AP581A - Fungicidal 2-imidazolein-5-one derivatives. - Google Patents

Abstract

The invention relates

Description

INVENTORS CONTINUED

2.	PHILIPPE OESBOROERS 30 Rue Bancel 69007 Lyon FRANCE	3.	GILBERT ENERIC 97, Chemin des Tuileries 69570 Oardilly FRANCE
4.	ALAIN GADRAS 208 Rue de St.Cyr 69009 Lyon FRANCE	5.	GUY LACROIX 332F Rue du Doyen Chapas 69009 Lyon FRANCE
6.	JOSEPH PEREZ 19 Allee D Rue Ernest Fabregue 69009 Lyon FRANCE	7.	CHRISTINE VEYRAT 21 Rue Nervieux 69450 St.Cyr au Mont-D'or FRANCE

— -~· A Γ Γ»

AK . V U 3 o I ^_

Fungicidal 2-imidazolln-S-one derivativea”

The present invention relates to new compounds vith a 2-imidazolin-5-one group for use in plant protection. It also relates to the processes for the preparation of the said compounds and to the products which can optionally be used as intermediates in the preparation processes. It also relates to the fungicidal compositions based on these compounds and to the processes for controlling fungal diseases of crops using these compounds.

2-Imidazolin-5-ones for use in plant protection ere knovn from European Patent Application EP 0,551,048 and from International Applications WO 93/24467 and WO 94/01410.

One aim of the present invention ia to provide new compounds containing a 2-imidazolin-5-one group which have improved properties in the treatment of fungal diseases of crops.

Another aim of the present invention ie to provide compounds vhich have a use spectrum, in the field of fungal diseases, vhich is also improved, especially for the treatment of fungal diseases of rice and for the treatment of brown rust of wheat.

It has now been found that these aims could be achieved, in all or in part, by means of the products of the invention, described hereinbelow.

The subject of the invention is, firstly, compounds which are 2-imidazolin-5-one derivatives of

AP/P/ 9 5 / 0 0 7 2 2

AP .00581 general formula (I):

At 2—X “At

in which:

- R_x represents a hydrogen atom or a vinyl or allyl group or an alkyl or haloalkyl radical, each containing

1 to 3 carbon atoms;

or alternatively, R_x and Ar-j-X-A^ can additionally form, with the carbon to which they are bonded on the imidazolinone ring, the following unit:

-n 0 or 1;

in which the dot in bold type represents the carbon of the imidazolinone ring of the formula (I) to which the R_x and

Ar₂-X-Ar_x radicals are bonded, and m is equal to 2, 3 or 4;

- Y represents an oxygen or sulphur atom;

- R₂ represents:

a hydrogen atom when n Is equal to 0 or an alkyl or haloalkyl group, each containing 1 to 3 carbon atoms, or a cyclopropyl group;

ΛΡ . Ο ^η 5 8 1

- R₃ represents an aryl or heteroaryl radical comprising phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, benzo thiazolyl or methylenedioxyphenyl, each of these radicale optionally being substituted hy 1 to 7 groups, preferably from 1 to 3 groups, chosen from the meanings of R_s defined hereinbelow;

R₄ represents a hydrogen atom, a formyl or aroyl, radical, an acyl radical containing 2 to 6 carbon atoms, an alkoxy carbonyl radical containing 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulphonyl radical, an alkylsulphonyl radical containing 1 to 6 carbon atoms or an alkyloxalyl or alkoxyoxalyl radical containing 3 to 6 carbon atoms;

- Rj represents:

- a halogen atom or a hydroxyl, mercapto, nitro, SF₅, cyano, thiocyanato or azido group; or

- an alkyl, haloalkyl, cyanoalkyl, alkoxy, ~ haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, alkylsulphinyl, alkylsulphonyl, haloalkylsulphinyl or haloalkylsulphonyl radical, each containing 1 to 6 carbon atoms; or • a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio radical, each containing 3 to 6 carbon atoms; or

- an amino radical, optionally mono- or disuhstituted by an alkyl or acyl radical

AP/F/9 5 / 0 0 722

AP . 0 0 5 8 1 containing 1 to 6 carbon atoms or an alkoxycarbonyl radical containing 2 to 6 carbon atoms; or

- an alkoxycarbonyl group containing 2 to 7 carbon atoms; or

- an N-alkylcarbamoyl group containing 2 to 7 carbon atoms; or

- an Ν,Ν-dialkylcarbamoyl group containing 3 to 13 carbon atoms;

- W represents 0/ 8 or SO;

- Ar, is a divalent radical which derives from an aryl or heteroaryl radical comprising phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indolyl, quinolyl, isoquinolyl or methylenedioxyphenyl radicals, each of these radicals optionally being substituted by 1 to 6 groups, preferably by 1 to 3 groups, chosen from the meanings of it;;

- Ar₂ represents a mono- or bicyclic system containing S to 10 atoms, vhich is aromatic, saturated or unsaturated, and vhich is either a carbocyelic system or a heterocyclic system containing from 1 to 4 hetero atoms chosen from O, S or N and vhich comprises phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indanyl, indolyl, quinolyl, isoquinolyl, methylenedioxyphenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,

AP/P/ 9 5 / 0 0 7 22

AP. 0 Ο 5 8 1 oxadiazolyl, thiadiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, naphthyridyl, quinoxazolyl, quinazolyl, cinsolyl or phthalazinyl radicals, each of these radicals optionally being substituted by 1 to 7 groups, preferably by 1 to 3 groups, chosen from the meanings Of Rj?

- z represents a linkage of general formula:

—(R)j—A—(R*)k— xo in vhich:

- j and k, vhich are identical or different, are equal to 0 or 1?

- R and R*, vhich are identical or different, represent a saturated or unsaturated hydrocarbon chain vhich contains from 1 to 6 carbon atoms, optionally substituted by 1 to 12 groups, preferably by 1 to 3 groups, chosen from R₇ defined hereinbelow; and in vhich one or a number of carbon atoms can be replaced by o, 8 or R(R_e), R* being defined hereinbelov;

- A represents 0, 8, N(R₆), 80, 6O₂, CO, CS, 6i(R,)(R',), H₂, C(R₁₀> <R'_w), or >

a <o

OI ro

ΙΌ

AP

0 5 8 1 —C=C— or

N R, N

Jl w I or or _!£ in which Z represents 0, 8 or CCR^)(R'„); Rg to R_n being defined hereinbelow;

- R₆ represents:

- a hydrogen atom or a cyano, hydroxyl, amino, formyl, morpholino, piperidino, pyrrolidino or piperazino group, or

- an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylsulphonyl, haloalkylsulphonyl or cyanoalkylsulphonyl radical, each comprising from 1 to 6 carbon atoms, or

- a monoalkylamino or dialkylamino radical, or

- a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy or alkynyloxy radical, each containing 3 to 6 carbon atoms; or

- an acyl or alkoxy carbonyl radical, each containing 2 to 6 carbon atoms; or

- a carbamoyl radical (optionally substituted by one or two alkyl radicals) containing 1 to carbon atoms or a sulphamoyl radical (optionally substituted by one or two alkyl radicals) containing 1 to 6 carbon atoms; or

- an aroyl or arylsulphonyl radical; or

- an alkyloxalyl or alkoxyoxalyl radical, each containing 3 to 8 carbon atoms; or

- an oxamoyl radical (optionally substituted by one or two alkyl radicals) containing 2 to carbon

AP/P/ 95/00722 atoms

- R₇ represents a halogen atom or a cyano, thiocyanato, hydroxycarbonyl, alkoxycarbonyl, aaino (optionally substituted), hydroxyl, oxo, alkoxy, haloalkoxy, alkoxyalkoxy, mercapto, alkylthio, haloalkylthio, alkoxyalkylthio, acyloxy, alkyl, haloalkyl, alkoxyalkyl, alkylidene, aroyloxy, heteroaroyloxy, arylacyloxy, cycloalkylcarbonyloxy, acylthio, aroylthio, heteroaroylthio, arylacylthio, cycloalkylcarbonylthio, carbamoyloxy (optionally substituted), carbamoylthio (optionally substituted), thiocarbamoyloxy (optionally substituted), thiocarbamoylthio (optionally substituted), acylamino, cycloalkylcarbonylamino, aroylamino, ureido (optionally substituted), thioureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulphonylamino, aryl sulphonylamino or aminosulphonylamino (optionally substituted) group, it being understood that optionally substituted groups within the definition of 11? are optionally substituted by one or two alkyl groups, each aliphatic hydrocarbon radical having from 1 to 4 carbon atoms and each cycloalkyl radical having from 3 to 7 carbon atoms;

- Rg and R'_a, which are identical or different, represent:

- an alkyl radical containing 1 to 6 carbon atoms; or

- a cycloalkyl radical containing 3 to 7 carbon atoms; or

- an alkenyl or alkynyl radical containing 2

AP/F/ 9 5 / 0 0 7 22

AP. Ο Ο 5 8 1 to 6 carbon atoms; or

- an arylalkyl, preferably benzyl, radical or an aryl radical which is optionally substituted, preferably phenyl optionally substituted by 1 to 5 groups, preferably by 1 to 3 groups, chosen from the meanings of fy

- R₉ represents:

- a hydrogen atom or a morpholino, piperidino, pyrrolidino or piperazino group; or

- an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio or cyanoalkylthio radical, each containing 1 to 6 carbon atoms, or a diaikylamino radical containing 2 to 6 carbon atoms;

- R₁₀ and R*₁₀, which are identical or different, represent a hydrogen atom, an alkoxy group containing 1 to 6 carbon atoms, or an R_? group;

- r₁₁ and R»₁₁, which are identical or different, represent a hydrogen atom or a halogen or an alkyl group containing l to 3 carbon atoms;

as well as the salts and the enantiomers and stereoisomers of these compounds, especially the 2 enantiomers of each of these compounds which correspond to the asymmetric carbon of the imidazolinone ring carrying R·,;

and with the exception of the compounds in which:

** when (Y^-Rj represents a methylthio, a

AP/F/ 9 5 / 0 0 7 22 © 25

AP . Ο (1 5 8 1 methyl or an ethyl, Ar₂-X-Ar, represents an optionally substituted phenoxyphenyl group;

- when (Y,_n—Rj represents a methoxy, when R₁ is a methyl, when Rj represents a phenyl or pyridyl radical optionally substituted by a fluorine atom or a methyl group, vhen R₄ is a hydrogen and vhen V represents an oxygen atom, then Ar^-X-Ar, represents either a 4-phenoxyphenyl group, optionally substituted on its phenoxy part by 1 or 2 fluorine atoms, or a

3-phenoxyphenyl group;

and with the exception of the compound of formula:

Xn the present text, the generic terms alkyl, acyl and aroyl have the following meanings:

• alkyl means a linear or branched aliphatic radical;

- acyl means:

- an alkylcarbonyi or haloalkylcarbonyl group; or

- an alkoxyalkylcarbonyl or alkylthioalkylearbonyl group; or

- an alkenylcarbonyl group; or

- an alkynylcarbonyl group; or

- a cycloalkylcarbonyl or

AP/F/ 9 5 / 0 0 7 2 2

Π Π - 9 1 ίο halocycloalkylcarbonyl group;

- aroyl means an arylcarbonyl group, the aryl group having the same meanings as those indicated as preferred for Ar₂ and optionally being substituted by R_s.

