NO890596L - PROCEDURE FOR PREPARING 4- (PYRAZOLYLOXY) NITROBENZENES. - Google Patents

Description

This invention relates to certain novel substituted 3-(4-nitrophenoxy)-pyrazoles and their use as herbicides.

Uncontrolled weed growth is still a problem in our environment. In agriculture, uncontrolled weed growth normally results in smaller yields and reduced quality of the crops, because weeds compete with the beneficial plants for light, water and nutrients in the soil. A number of herbicides have been developed to control weeds. However, many herbicides damage nearby beneficial plants when applied in the quantities of herbicide necessary to achieve control of the weed. In addition, many non-selective herbicides cause environmental problems.

US Patent No. 4,298,749 describes certain substituted pyrazole ether derivatives, including pyrazole phenyl ethers, which exhibit herbicidal activity. However, there is still a need in the art for a class of active herbicides with a broad spectrum.

The present invention relates to a new class of substituted 3-phenoxypyrazoles, herbicidal preparations containing these and their use as herbicides. It has thus been shown that certain 3-phenoxypyrazoles with a specific substitution pattern exhibit herbicidal activity, and that many of them exhibit exceptionally high herbicidal activity.

The unique substitution pattern includes as an important factor a para-nitro substituent on the phenyl ring. The unique substitution pattern also includes specific substituents in the 1-, 4- and 5-positions of the pyrazole ring. The phenyl ring also has in one meta position a substituent which is (i) a hydrido radical or, preferably, (ii) a substituent which is not a hydrido radical, and which has a molecular weight of up to 300. It has been shown that it is this unique combination of the para-nitro substituent on the phenyl ring and substituents on the 1-, 4- and 5-positions of the pyrazole ring which gives the class of compounds with herbicidal activity, and that the nature of the possible meta-substituent on the phenyl ring is not of decisive importance for whether the compounds should exhibit herbicidal activity or not.

The class of unique compounds consists of 3-phenoxypyrazoles and agriculturally acceptable salts thereof, where (a) the pyrazole ring has a methyl, ethyl, halomethyl or haloethyl substituent in the 1-position, a hydrido, halogen or nitro substituent in the 4-position and a chloro, cyano, halomethyl, haloethyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl or methoxymethyl substituent in the 5-position and (b) the phenyl ring has a para-nitro substituent and a meta -substituent with a molecular weight of up to 300 and consisting of one or more atoms selected from H, C, Cl,

F, Br, I, N, S, 0, Si and P. The meta-substituent is preferably an organic radical having up to 10 and preferably up to 8 carbon atoms, which preferably has a molecular weight of up to 300, preferably up to 250 and more preferably up to 200, and which has one or more atoms selected from H, C, Cl, F, Br, I, N, S, O, Si and P. More preferably, the organic radical has one or more atoms selected from H, C, Cl , F, Br, N, S and 0. Preferably, the pyrazole ring has a halogen substituent in the 4-position. This is preferably Cl or Br. Preferably, the pyrazole ring has a halogenmethyl, halogenethyl, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl substituent in the 5-position, more preferably a halogenmethyl or methylsulfonyl substituent in the 5-position.

The organic meta-radical will normally comprise a saturated or unsaturated carbon chain with up to 10 (preferably up to 8) carbon atoms, which can be straight-chain, branched or cyclic and possibly substituted with various substituents such as e.g. halogen, nitro, cyano, hydroxy etc. The radical has a molecular weight of up to 300 and preferably up to 250 (most preferably up to 200). The carbon chain may be attached to the phenyl ring directly or through one or more difunctional substituents selected from (i) substituents comprising (or consisting of) one or more heteroatoms selected from N, S, 0 and P (preferably 0 and N) and (ii) substituents comprising one or more atoms selected from C and S, which are bound to one or more of said heteroatoms (preferably carbonyl). The carbon chain is optionally broken off or terminated by one or more substituents selected from (i) substituents comprising one or more heteroatoms selected from N, S, 0 and P (preferably 0, N and S) and (ii) substituents comprising one or more atoms chosen from C and S, which is bound to one or more of these heteroatoms (preferably carbonyl or sulfonyl). The heteroatom may optionally be substituted with substituents such as e.g. alkyl, alkoxy, etc. The carbon chain can also optionally be substituted with (i) aryl, preferably phenyl or phenylalkyl, optionally substituted with substituents such as e.g. halogen, nitro, cyano, alkoxy, haloalkyl, amino, hydroxy, etc., or (ii) a 3-7 membered, saturated or unsaturated heterocyclic radical with 1-3 heteroatoms selected from N, O and S.

A preferred group within the unique class of 3-phenoxypyrazoles according to the invention consists of compounds represented by formula I and for agricultural purposes acceptable salts thereof:

where:

R-| is methyl, ethyl, halogenmethyl or halogenethyl,

R 2 is chlorine, cyano, halogenmethyl, halogenethyl, halogenethyl-, methylthio-, ethylthio-, methylsulfinyl-, ethylsulfinyl-, methylsulfonyl-, ethylsulfonyl- or methoxymethyl,

R 3 is hydrido, halogen or nitro, and

where:

Ra is selected from hydrido, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, unsubstituted or substituted one or more times by hydroxy, halogen, cyano, alkoxy, amino, alkylamino, alkylthio, phenyl, hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyloxy, di-(alkoxy)carbonyl, di-(alkoxycarbonyl), alkoxyalkylaminocarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylalkylsulfonyl, phosphonyl and alkylphosphinyl;

R]-, is selected from hydroxy, hydrido, halogen, alkyl, alkoxy, alkenyloxy, alkynyloxy, phenoxy, benzyloxy, hydrazino, alkylhydrazino, oximino, phenylamino, phenylthio, alkylthio, amino, alkylamino, alkenylamino, alkynylamino, di-, tri- or tetra-(Alkoxy), di-(alkylamino), AlkylaminoAlkoxy, Alkoxyalkylamino, Hydroxycarbonyl, Alkylaminooxy, Alkoxyamino, AlkylthioAlkoxy, Alkylthioalkyl, Alkoxyalkyl, Alkylsulfonylalkyloxy, Alkylsulfonylalkyloxy, Alkylsulfonylamino, Alkylsulfonylalkylamino, Hydroxycarbonylalkylamino, Alkoxycarbonylalkyl, Alkylcarbonylalkyl, Alkoxycarbonylalkylthio, Alkyl-carbonylamino, Aminocarbonylalkylamino, Di-(Alkoxycarbonyl)-Alkoxy, Alkylaminocarbonyl-Alkoxy, Hydroxycarbonylalkylamino, Alkoxycarbonylalkylamino, Alkylcarbonyloxy-Alkoxy, Alkyl-carbonyloxydi-(Alkoxy), Alkylcarbonyloxyalkylamino, Alkoxy-carbonyloxy-Alkoxy, Alkoxy-Alkylcarbonyloxy-Alkoxy, Alkoxy-carbonylmino-Alkoxy, Alkoxy-carbonyl-Alkoxyamino, Alkoxy-carbonylalkylcarbo nyloxyalkylamino, alkenylaminothiocarbonylamino, alkyloxycarbonyloximino, alkoxyoximino, alkylcarbonyloxynino and alkylphosphonylalkyloxy;

Rcer hydrido, alkyl, benzyl, alkenyl, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylimino, alkoxyimino, alkoxycarbonylimino, Rx-alkyl or Rx-alkenyl where Rx is halogen, hydroxy, cyano, mono-, di-, tri- or tetra-

(Alkoxy), alkynyloxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphonyl, alkylphosphinyl, halocarbonyl, alkylcarbonyl, hydroxycarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, phenylaminocarbonyl, alkylhydrazinocarbonyl, aminocarbonyl, alkenylaminocarbonyl, alkylaminocarbonyl, benzylaminocarbonyl, thiocarbonyl, phenylthiocarbonyl, alkylthiocarbonyl, alkoxyalkyl-thiocarbonyl, di-(alkyloxycarbonyl), alkylcarbonylalkoxy-carbonyl, alkylsulfinylalkyl-carbonyl, alkoxycarbonylalkyl-carbonyl, alkoxycarbonylalkylaminocarbonyl1, hydroxycarbonyl-alkylaminocarbonyl, di-, tri- and tetra-(alkoxy)-carbonyl, alkoxyalkenyloxycarbonyl, alkylthioalkylcarbonyl, Alkyl-AminoAlkoxycarbonyl, Di-(Alkylamino)-carbonyl, Alkoxyalkylaminocarbonyl, Alkoxyaminocarbonyl, Alkylsulfonylamino-carbonyl, Phenylsulfonylaminocarbonyl1, Alkoxycarbonyl-carbonyloxy, Alkoxycarbonylalkylcarbonyloxy, Alkoxycarbonyl-amino, Alkoxycarbonylalkylthio, Alkoxycarbonylalkylamino-carbonyl, Alky lcarbonylaminocarbonyl, alkylcarbonyloxydi-(alkyloxy)-carbonyl, alkoxyalkylcarbonyloxydi-(alkyloxy)-carbonyl, alkoxycarbonylcarbonyloxydi-(alkoxy)carbonyl, alkyloxycarbonyl-alkylcarbonyloxybis-(alkoxy)carbonyl, alkylsulfonylamino-alkylcarbonyl, alkylsulfonyl-aminocarbonyl, alkylsulfonyl-aminocarbonyl , alkoxyoximinocarbonyl or alkyloximinocarbonyl;

