presence of a base. Alternatively oxime ether derivatives of formula Xllc may also be prepared by

20    oximation of a ketone of formula XIV with 0-alkyl hydroxylamine derivatives of formula XI or a salt thereof.

Ketones of formula XIV may be prepared by conversion of nitroalkanes of formula VIII, by

Nef reaction according to the procedure described by J.M Aizpurua and C. Palomo THL, Vol.

25    28, No.44,pp 5361-5364 (1987}.

0-Aikylhydroxylamines of formula IIAa, IIAb and IIAc may be prepared by the reduction of 0-alkoxy oxime derivatives of formula Xlla, Xllb and Xllc.

Intermediates of formula IIA
~•    R13

HJ---t-~+j:>-• R (IIA),
~ /;        12
H    H
R,
30


wherein R4 , R5, R1, R11, R12 and R13 are as defined under formula I may be prepared as

described in reaction scheme 2.

Scheme 2:

R,3    R7
LiOH~0
            -    )lAo6H   
                    R,2            R,,   
(XV)        (XVI)                (XVII)   
            (COCI),, CH,Cl,, DMF   
                       
                    lHN(CH3)0CH3   
                    R13R7               
                            0       
                    R,        0    /   
                                   
    R;-MgBr, THF                        (XVIII)   
            R,ffiI           
                    j reduction   
R13R7    O            R13    R7    0   
                                   
    R                        H   
R 12roR11    (Xb)        R12        R11    (Xbl)   


(IIAb)

5    a-alkyl ated arylacetate derivatives of the formula XVI, can be synthesized by the alkylation of an arylacetate derivative of formula XV, with an halide, such as R7-Y, wherein R7 is as defined under formula IIA and Y represents a leaving group, such as halogen, mesyfate or tosylate, in the presence of a base. The compound of formula XVI is hydrolyzed by a

hydroxide, such as LiD H. The resultant acid of the formula XVII, can then be converted to 10 the corresponding acylchloride and this acylchloride can then in situ be reacted with N,O-
 


dimethylhydro•ylamine to afford a Weinreb amide of fonmula XVIII, in which R,, R,, R,and

R13 are as defined under formula /fA. A subsequent reaction with a Grignard reagent of the formula Rs-MgBr, wherein R5 is as defined under formula IIA, yields the ketone of formula Xb, which can be converted to a compound of formula IIAb by reactions described in

scheme 1.

Aldehyde derivatives of formula Xb1 may be prepared by the partial reduction of a Weinreb amide of formula XVIII with LiAIH,, or DIBAL-H.

10    Intermediates of formula IIA
~'    R,,
H-~-H--Hj:>-sR(IIA),

~  /;       12
H    H   R,,

wherein R4, Rs, R11 ,  R1z and R13 are as defined under formula I may be prepared as

described in reaction scheme 3.

Scheme 3:
 
Aldehyde derivatives of formula Xa1 can be prepared according to methods known in the art by reduction of acid derivatives of formula XIX into alcohol derivative of formula XX followed
by the transformation into activated benzylic derivative of formula XXI, transformation into

nitrile derivative of formula XXII followed by reduction into aldehyde derivative of formula Xa1, described in the preparation section. A subsequent reaction of nitrile derivative of formula XXII wilh a Grignard reagent of the formula R5-MgBr, wherein R5 is as defined under formula I lA, yields the ketone of formula Xa, which can be converted to a compound of
10    formula IIAb by reaclions as described in scheme 1.

Intermediates of formula liB

~•    R,

H-%--:r-1'-+I---ji--9-'•'"''•

R,

wherein R4,  Rs. R11 ,  R12 and R1 3 are as defined under formula I may be prepared as

5    described in reaction scheme 4. Scheme4:


10    formate to the corresponding acid of formula XXIII, as it is described, for example, by G.Toth
 

et. al.  in  Synlh. Commun. 25 (19), 3067-3074 {1995). Said acid can be converted to the

corresponding acylchloride and this acy[chloride can then in situ be reacted with N,O-

dimethylhydroxylamine to afford a Weinreb amide of formula XXIV. Subsequent reaction of

the Weinreb amide of formula XXIV with a Grignard reagent of the formula R5-MgY, wherein

5    Rs is as defined under formula IIA, yields the ketone of formula XXV a.

Aldehyde of fonmula XXVb may be prepared by the partial reduction of Weinreb amide of formula XXIV with LiAIH,, or DIBAL-H. Alternatively said aldehyd may be prepared by oxidation of alcohol of formula XXVI. Suitable oxidation reagents include pyridinium

chlorochromate (PCC), Swern reagent (oxalylchloride/DMSO), Dess-Martin Periodinane and

10    Mn02• Suitable solvents include dichloromethane and THF. The reaction temperature typically lies in the range of -50'Cto 20'C.

Ketone and aldehyde derivatives of formula XXV a and XXVb can be further converted to compounds of formula IIBa and IJBb by reactions as described in scheme 1.

15    Intermediates of formula liB

H~'-%--tl'-+1'R,3-+1-h-R,
r    (liB),
H    H    H
R11

wherein ~. Rs, R1, Ru, R12 and R13 are as defined under formula I may be prepared as

described in reaction scheme 5.

20    Scheme 5:

XXVII    XXVIII

II Be

Ketone or aldehyde derivatives of formula XXIX may be prepared by the palladium-catalyzed arylation of allylic alcohols of formula XXVIII with aryliodides of formula XXVII in water as described for example by Hong Zhao, Ming-Zhong Cai et. al. in Synth. Commun. 31 (23), 3665-3669 (2001); Alberto Scrtvanti, Ugo Malleoli et. al. in Tetrahedron 64, 543-548 (2008). Ketone and aldehyde derivatives of formula XXIX can be further converted to

compounds of formula JIBe by reactions described in scheme 1.

10    The compounds I and, where appropriate, the tautomers thereof, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.

It has now been found that the compounds of formula I according to the invention have, for

15    practical purposes, a very advantageous spectrum of activities for protecting useful plants against diseases that are caused by phytopathogenic microorganisams, such as fungi, bacteria or viruses.
 

The invention relates to a method of controlling or preventing infestation of useful plants by

phytopathogenic microorganisms, wherein a compound of formula f is applied as ac1tve

ingredient to the plants, to parts thereof or the locus thereof. The compounds of formula I

according to the invention are distinguished by excellent activity at low rates of application,

by being well tolerated by plants and by being environmentally safe. They have very useful

curative, preventive and systemic properties and are used for protecting numerous useful plants. The compounds of formula I can be used to inhibit or destroy the diseases that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later

10    e.g. from phytopathogenic microorganisms.

It is also possible to use compounds of formula 1 as dressing agents for the treatment of plant propagation material, in particular of seeds (fruit, tubers, grains) and plant cuttings (e.g.

rice), for the protection against fungal infections as well as against phytopathogenic fungi

15    occurring in the soil.

Furthermore the compounds of formula I according to the invention may be used for

controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage or in hygiene

20    management.

The compounds of formula I are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium,

Fusarium, Septaria, Cercospora and Alternaria) and Basidiomycetes (e.g. Rhizoctonia,

25    Hemileia, Puccinia). Additionally, they are also effective against the Ascomycetes classes

(e.g. Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula) and of the Oomycetes classes (e.g. Phytophthora, Pythium, Plasmopara). Outstanding activity has been observed against powdery mildew (Erysiphe spp.). Furthermore, the novel compounds of formula I are
effective against phytopathogenic bacteria and viruses (e.g. against Xanthomonas spp,

30    Pseudomonas spp, Erwinia amylovora as well as against the tobacco mosaic virus). Good activity has been observed against Asian soybean rust (Phakopsora pachyrhizi).

Within the scope of the invention, useful plants to be protected typically comprise the following species of plants: cereal (wheat, barley, rye, oat, rice, maize, sorghum and related

species); beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples, pears,

plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); le9uminous

plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers,

coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucum-

bers, melons); fibre plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit,

mandarins); vegetables (spinach, lettuce, asparagus, cabb~ges, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cinnamomum, camphor) or plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as ornamentals.

10

The term 11 Usefu1 plants" is to be understood as including also useful plants that have been rendered tolerant to herbi~ides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors: ALS inhibitors, for example primisulfuron, prosulfuron and

trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS

15    (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of

breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have

been rendered tolerant to herbicides or classes of herbicides by genetic engineering

20    methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and Libertylink®.

The term "useful plants" is to be understood as including also useful plants which have been

so transformed by the use of recombinant DNA techniques that they are capable of

25    synthesising one or more selectively acting toxins, such as are known, far example, from toxin-producing bacteria, especially those of the genus Bacillus.

Examples of such plants are: YieldGard® (maize variety that expresses a CryiA(b) toxin);

YieldGard Rootworm® (maize variety that expresses a CryiiiB(b1) toxin); YieldGard Plus®

30    (maize variety that expresses a CryiA(b) and a CryiiiB(b1) toxin); Starlink® (maize variety that expresses a Cry9(c) toxin); Herculex I® (maize variety that expresses a Crylf(a2) toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 338® (cotton variety that expresses a CryiA(c) toxin); Bollgard I® (cotton variety that expresses a CryiA(c) toxin); Bollgard II® (cotton


variety that expresses a CryiA(c) and a CryiiA(b) toxin); VIPCOT® (cotton variety that expresses a VIP toxin); Newleaf® (potato variety that expresses a CryiiiA toxin); Nature-Gard® Agrisure® GT Advantage (GA21 glyphosate-!oleran!lrail), Agrisure® CB Advantage (Bt11 corn borer (CB) trait), Agrisure® RW (corn rootworm trail) and Protec!a®.

The term "useful plants" is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising anti pathogenic substances having a selective action, such as, for example, the
so-called "pathogenesis-related proteins" (PRPs, see e.g. EP-A-0 392 225). Examples of

10    such antipathogenic substances and transgenic plants capable of synthesising such

anti pathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191. The methods of producing such transgenic plants are generally known

to the person ski!led in the art and are described, for example, in the publications mentioned

above.

15

The tenn "locus" of a useful plant as used herein is intended to embrace the place on which the useful plants are growing, where the plant propagation materials of the useful plants are sown or where the plant propagation materials of the useful plants will be placed into the soil. An example for such a locus is a field, on which crop plants are growing.
20

The term "plant propagation material" is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes. There may be mentioned for example seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes and parts of plants.
25    Germinated plants and young plants which are to be transplanted affer germination or after emergence from the soil, may also be mentioned. These young plants may be protected before transplantation by a total or partial treatment by immersion. Preferably "plant propagation materialn is understood to denote seeds.

30    The compounds of formula I can be used in unmodified form or, preferably, together with carriers and adjuvants conventionally employed in the art of formulation.

Therefore the invention also relates to compositions for controlling and protecting against phytopathogenic microorganisms, comprising a compound of formula 1and an inert carrier,
 



-18-

and to a method of controlling or preventing infestation of useful plants by phytopathogenic

microorganisms, wherein a composition, comprising a compound of formula las acitve

ingredient and an inert carrier, is applied to the plants, to parts thereof or the locus thereof.

5    To this end compounds of formu[a I and inert carriers are conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders•, dusts, granulates, and also encapsulations e.g. in polymeric substances. As with the type of the compositions, the
methods of application, such as spraying, atomising, dusting, scattering, coating or pouring,

10    are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackiflers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.

15    Suitable carriers and adjuvants can be solid or liquid and are substances useful in formula-tion technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.

20    The compounds of formula I or compositions, comprising a compound of formula I as acitve ingredient and an inert carrier, can be applied to the locus of the plant or plant to be treated,

~imul~aneously or in succession with further compounds. These further compounds can be e.g. fertili:c:ers or micronutrient donors or other preparations which influence the growth of plants. They can also be selective herbicides as welf as insecticides, fungicides,

25    bactericides, nematicides, mo\luscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.

A preferred method of applying a compound of formula I, or a composition, comprising a

30    compound of formula I as acitve ingredient and an inert carrier, is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen. However, the compounds of formula I can also penetrate the
plant through the roots via the soil (systemic action) by drenching the locus of the plant with

a liquid formulation, or by applying the compounds in solid fonn to the soil, e.g. in granular
 




-19-

form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of fonnula I may also be applied to seeds (coating) by impregna-

ting the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.

A formulation, i.e. a composition comprising the compound of formula 1and, if desired, a solid or liquid adjuvant, is prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, sefid carriers and, optionally, surface-active compounds (surtactants).

10

The agrochemical formulations will usually contain from 0.1 to 99% by weight, preferably

from 0.1 to 95% by weight, of the compound of formula /, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
15

Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.

Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per

20    hectare (ha), preferably from 1Og to 1kg a.l./ha, most preferably from 20g to 600g a.i./ha.

When used as seed drenching agent, convenient rates of application are from 10mg to 1g of active substance per kg of seeds. The rate of application for the desired action can be determined by experiments. It depends for example on the type of action, the developmental

stage of the useful plant, and on the the application (location, timing, application method)

25    and can, owing to these parameters, vary within wide limits.

Surprisingly, it has now been found that the compounds of formula I can also be used in

melhods of protecting crops of useful plants against attack by phytopathogenic organisms as well as the treatment of crops of useful plants infested by phytopathogenic organisms

30    comprising administering a combination of glyphosate and at least one compound of formula

I to the plant or locus thereof, wherein lhe plant is resistant or sensitive Ia glyphosale.

Said methods may provide unexpectedly improved control of diseases compared to using the compounds of formula I in the absence of glyphosale. Said methods may be effective at
 




-20-

enhancing the control of disease by compounds of formula I. While the mixture of glyphosate and at least one compound of formula I may increase the disease spectrum controlled, at least in part, by the compound of formula I, an increase in the activity of the compound of formula I on disease species already known to be controlled to some degree by the

5    compound of formula I can also be the effect obseNed.

Said methods are particularly effective against the phytopathogenic organisms of the

kingdom Fungi, phylum Basidiomyco( class Uredinomycetes, subclass Urediniomycetidae

and the order Uredina/es (commonly referred to as rusts).  Species of rusts having a

10    particularly large impact on agriculture include those of the family Phakopsoraceae, particularly those of the genus Phakopsora, for example Phakopsora pachyrhizi, which is also referred to as Asian soybean rust, and those of the family Pucciniaceae, particularly those of the genus Puccinla such as Puccinia graminis, also known as stem rust or black rust, which is a problem disease in cereal crops and Puccinia recondita, also known as
15    brown rust.