The preferred compounds of formula (I) are those in which:

- Ar_x represents a divalent radical derived from a phenyl, naphthyl, thienyl, pyridyl, benzothienyl or quinolyl, each of these radicals optionally being substituted by 1 to 3 groups chosen from the meanings of R_s;

- Ar₂ represents a phenyl, naphthyl, thienyl, pyridyl, benzothienyl, thiazolyl, benzothiazolyl or pyrimidinyl radical, each of these radicals optionally being substituted by 1 to 3 groups chosen from the meanings of R_s.

Preference is particularly given to the compounds of formula (I) in which:

- Ar_x represents a divalent radical derived from a phenyl, thienyl or pyridyl which is optionally substituted by 1 to 3 groups chosen from a halogen atom or an alkyl or haloalkyl radical;

- Ar₂ represents a phenyl, naphthyl, pyridyl or benzothiazolyl radical which is optionally substituted by 1 to 3 groups chosen from a halogen atom or an alkyl or haloalkyl radical;

- X represents the linkage of general formula

AP/P/ 9 5 / 0 0 7 2 2

AP. Ο Ο 5 S 1 indicated above in which:

- R and R', which are identical or different, represent a carbon chain containing 1 to carbon atoms, preferably a methylene group, in which 5 a carbon atom is optionally replaced by O or NH, and which is optionally substituted by 1 to 3 groups chosen from a halogen atom, a hydroxyl or oxo group or a alkyl radical;

- A is O, 8, 80, S0₂, CO, C(R_W, <R',₀>,

in which:

- R₁₀ and R*₁₀, which are identical or different, are a hydrogen or halogen atom or a hydroxyl, 0,-0} alkyl or Ο,-Cj alkoxy radical;

- z represents o or CfR,,) (R'^), where R_n and 15 R'_n, which are identical or different, are a hydrogen or chlorine atom.

Finally, very particularly advantageous compounds are obtained by choosing derivatives of formula Z in which, simultaneously:

- R, is a methyl radical;

- Rj is a methyl or ethyl radical;

- Rj represents a phenyl or pyridyl radical;

- R₄ is a hydrogen atom or a formyl radical;

- Rj is a halogen atom or a alkyl or

AP/P' 9 5 / 0 0 7 22

AP. 0 0 5 8 1

C,-Cj haloalkyi radical; and

- W is an oxygen atom.

The compounds of formula (I) are prepared according to the processes explained hereinbelov. All th· groups which appear in th· following chemical formulae and which are already defined in the general formula (I) retain the same meaning, unless otherwise specified. In the general description of preparative processes the conditions given are those which will generally he used: it is to be understood that conditions other than those specified may be used, depending on, for example, the particular reactants used.

Th· structures of all the products which illustrate these processes were established by at least one of the following spectral techniques: proton NMR spectrometry, ¹³C NMR spectrometry, infrared spectrometry and mass spectrometry.

When indicating the meanings of the groups of a general formula in the tables in which these products are collated, the methyl, ethyl, propyl, pyridyl, pyrimidinyl, acetyl, phenyl and benzyl radicals are represented respectively by Me, Et, Pr, Py, Pyrim, Ac, Ph and Bn, and M.p. means melting point (M.p.).

The compounds of formula (X), in which R₄ is other than a hydrogen atom, are prepared from the compounds of formula (Ia) by reaction with a compound of formula R₄L*, in the presence of a base and in a solvent medium, according to the following reaction scheme:

AP/FZ 9 5 / 0 0 7 22

(la) (I)

In this scheme:

- r₄ represents a formyl radical/ an acyl group containing 2 to 6 carbon atoms, an aroyl group, an alkoxycarbonyl group containing 2 to 6 carbon atoms, an aryloxycarbonyl group, an alkylsulphonyl group, an arylsulphonyl group or an alkyloxalyl or alkoxyoxalyl radicalj

- L' represents:

a halogen atom, preferably chlorine, bromine or iodine, a sulphate group, an optionally substituted aryloxy or arylthio radical, preferably phenoxy, an alkoxy or dialkylamino radical, or a group R₄O when R₄ is an acyl or arylsulphonyl or alkyl sulphonyl group.

Use is made, as base, of a strong base such as an alkali metal or alkaline-earth metal hydride or hydroxide, an alkoxide or tertiary amine. The reaction is carried out at a temperature of between -30 C and +50*c. The solvent is chosen from cyclic or non-cyclic ethers, dimethylformamide, dimethyl sulphoxide, acetonitrile or an aromatic solvent.

AP/P/ 9 5 / 0 0 7 22

Λ Γ, Γ Q ]

The preparation of the compound of formula la is described according to 2 embodiments.

First of all, a description is given of a first method of preparation of the compound of formula

Ia, according to which the imidazolinone ring is constructed from intermediates containing the Ar₂-E-Ar₁ group. This first method of preparation of the compounds according to the invention corresponds to Processes λ, B, C and D described hereinbelow.

Preparation of the compounds of formula Ia in which n « 1 and Y S:

Process A:

The compounds of formula (la) in which n 1 and Y S and W S or O, otherwise known as the compounds of formula II, are prepared according to one of the proceaaea described in European Patent Application EP 0,551,048, especially by S-alkylation of the 2-thiohydantoins of formula (III), in which H represents S or O, in the presence of a base and in a solvent, according to the following reaction scheme:

·. »“, ‘‘''XV'^5-'¹²

At;—X—Ar|^/y-^NK_NH__Rj AtJ—X—A« _Kj

W w (ΙΠ) (H)

AP/P; 9 5 / 0 0 7 2 2 in which L represents a group chosen from a halogen atom (preferably chlorine, bromine or iodine) or an15 alkyl sulphate, alkylsulphoayloxy or arylsulphonyloxy group. Use is made, as base, of a strong base such as an alkali metal or alkaline-earth metal alkoxide (preferably potassium tert-butoxide), an alkali metal or alkaline-earth metal hydroxide, an alkali metal or alkaline-earth metal carbonate or a tertiary amine. Use is made, as solvent, of a cyclic or non-cyclic ether, an alkyl ester, acetonitrile, an alcohol containing 1 to 4 carbon atoms, a chlorinated solvent or an aromatic solvent. Use is preferably made, as solvent, of tetrahydrofuran (THF). The reaction is carried out at a temperature of between -5°C and +80°C.

The following example illustrates this process.

Example CFlt Preparation of (4RS)-4-methyl-2methylthio-l-phenylamino-4- (4- (2-phenylethyl)phenyl) -2imidazoline-5-thione (Compound No. 14).

1.36 g (0.012 mol) of potassium tert-butoxide are added, at O’C, to 5 g (0.012 mol) of (4RS)-420 . methyl-l-phenylamiao-4-(4-(2-phenylethyl)phenyl) imidazolidine-2,5-dithione dissolved in 150 ml of THF. After stirring for 15 minutes at this temperature,

1.5 ml (0.024 mol) of methyl iodide are added. Stirring is continued at 0’C for 30 minutes and then, after having allowed the temperature to rise to room temperature, the medium is hydrolysed and then extracted with methylene chloride. After washing the organic extracts with a saturated sodium chloride

AP/P/ 9 5 / 0 07 22

AP.00581 solution, separating by settling, drying and evaporating the solvents, a brown oil is obtained. This oil is crystallized from a mixture of diisopropyl- ether and pentane. After (filtration, 2.7 g (0.006 moDjcrf (4RS)-4-methyl-2-methylthio-l-phenylamino-4-(4-(2phenylethyl)phenyl) -2-imidazoline-5-thione are recovered in the form of a brown powder melting at 118°C with a yield of 49%.

The preparation of the compound of formula 10 III according to whether W means S (compound of formula

Ilia) or O (compound of formula Illb) is now described. Preparation of the compound of formula Ilia:

The dithiohydantoins of formula (Ilia) are obtained from a compound of formula (IV) according to a process analogous to that described by T. Yamamoto et al. in J. Chem. Soc. Perkin Trans. I (1990), page 3003 to 3009, that is to say according to the reaction:

AP/P/ 9 5 / 0 0 7 2 2

The following example illustrates the preparation of a compound of formula (Ilia):

Example CI1:

Preparation of (4RS)-4-methyl-l-phenylamino-4-(4-(2phenylethyl)phenyl)imidazolidine-2,5-dithione, of

AP. Ο η 5 8 1 expanded formula:

6.7 ml (0.066 mol) of phenylhydrazine are added to 22.6 g (0.066 mol) of (4RS) -4-methyl-4-(4-(2phenylethyl) phenyl) thiazolidine-2,5 - di t hi one in 100 ml of toluene. The reaction mixture ia heated progressively to 60°C and then to reflux until gaa evolution has ceased. After cooling the mixture, hydrolyaia ia carried out and then extraction ia carried out with ethyl acetate. After separating hy settling, drying the organic phase and evaporating the solvents, a black oil ia obtained. After chromatography on a silica column (50/50 ethyl acetate/heptane),

11.2 g (0.027 mol) of (4RS)-4-methyl-1-phenylamino-4--(4- (2-phenylethyl)phenyl) imidazolidine-2,5-dlthion^ are recovered in the form of a brown powder melting at 171*C with a yield of 41%.