R(3 and Re independently of each other are selected from hydrido,

alkyl, alkenyl, alkynyl, benzyl, phenyl, alkoxy, alkenyloxy, benzyloxy, hydridocarbonyl1, alkylcarbonyl, phenylcarbonyl, alkylsulfonyl, aminocarbonyl, alkoxycarbonyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsulfonylalkyl, halo-carbonylalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, di- and tri-( alkoxy), phenylthioalkyl, di-(alkylamino)-alkyl, alkylphosphonylalkyl and alkylsilylalkyl, or R^ is hydrido or alkyl and Re is amino, alkylamino, phenylamino or alkoxycarbonylalkylamino, or R^ and Re together form a cycloalkyl chain of 2-6 carbon atoms;

Rg is selected from hydrido, alkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylaminocarbonylalkyl, alkylthiocarbonylalkyl, di-(alkoxy)carbonylalkyl and di-(alkoxycarbonyl)alkyl:

Rf is selected from hydrido, alkyl and alkoxyalkyl:

Rh is hydrido, halogen, alkyl, alkenyl, alkoxy, alkylamino, phenoxy, alkylaminocarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylthio, alkoxycarbonylalkylthio, and alkylsilylalkyloxycarbonylalkyl or alkylsulfinylamino;

Ri and Rj independently of each other are selected from hydrodo,

alkyl, alkoxy and alkylamino;

R^ is alkylphosphonyl, alkylaminoimino, alkylsulfinyl, alkylsulfonyl, alkylaminosulfonyl or halosulfonyl, wherein

Ra - Rj may also comprise a heterocyclic substituent selected from triazolyl, morpholinyl, piperidyl, indolyl, piperazinyl, pyrrolidinyl, pyrazolyl, pyrrolinyl, azetidinyl, thienyl, imidazolyl, pyrimidinyl, furyl, pyridyl, tetrahydro-2H-pyranyl, pyridinyl, pyrrolidinonyl, indazolyl , furanyl, dioxolanyl, 5,6-dihydro-1,4,2-dioxazinyl, tetrahydrofuranyl, tetrahydro~2-oxofuranyl, 4,5-dihydro-4-oxofuranyl, benz-imidazolyl, 4,5-dihydrooxazolyl, benzoxazolyl, piperidinyl , aziridinyl, 1H-2,5-dihydropyrrolyl, 1H-isoindole-1,3-(2H)-dionyl, furanonyl, thiomorpholinyl, azepinyl, oxocycloalkyl and oxocycloalkeny1.

Preferred compounds according to the invention include compounds where R-] is methyl, compounds where R 2 is halogenmethyl, methylsulfinyl or methylsulfonyl, and most preferably where R 2 is halogenmethyl, especially difluoromethyl or trifluoromethyl; and compounds wherein R3

is halogen, especially chlorine and bromine.

Preferred compounds according to the invention have a

Z which is:

and most preferably Rc0, where Rj-, Rc, Rd, Re, Rf and Rg are as indicated above. Z is preferably selected from alkyloxy, haloalkyloxy, bis-(alkyloxy), alkyloxycarbonyl, alkyloxycarbonylalkyloxy, aminocarbonylalkyloxy, alkylaminocarbonylalkyloxy, alkylsulfonylaminocarbonylalkyloxy, alkylamino, hydroxyalkylamino, alkoxyamino, alkoxyalkylamino, hydroxycarbonylalkylamino and alkyloxycarbonylalkyloxyimino.

The nature of the Z-substituent is not of decisive importance for the herbicidal activity of the unique class of compounds according to the invention. Compounds with other types of Z substituents are the following: (a) compounds of formula I with a substituent Z as indicated above and wherein the substituents Ra_R are selected from the collective group of substituents prescribed above for Ra-Rk, and (b) compounds with formula I with a substituent Z as indicated above and where Ra-R^ are substituents comprising one or more radicals selected from carbonyl, oxy, amino, thio, carbonyloxy, carbonylamino, imino, oximino, sulfonyl, sulfinyl, thiocarbonyl, phosphinyl, phosphonyl and hydrazino and the like and optionally also comprise bridging radicals selected from among alkylene, phenyl and the like.

The phenyl ring may optionally also be substituted in the other ring positions with one or more non-interacting substituents such as e.g. halogen (eg as an ortho-substituent, especially ortho-halogen), which does not unacceptably reduce the herbicidal activity. Compounds with such substituents are considered equivalent to the compounds claimed here.

The pyrazole ring can also be substituted in the 1-, 4- and 5-positions with other substituents which do not unacceptably interfere with the herbicidal activity of the molecule. These compounds are also considered equivalent to the compounds claimed here.

The terms "di-, tri- and tetra-" mean that they

groups in question are polymeric. Thus di-(methoxy) stands

for C<H>3<->O-CH2-O-.

The term "alkyl" herein stands for a straight-chain, branched or cyclic radical of 1-12 carbon atoms, preferably 1-3 carbon atoms, and includes, but is not limited to, ethyl, rnethyl, 2-propyl, 1-ethylpropyl, 1-methylpropyl , n-butyl, 1,1-dimethylethyl, 2,2-dimethylpropyl, pentyl, 2-methylpropyl, 1-methylethyl and dodecyl. The cyclic alkyl radicals include cycloalkylalkyl radicals and alkylcycloalkyl radicals where the cyclic group in the radical has from 3 to 6 carbon atoms. Examples of cycloalkyl radicals are cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl and cyclohexyl.

The terms "alkenyl" and "alkynyl" here mean a straight-chain, branched or cyclic group having 2-6 carbon atoms. Examples of such alkenyl groups are ethenyl, 1,propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-propenyl, 2methyl-2-propenyl, 1-methylethenyl and the like. Examples of such alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, etc. The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "haloalkyl" means an alkyl radical which is substituted with one or more halogen atoms, which are preferably selected from bromine, chlorine and fluorine. By the term "Alkoxycarbonyl" is meant the group

where R-] is alkyl which can be substituted with various substituents such as e.g. halogen, hydroxy, nitro, cyano or the like. The term "alkylamino" means the group R-|RmN-where R is hydrido or a lower alkyl group which can be substituted with various substituents. By the term "Alkoxycarbonylalkyl" is meant the group

The term "alkylthio" means the group R-|S-, and the term "alkylthiocarbonyl" means the group The term "oximino" means the group

The terms "alkylphosphonyl" and "alkylphosphinyl" mean respectively

The term "alkylsulfonyl" means the group The term "alkylsulfinyl" means the group

The term "imino" means the group -C=N-.

Salts of the compounds of the invention which are acceptable for agricultural purposes include alkali metal salts, alkaline earth metal salts, acid addition salts, base addition salts and alkylation salts. In general, the salts will have suitable cations, which include alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium; organic ammonium ions and ammonium salts, sulfonium, phosphonium salts and other salt complexes. Alkylation salts are usually formed by alkylation of nitrogen or sulfur atoms in the molecule.

It has also been shown that the 5-phenoxypyrazole regio-isomers of the compounds according to the invention can exhibit herbicidal activity. However, the 3-phenoxypyrazoles according to the invention are substantially more active as herbicides than their corresponding 5-phenoxypyrazole regioisomers. A 3-phenoxypyrazole regioisomer is structurally identical to its corresponding 5-phenoxypyrazole regioisomer except for the position of the substituent on the pyrazole nitrogen. It has also been shown that the R-isomer of compounds where Z is an alkoxy-carbonylethylideneoxy substituent has higher herbicidal activity than the corresponding S-isomer compounds.

The alkyl, alkenyl, alkynyl, phenyl and phenylalkyl radicals in the compounds according to the invention represented by formula I can in turn be substituted with various substituents which will not affect the biological activity of the compound, in addition to the substituents which specific examples are given here. Suitable substituents include, for example, substituents such as halogen, cyano, nitro, amino, hydroxy, haloalkyl, alkoxy, alkylthio, alkylsilyl, sulfonyl, phosphonyl and the like, and compounds with these substituents shall be considered to fall within the scope of the invention. Such substitution will normally only be mono-, di- or tri-substitution ("mono-/poly-substitution") on such radicals, but in the case where halogen and hydroxy are involved, a higher degree of substitution may be suitable. Furthermore, many of the compounds according to the invention may have more than one possible stereoisomer, and the structures shown are intended to include all such stereoisomers.

The applicability of the compounds according to the invention as active ingredients in herbicidal preparations and their use will now be described below.

Known methods are described below by means of which the compounds according to the invention can be prepared from compounds that are known in the art and/or can be easily obtained commercially. These methods described below are only illustrative, and experts in the field will be familiar with many other methods that can be used for the preparation of the compounds according to the invention.

The new compounds can generally be prepared by two methods, method A and method B. Some of the new compounds are prepared by method A, in two steps as follows: (i) 2,4-dichloronitrobenzene is reacted with at least two equivalents of the suitably substituted 3 -hydroxypyrazole in a suitable solvent, and (ii) the product from (i) is reacted with a suitable nucleophilic reactant selected from oxides, thiolates and amines. Suitable oxides are hydroxides, alkoxides, phenoxides and the like. Other compounds according to the invention can be prepared from these compounds using known chemical procedures.

The compounds according to the invention can also be prepared according to method B by reacting a 3-hydroxypyrazole intermediate with a 4-halogenitrobenzene intermediate with the following structure:

The halogen atom on the nitrobenzene is preferably fluorine or chlorine. W can be chosen from a number of different substituents and can e.g. be the desired substituent in the phenoxypyrazole product or a replaceable substituent, such as e.g. fluorine, which can then be displaced from the phenoxypyrazole by the desired substituent.