An embodiment of said method is a method of protecting crops of useful plants against attack by a phytopathogenic organism and/or the treatment of crops of useful plants infested by a phytopathogenic organism, said method comprising simultaneously applying

20    glyphosate, including salts or esters thereof, and at least one compound of formula I, which has activity against the phytopathogenic organism to at feast one member selected from the group consisting of the plant, a part of the plant and the locus of the plant.

The compounds of formula (I), or a pharmaceutical salt thereof, described above may also

25    have an advantageous spectrum of activity for the treatment and/or prevention of microbial infection in an animal. "Animal" can be any animal, for example, insect, mammal, reptile, fish, amphibian, preferably mammal, most preferably human. "Treatment" means the use on an animal which has microbial infection in order to reduce or slow or stop the increase or

spread of the infection, or to reduce the infection or to cure the infection. UPrevention" means

30    the use on an animal which has no apparent signs of microbial infection in order to prevent any future infection, or to reduce or slow the increase or spread of any future infection. According to the present invention there is provided the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment and/or prevention of microbial infection in an animal. There is also provided the use of a compound of formula (I) as a


pharm.aceutical agent. There is also provided the use of a compound of formula (I) as an antimicrobial agent in the treatment of an animal. According to the present invention there is also provided a pharmaceutical composition comprising as an active ingredient a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. This composition can be used for the treatment and/or prevention of antimicrobial infection in an animal. This pharmaceutical composition can be in a form suitable for oral administration, such as tablet, lozenges, hard capsules, aqueous suspensions, oily suspensions, emulsions dispersible powders, dispersible granules, syrups and elixirs. Alternatively this pharmaceutical composition can be in a form suitable for topical

10    application, such as a spray, a cream or lotion. Alternatively this pharmaceutical composition can be in a form suitable for parenteral administration, for example injection. Alternatively this pharmaceutical composition can be in inhalable form, such as an aerosol spray ...

The compounds of formula (I) may be effective against various microbial species able to

cause a microbial infection in an animal. Examples of such microbial species are those

15    causing Aspergillosis such as Aspergillus fumigatus, A. flavus, A. terrus, A. nidu/ans and A. niger, those causing Blastomycosis such as Blastomyces dermatitidis; those causing Candidiasis such as Candida albicans, C. glabrata, C. tropicalis, C. parapsi/osis, C. krusei and C. /usitaniae; those causing Coccidioidomycosis such as Coccidioides immitis; those

causing Cryptococcosis such as Cryptococcus neoformans; those causing Histoplasmosis

20    such as Histoplasma capsu/atum and those causing Zygomycosis such as Absidia corymbifera, Rhizomucor pusil/us and Rhizopus arrhizus. Further examples are Fusarium

Spp such as Fusarium oxysporum and Fusarium so/ani and Scedosporium Spp such as

Scedosporium apiospermum and Scedosporium prolificans. Still further examples are Microsporum Spp, Trichophyton Spp, Epidermophyton Spp, Mucor Spp, Sporothorix Spp,

25    Phialophora Spp, Cladosporium Spp, Petriellidium spp, Paracoccidioides Spp and Histoplasma Spp.

The following non-limiting Examples illustrate the above-described invention in greater detail without limiting it.
30

Preparation examples:

Example P1: Preparation of 3-dinuoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-{4-chloro-phenyll-1-methyl-ethyll-methoxv-amide (compound 1.001):
 

A solution of 3-difluoromethyl-1-melhyi-1H-pyrazole-4-carbonyl chloride (564 mg; 2.9 mmol) in dichloromethane (5ml) was added dropwise to a stirred solution of N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-0-methyl-hydroxylamine (600 mg; 2.9 mmol), prepared as described in example P13, triethylamine (0.80 ml; 5.8 mmol) in dichloromethane (10ml) at O'C.The

reaction mixture was stirred for 6 hours at ambient temperature. The reaction mixture was

washed with 1M NaOH (20ml), 1M HCI (20ml) brine (20ml) and then dried over Na2SO,.

After removal of the solvent ~he residue was purified by flash chromatography aver silica gel

(eluant: c-hexane/ethyl acetate 1:1).

10    0.99 9 (93.4 % of theory) of 3-dtnuoromethyl-1-methyi-1H-pyrazole-4-<>arboxylic acid [2-(4-chloro-phenyl)-1-methyl-ethyl]-methoxy-amide (compound 1.001) was obtained in form of a resin.
1H NMR: (CDC!,, 400MHz):

1.33-1.37(d,3H);   2.77-2.82(dd, 1H);   3.07-3.13(dd, 1H);   3.64(s,3H);   3.94(s,3H);   4.63-

15    4.68(m,1H); 6.98-7.28(m, 5H); 7.61(s,1H). MS [M+Ht 358/360.

Example P2: Preparation of 3-difluoromethyl-1-methyi-1H-oyrazole-4-carboxylic acid {2-

(2,4-dichlorophenyll-1-methyl-ethyl]-methoxv-amide (compound 1.002):

FVHFOWH,PIC/

~    N    ::,..
N,   I    6    Cl
}'/    HC'   
H3C    3   
20       

A solution of 3-difiuoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (0.91 g; 4.7 mmol) in dichloromethane (5ml) was added dropwise to a stirred solution of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-0-methyl-hydroxylamine (1.0 9; 4.27 mmol), prepared as described in example P14, triethylamine (0.90 ml; 6.4 mmol) in dichloromethane (7ml) at O'C. The

25    reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 1M NaOH (20ml), 1M HCI (20ml) brine (20ml) and then dried over Na2so,.
 




-23-

After removal of the solvent the residue was purified by flash chromatography over silica gel

(eluant: hexane/ethyl acetate 7:3).

1.35 g (80.3% of theory) of 3•difluoromethyl-1-methyi-1H-pyrazole-4-carboxylicacid [2-{2,4-dichlorophenyl)-1-methyl-ethyl]-methoxy-amide (compound 1.002) was obtained in form of a

5    white solid (m.p. 98-102'C). 1 H NMR: (CDCI3, 400MHz):

1.41-1.46(d,3H); 2.99-3.04(dd,1 H); 3.17-3.23(dd, 1H); 3.60(s,3H); 3.95(s,3H); 4.68-4.70(m,1H); 7.10-7.62(m, 5H).

MS [M+H]'392/394/396.

10

Example P3: Preparation of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carboxvtic acid

methoxv-C1-methyl-2-(2,4,6-trichlorophenyl}-ethyll-amjde /compound 1.003):





15 To a solution of 0-Methyi-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.65 g, 2.4 mmol) prepared as described in example P15d, in dichloromethane (5 ml) was added triethylamine (0.844 ml, 6.0 mmol) followed by drop wise addition of a solution 3-Difiuoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (0.519 g, 2.67 mmol) in dichloromethane at 0°C. After complete adddition of acid chloride the mixture was stirred 18
20 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3 x 60 ml). The

combined dichloromethane layer were washed with 2N HCI, followed by saturated NaHC03 , then with water and finally with brine solution before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass was purified by column

25    chromatography using 60-120 ~ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difiuoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide {0.51 g, 49%) as off white solid. m.p: 110-112'C
1H NMR (400MHz, CDC!,): d 1.38-1.39(d,3H), 3.20-3.26{dd,1H), 3.32-3.37(dd,1 H),

30    3.70(s,3H), 3.97{s,3H), 4.88-4.93(m,1H), 7.02-7.29{t,1H), 7.27{s,2H), 7.81{s,1H) MS [M+H]'426/428/430
 



-24-

Example P4: Preparation Fvof3~difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid£2-[4-

(4-chloro-phenoxvl-phenyll-1-methyl-ethyl)=methoxy-amide (compound 1.015):
H
9H,  FYO~
"' I    N~ ~CJ
N,    I
)'J  H3 c'0
H3C

A solution of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (797 mg; 4.1 mmol) in dichloromethane (5ml) was added dropwise to a stirred solution of N-{2-(4-(4-chlaro-phenoxy)-phenyl]-1-methyl-ethyl)-0-methyl-hydroxylamine (1.2 g; 4.1 mmol), prepared as described in example P16, triethylamine (1.10 ml; 8.2 mmol) in dichloromethane (10ml) at

ooc. The reaction mixture w~s stirred over night at ambient temperature. After removal of

the  solvent the  residue  was 'purified by flash  chromatography over silica  gel  (eluant:  c-

10    hexane/ethyl acetate 1:1).

1.2 g (66 %of theory) of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid{2-[4-(4-

chloro-phenoxy)-phenyl)-1-methyl-ethyl)-methoxy-amide (compound 1.015) was obtained in

form of a oil.

1H NMR: (CDC!,, 400MHz):

15    1.36-1.39(d,3H); 2.78-2.84(dd, 1H); 3.05-3.12(dd,1H); 3.65(s,3H); 3.94(s,3H); 4.64-4.68(m, 1 H); 6.80-6.90(m, 4H);6.95-7.23(t, 1H,CHF2);7. i7-7.26(m,4H);7.67(s, 1 H).

MS [M+Hf 4501452.

Example P5: Preparation of 3-difluoromethvl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-
20    (2,4-dichlorophenyll-1-methyl-ethyll-hydroxy-amide (compound01 1.028):
Fyo ~H,PJ
7    I    N    ::,..   
N        I    Cl   
}        OH       

H,c

A solution of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (2.10 g; 11.0 mmol) in dichloromethane (5ml) was added dropwise to a stirred suspension of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamine (2.0 g; 9.10 mmol), prepared as described in
25    example P17, triethylamine (3.10 ml; 22 mmol) in dichloromelhane (15ml) at O'C. The reaction mixture was stirred over night at ambient temperature. The reaction mixture was poured onto 1M HCI (50ml), extracted with dichtoromethane (3x20ml) and then dried over
 



-25-

Na,so,. After removal of the solvent the residue (5.08g) was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl acetate 7:3).

1.51 g (43.8% of theory) of 3-difiuoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid [2- (2,4-dichlorophenyt)-1-methyl-ethyl]-hydroxy-amide (compound 1.028) was obtained in form of a white solid (m.p. 162-167"C).

1H NMR: (CDC!,, 400MHz):

1.40-1.41 ( d ,3H);2.89-2.94(dd, 1 H);3.03-3.14( dd, 1H);3.86(s,3H);4.3-4.5(m,,, 1H);6.5-7.0(m,,.2H); 7.19-7.21(m, 2H); 7.36(m,1H); 7.8-8.6(m.,,1H).

MS [M+H]'378/380/382.

10

Example P6: Preparation of 3-difluoromethyl~1-methyi-1H-pyrazole-4-carboxylic acid [2-

12,4-dichlorophenyll-1-methyl-ethyl!-ethoxy-amide (compound 1.031):

Fvo~H,""iCI
,.-    N    '>--
N,~ I ( 6    Cl
HaC    CHa

A solution of 3-difluoromethyl-1-methy/-1 H-pyrazole-4-carbonyl chloride (0.86 g; 4.4 mmol) in

15    dichloromethane (5ml) was added dropwise to a stirred solution of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-0-ethyl-hydroxylamine (1.0 g; 4.0 mmol), prepared as described in example P18, triethylamine (0.82 ml; 6.0 mmol) in dichloromethane (7ml) at O'C.The reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 1M
NaOH (20ml), 1M HCI (20ml) brine (20m I) and then dried over Na,S04• After removal of the

20    solvent the residue was purified by flash chromatography over silica gel (eluant: hexane/ethyl acetate 7:3).

0.75 g (45.7% of theory) of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid [2- (2,4-dichlorophenyl)-1-methyl-ethyl]-ethoxy-amide (compound 1.031) was obtained in form of a white solid (m.p. 116-118'C).
25    1H NMR: (CDCI,, 400MHz):

1.14-1.20(t,3H); 1.36-1.45(2d,3H);2.g8-3.03(dd, 1H);3.1 9-3.25(dd, 1H);3.7 4-3.82(q,3H);

3.94(s,3H); 4.64-4. 70(m, 1H); 6.93-7.6S(m, SH).

MS [M+Hj'406/408/410.
 




-26-

Example P7: Preparation of 3-difluoramethyl-1-methyi-1H-pyrazoleA-carboxylic acid ethoxy-

[1-methyl-2-(2,4,6-trichlorophenyll-ethyll-amide (compound 1.032):

F-\F  ff)~CI

NT~:,  Cl
,N    (

H3C    CH3

5    To a solution of 0-ethyi-N-[1-methyl-2-(2,4,6-trich/oro-phenyl}-ethy/]-hydroxylamine (0.5g, 1.63 mmoles) in dichloromethane (5 ml) was added triethylamine (0.566 ml, 4.07 mmloes)
followed by drop wise addition of a solution 3-difiuoromethyl-1-methyl-1 H-pyrazole-4-

carbonyl chloride (0.34 g, 1.79 mmol) in dich/oromethane ala temperature of 0°C. After the

complete adddition of acid chloride the mixture was stirred for 18 hours at ambient

10    temperature. When the TLC confirmed completion of the reaction, the reaction mass was

diluted with water and extracted with dichloromethane (3 x 60 ml). The combined dichloromethane layer were washed with 2N HCI, followed by saturated NaHC03, then water and finally brine, dried over sodium sulfate and evaporated off solvent under reduced

pressure. Resulting crude mass was purified by column chromatography using 60-120 JJ

15    mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid ethoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.390 g, 50%) as off white solid. m.p: 111-114'C

1H NMR (400MHz, CDC!,): d 1.20-1.24(t,3H), 1.35-1.37(d,3H), 3.23-3.28(dd, 1H), 3.33-

3.38(dd, 1H), 3.84-3.88(q,2H), 3.96(s,3H), 4.86-4.91(m, 1H), 7.01-7.25(t,1H), 7.28(s,2H),

20    7.83(s, 1 H)

MS [M+H]'439.9/441.83

Example PB: Preparation of 3-difluoromethyl-1-methyl-1H-pyrazoleA-carboxylic acid [2-

(2,4-dichlorophenyll-1-methyl-ethyll-isopropoxy-amide (compound 1.033):

H       
F~o ?H3    (YCJ
7    N~
N,i    6  CHCI
j'l    -....,c    3
H3C    b~H   
25    3   
 




-27-

A solution of 3-dinuoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (1.1 g; 5.7 mmol) in dichloromethane (5ml) was added dropwise to a stirred s~lution of N-(2-(2,4-dichlorophenyl)-1-methyl-ethyl]-0-isopropyl-hydroxylamine (1.5 g; 5.7 mmol), prepared as described in example P20, triethylamine (1.6 ml; 11.4 mmol) in dichloromethane (10ml) at ooc. The

reaction mixture was stirred over night at ambient temperature. After removal of the solvent

the residue was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl acetate 7:3).