The thiazolidine-2,5-dithionea of formula (XV) are obtained from an isothiocyanate of formula (V) according to a process analogous to that described by

T. Yamamoto et al. in J. Chem. Soc. Perkin Trane. X (1990), page 2459 to 2463, according to the reaction:

AP/P/ 9 5 / 0 0 7 2 2

Arj—X— j

s (IV) (V)

The following example illustrates the preparation of a compound of formula (IV) :

Example CI2: Preparation of (4RS)-4-methyl-4-(4-(2phenylethyl)phenyl) thiazolidine-2,5-dithione, of expanded formula:

© /

© /

λ solution of 7 ml (0.11 mol) of carbon

AP/P/ 95/00722 .□disulphide and 20.4 g (0.076 mol, of 1-(4-(2-__ phenylethyl)phenyl] ethyl isothiocyanate in 50 ml .of THF is slowly added to 9.5 g (0.084 mol) of potassium tertbutoxide placed in 150 ml THF at -70*C. After stirring for 15 minutes at -70*C, the temperature is allowed to rise to room temperature. After hydrolysing the reaction mixture with an aqueous acetic acid solution, extracting with ethyl acetate, separating by settling, drying the organic extracts and evaporating the solvents, 22.6 g (0.065 mol) of (4RS)-4-methyl-4-(4-(2AP 00581 phenyl ethyl) phenyl) thiazolidine-2,5-dithione are recovered in the form of an oil with a crude yield of 86%. *

The isothiocyanate of formula (V) is prepared 5 from an amine of formula (VI), in which the substituents have the same meaning as in (V), according to one of the processes cited in Sulfur Reports (1989), Volume 8 (5), pages 327-375, i.e. according to the reaction:

C~

Ar₂—X— Arp ‘(VI) nh₂

Ύ + esci base

Solvent ♦ V’

Ar₂—X-Arf (V)

The following example illustrates the preparation of a compound of formula (V):

Examnle CI3: Preparation of 1-[4-(2-phenylethyl)_ .phenyl] ethyl isothiocyanate, of expanded formula_

AP/P/ 9 5 / 0 0 7 2 2 equivalent of sodium hydrogencarbonate is 15 added, es an aqueous solution, to a suspension of 20 g (0.076 mol) of 1-(4-(2-phenylethyl)phenyl)ethylamine

AP.00581 hydrochloride in 200 ml of toluene et 0°C. After having brought the temperature of the reaction mixture back to room temperature, 2 equivalents of sodium — * hydrogencarbonate axe added as an aqueous solutions

6.1 ml (0.076 mol) of thiophosgene, as a solution in ml of toluene, are then slowly added. At the end of the addition, stirring is continued for 15 minutes. After separating by settling, the organic extracts are washed with water, dried and then evaporated. 20.5 g (0.076 mol) of 1-[4-(2-phenylethyl)phenyl]ethyl isothiocyanate are thue obtained in the form of an oil with a yield of 100%.

Preparation of the compound of formula Illb:

The 2-thiohydantoins of formula (Illb), which are compounds of formula (III) in which W is an oxygen atom, are obtained according to the process described in European Patent Application EP 0,551,048 by a cyclization reaction of the isothiocyanates of formula

-.(VII) with the hydrazines of formula I^-NH-NHj,___ according to the following reaction scheme:

R, N=C^

X ⁺*3

A r₂—X-Arf h—OR_E

O (VII) —

A,₅-X-Ar/yN_>(H_ © (inb)

AP/F/ 3 5 / 0 0 7 2 2 in which Rg represents a alkyl radical.

The cyclization can be carried out according to 2 embodiments.

According to the first, the mixture of the reactants is heated at a temperature of between 110°C and 180*C in an aromatic solvent such as toluene».- « xylene, chlorobenzenes or nitrobenzene. j—

According to the second embodiment of the cyclization, the reaction ie carried out in the presence of e strong base such as an alkali metal or alkaline-earth metal alkoxide, an alkali metal or alkaline-earth metal hydroxide or a tertiary amine at a temperature of between -10 and -«-80°C and in a solvent chosen especially from an ether, a cyclic ether, an alcohol, an ester, DMF or DMSO.

The following example illustrates the preparation of a compound of formula (Illb) t

CI3 ·: Preparation of (5RS) -5-methyl-3phenylamino-5- (4- (phenylthio)phenyl) -2thioxoimidazolidin-4-one, of following expanded formula:

Π

AP/P/ 9 5 / 0 0 7 2 2

8.48 g (0.0258 mol) of methyl (2RS)-220 isothiocyanato-2-(4-(phenylthio)phenyl)propanoate are dissolved in 250 ml of tetrahydrofuran. 2.78 g (0.0258 mol) of phenylhydrazine are run in dropwise.

AP . 0 0 5 8 1

The reaction mixture is stirred for 30 minutes at room temperature, poured into water and reextracted with ether. After drying over magnesium sulphate, the^jether is evaporated to give 11.46 g of an oil which j— crystallizes. The crude reaction product ie mixed with ether, filtered and recrystallized to give 3.36 g (0.0082 mol) of (5RS) -5-methyl-3-phenylamino-5-(4(phenylthio)phenyl) -2-thioxoimidazolidin-4-one in the form of pink crystals melting at 158’C with a yield of

34%.

The α-isothiocyanato esters of formula (VII) are prepared from the a-amino acid esters of formula (VIII), in which the groups indicated have the same meaning as in the formula (VII), according to one of the processes cited in Sulfur Reports (1989), Volume 8 (5), pages 327-375, i.e. according to the reaction:

base

Solvent

O (VIII)

R, N=C=S

Arj—X —Arf \—©Rg e

(VII)

AP/F/ 95/00722

The following example illustrates the preparation of a compound of formula (VII):

Example CI4: Preparation of methyl (2RS)-2-(420 benzyloxyphenyl)-2-isothiocyanatopropanoate

143 g (0.501 mol) of methyl (RS)-2-(4benzyloxyphenyl)-2-methylglycinate and then 800 ml of »· toluene are added to a stirred solution of 84.2 g (1.002 mol) of sodium hydrogencarbonate in 800 ml of water; 40 ml (0.526 mol) of thiophosgene are then-- run in dropwise at room temperature over 1.5 h while j controlling gas evolution. After stirring for 2 h at room temperature, separating by settling from the aqueous phase, washing with water, drying over magnesium sulphate and concentrating the organic phase, 155.4 g (0.475 mol) of methyl (2RS)-2-(410 benzyloxyphenyl)-2-isothiocyanatopropanoate are isolated in the form of a very thick oil with a yield of 95%.

By carrying out the preparation in an analogous way, the following compounds of formula (VII) ware obtained:

AP/P/ 95/00722

R’	Re	Ri	Yd	M.p. (°C)
4-BnO	Me	Me	62%	oil
4-Bn	Me	Me	50%	oil
4-PhS	Me	Me	96%	oil
4-PhSO	Me	Me	100%	oil
4-PhSO2	Me	Me	85%	oil
3-BnO	Me	Me	80%	oil

The β-amino esters of formula (VIII) are obtained by eeterifying the a-amino acids of formula (IX), in which the groups indicated have the same meaning as in the formula (VIII), with an alcohol.-of formula RgOH in the presence of thionyl chloride r—which process is described in the literature by: M. Brenner and W. Huber: Helv. (1953), Volume 36, page 1109, according to the scheme:

At₂

Rl NH₂

SOCI r_eoh

Θ '(IX)

R, NH₂ Ar₂—X-ArfX—OR_E

O '(VIU)

The following example illustrates the preparation of a compound of formula (VIII) :

Example CI5: Preparation of methyl (RS)-2-(4benzyloxyphenyl) -2-methylglycinate

33.8 g (0.284 mol) of thionyl chloride are progressively added to a stirred suspension of 38.55 g

Γ (0.142 mol) of (RS)-2-(4-benzyloxyphenyl)-215 methylglycine in 400 ml of methanol maintained at

-20*C. At the end of addition, the solution obtained is allowed to rise to room temperature and is then brought to reflux for 16 h. After concentrating, the residue is taken up in water and the solution obtained is basified with a concentrated aqueous sodium hydroxide solution to a pH equal to 8. The precipitate is filtered, washed with water, sucked dry and dried under vacuum. After

AP/P/ 9 5 / 0 0 7 22 chromatography on 400 g of silica gel, elution being carried out with a 30/70 heptane/ethyl acetate mixture, and concentration under reduced pressure of the — * advantageous fractions, 14.7 g (0.0515 mol) of methyl (RS)-2-(4-benzyloxyphenyl)-2-methylglycinate are isolated in the form of a white powder having a melting point of 67°C with a yield of 36%.

Synthesized compounds of formula (VIII) are collated in the table below.

R'	Rl	«e	Yd	M.p. (°C) or nD
4-BnO	Me	Me	36%	67*C
4-Bn	Me	Me	95%	112-116*C
4-PhS	Me	Me	66%	1.6058
3-BnO	Me	Me	35%	50’C

⁽ 10 λ variant for the preparation of certain a-amino esters of formula (VIII), those for which Z represents an -S(O)_a group and which correspond to ths formula (Vlllb), is now described.

The a-amino esters of formula (Vlllb) are 15 obtained by oxidation of the α-amino esters of formula (Villa) according to processes described in Advanced

Organic Chemistry, J. March (1985), page 1089 and 1090,

3rd Edition and according to the scheme:

AP/P/9 5 / 0 0 7 2 2

ΑΡ.00581

Arj—S —j

© (Villa)

Solvent

Rj NH,

Θ (Vlllb) -In this scheme, n is equal to 1 or 2 and Rg has the meaning indicated in the definition of the formula (VII).

The following examples illustrate the preparation of compounds of formula (Vlllb):

Bmiirola CIS» Preparation of methyl (RS)-2-amino-2-(4 (phenyl sulphinyl) phenyl) propionate:

S'

II

17.22 g (0.06 mol) of methyl 2-amino-2-(4API?! 95/00722 (phenylthio)phenyl)propionate are charged to 350 ml of dichloromethane and cooled to 0’C. 14.1 g (0.06 mol) of 73% meta-chloroperbenzoic acid are progressively added over approximately 10 minutes. The reaction mixture ie stirred for 2 hours at 0°C. The precipitate is filtered and the organic phase is washed with normal sodium hydroxide solution and then with water and dried over magnesium sulphate. Evaporation leaves 15 g of an oil which is chromatographed on silica (eluent: ethyl acetate) to give 11.3 g (0.037 mol) of methyl (RS) -2-amino-2 - (4- (phenylsulphinyl) phenyl)propionate in the form of a slightly yellow oil having an sip 4L.5979 at 25*C with a yield of «2*.