Pyrazole intermediate

Some of the 3-hydroxypyrazole intermediates used for the preparation of the compounds according to the invention are new compounds. These new 3-hydroxypyrazoles have the following formula

where:

R-| is methyl or ethyl,

R 2 is halogenmethyl, halogenethyl, methylsulfinyl, ethylsulfinyl or methoxymethyl, and

F?3 is hydrido or halogen.

Examples of such new 3-hydroxypyrazoles (melting point in brackets) are: 5-trifluoromethyl-3-hydroxy-1-methylpyrazole

(130-131°C)

5-difluoromethyl-3-hydroxy-1-methylpyrazole

(115-119-C)

5-chlorodifluoromethyl-3-hydroxy-1-methylpyrazole

(122-123-C)

5-pentafluoroethy1-3-hydroxy-1-methylpyrazole

(119-124°C)

5-trifluoromethyl4-chloro-3-hydroxy-1-methylpyrazole

(136-140°C)

5-trifluoromethyl-4-bromo-3-hydroxy-1-methylpyrazole

(154-156<0>C)

5-trifluoromethyl-3-hydroxy-1-ethylpyrazole

(85.5-87.5°C)

5-trifluoromethyl-4-fluoro-3-hydroxy-1-methylpyrazole

(101.5-102.5°C)

5-trifluoromethyl-4-iod-3-hydroxy-1-methylpyrazole

(190-192°C)

5-difluoromethyl-4-fluoro-3-hydroxy-1-methylpyrazole (157-159°C).

The 3-hydroxypyrazole intermediates can conveniently be prepared according to the following methods.

The pyrazole intermediate is conveniently prepared by reacting an alkylhydrazine with an alkyl-3-haloalkylpropionate, which in turn can be prepared by the methods described in Huang et al., Scientia Sinica 25, 21

(1982). The phosphorane intermediate according to this publication can be prepared by reacting (carbethoxymethyl)-triphenyl-phosphonium bromide with trifluoroacetic anhydride in the presence of triethylamine and tetrahydrofuran.

The 5-trifluoromethyl-1-3-hydroxy-1-methylpyrazole intermediate can also be conveniently prepared by reaction of

4,4,4-trifluoro-2-butynoate with methylhydrazine in a suitable solvent such as e.g. methylene chloride or methanol/water, at a low temperature from -^78 °C to -^20 °C. At higher temperatures

rates, the reaction will result in a mixture of the 3-hydroxy and 5-hydroxypyrazole isomers. It is believed that reduced temperatures and more polar solvents give greater amounts of the desired 3-hydroxyisomer of the pyrazole. Before reacting the pyrazole with the nitrobenzene, it is usually preferred to purify the pyrazole to isolate the 5-hydroxypyrazole isomer. This purification can easily be carried out by stirring the isomer mixture in an aqueous solution of sodium bicarbonate. The 5-hydroxy isomer dissolves, while the 3-hydroxy isomer remains suspended and can be easily separated.

An alternative method for the production of 5-trifluoromethyl-3-hydroxy-1-methylpyrazole involves reacting ethyl-4,4,4-trifluoroacetoacetate in acetone with preferably triethylmethylammonium methylsulfate or with dimethylsulfate in the presence of anhydrous potassium carbonate, whereby 3-methoxy- The 4,4,4-trifluoro-2-butenoic acid ethyl ester is formed. This ester is then reacted directly with methylhydrazine, whereby a mixture of the 3- and 5-hydroxy isomers of the pyrazole intermediate is formed. The desired isomer can be separated as described above. Alternatively, 2,4,4-trifluoroacetoacetate can be subjected to reaction in a similar manner, whereby 1-methyl-3-hydroxy-4-fluoro-5-difluoromethylpyrazole is obtained.

Another method for producing the 3-hydroxypyrazole involves reacting the ethyl-4,4,4-trifluoroaceto-acetate directly with the methylhydrazine in ether to form a mixture of intermediates, namely 5-hydroxy-pyrazolidin-3-one and 3-hydroxypyrazolidin-5-one and dehydration of these intermediates by adding sulfuric acid in chloroform, whereby a mixture of the 3- and 5-hydroxy-pyrazoles is obtained. The desired isomer can then be separated as described above.

Referring to method I below, a preferred method for the preparation of 3-hydroxypyrazoles involves reacting a 3-(amino or substituted amino)-2-alkenic acid or a 3-(amino or substituted amino)-2-alkenic acid derivative with a alkyl substituted hydrazine. Suitable alkenoic acid derivatives include esters, thioesters and amides. In method I, Y denotes hydrido or halogen, preferably fluorine, while R denotes hydrido, alkyl or phenyl, preferably hydrido. The alkenoic acid can also have a halogen substituent in the 2-position.

The alkenoic acid may be substituted with non-interacting substituents, as will be known to those skilled in the art, such as e.g. halogen, nitrogen, hydroxy etc., and the use of a reactant with such non-interacting substituents is considered equivalent to the method according to the invention. Sterically hindered amines, such as diethylamine and morpholine, results in side reactions without product formation.

To prepare the 3-hydroxypyrazole, the 3-amino-2-alkenic acid derivative can be reacted without the use of a solvent with the substituted hydrazines. Optionally, the reactants can be dissolved in suitable solvents. The reaction is usually carried out at temperatures from 0°C to 200°C, preferably from 60°C to 100°C, for 1-24 hours. The reaction will result in the formation of the corresponding 3-hydroxypyrazole as product, with the simultaneous formation of a certain amount of 5-hydroxypyrazole.

A preferred method for preparing the 5-trifluoromethyl-3-hydroxy-1-methylpyrazole involves bubbling ammonia gas through ethyl 4,4,4-trifluoroacetoacetate at an elevated temperature of from 55°C to 85°C while removing water , whereby the 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester is obtained. This ester is then reacted directly with methylhydrazine at a temperature of from 60°C to 100°C, whereby the mixture of the 3- and 5-hydroxy isomers of the pyrazole intermediate is obtained. The desired isomer can be separated as described above.

Pyrazole intermediates with a 5-alkylthio substituent (e.g. methylthio) and a 4-halo substituent (e.g. chlorine) can be prepared by reacting methylhydrazine with 3-methylthio-2,3-dichloroacrylate and potassium carbonate in a suitable solvent. The corresponding phenoxypyrazole can be prepared by reacting the pyrazole with a 4-halonitrobenzene according to method B.

The corresponding phenoxypyrazole having either a 5-alkylsulfonyl substituent or a 5-alkylsulfonyl substituent can be prepared by oxidizing the corresponding 5-alkylthiophenoxypyrazole with suitable amounts of a suitable oxidizing agent, such as e.g. m-chloroperbenzoic acid, in a suitable solvent such as e.g. dichloromethane.

Pyrazole intermediates with a 5-alkylthio substituent (e.g. methylthio) and a 4-hydrido substituent can be prepared by a three-step process according to which (i) 1-methyl-3-alkylsilyloxypyrazole is reacted in anhydrous tetrahydrofuran with n-butyllithium at -e-78°C, (ii) dimethyl sulphide is added to the solution obtained in step (i),

and (iii) the product from (ii) is reacted with HF in acetonitrile. Corresponding sulfinyl and sulfonyl compounds are prepared according to the methods described above.

With the exceptions noted below, other pyrazole intermediates can also be prepared in general according to these methods. The 1-ethylpyrazoles are also generally prepared according to these methods. The ethylhydrazine is conveniently liberated from its oxalate salt in situ with a suitable base (eg triethylamine or sodium methoxide) during the reaction. Phenoxypyrazoles that have N-bromodifluoromethyl or N-difluoromethyl substituents are prepared by reacting dibromodifluoromethane and chlorodifluoromethane, respectively, with a phenoxypyrazole that has an N-hydrido substituent, and which is prepared from the corresponding N-tetrahydropyranylpyrazole. Phenoxypyrazoles with N-trifluoromethyl substituents are prepared by reacting an N-bromodifluoromethylphenoxypyrazole with AgBF4.

Procedure I

The 5-haloalkyl-1-3-hydroxypyrazole intermediates can be chlorinated or brominated to form the corresponding 5-haloalkyl-4-halo-3-hydroxypyrazole intermediate. Suitable chlorinating and brominating agents include bromine, chlorine, sulfuryl chloride and sulfuryl bromide. Preferred chlorinating and brominating agents are 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dibromo-5,5-dimethylhydantoin, used in a solvent such as e.g. diethyl ether.

The 5-haloalkylpyrazole can also be nitrated and in some cases chlorinated or brominated after the phenoxypyrazole has been formed, by reaction with sulfuryl halide or 1,3-dihalo-5,5-dimethylhydantoin in a suitable solvent such as e.g. acetonitrile. Nitriding is carried out according to standard nitriding methods under regulated conditions. Phenoxypyrazoles where Z is Rc0 can give certain side reactions.

The 5-haloalkylpyrazole intermediates containing a 4-fluoro-substituent, a 4-iodo-substituent, a 5-fluoromethyl-substituent or a 5-trichloromethyl-substituent can be prepared in another way. The pyrazole intermediate with a 4-fluoro substituent is prepared by reacting ethyl trifluoroacetate with ethyl fluoroacetate without a solvent and with a strong base, such as e.g. sodium hydride, to form ethyl 2,4,4,4-tetrafluoroacetoacetate, which is then reacted with (i) dimethyl sulfate in the presence of potassium carbonate and (ii) methylhydrazine to form the corresponding 4-fluoropyrazole. The 4-iodopyrazole is formed from the corresponding 4-bromopyrazole. To protect the 3-hydroxy group, the 4-bromopyrazole is reacted with trialkylsilyl chloride and a base. The resulting 3-trialkylsiloxy-4-bromopyrazole is then reacted

in sequence with (i) n-butyllithium at ^78°C in THF, (ii)

iodine and (iii) aqueous HF in acetonitrile, whereby the 4-iodopyrazole intermediate is obtained.