1.30 g (54.0% of theory) of 3-dinuoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2- (2,4-dichlorophenyl)-1-methyl-ethyl]-isopropoxy-amide (compound 1.033) was obtained in form of
10    a yellow oil.

1H NMR: (CDC!,, 400MHz):

0.91-0.93+1.11-1.13(2d,6H);1.42-1.48(2d,3H);3.00-3.07(dd,1H);3.29-3.36(dd,1 H);3.92(s,3H); 3.97-4.36(m, 1H);4.36-4.45(m,1H); 6.97-7.59(m, 5H). MS [M+Hj'420/422/424.

15

Example P9: Preparation of 3-difluoromethyl-1-methyi-1H-pvrazole-4-carboxylic acid [2-

(2,4-dichlorophenyll-pentvll-methoxy-amide (compound 1.059):

FVHFO~ICI
7    N    :::,_
N,   I    6    Cl
fl    H,c'   
H3C        CH3

A solution of 3-dinuoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride (2.20 g; 11.0 mmol)

20    in  dichloromethane  (10ml)  was  added  dropwise  to  a  stirred  solution  of  N-[2-{2,4-

dichlorophenyl)-pentyl]-0-methyl-hydroxylamine (3.0 g; 11.0 mmol), prepared as described in example P22, triethylamine (3.0 ml; 22 mmol) in dichloromethane {20ml) at ooc. The

reaction mixture was stirred for 6 hours at ambient temperature. After removal of the solvent

the residue was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl

25    acetate 1:1 ).

3.85 gm (83% of theory) of 3-dinuoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid [2- (2,4-dichlorophenyl)-pentyl]-methoxy-amide (compound 1.059) was obtained in form of a yellow oil.
1H NMR: (CDCI3,  400MHz):
 



-28-

0.84-0.8 7(t,3H);1.14-1.25(m,2H);1.61-1.69(m,2H);3.55(s,3H);3. 71-3.80(m, 1H);3.80-3.84(dd,1 H); 3.96(s,3H); 3.99-4.05(dd,1 H); 7.07-7.36(m, 4H);7.79(s,1H).

MS [M+H]'420/422/424.

Example P10: Preparation of 3-difluoromethyl-1-methyi-1H-pyrazoleA-carboxvlic acid

methoxv-[1-methyl-3-(2,4 6-trichloro-phenyll-propyll-amide (compound 2.003):

F~F ~ CH3    Cl
NT~~0
}'I   H c'    c1AAc1
H3C3   

To a solution of 0-Methyi-N-[1-m_ethyl-3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.6g, 2.1 mmol) prepared as described in example P23d, in dichloromethane (6 ml), was added

10    triethylamine (0.73 ml, 5.2 mmol) followed by drop wise addition of a solution of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride (0.415 g, 2.1 mmol) in dichloromethane at 0°C. After complete adddition of acid chloride, the reaction mixture was stirred for 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3 x

15    60 ml). The combined dichloromethane layer was washed with 2N HCI, followed by sat

NaHC03 then water and finally brine solution, dried over sodium sulfate and solvent was evaporated off under reduced pressure. The resulting crude mass was purified by column chromatography using 60-120 ~ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid

20    methoxy-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]-amide (0.53 g, 57%) as a gum like mass.
Physical data:

1H NMR: (CDCI,, 400MHz):

1.41(d,3H,CH3), 1.71-1.80(m, 1H,CH,), 1.94-2.04(m, 1H,CH2),1.87-1.92(m,2H,CH2),

25    3. 78( s,3H, CH3),3.98( s,3H, CH3),4.66-4. 71 (m, 1H,CH), 7.11 (t, 1H,CHF2), 7.28( s,2H,Ar-H), 7.88(s, 1H,pyrazole-H)
MS [M+H]'440/442/444/446.

Example P11: Preparation of 3-difluoromethyl-1-methyi-1H-ovrazole-4-carboxylic acid

30    methoxy-[3-(2 4 6-trichloro-phenyll-propyiJ-amide (compound 2.040):


To a stirred solution of 0-methyi-N-[3-[2,4,6-Irichloro-phenyl)-propyq-hydroxylamine (0.35 g, 1.3 mmol) prepared as described in example P24c in dichloromethane (5 ml), triethylamine (0.55 ml,3.9 mmol) and a solution of 3-difluoromethyl-1-methyi-1H-pyrazole-4-carbonyl chloride acid in dichloromelhane (2ml) was added slowly at a temperature of 0°C. After

complete adddition of the acid chloride the mixture was stirred at ambient temperature for the next 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass
was diluted with water and extracted with dichloromelhane (3 x 60 ml) .The combined

dichloromelhane layer was washed with 2N HCI followed by saturated NaHC03 solution,

10    water and finally brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was purified over column chromatography (silica gel60-120 mesh, 26% ethylacetate in hexane) to afford 3-Difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid methoxy-[3-(2,4,6-trichloro-phenyl)-propyl]-amide (0.5 g, 91%) as white crystalline solid. m.p- 95-96'C

15    Physical data:

1H NMR: (CDCI,, 400MHz):

1.89-1.96(m,2H,CH2), 2.91-2.95(m,2H,CH2), 3.66(s,3H,CH3), 3.83-3.86(l,2H,CH2), 3.97(s,3H,CH3), 7.31 (t, 1H,CHF2), 7.2B(s,2H,Ar-H), 7.89(s,1H,pyrazole-H)

MS [M+Hf 426/4281430/432

20

Example P12: Preparation of 3~difluoromethyl-1-methyi-1H-pyrazole-4-carboxylic acid f3- (4-

lert.-butyl-phenyl)-2-methyl-propyll-methoxy-amide (compound 2.057):

H3C~"'CH~H3

25    A solution of 3-difluoromethyl+methyl-1 H-pyrazole-4-carbonyl chloride (0.89 g; 4.6 mmol) in dichloromethane (5ml) was added dropwise to a stirred solution of N-[3-(4-tert- butyl-phenyl)-
 



-30-

2-methyl-propyl]-0-methyl-hydroxylamine (1.0 g; 4.2 mmol), prepared as described in example P25, triethylamine (0.86 ml; 6.3 mmol) in dichloromethane (7ml) at O'C. The

reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was

washed with  1M NaOH (20ml), 1M HCI (20m I) brine (20ml) and then dried over Na,so,.

After removal of the solvent the residue was purified by flash chromatography over silica gel

(eluant: hexane/ethyl acetate 7:3).

0.59 g (35.3% of theory) of 3-dilluoromethyl-1-methyi-1H•pyrazole-4-carboxylic acid [3- (4-tert.-butyl-phenyl)-2-methyl-propyl]-methoxy-amide (compound 2.057) was obtained in form

of a resin.

10    1H NMR: (CDCI3 , 400MHz):

0.90-0.95( d,3H); 1.30( s,9H);2.24-2.36(m, 1H);2.39-2.45( dd, 1H);2.67-2. 72( dd, 1 H); 3.58(s,3H); 3.68-3.70(d,2H);3.98(s,3H); 7.09-7.11(d, 2H); 7.15-7.42(m,3H);7.90(s, 1H).
MS [M+H]'394.    .

15    Example P13: Preparation of N-[2-(4-chloro-phenyll-1-methyl-ethyl]-0-methyl-hydroxvlamine:

a)    Preparation of 1~(4-chloro-ohenyll-propan-2-one 0-methyl-oxime:




20

A solution of 1-(4-chloro-phenyl)-propan-2-one (8.5 g, 50.4 mmole) in methanol (100 ml) was treated with pyridine (5.2 ml, 62 mmol) followed by 0-methyl hydroxylamine hydrochloride (5.20 g, 62 mmol). The resulting mixture was stirred at 23'Cover night for 16

hours.    The   reaction   mixture  was  poured  onto  water  {200m!)  and   extracted  with

25    dichlorometane (3x50ml). The organic layers were washed with brine and dried over anhydrous Na2S04• After removal of the solvent the residue was purified by flash chromatography over silica gel (eluent: c-hexane/ethyl acetate 9:1).
7.38 g (74% of theory) of 1-(4-chloro-phenyl)-propan-2-one 0-methyl-oxime was obtained in

form of a clear liquid.

30    1H NMR: (CDCI3, 400MHz):

1. 71 ( s,3H);3.48+3.52(2s,2H);3.87 -3.89(2s,3H); 7.13-7 .22(m,4H).
 




-31-

MS [M+Ht 198/200.

b) Preparation of N-[2-( 4-chloro-phenyll-1-methyl-ethyll-0-methyl-hydroxvlamine:






A solution of 1-(4-chloro-phenyl)-propan-2-one 0-methyl-oxime (1.0 g, 5.1 mmol) in acetic acid (7.6 ml) was treated at 10'Cwith sodium cyanoborohydride (641 mg, 10.2 mmol) added

in small portions over 10 minutes and the resulting solution was stirred at 24 oc for 5 hours.

10    The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) arld the residue was slurried with water and pH was adjusted to 9 with 1M NaOH. The aqueous phase was extracted with dichloromethane (2x20 ml), washed with brine and dried over
anhydrous Na,so,. After removal of the solvent (100mbar; 45'C), the residue (910mg) was

purified by flash chromatography over silica gel (eluent: c-hexane/ethyl acetate 9:1).

15    830 mg (82.0 % of theory) of N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-0-methyl-hydroxylamine was obtained in form of a clear liquid.
1H NMR: (CDCI,, 400MHz):

1.02-1.06(d,3H);2.54-2.59(dd, 1H);2. 79-2.84( dd, 1H);3.14-3.24(m, 1H),3.52(s,3H); 5.3-5.5(s,.,1H); 7.12-7.16(m,2H); 7.25-7.28(m,2H).

20    MS [M+Ht 200/202.

Example P14: Preparation of N-[2-(2 4-dichloropheny!)-1-methy!-ethyll-0-methyl-hydroxylamine:

a) Preparation of 1-(2 4-dichlorophenyll-propan-2-one 0-methyl-oxime:

25





A solution of 0-methyl hydroxylamine hydrochloride (7.04 g, 0.0843 mol) in a mixture of

water(130 ml) and THF(50 ml) was treated with sodium acetate (5.9 g, 0.0720 mol) followed
 



-32-

by 1-(2,4-dichlorophenyl)-propan-2-one (10 g, 0.0496 mole) and the resulting mixture was

stirred at 23"C for 4 hours. The reaction mixture was then diluted with ethylacetate, washed

•with brine and dried over anhydrous Na2S04• The solvent was evaporated under reduced

pressure (1 OOmbar; 45°C).

5    13.5 g (100% of theory) of crude 1-(2,4-dich/oropheny/)-propan-2-one 0-methy/-oxime was

obtained in form of a clear liquid which was used without further purification for the next step.

1H NMR: (CDCI3, 400MHz):

1.76(s,3H);3.60+3. 78(2s,2H);3.87(s,3H); 7.12-7.19(m,2H); 7.39(d, 1H). MS [M+H]'232/234/236.
10

bl Preparation of N-[2-(2 4-dichlorophenyl)-1-methyl-ethy/[-0-methyl-hydroxy/amine:





15    A solution of 1-(2,4-dichlorophenyl)-propan-2-one 0-methyl-oxime (10.0 g, 0.0431 mol) in acetic acid (100 ml) was treated at 10'Cwith sodium cyanoborohydride (5.41 g, 0.0862 mol) added in small portions over 15 minutes and the resulting solution was stirred at 24 "C for 6 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene

twice) and the residue was slurried with water and pH was adjusted to 9 with 2M NaOH. The 20 aqueous phase was extracted with dichloromethane (2x1 00 ml), washed with brine and dried

aver anhydrous Na2S04. The solvent was evaporated under reduced pressure (1 OOmbar;

45°C).

8.13 g (81.3% of theory) of crude N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-0-methyl-

hydroxylamine was obtained in form of a clear liquid which was used without further

25    purification for the next step.

1H NMR: (CDC!,, 400MHz):

1.04-1.09(d,3H);2.66-2. 71 (dd, 1 H);2.93-2.99(dd, 1H);3.25-3.33(m, 1H),3.52(s,3H); 5.2-5.4(s..,,1H); 7.17-7.18(m,2H); 7.35(d, 1H).

MS [M+Hr 234/236/238.

30
 




-33-



Example P15: Preoaralion of 0-melhyi-N-[1-melhyl-2-[2 4 6-lrichloropheny1l-elhyll-

hydroxylamine:

a) Preparation of 1.3.5-trichloro-2-UEl-2-nitro-propenyll-benzene:

~~):0.
CI~CitH,

To a slirred solulion of 2,4,6-trichloro-benzaldehyde (19g, 90.69mmol) and ammonium

10    acetate (16.75 g, 217mmol) in acelic acid (76ml, 4 Vol.), nilroethane (45.1ml, 625 mmol) was added in drops at a temperature of 0°C. The reaction mass was stirred at a temperature of 1 00°C for 90 minutes. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and was diluted with ice cold water
(700ml), further aqueous layer was then extracted with ethyl acetate (3x50 ml). Combined

15    ethyl acetate layer was washed with saturated sodium bicarbonate solution to neutral pH, then with water, followed by brine wash and dried under anhydrous Na2S04 before the camp Jete evaporation of solvents. The resulting crude mass was purified by column chromatography using 60-120 ~mesh silica gel and product collected at 1% ethyl acetate in hexane as elulion system to give 1,3,5-trichloro-2-((E)-2-nilro-propenyl)-benzene (15 g,

20    61%)

1H NMR (400MHz, CDCJ,): d 2.10(s,3H,CH3), 7.24(s,2H,Ar-H),7.77(s,1H,CH)

b)    Preparation of 1-(2.4.6-trichloro-phenyll-propan-2-one:

~0

CI~CitH,

25    To a stirred solution of above obtained nitrostyrene (5g, 18.72 mmol) in water (20 ml) and methanol (60 ml), was added Iron powder (2.355 gms, 42.12 mmol) followed by cone. HCI

(11.5 ml1 112 mmol) at ambient under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 1 hour. After 1 hour, the remaining quantity of iron powder (2.355 gms , 42.12 mmol) and cone. HCI (11.5 ml, 112 mmol) was added to this reaction mass and
 



-34-

stirring continued for 2 hours at 70°C. When TLC confirmed the completion of the reaction, reaction mass was cooled to ambient temperature and methanol was removed with a rotavapor. The resulting residue was then diluted with water and extracted with ethyl acetate
(3x 80 m\). The combined ethyl acetate layer was finally washed with water, followed by

brine wash and dried under anhydrous sodium sulfate before the complete evaporation of solvents. The resulting crude mass was purified by column chromatography using 60-120 J..l mesh silica gel and product collected at 5% ethyl acetate in hexane as elution system to
give 1-{2,4,6-trich\oro-pheny\)-propan-2-one {3.7 g, 83.3%).