Example CX7: Preparation of methyl (RS)-2-amino-2-(4(phenylsulphonyl) phenyl)propionate:

21.52 g (0.075 mol) of methyl (RS)-2-amino-2(4-(phenylthio)phenyl)propionate are charged to 400 al of methanol and cooled to O’C. 50.12 g (0.153 mol) of

49.5% potassium persulphate as a solution in 400 ml of water are added dropwise over 1 hour at O’C. The reaction mixture is stirred for 5 hours at room temperature. The residual oxidizing agent is destroyed .with 5 ml of a 30% sodium hydrogensulphite solution^

The pH of the mixture is brought to approximately- 8 by addition of 20 g of sodium carbonate and the solid is filtered. After stirring ths solid in 500 ml of dichloromethane and then filtering the residual solid, the filtrate is dried and the solvent evaporated to give 16.9 g (0.529 mol) of methyl (RS)-2-amino-2-(4(phenylsulphonyl)phenyl)propionate in the form of white crystals melting at 124°C with a yield of 70%.

The β-amino acids of formula (IX) are

AP/F; 95/00722

AP . υ ΰ 5 8 1 obtained by hydrolysis of the corresponding hydantoins (X) in acidic or basic medium according to a process analogous to that described in Dutch Patent NE 69-00349 or in J. Org. Chem. . (1985), Volume 50, pages 1876~to

1878, i.e. according to the scheme:

The following example illustrates the preparation of compounds of formula (IX).

Example CI8: Preparation of (4RS) -2-(4-benzyloxyphenyl)-2-methylglycine

17.2 g (0.0506 mol) of (5RS)-5-(4benzyloxyphenyl)-5-methylhydantoin are added to a stirred solution of 40 g (1 mol) of sodium hydroxide in 100 ml of water and the suspension obtained is brought to reflux for 24 h. After cooling, the reaction mixture is neutralized with a concentrated aqueous hydrochloric acid solution and the suspension is then diluted with 100 ml of water. The precipitate is filtered, washed with water and then with acetone, sucked dry and dried under vacuum. 16.2 g, containing 87 mol% of (4RS)-2-(420 benzyloxyphenyl)-2-methylglycine by NMR, are thus isolated in the form of a white powder having a melting point greater than 300*C.

AP/P, 95/00722

The synthesized or-amino acids of formula (IX) are collated in the table below:

^R1 νή₂

R’	Rl	Yd	M.p. (*C) or np
4-(3-Pyridyloxy)	Me	96%	>300*C
4-BnO	Me	42%	>300’C
4-Bn	Me	100%	>300*C
4-PhS	Me	100%	>300*C
3-BnO	Me	100%	270*C
3-PhS	Me	100%	>300*C

The hydantoins of formula (X) are obtained by a Bflcherer-Berg reaction on the corresponding acetophenones, which process is described in the O .literature: Chem. Rev. (1950), Volume 46, pages 422^-425 f or Chem. Pharm. Bull. (1973), Volume 21, pages 6B5 to

691. The said acetophenones are easily accessible to those skilled in the art.

Process B:

According to a preferred embodiment, the compounds according to the invention of formula (II) in which W represents an oxygen, in other words the compounds of formula (Ila), are prepared by successively reacting the compound of formula (VII)

AF/F.’ 9 5 / 0 0 7 22 f-.P . 00 58 1 with a hydrazine of formula Rj-NH-NHj, then with a base of formula B‘M* and finally with an alkylating agent of formula RjL, in vhich L and are defined as above, with the proviso that R^ is other than hydrogen.

The base is chosen from an alkali metal or alkaline-earth metal alkoxide, an alkali metal or alkaline-earth metal hydroxide or a tertiary amine. The reaction is carried out at a temperature of between -10 and +80 *C and in a solvent chosen especially from a cyclic or non-cyclic ether, an alcohol, an ester, DMF, DMSO, acetonitrile or from an aromatic. The scheme of the reaction is the following:

SM

Ar, d N=C=S —X—Ar, >-ORe

N=C=S Β' M

R.—NH—NH.-1

O (VH)

Ar,-X-Ar₁ ^z)J<^N>iH-R,

AP/P/ 9 5 / 0 0 7 2 2

The following example illustrates the preparation of compounds of formula (Ila).

Example CF2: Preparation of (4RS)-4-methy1-2methylthio-4-(4-phenylthiophenyl)-1-phenylamino-2imidazolin-5-one (Compound No. 25):

1.62 g (0.015 mol) of phenylhydrazine are added to a stirred solution of 5 g (0.015 mol) of methyl (2RS)-2-(4-phenylthiophenyl)-2isothiocyanatopropanoate in 120 ml of anhydrous tetrahydrofuran under a nitrogen blanket; the reaction

AP. C Ο 5 8 1

	mixture is allowed to react for 1 h at room temperature
5	and is then cooled to 0°C. 1.68 g (0.015 mol) of potassium tert-butoxide are added, reaction is allowed to take place for 0.25 h and then 2.13 g (0.015 mol) of methyl iodide are added. The temperature is allowed to rise to room temperature and stirring is carried out for 3 h. The reaction mixture ie poured into 100 ml of .
10 c	water and the product then extracted with ethyl acetate. After washing with water, drying over magnesium sulphate and concentrating the organic phase, 7.4 g of a honey are recovered, which honey is
15	dissolved in 30 ml of diieopropyl ether. The product precipitates at 5*C; after filtering and drying under reduced pressure, 4.8 g (76%) of (4RS)-4-methyl-2- methylthio-4- (4-phenylthiophenyl) -l-phenylamino-2- imidazolin-5-one (Compound No. 25) are obtained in the
e 20	form of beige crystals melting at 136*C. Preparation of the compounds of formula la in which n » 1 and Y « 0 The preparation of the compounds of formula (Ia) in which n « 1 and Y 0 and W 0, in other words the compounds of formula (XI), is now described.
25	Process C: These compounds are obtained by reacting the 2-&lkylthio-2-imidazolin-5-ones of formula (II) with an alcohol R2OH in a solvent in the presence of a strong base, according to the scheme:

AP/P/ 95/00722

ΔΡ. Ο Ο 5 8 1 ”vV“ ;

δ —R'a

RjOII *3

(II) in which R'₂ represents an alkyl group comprising from 1 to 3 carbon atoms.

It is possible to use, as strong base, an alkali metal alkoxide R₂O*M*, an alkali metal hydroxide, an alkaline5 earth metal hydroxide or a strong organic base. The reaction is preferably carried out in the alcohol R₂OH, as solvent, and by using the corresponding sodium alkoxide R₂O“Na* as base. The reaction is carried out at a temperature of between 20 and 80°C. According to a variant of the process, the reaction is carried out in the presence of an oxidizing agent. In particular, it is possible to use, as oxidizing agent, sodium or potassium periodate.

“VThe following example illustrates the {

preparation of the compounds of formula (XI) :

Example CF3: Preparation of (4RS)-4-(4benzyloxyphenyl ,-2 -methoxy- 4 -me thyl -1 -phenylamino-2 imidazolin-5-one (Compound No. 9) :

2.6 g (0.0062 mol, of (4RS,-4-(420 benzyloxyphenyl) -4-methyl-2-methylthio-l-phenylamino-2imidazolin-5-one and 1.3 g of sodium periodate are added to a solution of 0.5 g (0.0093 mol) of sodium methoxide in 50 ml of anhydrous methanol under an inert

AP/P/ 95/00722 atmosphere. Heating is carried out at reflux for 6 h. After cooling the reaction mixture, the latter ie neutralized with acetic acid, is run into 100 ml of » water end ie extracted with di chloromethane. The ~~ organic phase ie washed with water, dried over magnesium sulphate and than concentrated under reduced pressure. The crude product thus obtained is purified by chromatography on silica (eluent: 50/50 heptane/ ethyl acetate). The purified product is crystallized from diisopropyl ether. After filtering and drying tinder reduced pressure, 0.8 g (0.002 mol) of (4RS)-4(4-benzyloxyphenyl) -2-methoxy-4-methyl-1 -phenylamino-2 imidazolin-5-one (Compound No. 9) is obtained in the form of white crystals having a melting point of 127*C with a yield of 32%.

Preparation of the compounds of formula la in which n » 0:

Process D:

The preparation of the compounds of formula (Xa) in which n 0 and W 0, in other words thecompounds of formula (XII), is now described:

N.

NH—Rj

O (XK)

These compounds are prepared according to «-Η» process described in International Application

AP/P.’ 9 5 / 0 0 7 2 2 ^R,y ,-X-Ar,/y

Ar·

AP. Ο Ο 5 8 1

WO 94/01410, that is to say by reacting a hydrazine of formula R₃-NH-NH₂ with an azalactone of formula (XIII), according to the following reaction scheme: »

R₃NHNH₂

CH3COOH

CH₃COONa

A,j-X-A,/yNx_NH__Rj '(XU)

The reaction is carried out by heating the 5 mixture of the reactants in acetic acid at reflux, optionally in the presence of sodium acetate as catalyst.

The following example illustrates the preparation of compounds of formula (XII).

Example CI8*: Preparation of (4RS) -2-ethyl-4-methyl4- (4- (phenylthio)phenyl) -l-phenylamino-2-imidazolin-5one, of expanded formula:

AP/P/ 9 5 / 0 0 7 2 2 g (0.013 mol) of (4RS)-2-ethyl-4-methyl-4(4 -(phenylthio)phenyl)-2-oxazolin-5-one are added to

100 ml of acetic acid. 1.4 g (0.013 mol) of phenylhydrazine are run in dropwise into the reaction mixture. The reaction mixture is heated at reflux for hours and the acetic acid is then removed under w

r-* \ * yj M vacuum. The residue is mixed with water, neutralized and then reextracted with dichloromethane. After drying over magnesium sulphate, evaporation of the solvent* leaves 4.09 g of an. oil which is chromatographed .OO silica (eluent: 4/1 ethyl acetate/heptane) to give 3.41 g (0.0085 mol) of (4RS)-2-ethyl-4-methyl-4(4- (phenylthio)phenyl) -l-phenylamino-2-imidazolin-5-one in the form of an oil which is crystallized from diisopropyl ether in the form of beige crystals melting at 90°C with a yield of 66%.