Pyrazole intermediates with a 5-fluoromethyl substituent are prepared from the corresponding 5-methoxycarbonylpyrazole,

which in turn is produced by reacting dimethylacetylene dicarboxylate with methylhydrazine in ether. The 5-methoxycarbonyl-pyrazole is then reduced with lithium aluminum hydride and fluorinated with dimethylaminosulfur trifluoride (DAST), whereby

The 5-fluoromethylpyrazole intermediate is obtained. The 5-trichloromethyl-1-pyrazole can be prepared by suitable methods which will be known to those skilled in the art, e.g. by chlorination. The 4,5-dichloro-3-hydroxy-1-methylpyrazole intermediate is prepared from methyl 2,3,3-trichloroacrylate and methylhydrazine. The 5-methoxymethyl-4-chloro-1-methylpyrazole intermediate is prepared from 5-lithio-4-chloro-3-trialkylsiloxy-1-methyl-pyrazole and bromomethyl ether and subsequent desilylation. The compounds according to the invention which have a 5-cyano substituent on the pyrazole ring are prepared from phenoxypyrazoles with a 5-hydrocarbonyl substituent. The compounds with the 5-hydrocarbonyl substituent are prepared by lithiation, as mentioned above, by reaction with dimethylformamide. The 5-hydrocarbonyl-phenoxypyrazole is then reacted with hydroxylamine and acetic anhydride, whereby the corresponding 5-cyano compound is obtained.

Those skilled in the art will understand that the 3-hydroxypyrazoles can exist in one or the other of their tautomeric structures (3-hydroxypyrazole or pyrazolidin-3-one), and the 3-hydroxypyrazole structure used here is intended to should include both of the two tautomeric structures.

Nitrobenzene intermediates

The 2-(Alkoxy- or Alkoxycarbonyloxy)-4-fluoronitrobenzenes used as intermediates are produced from 2-hydroxy-4-fluoronitrobenzenes, which are either commercially available or produced by reacting 2,4-difluoronitrobenzene with sodium hydroxide in DMSO and subsequent extraction of the product from water with hexane. In order to form nitrobenzene intermediates with an alkoxy substituent or a halogenoalkyl substituent W, the 2-hydroxy-4-fluoronitrobenzene is reacted with a suitable alkylating agent (e.g. alkyl iodide, chlorodifluoromethane or alkylsulfonate) in a suitable solvent (e.g. acetone) , acetonitrile, dimethylformamide (DMF) or dimethylsulfoxide (DMSO) in the presence of a base (e.g. potassium carbonate or sodium hydroxide) for an extended period of time (e.g. for 2-3 days). The reaction can be carried out at room temperature or at higher temperatures. An alternative method for preparing a nitrobenzene intermediate with an alkoxy substituent or an alkylthio substituent W involves reacting 2,4-difluoronitrobenzene with a sodium alkoxide or sodium alkyl thiolate in a suitable solvent. The nitrobenzene intermediate is then isolated by standard laboratory methods.

The nitrobenzene intermediates where the substituent W is alkyloxycarbonylalkyloxy are formed from 2-hydroxy-4-fluoronitrobenzene. 2-hydroxy-4-fluoronitrobenzene is reacted with a haloalkylcarboxylate (e.g. ethyl-2-bromopropionate) in a suitable solvent (e.g. acetone, acetonitrile, DMF or DMSO) in the presence of a base (e.g. . potassium carbonate) for a longer period of time (e.g. for three days). The nitrobenzene intermediate is then isolated using standard laboratory methods.

A method for producing a nitrobenzene intermediate in which the substituent W is alkoxycarbonyl involves esterifying the corresponding commercially available 5-chloro-2-nitrobenzoic acid.

The 4-fluoro-2-alkylaminonitrobenzenes used as intermediates are prepared by reacting 2,4-difluoronitrobenzene with the appropriate amine in a suitable solvent, e.g. with triethylamine in methanol. The desired isomer is separated according to standard laboratory procedures. 4-Fluoronitrobenzene intermediates with an alkoxyamino substituent are prepared by reaction with the appropriate hydrogen chloride alkoxyamine salt in a base. The 4-fluoro-2-hydrazinenitrobenzenes are prepared in a similar way.

The compounds according to the invention - general method

Certain compounds according to the invention are prepared according to method A, carried out in two steps. In the first step, 2,4-dichloronitrobenzene is reacted with a two-molar excess of the appropriate 3-hydroxypyrazole in a suitable solvent, such as e.g. DMSO or DMF with potassium carbonate, under nitrogen and at elevated temperature. The product of the first step [2,4-bis-(pyrazolyloxy)-nitrobenzene] is then reacted with a nucleophilic reactant in a suitable coordination solvent, usually in the presence of a base. Suitable nucleophilic reactants include hydroxides, organic oxide salts, enolates, thiolates, ammonia, primary and secondary amines, hydrazines and cyanide. Suitable nucleophilic reactants are cyano, hydroxy, alkoxy, thio, alkylthio, amino, alkylamino, hydrazino, alkylhydrazino, alkoxyamino and alkylaminooxy, which are optionally substituted with one or more substituents selected from alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, halogen , cyano and nitro.

Generally, it is convenient to form the organic oxides and thiolates as salts in a strong base in order for the reaction to proceed at a suitable rate. Suitable bases include alkali metal bases, such as sodium or potassium hydroxide or carbonate. Nucleophilic reactants consisting of primary and secondary amines can be reacted with suitable bases, such as e.g. potassium carbonate, and in some cases without the use of any base.

In the process, the pyrazole radical is substituted on N and/or any C with a number of different non-interacting substituents which will be known to those skilled in the art. The nature of such non-interacting substituents is not essential, provided that the substituents do not interfere with the reaction. Nucleophilic reactants that are strongly sterically hindered or have a carboxylic acid ester radical can interfere with the reaction. Suitable solvents for use in the method according to the invention are coordination solvents which are able to solvate alkali metal and alkaline earth metal cations such as Li<+>, Na<+>, K<+>

and Mg<++>, and includes ether solvents and hindered alcohols. Suitable coordination solvents include t-butyl alcohol, isopropyl alcohol, glyme, DME, THF and dioxane.

In the method, the reactants are mixed at a temperature of from 50°C to 120°C, preferably from 70°C to 85°C, for 4-40 hours. The 4-(pyrazolyloxy)-nitrobenzene product can be separated from the reaction mixture using standard chemical methods, for example by extraction.

Other compounds according to the invention are prepared according to method B, by reacting a suitable pyrazole intermediate with a suitable halonitrobenzene intermediate to form the desired product according to method B below.

The pyrazole and the halonitrobenzene are mixed together in the presence of a base, such as potassium carbonate or potassium hydroxide, in a suitable solvent, such as e.g. DMSO, DMF or sulfolane, at an elevated temperature of from 20°C to 150°C, conveniently at a temperature of from 50°C to 80°C. The product is then isolated according to standard laboratory methods.

A. Compounds according to the invention where the substituent Z

is Rc0

Compounds according to the invention which have a substituent Rc0, e.g. an alkoxy substituent, can be formed by reacting an alkali metal alkoxide, such as e.g. sodium methoxide, with the corresponding 2,4-bis-(pyrazolyloxy)-nitrobenzene according to method A. Compounds according to the invention which have a substituent Rc0 such as e.g. Alkoxy or AlkoxycarbonylAlkoxy as the Z-substituent on the phenyl ring can be prepared by reacting the appropriate pyrazole intermediate with a halonitrobenzene intermediate in which the W-substituent is Alkoxy or AlkoxycarbonylAlkoxy, according to method B. Finally, compounds where Z is Rc0 can be prepared by reaction of the appropriate compound RcOH with the corresponding phenoxypyrazole where Z is fluorine or RCX (where X is (i) halogen selected from Cl, I and Br or (ii) X is CH3SO2O-) with the corresponding phenoxypyrazole where the Z substituent is hydroxy .

Compounds where the Z-substituent is hydroxy are prepared by (a) reaction of 2-methoxy-4-fluoronitrobenzene according to method B and subsequent demethylation with boron tribromide or (b) reaction of the appropriate pyrazole with 2-(methylcarbonyloxy)- 4-chloronitrobenzene according to method B and subsequent hydrolysis according to standard laboratory methods. Compounds where Z is alkyloxycarbonylalkyl can also be prepared by reacting a halogen acetate with a phenoxypyrazole where Z is hydroxy. Compounds where Z

is alkylaminoalkoxy, can be prepared by reacting a phenoxypyrazole where Z is fluorine, with a tertiary amine having a hydroxyalkyl substituent. Compounds in which Z is alkylthioalkoxy, alkylsulfonylalkyloxy or alkylphosphinylalkyloxy are prepared in a similar manner. A wide variety of compounds according to the invention can be prepared by standard esterification of the corresponding acid chloride where Z is

-0 CH(R)(CH2)n. Compounds according to the invention where Z is alkylcarbonylalkoxy are prepared by reacting a suitable pyrazole intermediate with a nitrobenzene having a corresponding ketal radical as a W-substituent, to protect the alkylcarbonylalkoxy group during the reaction. After the formation of the phenoxypyrazole product, acid is added to the reaction mixture to hydrolyze the ketal and form the corresponding alkylcarbonyl oxy radical as a Z-substituent. Compounds where Z is alkenyloxy can be prepared by dehydrobromination of the corresponding halogeno-alkoxy compound, which can be prepared according to method A. Compounds where Z is alkylimino are prepared by reacting a compound according to the invention where Z is fluorine with ketoxime. The compound according to example 877 has been prepared by reacting a compound according to the invention where Z is cyanoalkoxy, with hydroxylamine. The compound according to example 874 is prepared by protecting two of the hydroxy groups of a triol by forming a ketal, with subsequent hydrolysis. Compounds according to the invention where Z is phosphinyl are prepared by (i) reacting a phosphonite with an aldehyde, (ii) reacting the product from (i) with trifluoromethanesulfonic anhydride, (iii) reacting the product from (ii) with 2-hydroxy-4 -fluoronitrobenzene and (iv) reaction of the product from (iii) according to method B. B. Compounds according to the invention where the Z-substituent is

Compounds according to the invention which have an alkoxycarbonyl group as a Z-substituent on the phenyl ring are prepared by reacting the appropriate pyrazole with a 4-halonitrobenzene which has an alkoxycarbonyl group as a W-substituent, according to method B.