1H NMR (400MHz, CDCJ,): d 2.26 (s,3H,CH3 ), 4.05(s,2H,CH,), 7.34 (s,2H, Ar-H)

10

c) Preparation of 1-(2 4 6-trichlorophenyll-propan~2-one 0-methyl-oxime:





15    A solution of O-m ethyl-hydroxylamine hydrochloride (0.79 g, 9.4 mmol) in methanol (20 ml) was treated with triethylamine (1.32 ml, 9.4 mmol) followed by 1-(2,4,6-trichloropheny\)-propan-2-one (1.5 g, 6.31 mmole). The resulting mixture was stirred at
60°C for 3 hours. The reaction mixture was quenched with water and methanol was

evaporated off. The resulting aqueous medium was extracted wHh ethylacetate (3 x 50

20    ml). The combined organic layers were washed with brine and dried over anhydrous Na2S04• The solvent was evaporated under reduced pressure (100mbar; 45°C). The resulting crude mass was purified by column chromatography using 60-120 1-1 mesh silica gel and product collected at 2% ethyl acetate in hexane as elution system to give

1-(2,4,6-Trich\oro-pheny/)-propan-2-one 0-methy/-oxime (1.2 g, 76%), which was taken

25    up for further reduction.

dl Preparation of 0-methy\-N-[1-methyl-2-(2.4 6-trlchloropheny/l-ethy/J-hydroxvlamine:

To a stirred solution of the above obtained 1-{2,4,6-trichloro-phenyl)-propan-2-one 0-methyl-oxime (1.2g, 4.51 mmol) in 12 ml of acetic acid, sodiumcyanoborohydride

5    (0.568, 9 mmol) was added. The reaction mass was stirred at ambient temperature for 6 hours. When the TLC confirmed the completion of reaction, the solvent was evaporated under reduced pressure {co~evaporation with toluene twice). The resulting residue was diluted with water and the pH was adjusted to 9 with 2 N sodium hydroxide solution, which was then extracted with ethyl acetate (3x50 ml). The combined organic layer was
10    washed with brine followed by drying over anhydrous sodium sulfate before evaporating the solvent. The resulting crude mass was purified by column chromatography using 60-120 1-1 mesh silica gel and the product collected at 5% ethyl acetate in hexane as elution system to afford 0-Methyi-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine
(0.91 g, 75%).

15    1H NMR (400MHz, CDCI3): d 0.91-0.93 (d,3H), 2.72-2.77 (dd,1H), 2.98-3.03(dd,1H), 3.25-3.30 (m,1H), 3.93 (s,3H), 7.1S(s,2H)

Example P16: Preparation of N-12-(4-(4-chloro-phenoxyl-phenyll-1-methvl-ethyll-0-melhyl-

hydroxyfamine:

20    a) Preparation of 1-[4-(4-ch/orophenoxy)-phenyll-propan-2-one 0-methyl-oxime:





A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-propan-2-one (10.0 g, 38 mmole)  in methanol

25    (65 ml) was treated with 0-methy\ hydroxylamine hydrochloride (3.90 g, 47 mmol) followed by pyridine (4.0 ml, 47 mmol). The resulting mixture was slirred at ambient temperature over night. The reaction mixture was poured onto water (150m\) and extracted with
 




-36-

dichloromethane  (3x50ml). The  organic  layers were  washed  with  brine and  dried over

anhydrous Na2S04.

11.0g (100% of theory) of crude 1-[4-(4-chloro-phenoxy)-phenyl]-propan-2-one 0-melhyl-

oxime was obtained in form of a yellow liquid which was used without further purification for

the next step.

1H NMR: (CDCI3,  400MHz):

1. 73+1.81 (2s,3H);3.44+3.65(2s,2H);3.88+3.89(2s,3H); 6.89-6.94(m,4H);7 .15-7.28(m,4H).

MS [M+HJ'290/292.

10    b) Preparation of N-12-[4-(4-chloro-phenoxyl-phenyiJ-1-melhyl-ethyl\-0-melhyl-hydroxylamine:




A  solution of crude  1-[4-(4-chlorophenoxy)-phenyl]-propan-2-one 0-methyl-oxime  (6.0  g,

15    20.7 mmol) in acetic acid (50 ml) was treated at 10'Cwith sodium cyanoborohydride (2.6 g,

41.4 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 23 oc for 3.5 hours. The solvent was evaporated under reduced pressure (ca~evaporation

with toluene twice) and the residue was slurried with water and pH was adjusted to 11 with

1M NaOH. The aqueous phase was extracted with dichloromethane (2x20 ml), washed with 20 brine and dried aver anhydrous Na2804 • After removal of the solvent (100mbar; 45'C),the

residue (7.17g) was purified by nash chromatography over sifica gel (eluent: c-hexane). 3.91 g {65.0% of theory) of N-{2-[4-(4-chloro-phenoxy)-phenyl]-1-methyl-ethyl)-0-methyl-
hydroxy\amine was obtained in form of a clear liquid.

1H NMR: {CDC!,, 400MHz):

25    1.07-1.09(d,JH);2.53-2.62{dd,1 H);2.72-2.81(dd,1 H);3.16-3.26(m,1 H),J.54(s,3H); 5.3-5.5(s,, 1 H); 6.86-6.94(m,4H); 7.14-7.18(m,2H);7.24-7.29(m,2H).

MS [M+HJ'292/294.

Example P17: Preparation of N-[2-(2,4-dichlorophenyl\-1-methyl-ethyiJ-hydroxylamine:

30    al Preparation of 1-(2 4-dichloropheny1l-propan-2-one oxime:
 



-37-

CI
NIWI
OH    Ci

A solution of 1-(2,4-dichlorophenyl)-propan-2-one (3.46 g, 16.7 mmole) in methanol (40 ml) was treated with hydroxylamine hydrochloride (1.40 g, 20.6 mmol) followed by pyridine (1.7
ml, 20.6 mmol). The resulting mixture was stirred at ambient temperature over night for 16 hours. The reaction mixture was poured onto water (200ml). The solid product was collected
by filtration, washed with water and dried (40'C,100mbar).

3.63 g (100% of theory) of 1-(2,4-dichtoropheny/)-propan-2-one oxime was obtained In form of a white solid (m.p. 120-124'C).

10    1H NMR: (CDC!,, 400MHz):

1.86(s,3H);3.61(s,2H); 7.12-7.21(m,2H); 7.39-7.41(d,1H); 8.2(s ..,1H). MS [M+Hj'218/220/222.

b) Preparation of N-[2-(2 4-dichlorophenyl\-1-methyl-ethyll-hydroxylamine:

15




A solution of 1-(2,4-dlchlorophenyl)-propan-2-one oxime (3.3 g, 15.1 mmol) in acetic acid (30 ml) was treated at 1O'Cwith sodium cyanoborohydride (1.90 g, 30.3 mmol) added in small
20    portions over 10 minutes and the resulting solution was stirred at 23 oc for 5 hours. The solvent was evaporated under reduced pressure {co-evaporation with toluene twice} and the residue was slurried with water and pH was adjusted to 10 with 1M NaOH. The aqueous

phase was extracted with dichloromethane (3x20 ml), washed with brine and dried over anhydrous Na,S04• After removal of the solvent (1 OOmbar; 45'C),3.18 g (96.0 % of theory)
25    of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamlne was obtained in form of a white solid (m.p. 83-86'C).
1H NMR: (CDC!,, 400MHz):

1.08-1.11(d,3H);2.69-2.74(dd, 1H);2.98-3.03(dd, 1H);3.24-3.32(m, 1H); 5.3-5.6(s0" 1H); 7.18-

7.19(m,2H); 7.39(m, 1H);7.5-B.2(s," 1H).

30    MS [M+Hj'220/222/224.
 



-38-



Example P18: Preparalion of N-12-(2.4-dichlorophenyl\-1-methyl-ethyll-0-ethyl-

hydroxylamine:

a) Preparation of 1-(2.4-dichlorophenyl)-propan-2-one 0-ethyl-oxime:






A solution of 0-ethyl hydroxylamine hydrochloride (4.10 g, 42.1 mmol) in a mixture of water

10    (130 ml) and THF(50 ml) was treated with sodium acetate (2.95 g, 72 mmol) followed by 1-(2,4-dichlorophenyl)-propan-2-one (5 g, 24.8 mmole) and the resulting mixture was stirred at
23°C for 4 hours. The reaction mixture was then diluted with ethylacetate, washed with brine and dried over anhydrous Na2S04 . The solvent was evaporated under reduced pressure

(90mbar; 45°C).

15    6.0 g (99 % of theory) of crude 1-(2,4-dichlorophenyl)-propan-2-one 0-ethyl-oxime was obtained in form of a clear liquid as an Ell-mixture which was used without further purification for the next step.
1H NMR: (CDCI,, 400MHz):

1.23-1.28(2t,3H); 1.74+1. 76(2s,3H);3.60+3.78(2s,3H);4.09-4.16(2q,2H);7.12-7 .19(m,2H);

20    7.38(d, 1H).

MS [M+H]'246/248/250.

b) Preparation of N-[2-(2.4-dichlorophenyll-1-methyl-ethy\1-D-ethy\-hydroxvlamine:

CI
NIW
(0    Cl

25    CH3
 




-39-

A solution of 1-(2,4-dichlorophenyl)-propan-2-one a-methyl-oxime (10.0 g, 0.0406 mol) in acetic acid (1 00 ml) was treated at 1 O"C with sodium cyanoborohydride (5.41 g, 0.0862 mol)
added in small portions over 10 minutes and the resulting solution was stirred at 24 "C for 6 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene

twice) and the residue was slurried with water and pH was adjusted to 9 with 2M NaOH. The

aqueous phase was extracted with dichloromethane (2x1 00 ml), washed with brine and dried

over anhydrous Na2S04. The solvent was evaporated under reduced pressure (100mbar;

45"C).

5.09 g (51.0% of theory) of crude N-[2-(2,4-dichlorophenyl)-1-melhyl-ethyl]-0-ethyl-

10    hydroxylamine was obtained in form of a clear liquid which was used without further

purification for the next step.

1H NMR: (CDCI3, 400MHz):

0.98-1.02+1.08-1.12(2d,3H);1.13-1.18(2t,3H);2.63-2.68+2. 70-2. 78(2dd, 1H);2.94-3.1 0+3.15-

3.21 (m, 1 H),3.25-3.31 +3.71-3.78(2q,2H);5.0-5.5(s", 1H); 7 .16-7.19(m,2H); 7 .34-7.36(m, 1H).

15    MS [M+H]'248/250/252.

Example P20: Preparation of N-[2-(2,4-dichlorophenyll-1-methyl-ethyl!-0-isopropyl-hydroxylamine:

a) Preparation of 1-(2.4-dichlorophenyll-propan-2-one 0-isopropyl-oxime:

20





A solution of 1-(2,4-dichlorophenyl)-propan-2-one (5.1 g, 25.0 mmole) in methanol (45ml)

was treated with 0-isopropyl-hydroxylamine hydrochloride (3.50 g, 31 mmol) followed by

25    pyridine (2.6 ml, 31 mmole) and the resulting mixture was stirred at 23"C over night. The

reaction mixture was poured onto water {1 OOml) and extracted with dichloromethane

(3x50ml). Organic layers were washed with brine and dried over anhydrous Na2S04• The solvent was evaporated under reduced pressure (90mbar; 45°C).

6.48    g (99% of theory) of crude 1-(2,4-dichlorophenyl)•propan-2-one 0-isopropyl-oxime was

30    obtained  in  form  of a  clear  liquid  as  an  EIZ-mixture  which  was  used  without further

purification for the next step.
 




-40-

1H NMR: (CDC!,, 4DOMHz):

1.23-1.26( d,6H);1. 74(s,3H);3.60+3. 78(2s,3H);4.25-4.38(2m, 1H);7.14-7.21 (m,2H);7.39(d,

1H).

MS [M+Hj'260/262/264.

b) Preparation of N-f2-(2.4-dichlorophenyl)-1-mefhyl-ethyll-0-isoprapyl-hydroxylamine:

~~CI

H3~>(0    Cl

CH3

A solution of 1-(2,4-dichlorophenyl)-propan-2-one 0-isopropyl-oxime (6.0 g, 23 mmol) in

10    acetic acid (40 ml) was treated at 1ooc with sodium cyanoborohydride (2.90 g, 46 mmol) added in small portions over 15 minutes and the resulting solution was stirred at 24 "C for 4 hours. The solvent was evaporated under reduced pressure (co-evapOration with toluene twice) and the residue was slurried with water and pH was adjusted to 10 with 1M NaOH.

The aqueous phase was extracted with dichlorome!hane (.2.><60 ml), washed with brine and

15    dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure

(100mbar; 45°C).

5.90 g (98.0% of theory) of crude N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-0-isopropyl-

hydroxylamine was obtained in form of a clear liquid which was used without further

purification for the next step.

20    1H NMR: (CDC!3, 400MHz):

1.03-1.07(d,3H);1.13-1.1 9(m,6H);2.61-2.68+2.94-3.03(2dd,2H);3.21-3.31(m,1 H),3.76-

3.84(m, 1H);5.2(s,,, 1H); 7.14-7.18(m,2H); 7.35-7.36(m, 1H).

MS [M+H]'262/264/266.