The azalactones of formula (XIII) are obtained by reacting the a-amino acids of formula (XX) with a carboxylic acid anhydride according to a process described in the literature: R. Cotton et al., Int. J.

Peptide Protein Res. (1986), Volume 28, pages 230 to 244 and according to the scheme:

Ar₂—X—Ar ^Rlxy'^NH2 R₂COOCOR₂ ^R,\/^N’⁵ (DQ

Θ (XIII)

AP/P/ 9 5 / 0 0 7 22

The following example illustrates this process for the preparation of the compounds of formula (XIII).

Example CI9: Preparation of (4RS)-2-ethyl-4-methyl-4(4-(phenylthio)phenyl)-2-oxazolin-5-one, of expanded formula:

AP.00581

14.2 g (0.052 mol) of (2RS)-2-amino-2-(4(phenylthio)phenyl)propionic acid ar· suspended in 200 ml of propionic anhydride. The mixture is heated at reflux for 1 hour and the propionic anhydride is then driven off under pump vacuum by azeotropy vith addition of heptane. The residue (16 g) is dissolved while hot in 100 ml of ethanol. A white solid crystallizes (3.0 g) vhich is filtered and isolated. The liquors are reconcentrated to give 12.3 g of a brown oil vhich is chromatographed on silica (eluent: 4/1 ethyl acetate/heptane) to give 4.76 g (0.0153 mol) of (4RS)2-ethyl-4-methyl-4-(4-(phenylthio)phenyl)-2-oxazolin-5one in the form of an oil (250 MHz NMR-CHCl₃ - in ppm: 1.3 (t, 3H); 1.75 (s, 3H); 2.58 (q, 2H)ί 7.2 to 7.6 (m,

9H)) vith a yield of 29%.

A description is now given of the preparation of a second embodiment of the compound of formula la according to the invention, according to vhich a group ( Ar₂-X is introduced onto an imidazolinone of formula (XIV):

AP/P/ 9 5 / 0 0 7 2 2

Λ Λ υ η

AH

R

Ατ

P'NH-Rj

W '(XIV)

This second embodiment corresponds to Processes E, F, G, Β, I, J, K, L and M which are defined hereinbelow.

Process B:

λ description is first of all given of the preparation of the compounds of general formula (Za)»

Arj-X-Ar, jjr'^N'_NH_R₃ w

(la) ο

r ίο in which Z has the same meaning as an Z' group which is defined hereinbelow in the description of Process B.

-The compounds of general formula (Za) are obtained. J>y condensation of an organometallic derivative of an imidazolinone of formula (ZV) with an electrophilic radical Ar₂-Z'*, according to the reaction scheme:

AP/P/ 9 5 / 0 0 7 2 2 ^M.^_An '?-* * «I (XV) ‘

2)H2O

R, w

0») in which Mjrepresents a metal chosen from lithium

ΛΡ .0 0 5 8 1 sodium, magnesium, zinc, titanium, tin, copper, boron or silicon and is preferably lithium and in vhich l' is such that Ar₂-X' is an electrophilic radical generated by a compound chosen especially from:

-an aralkyl compound of formula Ar₂-R,₂-L in vhich:

- R₁₂ represents a saturated or unsaturated, linear or branched, aliphatic chain containing 1 to 6 carbon atoms, optionally substituted by a halogen or an alkoxy group or an oxo radical; and

- L has the same meaning as above;

- a carbonyl compound of formula:

Arj (Ru)p C—Ris

O in vhich:

©

- p = o or l;

r

- R₁₂ has the sane meaning as above; and

- R₁₃ represents a hydrogen atom, a ^ci“^C6 ^alJcY¹ group, a halogen or an alkoxy, aryloxy or dialkylamino group;

- a chloroformate of formula:

Arg—(Ri2)P^—θ—C^—Cl O

AP/P/ 9 5 / 0 0 7 2 2

AP 00581 in vhich p and R₁₂ have the sane meanings as above;

- an isocyanate or an isothiocyanate of formula:

Ar₂ (RijOP^-~ N—C—Q ©

r in vhich p and R,₂ have the same meanings as above and Q represents an oxygen or sulphur atom;

- a sulphonyl halide of formula:

O

II

Ar₂—(Ri2)P~S—Hal O in vhich r,2 and p have the same meanings as above and Hal represents a halogen atom, preferably a chlorine atom;

- an epoxide of formula:

Rio

Ar₂—γ-y—R'10 O

AP/P/ 9 5 / 0 0 7 2 2

When, according to a preferred variant of the invention, the letter M₁ of the formula (XV) represents lithium, the corresponding compounds of formula (XV),

ΔΡ .00581

i.e. the organolithiv«a compounds of formula (XVII), are obtained from the halogenated derivatives (XVI), in which Hal represents a halogen atom, preferably chlorine or bromine, by a metal/halogen (Hal) exchange as described hy R.G. Jones and H. Gilman, Organic

Reactions (19), Volume 6, page 339. The reaction is the following:

n-Butyllithium THF. -70^eC

-►

(XVI) (XVII)

When the letter MjOf the formula (XV) does not represent lithium, the corresponding organometallic compounds of formula (XV) can be obtained from the organolithium compounds (XVII) by a transmetallation reaction as described in Advanced Organic Chemistry, _ jl_t March, (1985), p. 557, 3rd Edition.

The following example illustrates the preparation of a compound of formula (Ia).

Example CF4: Preparation of (4RS)-4-(4-((4chlorophenyl)hydroxymethyl)phenyl] -4-methyl-2me thyl thio -1 -phenyl amino - 2 - imida z olin- 5- one (Compound No. 30):

1 g (0.0025 mol) of (4RS) -4-(4-bromophenyl) 4 -methyl - 2 -methyl thio-1 -phenylamino - 2 - imidazolin - 5 - one is dissolved under an inert atmosphere in 20 ml of

AP/P; 9 5 / 0 0 7 2 2

ΛΡ.00581 anhydrous THF and the reaction mixture is then cooled to -70°C. Two equivalents of n-butyllithium (3.2 ml of 1.6M hexane solution) are added at this temperaturei After stirring for 15 min at -70°C, 0.36 g (0.0025mol) of 4-chlorobenzaldehyde is added in solution in 3 ml of THF. After reacting for 30 min, the reaction mixture is hydrolysed at -70°C with a saturated ammonium chloride solution. After extracting with ethyl acetate, washing the organic extracts with a saturated eodium chloride solution, drying, evaporating the solvents and chromatography of the crude product on a silica column (ethyl acetate/heptane: 50/50), 0.95 g (0.002 mol) is recovered of a white solid which is (4RS)-4-[4-{(4chlorophenyl) hydroxymethyl) phenyl] -4-methyl- 2 15 methylthio-l-phenylamino-2-imidazolin-5-one, having a melting point of 94°C with a yield of 82%.

The 2-imidazolin-5-ones of formula (XVT) are obtained by one of the processes described in European

- Patent Application EP 0,551,048, published on

14 July 1993, in the case where Y S and n 1; according to a process analogous to Process C described above in the ease where n is equal to 1 and Y means O; or according to a process analogous to Process D described above when n is equal to 0.

Process F:

A description is now given of the preparation of the compounds of general formula (lb):

AP/P/ 95/00/22

Ri

Arj—(R’₁₂)P —Ζ—Arj

in which ρ and Ζ have the same meanings as above and R'₁₂ represents a saturated or uneaturated, linear or branched, aliphatic chain containing 1 to 6 carbon atoms.

These compounds are obtained according to known processes by reacting an imidazolinone of formula (XVI) with a nucleophile of formula (XVIII) according to a process analogous to that mentioned in Comprehensive Heterocyclic Chemistry, A.R. Katritzky, Volume 2,

Part 2A, page 359, i.e. according to the scheme:

Hal ^R,v^NV^<Y)n —Rj 12^P—ZH <xvm)

W (XVI)

Arj—(R' ,₂)p— Z—Ar j

AP/P/ 9 5 / 0 0 7 2 2

The reaction is carried out under the conditions conventionally used in aromatic substitution reactions.

The following example illustrates the 15 preparation of compounds of formula (Ib) .

Example CF5: Preparation of (4RS)-4-[6-(4fluorophenylthio) -5-nitropyrid-2-yl)-4-methyl-2Λ r inggi methyl thio-1 - phenyl amino-2 - imidazolin-5-one (Compound No. 64):

g of K₂CO₃ and then 0.27 ml (2.5 mooli of 4-fluorothiophenol are added et room temperature to

1.00 g (2.5 mmol) of 4-(6-chloro-5-nitropyrid-2-yl) -4me thyl - 2 -me thyl thio -1 -phenyl amino - 2 - imidazolin - 5 - one in solution in 50 ml of acetone under argon. After reacting for 2 hours at room temperature, the mixture ia diluted with water; the product is extracted with ethyl acetate; the extracts are dried over anhydrous magnesium sulphate and then concentrated under reduced pressure. The product, after chromatographic purification on silica (eluent: 20/80 ethyl acetate/ . heptane), ie crystallized from diisopropyl ether. After filtering and drying, 0.8 g (1.66 mmol) of (4RS)-4-[6(4-fluorophenylthio) -5-nitropyrid-2-yl) -4-methyl-2 me thyl thio -1 -phenyl amino - 2 - imi da z ol in - 5 - one (Compound No. 64) is recovered in the form of crystals having a _melting point of 171*C with a yield of 66%.

Process O:

A description is now given of the preparation of the compounds of formula (Ic):

AP/P/ 9 5 / 0 0 7 2 2 in which X' has the same meaning as above.

The compounds of formula (Ic) are obtained by reacting a 4-(hydroxyphenyl)-2-imidazolin-5-one, of formula (XIX), with an electrophilic radical Ar₂-X'*, according to the reaction scheme:

The reaction is carried out in basic medium under the conditions conventionally used for condensation between phenols and various electrophilic radicals (processes known per se in the literature). It is possible to use, as base, in particular, alkali metal or alkaline-earth metal carbonates and hydroxides or organic bases. The reaction is carried out at a temperature of between +2O’C and +150’C. It is carried out in solvents such as alcohols, ketones, acetonitrile, aliphatic esters, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, dimethylformamide, dimethyl sulphoxide or N-methylpyrrolidone.