Compounds according to the invention which have an alkoxycarbonyl group as a Z-substituent are then transferred to other compounds according to the invention which have derivative substituents of the alkoxycarbonyl substituent, by transesterification or by hydrolysis of the alkoxycarbonyl substituent to form the corresponding carboxylic acid, which can then (i) be transferred to other esters by esterification according to standard laboratory methods by forming the acid chloride and reacting this with the appropriate alcohol, with the proviso that hindered alcohols may necessitate reaction with the sodium salt of the alcohol (e.g. alkenyloxycarbonyl substituents) or (ii) are transferred to aminocarbonyl compounds by forming the acid chloride and subsequent amination by standard laboratory methods (e.g. alkylamino groups as Z-substituents), or (iii) transferred to the thioesters by esterification of the acid chloride by standard laboratory methods (e.g. alkylthiocarbonyl groups as Z-substituents), or (iv) transferred to sulfonylaminocarbonyl compounds by formation of the acid chloride and subsequent amination with a sulfonamide, without the use of a solvent, according to standard laboratory methods (e.g. an alkylsulfonylaminocarbonyl group as Z-substituent), which compounds can be N-alkylated by reaction with methyl iodide and potassium carbonate in acetone, or (v) transferred to oximinocarbonyl compounds by formation of the acid chloride and subsequent reaction with a ketoxime (e.g. oximinocarbonyl as Z-substituent ).

Compounds where R 1 is alkyl can be prepared by reacting a 4-fluoronitrobenzene intermediate having a 2-alkylcarbonyl substituent, according to method B. Compounds where R 1 is an alkoxyalkyl group are prepared in the same way, and the nitrobenzene intermediate is prepared by reaction of alkoxyalkylnitrile with 3-fluorophenyl-magnesium bromide and subsequent nitration. Compounds where R]- is oximino are prepared by reacting the corresponding acid chloride with N-hydroxyethylacetimidate. Compounds where Rj-, is hydroxycarbonyl, can be prepared by oxidation of the corresponding phenoxypyrazole, which has a methylcarbonyl group as Z-substituent, with selenium dioxyd. Compounds where Rj- is poly(alkoxy) are prepared by reacting the corresponding phenoxypyrazole with a bromoether or bromopolyether compound. The compound according to example 903 was prepared by reacting the acid chloride with 2-aminooxypropionic acid hydrochloride. The compound according to 367 was prepared by reacting the acid chloride with the sodium salt of dimethylmethylmalonate. The compound according to example 437 was prepared by reacting the acid chloride in turn with (i) potassium thiocyanate and (ii) dipropargylamine.

C. Compounds according to the invention where the substituent Z is Ra

A number of different compounds where Ra is an alkyl substituent can be prepared by reduction of the compound according to the invention where Z is chlorocarbonyl, with sodium borohydride to the corresponding benzyl alcohol which, in turn, can be reacted with suitable reactants to form compounds according to the invention with various types of substituted methyl radicals as Z-substituent. For example, benzyl alcohol can be oxidized to benzaldehyde. The compound where Z is iodomethyl is formed by reacting the benzyl alcohol in turn with (i) methanesulfonyl chloride and (ii) sodium iodide. The compounds where Z is alkylaminoalkyl are prepared by reacting the compound where Z is iodomethyl with the appropriate amine. The compound where Z is bromomethyl or chloromethyl can be prepared by reacting the corresponding alcohol with phosphorus tribromide and thionyl chloride, in a suitable solvent. Compounds where the Z-substituent is -CX2H are conveniently prepared by halogenating the benzaldehyde with a suitable reagent, such as e.g. diethylaminosulfur trifluoride (DAST) or thionyl chloride. This method for the preparation of other substituted methyl radicals such as Z will be known to those skilled in the art.

Compounds with a methyl or trifluoromethyl substituent as a substituent Z on the phenyl ring are prepared by reacting the appropriate pyrazole intermediate with or 2-methyl-4-halogenitrobenzene and 2-trifluoromethyl-4-halogenitrobenzene according to method B.

Other compounds according to the invention which have a substituent Ra can be prepared by reacting the corresponding benzyl alcohol with methanesulfonyl chloride and subsequent reaction with suitable nucleophilic compounds such as e.g. alkoxides, amines, or mercaptans in a base. Compounds according to the invention which have an alkylcarbonyloxymethyl group as a substituent Z can be prepared by reacting the corresponding benzyl alcohol with the appropriate acid chloride. Compounds according to the invention which have an alkoxycarbonyl-methyl group as substituent Z, are prepared by reacting the appropriate pyrazole with 2-alkoxycarbonylmethyl-4-fluoronitrobenzene according to method B. The corresponding acid, ester and amide derivatives can then be prepared according to standard laboratory methods. Compounds where Z is alkoxy-carbonylethyl can be prepared by reacting the compound where Z is amino with (i) tert-butyl nitrite and then with (ii) methyl acrylate and CuCl2- Compounds with alkenyl substituents can be prepared from the corresponding compound where Z is an aldehyde, according to the Wittig reaction. Compounds where the Z substituent is alkynyl can be prepared by reacting the corresponding compound where Z is hydroxy with trimethylsilylacetylene and bis-(triphenylphosphine)-palladium chloride. Compounds where Z is cyanoalkyl or cyanoalkenyl are prepared by reacting the corresponding aldehyde with cyanoacetic acid. Compounds where Z is cyano are prepared from the corresponding 2-nitro-5-halo-benzonitrile according to method B. The compounds according to examples 317 and 319 can be prepared by reacting the corresponding aldehyde with respectively trichloroacetoacetate and malonic acid. Compounds where the Z-substituent is methylthiomethyl can be prepared by reacting the methanesulfonate of the benzyl alcohol with sodium methylmercaptan. The compound according to example 720 can be prepared by reacting the corresponding compound where Z is fluorine with sodium diethyl malonate. The compound according to example 825 can be prepared by reacting the corresponding compound where Z is methyl iodide with triethyl phosphite. The compound according to example 322 is prepared by reacting the benzyl alcohol with dihydro-2H-pyran. The compound according to example 520 is prepared by reacting a compound where Z is fluorine with the sodium salt of diethyl methylmalonate. The compound according to example 380 can be prepared by reacting the acid chloride with o-phenyenediamine. The compound according to example 896 can be prepared by reacting the compound where Z is chloromethyl with a reactant prepared from carbon disulfide and potassium methoxy.

D. Compounds according to the invention where the substituent Z is RdReN

Compounds according to the invention which have an amino group or hydrazino group as substituent Z are prepared by reacting the appropriate nucleophilic amino or hydrazino reactant with (a) 2,4-bis-(pyrazolyloxy)-nitrobenzene according to method A or (b ) with 2,4-difluoronitrobenzene to produce the corresponding 2-amino- or 2-hydrazino-4-fluoronitrobenzene or with the corresponding phenoxypyrazole having a fluorine group as substituent Z, according to the displacement methods described above. A compound where Z is aminocarbonylamino can be prepared by reacting a compound according to the invention where Z is amino with chlorosulfonyl isocyanate. Compounds having an alkylphosphonylalkylamino group as substituent Z can be prepared by reacting the corresponding phenoxypyrazole where Z is fluorine with diethyl-2-aminoalkyl phosphonate.

E. Compounds according to the invention where the substituent Z is

The compound according to the invention where the substituent

can be produced by two methods. The first

method involves reacting a phenoxypyrazole where Z is methylcarbonyl with 2-aminooxyacetic acid. The resulting carboxylic acid can be esterified by refluxing in a suitable alcohol in the presence of an acid catalyst such as e.g. toluenesulfonic acid. The acid can also be transferred to amides and thioesters via the acid chloride.

These compounds can also be prepared by reacting the phenoxypyrazole where Z is lower alkylcarbonyl with hydroxylamine hydrochloride and alkylating the resulting oxime. Suitable methods for alkylation include treatment of the oxime obtained as an intermediate with an alkyl halide (eg methyl iodide or methyl bromoacetate) and potassium carbonate in acetonitrile. The oxime can also be alkylated under standard phase transfer conditions.