25    Example P21: Preparation of 0-Methyi-N-[2-(2 4,6-trichloro-phenyll-ethyll-hydroxylamine: a) Preparation of 1 3.5-trichloro-2-c.hloromethyl-benzene:

~CI

CI.Jl.ACI
 




-41-

To a stirred solution of 2,4,6-trichlorobenzylalcohol (10.0g; 47.3 mmoles) in chloroform (100ml) kept under nitrogen atmosphere, thionyl chloride (6.07mL, 85.1mmole) was added slowly at O'Cover a period of 15 minutes followed by catalytic amount of DMF .The reaction

mix was allowed to stir at ambient temp for 3 hours. The reaction mixture was quenched with

50mL of water; the aqueous layer was extracted with DCM (3 X 100ml). The combined organic layer was washed with 5% sodium bicarbonate solution (2 x 50ml) followed by brine

(50ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under

reduced pressure.  10.9g (1 00.0% of theory) of 1,3,5-trichloro-2-chloromethyl-benzene was

obtained in form of a white solid.

10    1HNMR (CDCI3, 400MHz): d= 7.37 (2H, s); 4.82 (2H, s) Mass: M =229.8

b)    Preoaration of (2 4.6-trichloro~phenyll-acetonitrile:

C/~N

15    To a stirred solution of 1,3,5-trichloro-2-chloromethyl-benzene (12.65 g, 58.8mmole) in ethanol (45ml), NaCN (3.20, 67.0mmole) solution in water (15ml) was added at ambient temperature. The reaction mixture was refluxed for 4hours to complete the reaction. Ethanol was evaporated and the reaction mixture was diluted with water (50 ml). The aqueous layer was extracted with EtOAc (3 x 100mi).The combined organic layer was washed with brine

20    (30m I) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give white solid. Crude product was purified by chromatography on silica-gel column to afford 9.0g (75.0% of theory) of (2,4,6-trichloro-phenyl)-acetonitrile
1HNMR (CDCI,, 400MHz): 7.41 (s, 2H); 3.97 (s, 2H).

Mass:M = 218.9

25

cl Preparation of (2 4 6-trichloro-phenyll-acetaldehyde:

~0

CIAACI

To the stirred, cold solution (-70' C) of (2,4,6-trichloro-phenyl)-acetonitrile (5.7g, 26.0mmole) in toluene (120ml) kept under N2 atmosphere, DIBAL-H (28.1mi1M solution in
 




-42-

THF, 28.6 mmole) was added dropwise over a period of 30 min. Reaction was stirred for

3hrs at -70"C. After completion of reaction, it was quenched by dropwise addition of HCJ

(60ml, 2N) at

-40°C and was kept for 30m in at ambient temperature. Toluene layer was separated and

aq.Jayerwas extracted with ethyl acetate (3 x 100m!) and. The combined organic layer was

washed with brine {30m!) and dried over sodium sulfate. The organic layer was concentrated

under vacuum. 4.5g (78.0% of theory) of (2,4,6-trichloro-phenyl)-acetaldehyde was obtained in form of a white solid.

1HNMR (CDCI,, 400MHz: 9.70 (s, 1H); 7.38 (s, 2H); 4.08 (s, 2H)

10    Mass: M = 246.9

Example P22: Preparation of N-[2-(2,4-dichlorophenyll-pentyJJ-0-methyl-hydroxylamine: a) Preparation of 2-{2.4-dichlorophenyl)-pentanal 0-methyl-oxime:




15

A solution of 2-( 4-chloro-phenyl)-pentanai (1 0.0 g, 43.0 mmole) in methanol (75 ml) was treated with 0-methyl hydroxylamine hydrochloride (4.40 g, 53 mmoi) followed by pyridine (4.5 ml, 53 mmol). The resulting mixture was stirred at 23"C over night. The reaction mixture

20    was poured onto water (200m/) and extracted with dichlorometane (3x50ml). The organic layers were washed with brine and dried over anhydrous Na2S04• The solvent was evaporated under reduced pressure (1 OOmbar; 45"C).

11.20 g (100.0 % of theory) of crude 2-(2,4-dichlorophenyl)-pentanal 0-methyl-oxime was

obtained in form of a clear liquid which was used without further purification for the next step.

25    MS [M+Hf 260/262/264.

bl Preparation of N-[2-(2,4-dichlorophenyll-pentyll-0-methyl-hydroxylamine:
 




-43-

~~CI

H,c'0    ~

CH3

A solution of 2-(2,4-dichlorophenyl)-penlanal 0-methyl-oxime (6.0 g, 23 mmol) in acetic acid (50 ml) was treated at 10'Cwith sodium cyanoborohydride (2.90 g, 46 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 24 oc for 4 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water and pH was adjusted to 11 with 1M NaOH. The aqueous phase was extracted with dichloromethane {2x50 ml), washed with brine and dried over
anhydrous Na,S04•  After removal of the solvent (100mbar; 45'C),the residue (6.2g) was

purified by flash chromatography over silica gel (250g; eluent: c-hexane).

10    5.15 g (79.0 % of theory) of N-[2-(2,4-dichlorophenyl)-pentyl]-0-methyl-hydroxylamine was obtained in form of a clear liquid.
1H NMR: (CDC!,, 400MHz):

0.82-0.89(t,3H); 1.12-1.27(m,2H); 1.49-1.58(m, 1H);1.63-1.72(m, 1H);3.05-3.1 0( dd, 1H);3.12-3.18(dd, 1 H);3.47(s,3H),3.50-3.51(m, 1H); 5.0-5.50(s,,, 1H); 7.14-7.16(m, 1H); 7.21-

15    7.25(m,1H);7.37-7.39(m,1H). MS [M+Hj'262/264/266.

Example P23: Preparation of 0-Methyi-N-[1-methyl-3-12.4.6-trichloro-phenyll-propyll-

hydroxylamine:

20    a) Preparation of 3-(2.4.6-trichloro-phenyll-propionic acid:

LJOH

Cl)l).__CI

Meldrum'sacid (2.06 g, 14.32 mmoles) was added to TEAF (7.05 ml) at ambient

25    temperature under stirring and the reaction mixture was kept under nitrogen atmosphere.

After 1Om in 2,4,6-trichloro benzaldehyde (3g, 14.32mmoles) was added to the reaction mixture. It was then refluxed at 120°C for 3hrs. On completion of the reaction, the mixture was cooled at ambient and was poured into ice water (50 ml}. Then aq. layer was extracted
 




-44-

with ethyl acetate (3 x 80 ml), the combined organic layer was washed with brine (40 ml) and

dried over sodium sulphate. Organic layer was concentrated under vacuum. 3.10g (86.0% of

the01y) of 3-(2,4,6-trichloro-phenyl)-propionic acid was obtained in form of a white solid.

1H NMR ( 400 MHz, CDCI3):

7.32(s, 2H); 3.26-3.22 (m, 2H); 2.63-2.58 (m, 2H). MS [M+HJ'253/255/257

TEAF (triethyl ammonium fonmate) preparation: To fonmic acid (1.12g -0.93 ml, 24.5mmoles) solution kept under nitrogen was added slowly triethylamine (1g -1.37ml,

9.Bmmoles) at 0°C and the mixture was stirred for one and half hour at ambient temperature.

10    b) Preparation of N~methoxv-N-methyl-3-{2.4.6-trichloro-phenyll-propionamide:




To a solution of acid chloride in chloroform [acid chloride was prepared from corresponding

15    3-(2,4,6-trichloro-phenyl)-propionic acid (5g ,19.7mmoles) using thionyl chloride(5.87g ,49.4mmole) under refluxing condition at 110'Cfor 3 hours] N,O-dimethylhydroxylamine hydrochloride (2.3g, 23.9mmoles) followed by pyridine (3.77ml,47.7mmole) was added drop wise at 0 oc . The reaction mix was stirred at ambient temperature for 3 .hours. On completion, the reaction mix was diluted with 70ml DCM and 40 ml of water. Organic layer

20    was separated and the aqueous layer was extracted two times with DCM (50ml x 2). The combined organic layer was washed with brine (40ml) and dried over sodium sulfate. After removal of the solvent the residue was purified by chromatography over silica geL 3.0g
(52.0% of theory) of N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide was obtained in form of a solid.
25    1H NMR (CDCI3 , 400MHz):

7.31(s, 2H); 3.67 (s, 3H); 3.24-3.19 (m, 2H); 3.19 (s, 3H); 2.67-2.63 (m, 2H) MS [M+Hr 296/298/300

c) Preparation of 4-(2,4,6-trichloro-phenyll-butan-2-one:

~CH3

Cl)lACI
30
 




-45-

To the stirred and cold solution (0'C) of N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide (1g, 3.37mmol) in THF (15ml) kept under nitrogen atmosphere, MeMgl (1.3mL
of 3M ether solution, 3.9 mmole) was added and stirring was continued at ooc for 2 hours.

Reaction mixture was quenched with 5% of HCI (10 ml) at O'Cand aqueous layer was extracted with EtOAc (3 x 30ml). The combined organic layer was washed with 20ml of brine

and dried over sodium sulfate; concentrated under vacuum to give off-white solid. The

residue was purified by chromatography over silica gel. 0.50g (60.0% of theory) of 4-(2,4,6-trichloro-phenyl)-butan-2-one was obtained in form of a solid.
1H NMR (CDCI3,  400MHz):

10    2. 14(s,3H,CH,), 2.72-2.76(t,2H,CH 2), 2.93-2.97(t,2H,CH2), 7.13-7.16+7.16-7. 19(2d,2H,Ar-H), 7.34-7.35(d, 1 H,Ar-H).

MS [M+Hf 25212541256

d) Preparation of 0-Methyi-N-[1-methyl-3-(2 4 6-trichloro-phenyll-propyll- hydroxvlamine:

15

?H3
C/h!:H,

To a stirred solution of 4-(2,4,6-trichloro-phenyl)-butan-2-one (0.9 g, 3.57 mmol) in methanol (5 ml), was added triethylamine (0.73 ml, 5.3 mmol) and 0-methyl-hydroxylamine hydrochloride (0.447 g, 5.3mmol). The reaction mixture was heated at a temperature of
20    60°C for 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature. After the reaction mixture was diluted with water and methanol was evaporated off, the aqueous fayer was extracted with ethyl acetate
(3 x 30 ml ). The combined ethyl acetate layers were washed with water followed by brine

solution and dried over sodium sulfate before complete evaporation of the solvents to give

25    4-(2,4,6-trichloro-phenyl)-butan-2-one 0-methyl-oxime (0.980g) crude, which was taken up for reduction without any further purification.

To a solution of 4-(2,4,6-trichloro-phenyl)-butan-2-one 0-methyl-oxime (0,650 g, 2.33 mmol) in acetic acid, sodiumcyanoborohydride (0.293 g, 4.66 mmol) was added. The reaction

mass was stirred at room temp for 6 hours. When the TLC confirmed the completion of the

30    reaction, the acetic acid in the reaction mass was removed by azeotropic distillation. The residue was then basifled with 10% NaOH solution and it was extracted with ethyl acetate
 



-46-

(3x30 ml). The combined ethyl acetate layers were washed with water followed by brine

solution and dried over sodium sulfate before concentration. Resulting crude mass was

purified by column chromatography using 60-120 ~mesh silica gel and product collected at 3% ethyl acetate in hexane as eluent to give 0-Methyi-N-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.6 g, 90%).

1H NMR (400MHz, CDC!,): d 1.21(d,3H),1.52-1.59(m,1H),1.68-1.76(m,1H), 2.80-2.83(q,2H), 3.06-3.13(m,1 H), 3.55 (s,3H), 5.45(s,1H), 7.29(s,2H)
Physical data:

1H NMR (CDCI3 , 400MHz):

10    1.21 (d,3H,CH,), 1.52-1.59(m,1 H,CH2), 1.68-1.76(m,1 H,CH,), 2.80-2.83(m,2H,CH2), 3.06-3.13(m,1H,CH),1.45(s,1H,NH), 7.29(s,2H,Ar-H)

Example P24: Preparation of 0-Methyi-N-[3-(2.4.6-trichloro-phenyl\-propyiJ-hydroxylamine:

a) Preparation of 3-(2.4.6-trichloro-phenyl\-propan-1-ol:

15

~OH

Cl)l,lCI

Physical data:

1H NMR (CDCI3, 400MHz):

1.79-1.86(m,2H,CH,), 2.95-2.99(m,2H,CH2),  3.71-3.749(t,2H,CH2),  7.30(s,2H,Ar-H)

20    bl Preparation of 3-(2.4 6-trich/oro-phenyD=propiona!dehyde:

c1~0

To a stirred solution N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide (0.9 g, 3.04mmol) in toluene (18ml), DIBAl- H (15.2ml, 15.2mmol) was added at -OO'Cslowly in

25    drops over a period of 20 minutes and the reaction mass was stirred at -60°C for 3 hours.

Reaction mass was then quenched with dil. HCI (20ml) in drops, followed by dilution with

water(10 ml) and stirred for 15 minutes. Toluene layer was separated and resulting aqueous

phase was extracted with ethyl acetate (30ml X 3). The combined organic layer was washed

with water and brine. The organic layer was then dried over anhydrous sodium sulphate and

30    concentrated under reduced pressure. The resulting crude mass was  purified over column
 




-47-

chromatography (silica gel60-120 mesh, 2% ethyl acetate in hexane) to afford white crysatalline solid of 3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45g,62.5%)

1H NMR (400MHz, CDCI,): d 2.68(t,2H), 3.19-3.23(t,2H), 7.29(s,2H), 9.86(s,1H) MS [M+H]': 235.9 /239.9

Physical data:

1H NMR (CDCI3, 400MHz):
2.68-2.72(m,2H,CH2),  3.19-3.23(m,2H,CH2),  7.29(s,2H,Ar-H), 9.86(s, 1H,CHO)

c) Preparation of 0-methyi-N-[3-(2 4,6-trichloro-phenyl)-propyiJ- hydroxvlamine:

10

Cl
~N'0'cH,

Cl)lACI

To a solution of3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45 g, 1.8 mmol) in methanol (5 ml), triethylamine (0.4 ml, 2.8 mmol) (allowed by 0-methylhydroxylamine-hydrochloride

15    (0.24 g, 2.8mmol) was added and the mixture was heated at 60°C for 2 hours. When the

TLC confirmed the completion of the reaction, the reaction mass was allowed to attain amabient temperature and quenched with water and methanol was removed with a rotavapor. The resulting aqueous solution was extracted with ethyl acetate (3 x 30 ml ). The

combined ethyl acetate layers were washed with water and dried over sodium sulfate before

20    complete evaporation of the solvents to give the crude mass. The resulting crude mass was purified over column chromatography (silica 9el60-120 mesh, 1% ethyl acetate in hexane) to afford 3-(2,4,6-trichloro-phenyl)-propionaldehyde 0-methyl-oxime (0.5 g, 80%)
To a stirred solution of 3-{2,4,6-trichloro-phenyl)-propionaldehyde 0-melhyl-oxime in acetic

acid, NaCNBH3  was added at 0°C-10°C. The reaction mass was then stirred at ambient

25    temperature for 6 hours. When the TLC confirmed completion of the reaction, acetic acid was removed by azeatropic distillation. The residue was basified with 10% NaOH solution
and aqueous solution was extracted with ethyl acetate (3x30 ml) . The combined organic

layer was washed with water and brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was
30    purified over column chromatography (silica gel60-120 mesh, 3% ethyl acetate in hexane) to afford 0-methyi-N-[3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.4 g, 88%).
 