The following example illustrates the preparation of compounds of formula (Ic) .

Example CF6: Preparation of (4RS)-4-methyl-4-(4-(3methylbenzyloxy)phenyl) -2-methylthio-l-phenylamino-2imidazolin-5-one (Compound No. 22):

0.92 g (0.0067 mol) of potassium carbonate,

AP/P-' 95/00/**

AP. Ο π 5 8 1

0.94 g (0.0067 mol) of 3-methylbenzyl chloride and 0.1 g (0.00061 mol) of potassium iodide are added to a stirred solution of 2 g (0.0061 mol) of (4RS)-4-t4-_T hydroxyphenyl) -4 -methyl - 2 -methyl thio -1 -phenylamino* 2 5 imidazolin-5-one in 50 ml of ethanol. The reaction mixture is brought to reflux for 8 h. The latter ie poured into 150 ml of water. The precipitate formed ie washed with a IN aqueous sodium hydroxide solution and then with water to neutrality, sucked dry, washed with diisopropyl ether and then dried under reduced pressure. 1.94 g (0.0045 mol) of (4RS)-4-methyl-4-(4(3-methylbenzyloxy) phenyl) -2-methylthio-1 -phenylamino2-imidazolin-5-one (Compound No. 22) are thus obtained in the form of white crystals having a melting point of

151*C with a yield of 75%.

The hydroxylated compounds of formulae (XIX) are obtained from the corresponding benzylated compounds (Id) by removing the benzyl group by means of o _a. so-called debenzylation reaction. Debenzylation _J^e (- 20 carried out according to processes which are conventionally used, either by a hydracid or by catalytic hydrogenation, and which are known in the literature: O. Buchi and S.M. Weinreb, J. Am. Chem.

Soc. (1971), Volume 93, page 746 or O. Th. Schmidt and

BL Schmadel, Annalen (1961), Volume 649, page 149. The reaction scheme is the following:

AP/P/ 9 5 / 0 0 7 2 2

AP.00581

The following example illustrates this _ process for the preparation of the compounds of formula (XIX).

(

Example CI10: Preparation of (4RS)-4-(4-hydroxyphenyl) 5 4-methyl-2-methyl thio-l-phenylamino-2-imidazolin-5-one, of expanded formula:

ml of concentrated hydrochloric acid (d « 1.18) are added to a suspension, kept stirred, of 31.2 g (0.075 mol) of (4RS)-4-(4-benzyloxyphenyl)-410 methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one in 370 ml of acetic acid and heating ie carried out at 75°C for 2 h. After having cooled the reaction mixture to room temperature, the latter is poured into 500 ml of ice-cold water and the mixture is then neutralized with a concentrated agueous βodium hydroxide solution. The precipitate formed is stirred for 1 h at 5°C and then filtered, washed with water, sucked dry and dried

AP/P/ 9 5 / 0 0 7 2 2

ΛΡ.00581 under reduced pressure. 22 g (0.067 mol) of (4RS)-4-(4hydr oxypheny 1) - 4 -me thyl - 2 -me thyl thi o -1 -phenyl amino - 2 imidazolin-5-one are thus obtained in the form o# white crystals having a melting point of 206°C with a yield of 90%.

The synthesized imidazolinonee of formula (XIX) are collated in the table below:

OH Position	Yd (%)	M.p. CO
3	68	159
4	90	206

The 4- (benzy 1 oxypheny1) -2-imidazolin-5-onee ..(.Id) are obtained according to one of the processes.

described above.

Process B:

AP/P/ 9 5 / 0 0 7 22

A description is now given of the preparation of the compounds of formula (le):

AP. Ο Ο 5 8 1 in vhich p and R*₁₂ have the same meaning as above and Z^# represents an oxygen or sulphur atom or an N-R_u group in vhich R_u represents a hydrogen atom or a C,-C₆ alkyl group.

These compounds are obtained by reacting

4-(carboxyphenyl)-2-imidazolin-5-one derivatives of formula (XX) vith a chlorinating agent such as thionyl chloride, oxalyl chloride or phosgene, optionally in the presence of a catalyst such as dimethylformamide and in an inert solvent; and vith a nucleophilic compound of formula: Ar₂-(R'₁₂)_p-Z'H (XVIII), in the presence of a base such as an alkali metal or alkalineearth metal carbonate or of an organic base, according to the scheme:

AP/P/ 9 5 / 0 0 7 2 2 (Ie)

The following example illustrates this process for the preparation of the compounds of formula (ie).

Example CF7: Preparation of (4RS)-4-(4-(4chlorophenylaminocarbonyl)phenyl)-4-methyl-2π τ ι η /* r- 4* * *V' . υ υ 38 1 methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 45):

g (0.0028 mol) of (4RS)-4-(4- -- \ carboxyphenyl) -4 -methyl-2 -methylthio-1 -phenylamind=2 5 imidazolin-5-one is dissolved in 20 ml of

1,2-dichloroethane at room temperature. 0.5 ml (0.0056 mol) of oxalyl chloride and then one drop of dimethylformamide are added at this temperature. When gas evolution has ceased, the solvent is evaporated and the acid chloride is taken up in 20 ml of anhydrous THF. 0.4 ml (0.0028 mol) of triethylamine and then 0.71 g (0.0056 mol) of 4-chloroaniline are then added at room temperature. After stirring for 1 h, tha mixture is hydrolysed. After extracting with ethyl acetate, washing the organic phases with a saturated sodium chloride solution, drying and evaporating the solvents, 1 g of brown oil is recovered. After crystallization from diisopropyl ether, filtration and .drying, 0.85 g (0.0018 mol) of (4RS)-4-(4-(420 chlorophenyl aminoc arbonyl) phenyl)-4 -methyl-2methylthio-1-phenylamino-2-imidazolin-5-one is isolated in the form of a beige solid having a melting point of 210*C, with a yield of 65%.

The 4-(carboxyphenyl)-2-imidazolin-5-onee of formula (XX) are prepared by reacting an organolithium compound of formula (XVII) with carbon dioxide gas according to a process analogous to that mentioned in

Advanced Organic Chemistry, J. March, (1985), page 826,

7. 7. I 0 0 / S 6 Zd/dV

AP. 00581

3rd Edition, in other words according to the reaction:

(XVH) (XX)

The reaction is carried out by sparging carbon dioxide gas into the reaction mixture containing the organolithium compound.

The following example illustrates this process for the preparation of the compounds of formula (XX) ·

Example Clll: Preparation of (4RS)-4-(4-carboxyphenyl)4-methyl-2-methylth±o-l-phenylamino-2-imidazolin-5-one, of expanded formula:

g (0.0025 mol) of (4RS)-4-(4-bromophenyl)4-methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one is dissolved under an inert atmosphere in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is cooled to -70*C. 2 equivalents of n-butyllithium (3.2 ml of 1.6M hexane solution) are added at this temperature. After stirring for 15 min at -70*C,

AP/P/ 95/00/2Z sparging is carried out vith dry carbon dioxide. After 30 min, the reaction mixture is hydrolysed at -70C. After extracting vith ethyl acetate and then vashing the organic phase vith a saturated potassium carbonate solution, the aqueous phases are combined and then acidified. After extracting vith ethyl acetate, drying and evaporating the solvents, 0.5 g (0.0014 mol) of (4RS)-4-(4-earhoxyphenyl)-4-methyl-2-methylthio-lphenylamino-2-imidazolin-5-one is recovered in the form of a vhite povder melting at 183C vith a yield of 56%. Process Z:

A description is nov given of the preparation

(If) in vhich R'₁₂, P ^{and 27} have the same meaning as above, 15 and R represents a hydrogen atom, an alkyl, haloalkyl or alkoxyalkyl radical, or an alkylidene radical, the alkyl or alkylidene parts of these radicals containing from 1 to 6 carbon atoms. R retains this definition f~ throughout the specification.

These compounds are obtained by reacting a nucleophilic compound of formula Ar₂-(R'₁₂)_p-Z'H (XVIII) vith a 4-(chloromethylphenyl)-2-imidazolin-5-one of structure (XXIII).

The reaction is carried out in the presence of a base 25 under the conditions conventionally used for condensation between alcohols and various electrophiles and known in the literature: Advanced Organic Chemistry, J. March, (1985), page 342, 3rd Edition, in

AP/P/ 9 5 / 0 0 7 2 2 other words according to the reaction scheme:

(xvm)

Arj—(ΤΤπ)ρ-ΖΉ

Ο

4*'“ *

(If)

Use can be made, as base, of alkali metal or alkaline-earth metal carbonates and hydroxides or of organic bases. The reaction is carried out at a temperature of between 20*C and 150’C. The reaction is carried out in solvents such as alcohols, acetonitrile, aliphatic esters, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, ketones, dimethylformamide, dimethyl sulphoxide or 10 N-methylpyrrolidone.

The following example illustrates this process for the preparation of the compounds of formula (If).

Example CF8; Preparation of (4RS)-4-(4-((2,415 di fluorophenoxy)methyl) phenyl)-4-methyl-2-methy1thio-1phenylamino-2-imidazolin-5-one (Compound No. 47)

0.3 g (0.0083 mol) Of (4RSJ-4-(4chloromethylphenyl)-4-methyl-2-methylthio-iphenylamino-2-imidazolin-5-one is mixed in DMP with

0.11 g (0.0083 mol) of 2,4-difluorophenol, 0.12 g (0.0083 mol) of potassium carbonate and 0.14 g (0.0083 mol) of potassium iodide. The reaction mixture is brought to 80*C for 2 h. After hydrolysing with

Z z L 0 0 / S 6 /d/dV

AP .00581 water, extracting with ethyl acetate, washing the organic extracts with a saturated lithium chloride solution, drying and evaporating the solvents, the honey obtained is crystallized from diisopropyl ether and then filtered. 0.250 g (0.0055 mol) of (4RS)-<-(<((2,4-dif luorophenoxy) methyl) phenyl)-4-methyl-2methylthio-l-phenylamino-2-imidazolin-5-one is thus recovered in the form of a beige precipitate melting at 152*C with a yield of 66%.