F. Compounds according to the invention where the substituent R is RhS

Compounds according to the invention where the substituent Z is R^S are generally prepared according to the same methods as those used for the preparation of compounds where Z is amino. Compounds where Rj-, is alkyl, are prepared by reacting the phenoxypyrazole where Z is fluorine,

with a mercaptan and treatment of the resulting 2-alkylthio-fluoronitrobenzene according to method B. Compounds where Z is alkylaminothio, alkoxythio or the like are prepared by reacting the corresponding phenoxypyrazole where Z is fluorine with (i) Na 2 S 2 to form the disulfide according to Example 587 (which can be reduced to a compound where Z is HS-), then with (ii) CI2i CH2CI2 (to form a

compound where Z is SCI) and then (iii) a suitable, nucleophilic thiolate compound, such as e.g. a mercaptan or the like, with a base. Compounds where Z is alkylaminosulfonyl are formed in a similar manner, except that they are chlorinated in aqueous acetic acid. Compounds where Z is alkylaminocarbonyl-thio are prepared by reacting the phenoxypyrazole where Z is HS- with an isocyanate.

G. Compounds according to the invention where the substituent Z is

The compound according to the invention where the substituent Z is imino is produced by reaction of the phenoxypyrazole

where Z is an aldehyde group, with a suitable amine. The compound according to example 340 is prepared by reacting a compound where Z is methylaminocarbonyl, with (i) phosphorus pentachloride and then with (ii) sodium methoxyd.. The compound according to example 341 is prepared by reacting the precursor for the compound according to example 340 with dimethylamine.

H. Compounds according to the invention where the substituent Z is Rk

Compounds according to the invention where Z is R^ can be prepared by a number of different methods which will be well known to those skilled in the art. The following methods will be suitable. Thiocarbonyl compounds where Z e.g. is amino-(thiocarbonyl), is produced by reacting the corresponding carbonyl compound with phosphorus pentasulphide. Compounds where Z is alkylsulfinyl and alkylsulfonyl can be prepared by oxidation of the corresponding alkylthiofor compound with m-chloroperbenzoic acid. Compounds where Z is imino can be prepared by reacting compounds where Z

is amino, with the corresponding carbonyl compound. For the preparation of the compound according to example 416, reaction is thus carried out with N,N-dimethylformamide dimethyl acetal. The compound according to example 522 is prepared by reaction of a

compound where Z is fluorine, with triethylphosphite.

I. Compounds according to the invention which have an ortho-substituent, or which exist as dimers Compounds with an ortho-halogen substituent (in the ortho-position to the pyrazolyloxy group) can be formed by reacting the appropriate pyrazole with 3,4-difluoronitrobenzene or 3,4, 6-trifluoronitrobenzene according to method B. The meta-fluoro substituent (in the meta-position to the pyrazole group) can then be displaced by hydroxide or alkoxide to form the corresponding phenol or the corresponding alkoxide. Compounds according to the invention which comprise dimers, such as the compounds according to examples 531 and 681, can be prepared by reacting compounds according to the invention with a reactive Z-substituent such as e.g. fluorine or chlorocarbonyl by means of a bridging reactant such as e.g. a diamine or a diol.

The following examples 1-14 describe in detail methods for producing certain compounds according to the invention. These detailed representations fall within the scope of and serve to exemplify the methods described more generally above. These examples are given for illustration purposes only. All parts are calculated on a weight basis, unless otherwise stated.

Preparation of an intermediate 1-methyl-3-hydroxy-5-trifluoromethylpyrazole

1. A mixture of 33.82 g (0.20 mol) methyl 4,4,4-trifluoro-3-amino-2-butenoate and 10.1 g (0.22 mol) methylhydrazine was heated at 50°C for 22.25 hours. The mixture was then cooled, and 15 ml of water and approx. 12 ml of concentrated hydrochloric acid was added to adjust the pH of the mixture to 6.5-7.0. The precipitated product was filtered off and dried, whereby 25.26 g (yield = 76%) of the product was obtained. Melting point 130.5-131°C. 2. 30.82 g (0.2 mol) of 4,4,4-trifluoro-3-amino-2-butenamide (prepared by adding 2 equivalents of ammonia to the corresponding alkenoic acid ester) was added to 10.1 g (0, 22) methylhydrazine at room temperature. A weak exotherm increased the temperature to 30°C. The mixture was stirred for one hour, at which time the mixture became semi-solid. 10 mL of ethanol was added to facilitate stirring. After a further 1.5 hours, 7 ml of ethanol were added, also this time to facilitate stirring. After a total of 24 hours, the mixture was taken up in 25 ml of water and the pH adjusted to 6.5-7.0 with concentrated hydrochloric acid (17 ml). The precipitated product was filtered off and dried, whereby 21.37 g of product were obtained. Yield = 65%. Melting point 129-131°C. 3. A 50 mL flask equipped with a mechanical stirrer and reflux condenser was charged with 19.7 g of ethyl 3-methylamino-4,4,4-trifluoro-2-butenoate and 4.8 g of methylhydrazine and heated at 50-65 °C for 2.75 hours and then at 40-45°C for two hours, after which the mixture was allowed to cool to room temperature and stand overnight. The clear reaction mixture was taken up in 15 ml of water, and concentrated hydrochloric acid was added dropwise to pH 6.0-6.5, which required 5.2 ml of acid. The precipitated product was filtered off and dried, whereby 7.06 g of product was obtained. Dividend = 42.5%. Melting point 127-128.5"C.

EXAMPLES OF PROCEDURE A

1. 4-(5'-trifluoromethyl-4<1->chloro-1<1->methylpyrazolyl-3<1->oxy)-2-hydroxynitrobenzene

A suspension of 260 g of 2,4-bis-(5'-trifluoromethyl-41-chloro-11-methylpyrazolyl-31-oxy)-nitrobenzene in 200 ml of tert-butyl alcohol was heated to the reflux temperature and treated with 80 g of a mixture consisting of 50% sodium hydroxide in water. The mixture was refluxed and stirred for 26 hours. An additional 3 g of 50% sodium hydroxide was added and the mixture was boiled under reflux for a further three hours. A portion (1/3) of the alcohol was distilled off, and the mixture was diluted with 1500 ml of water and 10% HCl was added until a pH of 9 was reached. The residue was filtered off and dried, whereby 158 g (94%) of a yellow solid product was obtained. Melting point 67-69°C

2. 4-(5'-trifluoromethyl-4'-chloro-1'-methylpyrazolyl-3<1->oxy)-2-diethylaminonitrobenzene

A mixture of 5.2 g (10 mmol) 2,4-bis-(5<1->trifluoromethyl-4<1->chloro-1<1->methylpyrazolyl-3'-oxy)-nitrobenzene, 0.8 g (11 mmol) of diethylamine and 1.66 g (12 mmol) of potassium carbonate in 20 ml of tert-butanol were refluxed and stirred for 90 hours and 0.2 g of amine was added after 44 hours and after 66 hours. The mixture was added to 80 ml of water. The organic layer was diluted with ether. The mixture was dried and evaporated under vacuum, whereby 3.89 g of an orange colored oil with a refractive index of 1.5024 was obtained.

5-trifluoromethyl-4-chloro-3-(31-methyl-41-nitrophenoxy)-1-methylpyrazole (a) 3.94 g (0.0237 mol) 5-trifluoromethyl-3-hydroxy-1-methyl-pyrazole and 3.68 g (0.0237 mol) of 4-fluoro-2-methylnitrobenzene was stirred overnight with 3.27 g (0.0237 mol) of potassium carbonate in 20 ml of DMSO (dimethylsulfoxide) at 115°C. The reaction mixture was poured into 400 ml of water, after which filtration, washing and drying were carried out. The solid was recrystallized from methylcyclohexane, whereby a yellow solid according to Example 15 in Table I was obtained as an intermediate product. (b) 3.24 g (0, 0108 mol) of the product from step (a) was then dissolved in 30 ml of acetonitrile, and 1.62 g (0.012 mol) of sulfuryl chloride was added to the solution. After about 10 minutes, the reaction solution was poured into a solution of 4 g sodium bicarbonate in 150 ml of water, after which extraction was carried out twice with ether. The ether extracts were combined, washed twice with brine, dried with magnesium sulfate and decolorized with charcoal, after which the solvent was removed by evaporation (in a rotary evaporator). 3.0 g (yield = 83%) of a pale yellow solid was obtained as stated at the beginning of this example. Melting point 72-73.5°C.

Elemental analysis for C-| 2H9CIF3N3O3 =

Example 2 5-trifluoromethyl-4-chloro-3-(31-methoxycarbonylmethyl-41-nitrophenoxy)-1-methylpyrazole (a) 8.3 g (0.05 mol) 5-trifluoromethyl-3-hydroxy-1-methyl- pyrazole and 11.36 g (0.05 mol) of 4-fluoro-2-ethoxycarbonyl-methylnitrobenzene were stirred and heated at approx. 50°C for 40 hours and at 75°C for 17 hours with 7.6 g potassium carbonate in 40 ml DMSO. The product was isolated following the procedures of Example 1(a) and purified by high pressure liquid chromatography (HPLC), whereby 17.4 g of the yellow solid according to Example 29 in Table I was obtained. (b) 12.1 g of the product from step (a) was dissolved in 50 ml of acetonitrile, and 3.0 ml of sulfuryl chloride was added to the solution. After 1.5 hours, the reaction mixture was poured into a solution of 11 g of sodium bicarbonate in 600 ml of ice water with vigorous stirring. The resulting slurry was filtered, after which washing was carried out twice with water and recrystallization from ethanol. The yellow solid according to example 28 was thereby obtained. (c) 20.4 g (0.05 mol) of the product from step (b) was dissolved in a solution of 100 ml of ether and 100 ml of THF (tetrahydrofuran), and 22 ml of 2.5N sodium hydroxide was added to the solution. After 20 minutes, the reaction mixture was poured into a solution of 5 ml of concentrated HCl in 1 L of ice water. The product was isolated from the mixture by extraction twice with ether, and the ether extracts were combined, washed twice with brine, dried with MgSO4 and decolorized with charcoal, followed by filtration and evaporation in a rotary evaporator. The product was then recrystallized from toluene/methylcyclohexane, whereby 13 g of the yellow solid according to Example 25 was obtained. (d) 2.8 g (0.0074 mol) of the product from step (c) was added to 5 ml oxalyl chloride, and 1 drop of DMF (dimethylformamide) was added to the mixture. After stirring overnight, the solution was evaporated in a rotary evaporator, whereby a solid was obtained. The solid was added to a solution of 1 ml of methanol in 30 ml of pyridine. The product was isolated according to the procedures of step (a) and recrystallized from 15% ethyl acetate in hexane, whereby 1.2 g of a yellow solid with melting point 112-115°C was obtained.