-48-

1H NMR (400MHz, DMSO): d 1.74-1.82(m,2H), 2.92-3,01(m,4H), 3.55(s,3H), 5.60(s,1H),

7.29(s,2H)

MS [M+H]':268.13/272.17 Physical data:
5    1H NMR (CDC!,, 400MHz):

1. 74-1.82(m,2H,CH2), 2.92-3.01 (m,4H,CH2-CH2), 3.55(s,3H,CH,), 5.60(s, 1H,NH), 7.29(s,2H,Ar-H).

10    Example P25: Preparation of N-[3-(4-tert- butvl-phenyll-2-methyl-propyll-0-methyl-hydroxylamine:

a)    Preparation of 3-(4-tert-butyl-phenyD-methyl-propionaldehyde 0-methyl-oxime:




15

A solution of 0-methyl hydroxylamine hydrochloride (3.30 g, 0.041 mol) in a mixture of water(65 ml) and THF(25 ml) was treated with sodium acetate (2.85 g, 0.0348 mol) followed by 3-(4-tert-butyl-phenyl)-methyl-propionaldehyde (5 g, 0.024 mole) and the resulting mixture

was stirred at 23°C for 4 hours. The reaction mixture was then diluted with ethylacetate,

20    washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure (100mbar; 45°C).
6.01 g (100% of theory) of crude 3-(4-tert-butyl-phenyl)-methyl-propionaldehyde 0-methyl-

oxime was obtained in form of a clear liquid which was used without further purification for

the next step.

25    MS [M+Hj'234.

b)    Preparation of N-[3-(4-tert- butyl-phenyll-2-methyl-propyl!-0-methyl-hydroxylamine:
 




-49-


A solution of 3-(4-tert-bu!y/-phenyf)-methy/-propionaldehyde 0-methy/-oxime (5.0 g, 0.0213 mol) in acetic acid (50 ml) was treated at10'Cwith sodium cyanoborohydride (2.63 g, 0.042

mol} added in small portions over 15 minutes and the resulting solution was stirred at 24 "C for 6 hours. The solvent was evaporated under reduced pressure (co~evaporaf1on wlfh toluene twice) and the residue was slurried with water and pH was adjusted to 9 with 2M
NaOH . The aqueous phase was extracted with dichloromethane (2x1 00 ml), washed with

brine and dried over anhydrous Na2S04• The solvent was evaporated under reduced

pressure (1 OOmbar; 45'C).

10    4.52 g (89.5% of theory) of crude N-[3-(4-tert- butyl-phenyl)-2-methyl-propyi]-O-methyl-hydroxylamine was obtained in form of a clear liquid which was used without further purification for the next step.

MS [M+Hf 236.

15

Example P26: Preparation of 2.4-dichloro-1-(1-methoxy-2-nitro-propyl)-benzene:

a) Preparation of 2.4-dichloro-1-((E)-2-nitro-propenyO-benzene:

~~:0_
Cl)l)    6~3
20

In a sulfonation flask 2,4-dichloro-benza/dehyde (77g, 0.44mo/), nilroethane (216ml, 3.04mol) and ammonium acetate (81.4g, 1.06mol) were added to glacial acetic acid (600ml).
The resulting solution was heated to gaoc for three hours. After removal of the solvent ice~

water (400m/) was added. The solid product was collected by filtration, washed with water

25    and recrystallized from ethanol. 55.9 g (55% of theory) of 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene was obtained in the form of a yellow solid (m.p. 79-81'C).
1H NMR (400MHz, CDC!,): d 8.11(s,1H), 7.51(d,1H), 7.34(dd,1H), 7.27(d,1H),
2.33(s,3H,CH3).

bl Preparation of 2.4-dichloro-1-(1-methoxy-2-nitro-propyll-benzene:
 



-50-

CH

J~f):o3_

Cl)LJ    6H,

To a stirred yellow solution of the 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene (4 mmol, 0.93 g), in dry toluene (20ml) under N2 was added at O'Cdropwise during 2 minutes a mixture of 5.4M CH30Na in methanol (16.2mmol, 3ml) and methanol (2ml). After stirring for 1.5h glacial acid (3ml) was added, followed by water (20ml). The aqueous solution was extracted with dichloromethane (2x30ml), the organic layers were combined, dried (MgS04),

filtered, a_nd evaporated under reduced pressure to give 0.78g crude 1-aryl-1-methoxy-2-

nitropropanea yellow oil. This raw material was purified by column chromatography (silicagel,

hexane/ethylacetate 8:2) to afford 0.45g (43% •oftheory) of 2,4-dichloro-1-(1-methoxy-2-

10    nitro-propyl)-benzene in the form of liquid, as a mixture of diastereomeres.

1H NMR (400MHz, CDC!,): d 1.35-1.37+1 .39-1.40(2d,3H,CH3), 3. 18+3.21(2s,3H, CH,), 3.88+3,g2(2s, 3H,CH3), 4.69-4.75(m, 1H,CH), 5. 16-5.18+5.39-5.40(2d, 1H,CH), 7.15-7.47(m,3H,Ar-H).

MS [M+H]'264/266/268.

15

Example P27: Preparation of 2 4-dichloro-1-(1-fluoro-2-nitro-proovl)-benzene:

a) Preparation of 1-(2 4-dichlorophenyn-2-nitro-propan-1-ol:

~~:0_
Cl)l)    tH,

20    To a stirred solution of nitroethane (8.3g, 0.11mol) in acetonitrile (150 ml)was added anhydrous potassium phosphate (1 .Og, 4.6mmol) followed by 2,4-dichloro-benzaldehyde (17.5g, 0.10mol). The reaction mixture was stirred for 4 hours. Water (300m\) was added

and the reaction mixture was extracted with diethy\ ether (200m\). The organic extract was

washed with water and dried over anhydrous Na2S04, the solvent was removed and the

25    resulting residue was purified by flash chromatography over silicagel

(eluent:cyc\ohexane/ethy\acetate 9:1). 20.7 g (82.5% of theory) of a threo/erythro-mixture of 1-(2,4-dich\oropheny\)-2-nitro-propan-1-o\ was obtained. Crystallisation from cyc\ohexane yielded pure erythro 1-(2,4-dich\oropheny\)-2-nitro-propan-1-<>1.
 






(erythro-form) 1H NMR ( 400MHz, CDCI3): d 1.43(d,3H,CH3), 2.92(d, 1H,OH), 4. 84(m, 1H,CH), 5.79(t, 1H,CH), 7.34(d, 1H,Ar-H), 7.40(d, 1H,Ar-H), 7.59(d, 1H,Ar-H).

b) Preparation of 2.4-dichloro-1-(1-fluoro-2-nitro-propy\)-benzene:

~~:0_
cJ).lJ   tr,

To a stirred mixture of erythro 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol (2.5g, 10.0mmol) in dry dichloromethane (20ml) under nitrogen atmosphere DAST (1.3ml, 10.0mmal) in

dichloromethane (5ml} was added dropwise under cooling to 5°C, The solution was stirred at

10    ambient temperature for 1 hour. Dichloromethane (BOml) was added and the organic layer was washed sequentially with saturated NaHCO, (50ml), 1M HCI (30ml) and sole (30m I).
The organic layer was dried over NaS04, filtered, and concentrated. 2.5g of 2,4-dichloro-1-

(1-fluaro-2-nitro-propyl)-benzene was obtained in the form of a brown oil.

15    Example P28: Preparation of 1-(2.4.6-trichloro-phenyll-propan-2-one:

~0

Ci~CitH,

To the stirred solution of 1,3,5-trichloro-2-((E)-2-nitro-propenyl)-benzene (5g, 18.72 mmal) in H20 (20 ml) and MeOH (60 ml), iran powder (2.355 g, 42.12 mmales) and cone. HCI (11.5
ml, 112 mmol} was added at ambient temperature under nitrogen environment. The reaction

20    mixture was stirred at 70°C for 1 hour. After 1 hour additional iran powder (2.355 g, 42.12 mmoles) and cone. HCI (11.5 ml, 112 mmol) was added, while stirring was continued for 2 hours at 70°C. After completion of the reaction, (confirmed by TLC} reaction mass was cooled to ambient temperature and MeOH was evaporated. The resulting residue was

diluted with water and extracted with ethyl acetate (3x 80 ml). Combined ethyl acetate layer

25    was washed with water and brine and dried over anhydrous Na2S04• The organic layer was concentrated under vacuum. The crude material was purified by column chromatography

(silicagel60-120 ~mesh, hexane/ethylacetate 95:5) to afford 3.7g (83.3% of theory) of 1-(2,4,6-Trichlaro-phenyl)-propan-<!-one.

30
 



-52-

Tables 1 to 6: Compounds of formula Ia:

The invention was further illustrated by the preferred individual compounds of formula (Ia)

listed below in Tables 1 to 6. Characterising data are given in Table 9.

~•    ~'   R13
A.-_u_o_%-+1•-+f-+[ H+-llrnn~hr-R,2 (Ia),
H    H  H
R,

In the compounds of formula Ia, A is selected from the groups consisting of A1,
 










10    and A3 ,
 
CF2HW

~~'N ~ (A,),
I
CH3





H3Ct(
I  ~
N,    F
~    (A,),

CH3
 

and n is 0 or 1.

Each of Tables 1 to 6, which follow the Table Y below, comprises 100 compounds of the

formula (Ia) in which R4, R5, R1, X, R11 , R12 and R13 have the values given in Table YandA

15    has the value given in the relevant Table 1 to 6 and n has the value given in the relevant

Table 1 to 6. Thus Table 1 corresponds to Table Y when Y is 1 and A has the value given under the Table 1 heading, Table 2 corresponds to Table Ywhen Y is 2 and A has the value given under the Table 2 heading, and so on for Tables 3 to 6.
 



-53-


In Tables 1 to 6 below "Me" stands for methyl, "Et" stands for ethyl, "i-Pr" stands for

isopropyl, "c-Pr" stands for cyclopropyl and "t-Bu" stands for tertiary butyl.



Cpd No.    R,    Rs    R,    X    R,    Ru    R,   
                               
Y.001    Me    Me    H    absent    H    Cl    H   
                               
Y.002    Me    Me    H    absent    Cl    Cl    H   
                               
Y.003    Me    Me    H    absent    Ct    Cl    Cl   
                               
Y.004    Me    Me    H    absent    C/    Br    Cl   
                               
Y.005    Me    Me    H    absent    Cl    I    Cl   
                               
Y.006    Me    Me    H    absent    Cl    Me    Cl   
                               
Y.007    Me    Me    H    absent    Ci    CHF2    Cl   
                               
                               
Y.OOB    Me    Me    H    absent    Cl    CF3    Cl   
                               
Y.009    Me    Me    H    absent    Cl    C=CH    Cl   
                               
Y.010    Me    Me    H    absent    Cl    t-Bu    Cl   
                               
        Me        absent               
Y.011    Me        H        Cl    CH=NOCH3    Cl   
                               
Y.012    Me    Me    H    absent    H    4•CI-phenyl    H   
                               
                               
Y.013    Me    Me    H    absent    Cl    4-CI-pheny/    H   
                               
                               
Y.014    Me    Me    H    absent    Cl    4-C/-phenyl    Cl   
                               
Y.015    Me    Me    H    absent    H    4•CI-phenoxy    H   
                               
Y.016    Me    Me    H    absent    Ci    4-CI-phenoxy    H   
                               
Y.017    Me    Me    H    absent    C/    4-C/•phenoxy    C/   
                               
Y.018    Me    Me    H    absent    Me    Cl    H   
                               
Y.019    Me    Me    H    absent    Me    Cl    Cl   
                               
                               
Y.020    Me    Me    H    absent    Me    Br    Cl   
                               
                               
Y.021    Me    Me    H    absent    Me    I    Cl   
                               
 



-54-

Cpd No.    R,    Rs        R,    X    R,    R,    R,   
                                       
                                       
Y.022    Me    Me        H    absent    Me    Me    Cl   
                                       
Y.023    Me    Me        H    absent    Me    Me    Me   
                                   
                                       
Y.024    Me    Me        H    absent    H    Br    H   
                                       
Y.025    Me    Me        H    absent    Br    Br    H   
                                       
Y.026    Me    Me        H    absent    Br    Br    Br   
                                       
Y.027    H    Me        H    absent    H    Ci    H   
                                   
                                       
Y.028    H    Me        H    absent    Cl    Ci    H   
                                       
Y.029    H    Me        H    absent    Cl    Cl    Cl   
                                       
Y.030    Et    Me        H    •. absent    H    Ci    H   
                                       
Y.031    El    Me        H    absent    Cl    Cl    H   
                                       
Y.032    Et    Me        H    absent    Cl    Cl    Cl   
                                       
Y.033    f•Pr    Me        H    absent    Cl    Ci    H   
                                       
Y.034    CHF2    Me        H    absent    Cl    Cl    H   
                                       
                                       
Y.035    CHF2    Me        H    absent    Cl    Ci    Cl   
                                       
Y.036    CF,    Me        H    absent    Cl    Ci    H   
                                       
Y.037    CF,    Me        H    absent    Cl    Cl    Cl   
                                       
Y.038    Me    H        H    absent    H    Cl    H   
                                       
Y.039    Me    H        H    absent    Cl    Cl    H   
                                       
Y.040    Me    H        H    absent    Cl    Cl    Cl   
                                       
                                       
Y.041    Me    H        H    absent    Cl    Br    Cl   
                                       
Y.042    Me    H        H    absent    Cl    I    Cl   
                                       
Y.043    Me    H        H    absent    Cl    Me    Cl   
                                       
Y.044    Me    H        H    absent    H    4~CI-phenoxy    H   
                                       
Y.045    Me    H        H    absent    Cl    4-CI-phenoxy    H   
                                   
                                       
Y.046    Me    H        H    absent    Cl    4-CI-phenoxy    Cl   
                                       
Y.047    Me        H        H    absent    Me    Me    Cl   
                                       
 