The 4-(chioromethylphenyl)-2-imidazolin-5ones of structure (XXIII) are obtained by halogenation of the 4-(hydroxymethylphenyl)-2-imidazolin-5-ones of structure (XXII). Halogenation is carried out according to processes conventionally used for this type of reaction using a hy dr acid or an inorganic acid halide such as SOC1₂, PC1₅, PC1₃ or POC1₃, as mentioned in Advanced Organic Chemistry, J. March, (1985), page 382, 3rd Edition and according to the reaction scheme:

POX, or PX, or PX. or KX or SOO, XCKR

(ΧΧΠ)

The following example illustrates 20 process for the preparation of the compounds of structure (xxill):

Example CI12: Preparation of (4RS)-4-(4chloromethylphenyl) -4-methyl-2-methylthio-l(ΧΧΠΙ) this

AP/P/ 9 5 / 0 0 7 2 2

AP. Ο Ο 5 8 1 phenyl amino-2-imidazolin-5-one, of expanded formula:

0.22 ml (0.0026 mol) of pyridine and then 0.2 ml (0.0026 mol) of thionyl chloride in solution in 1 ml of toluene are added at room temperature to a solution of 0.9 g (0.0026 mol) of (4RS)-4-(4hydr oxyme thy lpheny 1) - 4 -methyl - 2 -me thyl thio -1 phenylamino-2-imidazolin-5-one in 10 ml of toluene. The reaction mixture is brought to 60°C for 3 h and then cooled and hydrolysed. After extracting with ethyl acetate, washing the organic extracts with a saturated sodium chloride solution, drying and evaporating the solvents, a yellow honey is obtained. After chromatography on a silica column (ethyl acetate/ heptane: 50/50), 0.36 g (0.001 mol) of (4RS)-4-(415 -chloromethylphenyl) -4-methyl-2-methylthio-lphenylamino-2-imidazolin-5-one is recovered in the form of a yellow powder melting at 130°C with a yield of 38%.

The (hydroxymethyl)phenyl-2-imidazolin-5-ones of formula (XXIX) are obtained by reduction of the corresponding carbonyl compounds (XXIV). This reduction can be carried out according to processes conventionally used for this type of reaction and described in the literature: Advanced Organic

AP/P/ 95/00722

ΑΡ. Ο Ο 5 8 1

Chemistry, J. March, (1985), pages 1093-6, 3rd Edition and according to the scheme:

The following example illustrates this process for the preparation of the compounds of structure (XXII):

Example CI13: Preparation of (4RS)-4-(4hydroxymethylpheny1)-4-methyl-2-methylthio-lphenylamino-2-imidazolin-5-one, of expanded formula:

1.02 g (0.0026 mol) of MaBH₄ are added to a solution of 9 g (0.0026 mol) of (4RS,-4-(4formylphenyl,-4-methyl-2-methylthio-l-phenylamino-2imidazolin-5-one in 100 ml of absolute ethanol at 0*C. After stirring for 4 h at room temperature, the mixture is hydrolysed and then extracted with ethyl acetate.

The organic extracts are washed with a saturated sodium chloride solution, dried, evaporated and chromatographed on a silica column (ethyl acetate/ heptane: 50/50). 0.9 g (0.00026 mol) of (4RS)-4-(4hydroxymethylphenyl)-4-methyl-2-methylthio-1AP/P/ 95/00722 phenylamino-2-imidazolin-5-one is recovered in the form of a brown powder melting at 146*C with a yield of 10¾.

The synthesized imidazolinones of formula (XXII) are collated in the table below:

OH Position	X	Yd (¾)	M.p. CC)
3	s	76	147
4	8	10	146
5	0	76	157

The carbonyl compounds of formula (XXIV) are 10 prepared by reaction of an organolithium compound of formula (XVII) vith an electrophilic carbonyl compound as described by J. Evans, J. Chem. Soc., (1956), page 4691 and according to the reaction scheme:

AP/P/ 9 5 / 0 0 7 2 2

The following example illustrates this 15 process for the preparation of the compounds of «I structure (XXIV):

Example CI14: Preparation of (4RS)-4-(4-formylphenyl)4-methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one, of expanded formula:

Ο 15 g (0.0025 mol) of 4-(4-bromophenyl)-4methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one is dissolved under an inert atmosphere in 20 ml of anhydrous THP and brought to -70*C. 2 equivalents of n-BuLi (3.2 ml; 1.6M) are added at this temperature. After stirring for 15 min at -70*c, 0.2 ml (0.0025 mol) of dimethylformamide is added in solution in 1 ml of THP. After 30 min, the mixture is hydrolysed at -70*C with a saturated ammonium chloride solution. After extracting with ethyl acetate, washing the organic phases with a saturated sodium chloride solution, drying, evaporating the solvents and chromatography of the crude product on a silica column (ethyl acetate/ heptane: 50/50), 0.55 g of a pale-yellow oil, which precipitates from isopropyl ether, is obtained. 0.35 g (0.001 mol) of (4RS)-4-(4-formylphenyl)-4-methyl-2methylthio-l-phenylamino-2-imidazolin-5-one is thus recovered in the form of a white powder melting at 181*C, i.e. a 40% yield.

AP/P/ 9 5 / 0 0 7 2 2

AP.00581

The eynthesized imidazolinones of formula (XXIV) are collated in the table below:

HCO-Position	Yd (%)	M.p.(’C)
3	48	157
4	40	181

Process J:

A description is now given of the preparation 5 of the compounds of formula (Ig):

in which X' has the same meaning as above.

These compounds are obtained by reaction of a

4-(aminophenyl)-2-imidazolin-5-one of formula (XXV) with an electrophilic radical of formula Ar₂X' + , as defined above, according to the reaction scheme:

AP/P/ 95/00722

AP . Ο Ο 5 8 1

The reaction ie carried out under the conditions conventionally used for condensation between anilines and the various electrophilic compoundsThe reaction ie carried out in the presence of a base. Use may be made, as base, of alkali metal or alkaline-earth metal carbonates or hydroxides or of organic bases. The reaction is carried out at a temperature of between 20*C and 150*C and ie carried out in a solvent such as: alcohols, acetonitrile, aliphatic esters, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, dimethylformamide, dimethyl eulphoxide or N-methylpyrrolidone.

The following example illustrates this process for the preparation of the compounds of formula (lg).

CF9: Preparation of (4RS)-4-(4benz oy laminophenyl ,-4 -me thyl - 2 -me thyl thio -1 phenylamino-2-imidazolin-5-one (Compound No. 1) :

0.86 g (6.1 mmol) of benzoyl chloride is 20 added to a solution of 2 g (6.1 mmol) of (4RS)-4-(4aminophenyl )-4 -methyl - 2 -methyl thio -1 -phenyl amino-2 imidazolin-5-one and 0.62 g (6.1 mmol) of triethylamine in 50 ml of tetrahydrofuran. The mixture is allowed to

AP/P/ 95/00722

AP.=0581 react for 2 h at room temperature, the triethylamine hydrochloride precipitate ie filtered and the filtrate is then concentrated under reduced pressure. The scrude product is crystallized from diethyl ether. 2.47 375 (5.7 mmol) of (4RS)-4-(4-benzoylaminophenyl)-4-methyl2 -me t hy 1 thi 0 -1 - phenyl amino - 2 - imida zolin-5-one (Compound No. 1) are thus recovered in the form of a white solid melting at 212°C with a yield of 94%.

The 4-(aminophenyl)-2-imidazolin-5-ones of 10 formula (XXV) are prepared by reduction of the

4-(nitrophenyl)-2-imidazolin-5-ones of formula (XXVI). Reduction is carried out according to the usual methods for the reduction of nitro groups, such as, for example, by catalytic hydrogenation in the presence of a mixture of charcoal and palladium (palladiumcharcoal) : F. Melani, L. Cecchi and Q. Filacchion,

J. Heterocyclic Chem. (1984), Volume 21, page 813, according to the scheme:

AP/P/ 95/00722

The following example illustrates this process for the preparation of the compounds of formula (XXV).

Example CII5: Preparation of (4RS)-4-(4-aminophenyl)-4methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one, of expanded formula:

AP . C ύ 5 8 1

g (39 mmol) of (4RS)-4-(4-nitropnenyl)-4me t hy 1 - 2 - me thy 1 thi o -1 - pheny 1 amino - 2 - imi da ζ ο 1 in - 5 - one, 100 ml of ethyl acetate and 3 g of 10¾ palladiumcharcoal are charged to a 500 ml autoclave. The autoclave ie pressurized with 9 bars of hydrogen and heated for 12 hours at 50*C. After filtering the catalyst and concentrating under reduced pressure, a yellow honey is recovered which crystallises from ether. After filtering and drying, 11 g of (4RS) -4-(410 aminophenyl) -4-methyl-2-methylthio-l-phenylamino-2imidazolin-5-one are obtained in the form of a yellow solid melting at 194*C, i.e. a yield of 87¾.

By carrying out the preparation in an ..analogous way, (4RS) -4-(3-aminophenyl) -4-methyl-i=_^ methylthio-l-phenylamino-2-imidazolin-5-one was obtained with a yield of 95¾ in the form of a yellow solid melting at 100*C.

The 4-(nitrophenyl)-2-imidazolin-5-ones of formula (XXVI) are obtained by one of the processes described in European Patent Application EP 0,551,048, published on 14 July 1993, in the case where Y S and n 1; according to a process analogous to Process C

AP/P/ 9 5 / 0 0 7 2 2 described above in the case where n is equal to 1 and Y

AP . 0 0 5 8 1 means O; or according to a process analogous to Process D described above when n is equal to 0.

Process K:

λ description is now given of the preparation of the compounds of formula (Ih):

Ar₂-(R· 12)P“C'Z-CHR 0

in which R'₁₂, p and Z' have the same meaning as above. These compounds are obtained by reacting derivatives of (XXVII) type with an electrophilic agent of formula Xr₂-(R'₁₂)_p-CO-Cl in the presence of a base such as an alkali metal or alkaline-earth metal carbonate or of an organic base in an inert solvent, according to the scheme:

HT-CHR l/yN w

H (XXVI I)

A'J-»' ₁₂>ρ-ς-ζ·-<:ι« -r₂

W 'f»» (Ih) H

u.

r\

The following example illustrates this process for the preparation of the compounds of formula (Ih) .