Elemental analysis for C-\ 4H-1 -\ CIF3N3O5 =

Example 3 5-trifluoromethyl-4-bromo-3-(3<1->methoxycarbonyl-4<1->nitro-phenoxy)-1-methylpyrazole (a) 24.9 g (0.15 mol) 5-trifluoromethyl- 3-hydroxy-1-methyl-pyrazole and 32.4 g (0.15 mol) of 4-chloro-2-methoxycarbonylnitro-benzene were stirred with 20.7 g (0.15 mol) of potassium carbonate in 200 ml of DMSO at 80° C for 16 hours. The mixture was then added to 3.5 l of ice water, after which filtration, stirring in a mixer with water, filtration and drying were carried out. 43.5 g (yield 82%) of a whitish solid according to Example 42 in Table I was obtained. (b) 35.4 g (0.10 mol) of the product from step (a) was dissolved in 100 ml of acetic acid, and 5.63 mL (0.11 mol) of bromine were added to the solution. The mixture was stirred overnight at 70-80°C. 0.6 ml of bromine was then added, and the mixture was stirred for a further three hours at 85°C. The product was isolated according to the procedure of Example 1(b), whereby a yellow oil was obtained. The product consisted of a mixture of the ester and the acid. To purify the product, the oil was added to 250 mL of ethanol and 85 mL of 10% sodium hydroxide. After one hour, the mixture was poured into a solution of 34 mL of concentrated HCl in 2 L of ice water. The mixture was extracted with ether and dried , filtered and evaporated in a rotary evaporator to give a viscous oil. The oil was then recrystallized from a hot mixture of methylcyclohexane and 5-10% toluene with stirring and rapid cooling in dry ice to give a white solid according to Example 35. (c) 4.1 g (0.01 mol) of the product from step (b) was mixed overnight with 2 ml (0.023 mol) of oxalyl chloride in 6 ml of methylene chloride and 1 drop of DMF.The mixture was then evaporated in a rotary evaporator, whereby the solid acid chloride was obtained, which was then mixed with 0.8 ml (0.02 mol) of methanol in 30 ml of pyridine. After three hours, the mixture was evaporated in a rotary evaporator and the residue stirred with 100 ml of 2N HCl. The product was isolated by extraction with ether, and evaporation was carried out in a rotary evaporator, whereby an oil was obtained, which was stirred with petroleum ether. 3.7 g (yield 87%) of a white solid with a melting point of 72-73.5°C were obtained.

Elementary analysis for Ci 31196^3^05 =

Example 4

5-trifluoromethyl-4-chloro-3-(3'-ethylaminocarbonyl-4'-nitro-phenoxy)-1-methylpyrazole

(a) 24.07 g (0.12 mol) of 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazole and 27.55 g (0.12 mol) of 4-chloro-2-ethoxycarbonyl-nitrobenzene were stirred with 18 g potassium carbonate in 150 ml DMSO

for one hour at 110°C and then overnight at 87°C. The product was isolated according to the procedure of Example 2(c), whereby the product of Example 46 in Table I was obtained.

(b) 59.1 g (0.15 mol) of the product from step (a) was dissolved

in 350 ml of ethanol with 80 ml of 2.5N sodium hydroxide. The product was isolated according to the procedures of Example 2(c)

and recrystallized from toluene/methylcyclohexane, thereby obtaining the product according to Example 38 in Table I. (c) 3.65 g (0.01 mol) of the product from step (b) was mixed overnight with 2 ml (0.023 mol) of oxalyl chloride in 6 ml of methylene chloride and 1 drop of DMF. The mixture was then evaporated in a rotary evaporator, whereby the acid chloride according to example 37 in Table I was obtained. The acid chloride product was then dissolved in 50 ml of ether, and 40 ml of 50% aqueous ethylamine was added to the solution while stirring. The mixture was evaporated in a rotary evaporator, whereby a yellow slurry was obtained which was filtered. The solid was triturated with water in a blender. After filtering off and drying, 3.5 g (yield = 89%) of a white solid with a melting point of 129.5-130.5°C were obtained.

Elemental analysis for C-| 4H1 2CIF3N4O4 =

Example 5

5-trifluoromethyl-4-chloro-3-(31-methoxy-41-nitrophenoxy)-1-methylpyrazole

8.03 g (0.04 mol) of 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazole and 6.85 g (0.04 mol) of 4-fluoro-2-methoxynitrobenzene were mixed together with 6 .22 g (0.045 mol) potassium carbonate in 50 ml DMSO for four hours at 72°C and overnight

at 85°C. The product was isolated according to example 2(c), whereby 13.1 g (yield = 93%) of a yellow solid with melting point 71-73.5°C was obtained.

Alternative manufacturing

1.1 g (2.1 mmol) of 2,4-bis-(5<1->trifluoromethyl-4'-chloro-1'-methylpyrazolyl-3'-oxy)-nitrobenzene and 0.12 g (2.3 mmol) of sodium methoxide was stirred in 8 ml of anhydrous glyme under nitrogen for five hours at room temperature and then for one hour at 70°C. First 0.05 g and then 0.03 g of sodium methoxide were then added, and the mixture was stirred overnight at room temperature. The mixture was diluted with 100 ml of ether, and the ether was washed with water and brine, dried over magnesium sulfate and evaporated under vacuum to give 0.72 g of a yellow solid. Yield = 93%. Melting point 74-76°C.

Example 6

5-trifluoromethyl-4-chloro-3-(3'-[1-ethoxycarbonyl]-ethoxy-41-nitrophenoxy)-1-methylpyrazole

961 g (4.80 mol) 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazole, 1317 g (5.12 mol) ethyl 2-(5-fluoro-2-nitrophenoxy)-propanoate and 380 g (2.75 mol) of potassium carbonate was stirred with 6000 mL of DMSO at 70°C for 20 hours. A further 100 g (0.72 mol) of potassium carbonate was then added. After a further 16 hours at 70°C, a further 163 g (1.18 mol) of potassium carbonate was added. After stirring for a further six hours at 70°C, the product was isolated in accordance with the procedure of Example 2(c), whereby a black oil Purification by silica gel chromatography gave 1733 g

of a dark oil. Upon further purification by vacuum distillation (molecular distillation), a reddish oil was obtained, which on standing for a longer time gave a reddish-orange solid with a melting point of 40-44°C.

Elementary analysis for C-j gH-| 5F3CI-1 N3O6 =

Example 7 5-trifluoromethyl-4-chloro-3-(3'-[1-methylaminocarbonylethoxy]-4'-nitrophenoxy)-1-methylpyrazole a) 49.2 g (0.12 mol) of the product from example 6 was dissolved in 160 ml of ethanol, and 55 ml of 10% NaOH was added with stirring. The solution was evaporated in a rotary evaporator with the addition of water, washed with ether and then added to a solution of 14 ml of 12N HCl in ice water, whereby a sticky semi-solid was obtained. After standing overnight, the solid was stirred with water. After filtering off and drying, 42.9 g of a white, solid substance according to example 115 in Table I was obtained. b) 2.46 g (0.006 mol) of the product according to step (a) was stirred with 6 ml of oxalyl chloride and 1 drop DMF. After stirring overnight, the solution was decanted from insoluble material and evaporated in a rotary evaporator, whereby the acid chloride according to example 121 was obtained. c) The product from step (b) was dissolved in 20 ml of hexane, and 2 ml of ether and 13 ml 40% aqueous methylamine was added to the solution with stirring. After ten minutes, the solution was filtered, and the solid was washed with water and hexane and dried. The solid was recrystallized from aqueous hot ethanol to give a white solid. The white solid was dissolved in CHCl3. After filtration, evaporation in a rotary evaporator and recrystallization from aqueous ethanol, 2.1 g (yield = 83%) of a white solid with melting point 140-142-C were obtained.