-55-

Cpd No.    R,    R,    R,    X    R,    R,    R"
                               
Y.048    Me    H    H    absent    Me    Me    Me
                               
Y.049    Me    H    H    absent    H    Br    H
                               
Y.050    Me    H    H    absent    Br    Br    H
                               
Y.051    Me    H    H    absent    Br    Br    Br
                               
Y.052    H    H    H    absent    H    Cl    H
                               
Y.053    H    H    H    absent    Cl    Cl    H
                               
Y.054    H    H    H    absent    Cl    Cl    Cl
                               
Y.055    Me    H    Me    absent    Cl    Cl    H
                               
Y.056    Me    H    Me    absent    Cl    Cl    Cl
                               
Y.057    Me    H    Me    absent    H    t-Bu    H
                               
Y.058    Me    H    El    absent    Cl    Cl    Cl
                               
Y.059    Me    H    n-Pr    absent    Cl    Cl    H
                               
Y.060    Me    H    n-Pr    absent    Cl    Cl    Cl
                               
Y.061    Me    Me    Me    0    H    Cl    H
                               
Y.062    Me    Me    Me    0    Cl    Cl    H
                               
Y.063    Me    Me    Me    0    Cl    Cl    Cl
                               
Y.064    Me    Me    Me    0    Cl    Br    Cl
                               
Y.065    Me    Me    Me    0    Cl    I    Cl
                               
Y.066    Me    Me    Me    0    Cl    Me    Cl
                               
Y.067    Me    Me    Me    0    Cl    CHF,    Cl
                               
Y.068    Me    Me    Me    0    Cl    CF,    Cl
                               
Y.069    Me    Me    Me    0    Cl    C=CH    Cl
                               
Y.070    Me    Me    Me    0    H    4-CI-phenoxy    H
                               
Y.071    Me    Me    Me    0    Cl    4-CI-phenoxy    H
                               
Y.072    Me    Me    Me    0    Cl    4-CI-phenoxy    Cl
                               
Y.073    Me    Me    Me    0    Me    Me    Me
                               
 



-56-

Cpd No.    R,    R,        R,    X    R\1    R,    R,   
                                       
Y.074    Me    Me        Me    0        Br    Br    Br   
                                       
Y.075    H    Me        Me    0        H    Cl    H   
                                       
Y.076    H    Me        Me    0        Ci    Cl    H   
                                       
Y.077    H    Me        Me    0        Cl    Cl    Ci   
                                       
Y.078    Me    Me        Et    0        H    Cl    H   
                                       
Y.079    Me    Me        Et    0        Cl    Cl    H   
                                       
Y.OBO    Me    Me        Et    0        Ci    Cl    Cl   
                                       
                                       
Y.OB1    Me    Me        CH,C=CH    0        H    Cl    H   
                                       
Y.OB2    Me    Me        CH,C=CH    0        Ci    Cl    H   
                                       
                                       
                                       
Y.083    Me    Me        CH2C=CH    0        Ci    Cl    Cl   
                                   
Y.OB4    Me    Me        Me    s    H    Cl    H   
                                   
                                       
Y.OB5    Me    Me        Me    s    Ci    Cl    H   
                                   
Y.OB6    Me    Me        Me    s    Ci    Cl    Cl   
                                   
                                       
Y.OB7    Me    Me        Me    s    Cl    Br    Cl   
                                       
Y.OBB    Me    Me        Me    s    Ci    I    Cl   
                                   
                                       
Y.OB9    Me    Me        Me    s    Ci    Me    Cl   
                                   
        Me        Me    s    Cl    CHF2       
Y.090    Me                            Cl   
                                       
Y.091    Me    Me        Me    s    Ci    CF3    Cl   
                                   
Y.092    Me    Me        Me    s    Cl    C=CH    Cl   
                                   
                                       
Y.093    Me    Me        Me    s    H    4~CI-phenoxy    H   
                                   
Y.094    Me    Me        Me    s    Cl    4-CI-phenoxy    H   
                                   
                                   
                                       
Y.095    Me    Me        Me    s        Cl    4-CI-phenoxy    Cl   
                                   
Y.096    Me    Me        CH,C=CH    s    Cl    Cl    H   
                                   
                                   
Y.097    Me    Me        CH,C=CH    s    Cl    Cl    Cl   
                                   
Y.098    H    Me        Me    s    H    Cl    H   
                                       
Y.099    H    Me        Me    s    Cl    Cl    H   
                                       
 



-57-




Table 1 provides 100 compounds of formula (Ia), wherein A is A1

F2HCW
~~ ~

N,~  (A,),

CH3

n is 0, and ~. Rs. R1, X, R11,  R12 and R13 are as defined in Table Y.

For example, compound 1.001 has the following structure:

FVH0 yH, r7'yCI

~    N~ (1.001).

N,    I   6
,N    H c""
H,c    '

Table 2 provides 100 compounds of formula (Ia), wherein A is A1
F,HCW

~~'~.) (A,),
10    CH3

n is 1, and~. Rs. R1, X, R11, R12 and R13 are as defined in Table Y.

For example, compound 2.057 has the following structure:






15
 



-58-


Table 3 provides 100 compounds of formula (Ia), wherein A is A2

F3Co
I    ~
N,7  (A,),
CH3

n is 0, and R4, Rs, R1, x, R,1, R12 and R,3 are as defined in Table Y.

5

For example, compound 3.002 has the following structure;

F1F    ~ N~CI (3.002).
"\J6    Cl

,N    H C~
H3c    3

Table 4 provides 100 compounds of formula (Ia), wherein A is A2

F3Co
I  ~
N, 7  (A,),
10    CH3
n is 1, and R,, R5,  R1, X, R11 , R12 and R13 are as defined in Table Y. For example, compound

4.003 has the following structure:

F    F           
F~ CH 3    Cl   
v    I    N~ (4.003) .   
N,        6    I   
,NHC~    Cl    °CI   
H3C    3           
               

Table 5 provides 100 compounds of formula (Ia), wherein A is A,



15
 



-59-

n is 0, and R4, R5, R1, X, R,,, R12 and R13 are as defined in Table Y. For example, compound
5.002 has the following structure:    0    WCI   
H,C       
N~~    (5.002).   
'NJ(_ 0,    Cl   
1    F    CH3   
H,c           

Table 6 provides 100 compounds of formula (Ia), wherein A is A3











Tables 7 and 8:

10    Each of Tables 7 to 8, which follow the Table Y above, comprises 100 compounds of the formula (lib) in which R.,, R,, R,, X, Ru, R,2 and R13 have the values given in Table Y and n has the value given in the relevant Table 7 to 8. Thus Table 7 corresponds to Table Y when Y is 7, Table 8 corresponds to Table Y when Y is 8.

15    Table 7 provides 100 compounds of formula (lib)

~'    ~~   R13

H-N?~sXHR (lib), n ~ ;/ 12
H    H    H

R11

wherein n is 0, and ~. Rs, R7, X, R11o R12 and R,3 are as defined in Table Y.
 



-60-

For example, compound 7.001 has the following structure:





Table 8 provides 100 compounds of formula (lib)

~'    ~'   R13
? - + - Hj=>X - s
H-N    .    ~ /;    R  (lib),   
".            12   
H    H    H

Rtt

wherein n is 1, and ~, R5, R7, X, R11. R12 and R13 are as defined in Table Y.

Table 9 : Characterising data:

10    Table 9 shows selected melting point and selected NMR data for compounds of Table

1 to 6. CDCb is used as the solvent for NMR measurements, unless otherwise stated. If a

mixture of solvents is present, this is indicated as, for example: CDCI:,Id6-DMSO). No attempt

is made to list all characterising data in all cases.

In Table 9 and throughout the description that follows, temperatures are given in

15    degrees Celsius; 11 NMR" means nuclear magnetic resonance spectrum; MS stands for mass spectrum;"%" is percent by weight, unless corresponding concentrations are indicated in other units. The following abbreviations are used throughout this description:

m.p.  =    melting point    b.p.=    boiling point.
s =    singlet    br    =    broad
d    =    doublet    dd    =    doublet of doublets
t    =    triplet    q    =    quartet
m    =    mulliplet    ppm=    parts per million

20    Table 9:
 



-61-

Cpd    1H-NMR data: ppm (multiplicity/number    MS [M+H]'    m.p.  ('C)    LCMS data   
No.    o!Hs)               
                   
1.001    1.33-1.37(d,3H); 2.77-2.82(dd,1H); 3.07-    358/360    oil       
    ~:~~~~~11~~; :.:i-o/~8~~\9~l\573~{is~i~l~               
1.002    1.41-1.46(d,3H); 2.99-3.04(dd,1H); 3.17-    3921394/396    98-102       
    ~:~3/_~~1i~W7~;~o/:2~~.35~l(s,3H); 4.68-               
                   
                   
1.003    1.38-1.39(d,3H), 3.20-3.26(dd, 1 H), 3.32-    426/428/430    110-112       
    3.37(dd,1H), 3.70(s,3H), 3.97(s,3H), 4.88-               
    4.93(m,1H), 7.02-7.29(t,1H), 7.27(s,2H),               
    7.81(s,1H)               
                   
1.015    1.36-1.39(d,3H); 2.78-2.84(dd,1 H); 3.05-    450/452    oil       
    3.12(dd, 1H); 3.65(s,3H); 3.94(s,3H); 4.64-               
    4.68(m,1H); 6.80-6.90(m, 4H);6.95-               
    7.23(t,1H,CHF2);7.17-7.26(m,4H);7.67(s,1H)               
1.028    1.40-1.41.(d,3H);2.89-2.94(dd, 1 H);3.03-    378/380/382           
    3.14(dd, 1 H);3.86(s,3H);4.3-4.5(m~, 1 H);6.5-               
    7.0(m,,2H); 7.19-7.21(m, 2H); 7.36(m,1H);               
    7.8-8.6(m,,1 H)               
                   
1.031    1.14-1.20(t,3H);1.36-1.45(2d,3H);2.98-    406/408/410    116-118       
    3.03(dd, 1 H);3.1 9-3.25(dd, 1 H);3.74-               
                   
    ~:~~~j:~~~~3.~~~s,3H); 4.64-4.70(m, 1 H);               
                   
                   
1.032    1.20-1.24(t,3H), 1.35-1.37(d,3H), 3.23-    440/4421444    111-114       
    3.28(dd,1H), 3.33-3.38(dd,1H), 3.84-               
                   
    ~:~~~i:~~k~~~o/~8~~.iii~~ii3i~~•~~),               
                   
                   
1.033    0.91-0.93+1.11-1.13(2d,6H);1.42-    420/422/424    oil       
    1.48(2d,3H);3.00-3.07(dd, 1 H);3.29-               
    3.36(dd,1H);3.92(s,3H); 3.97-               
    ~~~(m, 1 H);4.36-4.45(m, 1 H); 6.97-7.59(m,               
                   
1.059    0.84-0.87(t,3H);1.14-1.25(m,2H);1.61-    420/4221424    oil       
    1.69(m,2H);3.55(s,3H);3.71-               
    3.80(m,1H);3.80-3.84(dd,1H); 3.96(s,3H);               
    ~~~i:,~~~~1H;H); 7.07-7.36(m,               
                   
                   
                   
2.003    1.41 (d,3H,CH3), 1.71-1.80(m,1 H,CH2), 1.94-    440/4421444/446    resin       
    2.04(m, 1 H,CH2), 1.87-1.92(m,2H,CH2),               
    3.78(s,3H,CH3),3.98(s,3H,CH3),4.66-               
    !•[.~t; 1~sz~>:,~~~~~~~~~F2),7.28(s,2H,               
                   
                   
2.040    1.89-1.96(m,2H,CH2), 2.91-    426/428/430/432    95-96       
    2.95(m,2H,CH2),  3.66(s,3H,CH3), 3,83-               
    3.86(t,2H,CH2), 3.97(s,3H,CH3), 7.31 (t,               
    1 H,CHF2), 7.28(s,2H,Ar-H),               
                   
    7 .89(s, 1 H,pyrazote-H)               
                   
 



-62-

Cpd    1H-NMR data: ppm (multiplicity/number    MS [M+HJ'    m.p.  ('C)    LCMS data   
No.    ofHs)               
                       
2.057        0.90•0.95(d,3H);1.30(s,9H);2.24-    394    resin       
        2.36(m, 1 H);2.39-2.45(dd, 1 H);2.67-               
        2.72(dd,1H);3.58(s,3H); 3.68-               
                       
        3.70(d,2H);3.98(s,3H); 7.09-7.11(d, 2H);               
                       
        7.1&-7.42(m,3H);7.90(s, 1H)               
                       
7.001        1.02-1.06(d,3H);2.54-2.59(dd, 1 H);2. 79-    200/202    liquid       
                       
        2.84(dd, 1 H);3.14-3.24(m,1 H),3.52(s,3H);               
                       
        5.3-5.5(s,,,1 H); 7.12-7 .16(m,2H); 7.25-               
        7.28(m,2H).               
7.002        1.04-1.09(d,3H);2.66-2.71 (dd, 1 H);2.93-    234/236/238    liquid       
        2.99(dd, 1 H);3.25-3.33(m, 1 H),3.52(s,3H);               
        5.2-5.4(s",1H); 7.17-7.18(m,2H); 7.35(d,               
        1H)               
                       
                       
7.015        1.07-1.09(d,3H);2.53-2.62(dd, 1 H);2.72-    292/294    liquid       
        2.81 (dd,1 H);3.16-3.26(m, 1 H),3.54(s,3H);               
        5.3-5.5(s,,, 1 H); 6.86-6.94(m,4H); 7.14-               
        7.18(m,2H);7.24-7.29(m,2H)               
                       