Elemental analysis for C-| 5H1 4CIF3N4O5 =

Example 8 5-trifluoromethyl-4-chloro-3-(3<1->methylsulfamoylcarbonylethoxy-4'-nitrophenoxy)-1-methylpyrazole a) 10.24 g (0.025 mol) of the product according to example 7(a) was stirred in three days in 25 ml of toluene together with 10 ml of oxalyl chloride and 1 drop of DMF. The mixture was evaporated in a rotary evaporator, whereby the acid chloride intermediate was obtained. b) 2.61 g (0.0275 mol) of methanesulfonamide was mixed, without the use of solvent, with the acid chloride from step (a) at 150°C for two hours. The mixture was crystallized from ethanol, whereby 8.7 g (yield = 71%) of a golden brown solid with melting point 170.5-171.5°C was obtained. Example 9 5-pentafluoroethyl-4-chloro-3-(3'-methoxy-4'-nitrophenoxy)-1-methylpyrazole a) 1.88 g (0.0075 mol) 5-pentafluoroethyl-4-chloro-3-hydroxy -1-methylpyrazole and 1.28 g (0.0075 mol) of 4-fluoro-2-methoxynitrobenzene were stirred in 7.5 ml of DMSO with 1.10 g (0.08 mol) of potassium carbonate at approx. 85-90°C for 18 hours. The reaction mixture was poured into 150 ml of water and washed three times with 50 ml of ether. The ether extracts were combined and extracted twice with 50 ml of brine. The ether mixture was then treated with magnesium sulfate and charcoal, filtered and evaporated. The white solid that formed was recrystallized from hexane to give 2.15 g (yield = 71%) of a white solid with a melting point of 71-72°C. Elemental analysis for C-] 3H9CIF5N3O4 =

Example 10

5-trifluoromethyl-4-chloro-3-( 3 1 -methoxycarbonylmethoxim-4 1 - nitrophenoxy)-1-methylpyrazole a) 350 ml of fuming nitric acid was cooled to + 10°C, and dripped into 65 g (0.47 mol ) 3-fluoroacetophenone (commercial product), and the mixture was stirred for 30 minutes at ^5°C. The mixture was then poured into ice water. After filtering off, washing with water and recrystallization from aqueous ethanol, 61 g of a white solid were obtained. Melting point 49-52°C. b) 2.75 g (0.015 mol) of the product from step (a) was stirred with 3.01 g (0.015 mol) 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazole for 45 minutes at 90°C . The mixture was poured into 400 ml of ice water, after which filtration was carried out and the solid was washed with water and dried. The solid was then dissolved in ether, after which washing with salt solution, treatment with MgSC>4 and addition of carbon was carried out. The solution was filtered and evaporated in a rotary evaporator, whereby 4.8 g of a yellow solid according to example 44 was obtained. c) 10.91 g (0.03 mol) of the product from step (b) was stirred out in 50 ml cyclohexane and 50 ml absolute ethanol. To this one

mixture, a slurry of 4.17 g of hydroxylamine hydrochloride and 5.7 ml of triethylamine in 75 ml of ethanol was added. 75 ml of the solvent was distilled off, after which 75 ml of cyclohexane was added and the solution was refluxed overnight. The mixture was evaporated in a rotary evaporator, after which dissolution in CHCl 3 , washing with water and saline solution, stirring with MgSO 4 and charcoal, filtration and evaporation in a rotary evaporator were carried out. 11.0 g (yield = 97%) of the product according to example 178 was thereby obtained.

d) 19.39 g (0.05 mol) of the product from step (c) was stirred under reflux for 28 hours with 12.24 g

(0.08 mol) methyl bromacet, 8.3 g (0.06 mol) potassium carbonate and 0.5a (0.003 mol) potassium iodide in 100 ml arp.tnnihril .

The mixture was evaporated in a rotary evaporator, and the residue was stirred with ether, washed with water and brine, mixed with MgSO 4 and carbon, filtered and evaporated in a rotary evaporator, whereby 22.3 g of an amber colored oil was obtained. The oil was purified by HPLC (20% ethyl acetate in hexane), whereby 7.4 g of a yellow oil was obtained.

Elemental analysis for C-| gH-| 4CIF3N4O6 =

Example 11 5-trifluoromethyl-4-chloro-3-(31-methyl-[methoxy]-amino-4'-nitrophenoxy)-1-methylpyrazole a) 15.9 g (0.1 mol) of 2,4-difluoronitrobenzene were mixed for 18 days in 50 ml methanol with 16 ml triethylamine and 0.75 g (0.1 mol) N,O-dimethylhydroxyamine hydrochloride. The mixture was concentrated, taken up in 400 ml of ether, washed with water and brine and dried over MgSO 4 to remove the solvent. 16 g of compound were obtained. The compound was flash chromatographed with hexane/ethyl acetate (99:1), whereby 11.8 g of yellow oil was obtained. b) 2.09 g (0.01 mol) of the product from step (a) was mixed at 90°C for 19 hours under nitrogen with 2.2 g (0.011 mol) of 5-trifluoromethyl-4-chloro-3-hydroxy -1-methylpyrazole and 1.51 g potassium carbonate in 15 ml DMSO. The mixture was poured into water and extracted with ether. The ether was washed with water and brine and dried with MgSO 4 , after which the solvent was removed. The product was then flash chromatographed with hexane, whereby 2.7 g (yield = 71%) of an orange colored oil was obtained.

Elemental analysis for C-| 3H-1 2CIF3N4O4 =

Example 12 5-trifluoromethyl-4-chloro-3-(3'-dimethylhydrazino-4<1->nitro-phenoxy)-1-methylpyrazole a) 10 g (0.0628 mol) of 2,4-difluoronitrobenzene was stirred for four days with 4.36 g (0.0728 mol) of N,N-dimethylhydrazine in 7.08 g of triethylamine and 100 ml of methanol. The mixture was evaporated and the resulting solid was dissolved in methylene chloride, washed with water and brine, dried with MgSO4 and evaporated to give an orange solid. The solid was triturated in 95% ethanol/water, filtered off and dried, whereby 6.1 g of 4-fluoro-2-(2,2-dimethylhydrazino)-nitrobenzene with a melting point of 67-71°C were obtained. b) 1.98 g (0.01 mol) of the product from step (a) was mixed with 2.2 g (0.011 mol) 5-trifluoromethyl-4-chloro-3-hydroxy-1-methylpyrazole and 1.65 g potassium carbonate in 15 ml of DMSO, and the mixture was heated for 24 hours at 90°C. The mixture was poured into 400 ml of H 2 O and extracted with ether. The organic layer was separated, washed with H 2 O and brine and dried over MgSO 4 , after which the solvent was removed to give 3.7 g of solid, m.p. 72-76°C.

Elemental analysis for C-j 3H-1 3CIF3N5O3 =

Example 13 5-methylsulfonyl-4-chloro-3-[31-(N-methoxy-N-methylamino)-4-nitrophenoxy]-1-methylpyrazole 1) 3.96 ml of methylhydrazine was added dropwise and with stirring to a mixture of 15 g methyl-2,3-dichloro-3-methyl-thioacrylate and 10.3 potassium carbonate in toluene. The mixture was stirred for 18 hours at room temperature and then boiled for 18 hours under reflux. The mixture was filtered, and the filtrate was washed with water, dried and evaporated, and the residue was recrystallized from acetone, whereby 1.8 g of product was obtained. The washing water from the filtration was extracted with ethyl acetate, and the aqueous layer was acidified with 1N HCl, cooled and filtered, whereby a further 8.5 g of product with a melting point of 164-166°C were obtained. 2) 8 g of product from step (1), 9 g of 2-(N-methoxy-N-methyl-amino)-4-fluoronitrobenzene and 6.5 g of potassium carbonate in 15 ml of dimethylsulfoxide were stirred at 80°C for 15 hours . The mixture was poured into 300 ml of water, and the precipitate was collected and recrystallized from methylcyclohexane to give 9.83 g of a whitish solid. Yield = 61%. Melting point 63-64°C. 3) To a solution of 4.26 g (11.88 mmol) of the product from step 2 in 50 ml of dichloromethane at ice temperature was added 4.51 g (80%, technical grade) (26.14 mmol) of m-chloroperbenzoic acid in 50 ml of dichloromethane, and the mixture was stirred for 15 hours. The mixture was then washed with aqueous sodium carbonate, aqueous sodium thiosulfate and water. The organic layer was dried and recrystallized from ethyl acetate-petroleum ether, whereby 4.18 g of product according to example 13 were obtained. Yield = 90%. Melting point 133-135°C.

Example 14

5-trifluoromethyl-4-chloro-3-(31-methoxy-4-nitrophenoxy)-1 - bromodifluoromethylpyrazole 1) 5.29 g (15.7 mmol) 5-trifluoromethyl-4-chloro-3-(3'-methoxy -4'-nitrophenoxy)-1-hydridopyrazole was dissolved in 25 ml of anhydrous THF and added to a stirred suspension of 0.45 g of 97% sodium hydride (18.2 mmol) in 25 ml of THF. After hydrogen evolution had ceased, 36.3 g (170 mmol) of dibromodifluoromethane was bubbled through the solution for 20 minutes. A precipitate formed and the reaction mixture was stirred over the weekend. An additional 7.3 g (34.8 mmol) of dibromodifluoromethane was added and the mixture was then diluted with 75 mL of water and 100 mL of ethyl acetate. The layers were evaporated, and the aqueous layer was washed twice with 100 ml of ether. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated, whereby 5.79 g of light brown oil was obtained. The oil was combined with oil from other experiments and purified by HPLC using 10% ethyl acetate-hexane, whereby 1.5 g of a whitish solid with a melting point of 61.5-62.5°C was obtained.

Elemental analysis for C-j 2H6N3°4BrClF5 =

Claims (2)

1. Process for the production of 4-(pyrazolyloxy)-nitrobenzene, characterized in that 2,4-bis-(pyrazolyloxy)-nitrobenzene is reacted with a nucleophilic reactant selected from hydroxides, organic oxide salts, enolates, thiolates, ammonia, primary amines, secondary amines, hydrazines and cyanide. 2. Method according to claim 1, characterized in that a nucleophilic reactant selected from cyano, hydroxy, alkoxy, thio, alkylthio, amino, alkylamino, hydrazino, alkylhydrazino, alkoxyamino and alkylaminooxy is used, which are unsubstituted or are substituted with one or more substituents selected from alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, halogen, cyano and nitro.