7.028        1.08-1.11 (d,3H);2.69-2.7 4(dd, 1 H);2.98•    220/2221224    83-86       
        3.03(dd, 1 H);3.24-3.32(m, 1 H); 5.3-               
        5.6(s~r,1H); 7.18-7.19(m,2H);               
        7.39(m, 1 H);7.5-8.2(s", 1 H)               
                       
7.031        0.98-1.02+1.0B-1.12(2d,3H);1.13-    248/250/252    liquid       
        1.18(2t,3H);2.63-2.68+2. 70-               
        2.78(2dd, 1 H);2.94-3.1 0+3.15-               
        3.21 (m, 1 H),3.25-3.31 +3. 71-3.78(2q,2H);5.0-               
        5.5(s~r,1H); 7.16-7.19(m,2H); 7.34-               
        7.36(m,1H)               
                       
7.033        1.03-1.07(d,3H);1.13-1.19(m,6H);2.61-    2621264/266    liquid       
        2.68+2.94-3.03(2dd,2H);3.21-               
        3.31(m, 1 H),3.78-3.84(m,1 H);5.2(s~r,1 H);               
                       
        7.14-7.18(m,2H); 7.35-7.36(m,1 H)               
                       
7.059        0.82-0.89(t,3H);1.12-1.27(m,2H);1.49-    262/264/266    liquid       
        1.5B(m, 1 H);1.63-1.72(m,1 H);3.05-               
        3.1 0( dd, 1 H);3.12-               
                       
        3.18(dd, 1 H);3.47(s,3H),3.50-3.51(m, 1 H);               
        5.0-5.50(s",1H); 7.14-7.16(m,1 H); 7.21-               
        7.25(m, 1 H);7.37-7 .39(m,1 H)               
                       
8.003        1.21(d,3H,CH3),1.52-1.59(m,1H,CH2), 1.68-        liquid       
        1.76(m,1 H,CH2), 2.80-2.83(m,2H,CH2),               
        3.06-3.13(m,1H,CH), 1.45(s,1H,NH),               
        7.29(s,2H,Ar-H)               
8.040        1.74-1.82(m,2H,CH2), 2.92-3.01(m,4H,CH2-        liquid       
        CH2), 3.55(s,3H,CH3), 5.60(s,1H,NH),               
        7.29(s,2H,Ar-H)               
                       
 



-63-

Cpd    1H-NMR data: ppm (multiplicity/number    MS[M+Hj'    m.p.  ('C)    LCMSdata

No.    ofHs)

8.057    236    liquid

Formulation examples for compounds of formula 1:

Example F-1.1 to F-1.2: Emulsifiable concentrates

Components    F-1.1F-1.2   
compound ofTabies 1-6    25%    50%
calcium dodecyll:>enzenesulfonate    5%    6%
10    castor oil polyethylene glycol ether       
(36 mol ethylenoxy units)    5%   
tributylphenolpolyethylene glycol ether       
(30 mol ethylenoxy units)        4%
cyctohexanone        20%
15    xylene mixture    65%    20%

Emulsions of any desired concentration can be prepared by diluting such concentrates with

water.

20    Examole F-2: Emulsifiable concentrate   
       
    Components    F-2
       
    compound ofTabies 1-6    10%
25    octylphenolpolyethylene glycol ether   
    (4 to 5 mol ethylenoxy units)    3%
    calcium dodecylbenzenesulfonate    3%
    castor oil polyglycol ether   
    (36 mol ethylenoxy units)    4%
30    cyclohexanone    30%
    xylene mixture    50%
 



-64-


Emulsions of any desired concentration can be prepared by diluting such concentrates with

water.

Examples F-3.1 to F-3.4: Solutions

    Components    F-3.1    F-3.2    F-3.3    F-3.4
    compound ofTables 1-6    80%    10%    5%    95%
10    propylene glycol monomethyl ether    20%           
    polyelhylene glycol (relalive molecular               
    mass: 400 atomic mass units)        70%       
    N-methylpyrrolid-2-one        20%       
    epoxidised coconut oil            1%    5%
15    benzin (boiling range: 160-190°)            94%   

The solutions are suitable for use in the form of micradrops.

        Examgles F-4.1 to F-4.4: Granulates                   
20                           
                           
        Components    F-4.1    F-4.2    F-4.3    F-4.4   
        compound ofTables 1-6    5%    10%    8%    21%   
        kaolin    94%        79%    54%   
25        highly dispersed silicic acid    1%        13%    7%   
        attapulgite        90%        18%   

The novel compound is dissolved in dichloromethane, the solution is sprayed onto the carrier and the solvent is then removed by distillation under vacuum.

30

Examgles F-5.1 and F-5.2: Dusls

Components    F-5.1    F-5.2
       
 



        -65-
compound ofTables 1-6    2%    5%
highly dispersed silicic acid    1%    5%
talcum    97%   
kaolin        90%

5

Ready for use dusts are obtained by intimately mixing all components.

Examples F-6.1 fa F-6.3: Wettable powders

10    Components    F-6.1    F-6.2    F-6.3
               
    compound ofTab)es 1-6    25%    50%    75%
    sodium lignin sulFOnate    5%    5%   
    sodium lauryl sulfate    3%        5%
15    sodium diisobutylnaphthalene sulfonate        6%    10%
    octylphenolpolyethylene glycol ether           
    (7 to 8 mol ethylenoxy units)        2%   
    highly dispersed silicic acid    5%    10%    10%
    kaolin    62%    27%   
20               

All components are mixed and the mixture is thoroughly ground in a suitable mill to give

wettable powders which can be diluted with water to suspensions of any desired

concentration.

25Examole F7: Flowable concentrate for seed treatment   
compound ofTables 1-6    40%
propylene glycol    5%
oopolymer butanol POIEO    2%
tristyrenephenole with 10-20 moles EO    2%
1,2Mbenzisothiazolin-3-one {in the form of a 20% solution in    0.5%
water)   
monoazo-pigment calcium salt    5%
Silicone oil (in the form of a 75 % emulsion in water)    0.2%
Water    45.3%
 



-66-

The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or
immersion.

BIOLOGICAL EXAMPLES: FUNGICIDAL ACTION:

Example 8-1: Action against Botrvtis cinerea   fungal growth assay

10    Conidia of the fungus from cryogenic storage was directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds (0.002% active ingredient) into a microliter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24°C and the inhibition of

growth was measured photometrically after 3-4 days. The activity of a compound was

15    expressed as fungal growth inhibition (0 ;:; no growth inhibition, ratings of 80 % to 99 % mean good to very good inhibition, 100 % ;:; complete inhibition).

Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.059 and 2.003 show very good activity in this test (!>80% inhibition).

20    Example 8-2: Action against Mycosphaerella arachidis (early leaf spot of ground nut: Cercospora arachidicola [anamorohU- fungal growth assay
Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds (0.002%
active ingredient) into a microliter plate (96-well fonnat) the nutrient broth containing the

25    fungal spores was added. The test plates were incubated at 24°C and the inhibition of growth was measured photometrically after 6-7 days. The activity of a compound was expressed as fungal growth inhibition (0 = no growth inhibition, ratings of 80 % to 99% mean good to very good inhibition, 100 % ;:; complete inhibition).
Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.059, 2.003 and 1.057 show very

30    good activity in this test (S80% inhibition).

Example 8-3: Action against Septaria tritici- fungal growth assay

Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds (0.002%
 

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active ingredient) into a microliter plate (96-well format) the nutrient broth containing the

Fungal spores was added. The test plates were incubated at 24°C and the inhibition of growth was determined photometrically after 72 hrs. The activity of a compound was expressed as fungal growth inhibition (0::: no growth inhibition, ratings of 80 % to 99 %

mean good to vel)'good inhibition, 100% =complete inhibition).

Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.059, 2.003 and 1.057 show vel)' good activity in this test (sBO% inhibition).

Example 8-4: Action against Tapesia yallundae   fungal growth assav

10    Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds (0.002% active ingredient) i~to a microliter plate (96-well format) the nutrient broth containing the fungal spores was ci.dded. The test plates were incubated at 24"C and the inhibition of
growth was measured photometrically after 6-7 days. The activity of a compound was

16    expressed as fungal growth inhibition (0;::; no growth inhibition, ratings of 80 % to 99 % mean good to very good inhibition, 100% =complete inhibition).

Compound 1.001 shows vel)'good activity in this test (SBO% inhibition).

Example 8-5: Action against Monographella nivalis (anamorph: Fusarium nivale.

20    Microdochium nivale: Snow mould)- fungal growth assay

Conidia of the fungus from Cl)'ogenicstorage were directly mixed into nutrient broth (PDB potato dextrose broth). Arter placing a DMSO-solution of the test compounds (0.002% active ingredient) into a microliter plate (96-well fonmat) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24°C and the inhibition of growth was
25    measured photometrically after 72 hrs (0" no growth inh'1bition,ratings of 80 %to 99% mean good to very good inhibition, 100 % = complete inhibition).

Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.059 and 2.003 show very good activity in this test (SBO% inhibition).
Compound 1.057 shows good activity in this test (S50% inhibition).

30

Example B-6: Action against Rhizoctonia so/ani- fungal growth assay

Mycelial fragments of a newly grown liquid culture of the fungus were directly mixed into nutrient broth (PDB potato dextrose broth), After placing a (DMSO) solution of the test compounds (0.002% active ingredient) into a microliter plate (96-welt format) the nutrient
 



-68-

broth containing the fungal spores was added. The test plates were incubated a124•c and

the inhibition of growth was measured photometrically after 3M4 days. The activity of a compound was expressed as fungal growth inhibition (0::: no growth inhibition, ratings of 80 %to 99% mean good to very good inhibition, 100% =complete inhibition).
Compound 2.003 shows very good activity in this test (,;80% inhibition).

Compound 1.003 shows good activity in this lest {,;50% inhibition).

Example 8-7: Action against Erysiphe graminis f.sp. tritici (wheat powdery mildew)

Wheal leaf segments were placed on agar in multiwell plates (24-well format) and sprayed

with lest solutions (0.02% active ingredient). After drying, the leaf disks were inoculated with

10    a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed 7 days after inoculation as preventive fungicidal activity.
Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.033, 1.059 and 2.003 show very good activity in this lest (,;80% inhibition).

Example 8-8: Protective action against Puccinia recondita (brown rust) on wheat

15    Wheal leaf segments were placed on agar in mulliwell plates (24-well formal) and sprayed with test solutions (0.02% active ingredient). After dl)ling, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed 8 days after inoculation as preventive fungicidal activity.
Compounds 1.001, 1.002, 1.003, 1.015, 1.059 and 2.003 show very good activity in this lest

20    (,;80% inhibition).

Compounds 1.032 and 1.057 show good activity in this test (,;50% inhibition).

Example 8-9: Curative action against Puccinia recondita {brown rust) on wheat

Wheat leaf segments were placed on agar in multiwell plates (24•wellformal) and inoculated

with a spore suspension of the fungus. One day after inoculation the leaf segments were

25    sprayed with lest solutions (0.02% active ingredient). After appropriate incubation the activity of a compound was assessed 8 days after inoculation as curative fungicidal activity.
Compounds 1.002 and 1.003 show very good activity in this lest (sBO% inhibition). Compound 1.015 shows good activity in this test (,;50% inhibition).

30    Example 8-10: Action against Pyrenophora teres {net blotch) on barley

Barley leaf segments were placed on agar in multiwell plates (24•well formal) and sprayed with test solutions (0.02% active ingredient). After drying, the leaf disks were inoculated with
 



-69-

a spore suspension of the fungus. After appropriate incubation the activity of a compound

was assessed 4 days after inoculation as preventive fungicidal activity.

Compounds 1.001, 1.002, 1.003, 1.015, 1.031, 1.032, 1.033, 1.059 and 1.057 show very

good activity in this test (,;80% inhibition).

5
 



-70-




1. A compound of formula I


R    (1),
12


wherein

R1 is C,-C,alkyl or C1-C,haloalkyl;

R2 is C1-C4alkyl;

R3 is hydrogeh or halogen;

R, is hydrogen, C,-C,alkyl or c,-C,halogenalkYI;

Rs, R0 ,  Ra , Rs and Rto are, independently from each other, hydrogen, halOgen, C1~C4a\kyl

or C1-C4hafoafkyl;

R7 is hydrogen, halogen, C,-c,alkyl, c,-C,alkenyl or c,-C,alkinyl;

R11 is hydrogen, halogen or C,-Coalkyl;

10    R, is hydrogen, halogen, C,-C,alkyl, C2-C6alkenyl, C,-c,alkinyl, C,-C,cycloalkyi-C3-C,alkinyl, halophenoxy, halophenyi-C,-C,alkinyl, C(C,-C,alkyi)=NO-C,-C,alkyl, C,-c,haloalkyl,

C1-Caha\oalkoxy, CrCehaloalkenyl, or C2-C~haloalkenyloxy;

R13 is hydrogen, halogen, C1-C6alkyl;

X is oxygen, sulfur or absent; with the proviso that R7 is different from halogen if X is oxygen

15    or sulfur;

n is 0 or 1; and agronomically acceptable salts/stereofsomers/diastereoisomers/enanlio-mers/tautomers and N-oxides of those compounds.

2.    A compound according to claim 1, wherein R1 is difluoromethyl, trifluoromelhyl or methyl.

3.    A compaond according to claim 1, wherein R2 is methyl.

20    4. A compound according to claim 1, wherein R~ is hydrogen orfluoro.

5. A compound accordfng to claim 1, wherein R4 is hydrogen, methyl or ethyl.

6.    A compound according to claim 1, wherein R4 is methyl.

7.    A compound according to claim 1, wherein R5 is hydrogen or methyl.

8.    A compound according to claim 1, wherein n is 0.

9.    A compound according to claim 1, wherein X is oxygen.

10.    A compound according to claim 1, wherein R8 , R9 and R1o are hydrogen.

11.    A compound aCcording to claim 1, wherein R11 ,  R12 and R13 is hydrogen or chloro.

12.    A compound according to claim 1, wherein R12 is chloro or C1-C4alkyl:

13.    A method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms, wherein a compound of formula I according to claim 1 or a composition, comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.

14.    A composition for controlling and protecting against phytopathogenic microorganisms,

comprising a compound of fonnula I according to claim 1 and an Inert carrier.

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