ΛΡ. 0 0 5 3 1

Example CF10: Preparation of (4RS)-4-(4-(4chlorobenzoyloxymethyl) phenyl) - 4 -me thy 1 - 2 -me thyl thio -1 phenylamino-2-imidazolin-5-one (Compound No. 94),-off expanded formula: IT'

0.42 ml (0.0029 mol) of triethylamine and then 0.38 ml (0.0029 mol) of para-chlorobenzoyl chloride are added at room temperature to a solution of 1 g (0.0029 mol) of (4RS)-4-(4-hydroxymethylphenyl)-4methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one in

20 al ef THT. After stirring for a half-hour at room temperature, the mixture is hydrolysed and than extracted with ethyl acetate. The organic extracts are washed, dried and then evaporated. After mixing with -isopropyl ether, 0.6 g of (4RS)-4-(4-(4- .— chlorobenzoyloxymethyDphenyl) -4-methyl-2-methylthio-1phenylamino-2-imidazolin-5-one is recovered in the form of a white powder melting at 129°C with a yield of 43%.

The imidazolinone of formula (XXVII) can be prepared according to one of the processes described above, especially by a process analogous to that used for the preparation of the imidazolinone of formula

AP/P/ 95/00722 (XXII).

A P . -- -581

Process L:

A description is now given of the preparation of the compounds of general formula (Ii):

(Ii) in vhich Ar₂, R'₁₂ and Z' have the same meaning as above 5 and R'₂ represents a hydrogen atom, an alkyl or haloalkyl group, each containing 1 to 3 carbon atoms, or a cyclopropyl group.

These compounds are obtained by reacting benzyl derivatives of 2-imidazolin-5-ones of formula 10 (XXVIII) with a nucleophile of formula BZ'Rj', optionally in the presence of a base such as an alkali metal or alkaline-earth metal carbonate organic base, according to the scheme:

or of an

HZR₂‘ bass, solvent (xxvm)

AP/P/ 95/00722

The following example illustrates this process for the preparation of compounds of

AP . Ο Ο 5 8 1 formula (Zi) .

Example CPU: Preparation of (4RS)-4-(4(methoxybenzyl)phenyl)-4-methyl-2-methylthio-l- — ♦ phenylamino-2-imidakolin-5-one (Compound No. 107lT*Of expanded formula:

1.5 g (0.0035 mol) of (4RS)-4-(4(chlorobenzyl) phenyl) -4-methyl-2-methylthio-lphenylamino-2-imidazolin-5-one are added to a solution of 0.37 g (0.007 mol) of sodium methoxide in 30 ml of methanol under an inert atmosphere. The reaction mixture is heated at 50*C for a half-hour. After cooling, the mixture la hydrolysed and then extracted .with ethyl acetate. The organic extracts are washed with a saturated sodium chloride solution, dried and then evaporated. The crude product thus obtained is then chromatographed on a silica column (eluent: 50/50 heptane/ethyl acetate). 0.7 g of (4RS)-4-(4(me thoxybenzy1) phenyl) - 4 -me thyl - 2 -me thyl thio -1 phenylamino-2-imidazolin-5-one is recovered in the form of a white powder melting at 161^eC with 47% yield.

The benzyl derivatives of 2-imidazolin-5-ones of formula (XXVIII) are prepared according to one of

AP/P/ 95/00722 et the processes described above, especially according to a process analogous to that used for the preparation of the compound of formula (XXIII) from the compound-of formula (XXII).

Process M:

A description is now given of the preparation of the compounds of formula (Ij):

in which R'xa and p have the same meaning as above, Y represents a sulphur atom and X represents a halogen atom, preferably a chlorine atom.

These compounds are obtained by halogenation of the compounds of formula (XXIX). Halogenation is carried out according to processes conventionally used _fpr this type of reaction using a hydracid or an 15 inorganic acid halide such as SOCl₂, PC1₅, PC1₃ or

POC1₃, as mentioned in Advanced Organic Chemistry,

J. March, (1985), page 382, 3rd Edition and according to the reaction scheme:

AP/P/ 9 5 / 0 0 7 2 2

AP. 0 0$« 1

TO

The following example illustrates this process for the preparation of the compounds of formula dj) I

Example Cri2> Preparation of HRS)-4-(45 (chlorobenzyl)phenyl)-4-methyl-2-methylthio-1phenylamino-2-imidazolin-5-one (Compound No. 106), of expanded formulai

AP/P/ 9 5 / 0 0 7 2 2

1.4 ml (0.015 mol) of pyridine and then 1.15 ml (0.015 mol) of thionyl chloride are added at

0^eC to a solution of 6.5 g (0.015 mol) of (4RS)-4-(4((phenyl)hydroxymethyl)phenyl)-4-methyl-2-methylthio-1phenylamino-2-imidazolin-5-one in 100 ml of methylene chloride. The reaction mixture is then brought to

AP. 00581 e

²⁰ reflux for a half-hour and is then cooled to room temperature, hydrolysed and extracted with methylene chloride. The organic extracts are washed, dried and then evaporated. After mixing the crude product diisopropyl ether, 4.7 g of (4RS)-4-(4(chlorohenzy 1) phenyl) -4-methyl-2-methylthio-1phenylamino-2-imidazolin-5-one are recovered in the form of a white powder melting at 153 °C with a yield of

69%.

The compound of formula (XXIX) is obtained according to one of the processes described above, especially according to the process used for preparing the compound of formula (XXII).

The imidazolinones of formula (I), also corresponding to one of the formulae (Ik) or (II) Π indicated below, are collated in the following tables, ^α c

these imidazolinonee having been prepared according to ·*>

c one of the processes which have been described above .Xindicated in the corresponding column). _

In these tables, the methyl, ethyl, propyl, pyridyl, pyrimidinyl, acetyl, phenyl and benzyl radicals are represented respectively by Me, Et, Pr, Py, Pyrim, Ac,

Ph and Bn and M.p. means melting point (M.p.).

AP . 0 0 5 8 1

(Ik)

Ν*	W	Ar2x	(Y)n- r2	*3	Mp. CC)	PlOCCH
1	0	4-(PhC(O)NH)	SMe	Ph	212	J
2	0	4-(PhC(O)NH)	OMe	Ph	150	c
3	0	4-(4-Cl-PhC(O)NH)	SMe	Ph	219	J
4	0	4-<4-Cl-PhC(O)NH)	OMe	Ph	182	c
5	0	4-(PhNHC(O)NH)	SMe	Ph	160	J
6	0	4-(PhNHC(O)NH)	OMe	Ph	135	c
7	0	4-(PhSO2NH)	SMe	Ph	185	J
8	0	3-BnO	SMe	Ph	112	B

AP.00581

9	0	4-BnO	OMe	Ph	127	C
10	0	4-BnNH	SMe	Ph	114	'Ί
11	0	4^Bn	OMe	Ph	148
12	0	4-Bn	SMe	Pb	145	B
13	0	4-BnO	SMe	3-F-Ph	honey	B
14	s	4-<2-PhenethyI)	SMe	Pb	118	A
15	0	4-<4-F-BnO)	SMe	Ph	167	G
16	0	4-(3-F-BnO)	SMe	Ph	133	G
17	0	, 4-(2-F-BnO)	SMe	Ph	159	G
18	0	4-((5-CF3-2-Py)-O]	SMe	Ph	163	G
19	0	4-{4-Me-BnO)	SMe	Ph	176	G
20	0	4-<4-CFrBnO)	SMe	Ph	170	G
21	0	3-<PhC(O)NH)	SMe	Ph	130	J
22	0	4-{3-Me-BnO)	SMe	Ph	151	G
23	0	4-(2-Me-BnO)	SMe	Ph	146	G
24	0	4-P,5-<Me)2-BnO]	SMe	Ph	149	G
25	0	4-PhS	SMe	Ph	138	B
26	0	4-PhS	SMe	3-F-Ph	118	B~ '
27	0	4-PhS	SMe	3-CI-Ph	95	B
28	0	4-[Ph(CH2)2]	SMe	Ph	155	B
29	0	3-<BnNH)	SMe	Ph	72	J
30	0	4-[4-Cl-PhCH(OH)]	SMe	Ph	94	E
31	0	4-[PhCH2CH(OH)]	SMe	Ph	83	E
32	0	4-(2-Py-CH2O)	SMe	Ph	139	G
33	0	4-(PhCH(CH3)O]	SMe	Ph	137	G
34	0	4-<4-Py-CH2O)	SMe	Ph	215	G

AP/P/ 9 5 / 0 0 7 2 2

AP . Οϋ5 8 1

35	0	4-(3-Py-CH2O)	SMe	Ph	138	G
36	0	4-<5-CF3-2-PyO)	OMe	Ph	88	c
37	0	4-(PhNHC(0)0)	SMe	Ph	201
38	0	4-(PhS(0)]	SMe	Ph	132	8
39	0	4-[PhS(0)J	SMe	3-Cl-Ph	164	8
40	0	4-(PhS(0)]	SMe	3-F-Ph	115	B
41	0	4-(PhS02)	SMe	Ph	80	B
42	0	4-[Ph(CH2)2]	OMe	Ph	100	C
43	0	4-(PhCO2)	SMe	Ph	170	G
44	0	PhC0CH20	SMe	Ph	163	G
45	0	4-[4-Cl-PhNHC(O)]	SMe	Ph	210	H
46	0	4-(PhNHC(0)]	SMe	Ph	105	H
47	0	4-(2,4-diF-PhOCH2)	SMe	Ph	152	I
48	0	4-<3-Cl-PhNHCO)	S-Me	Ph	115	H
49	0	4-(4-Cl-PhCMe(0H))	S-Me	Ph	90	E
50	0	4-(2-(4,6-diMePyrim)O)	S-Me	Ph	87	G
51	0	4-(2-Me-PbCH2O)	S-Me	Ph	129	G_..
52	0	4-(PhS0j)	S-Me	3-Cl-Ph	153	B
53	0	4-(PhSO2)	S-Me	3-F-Ph	188	B
54	0	4-(PhS)	Et	Ph	85	D
56	0	4-(PhOCH2)	MeS	Ph	153	I
57	0	4-<4-Cl-PhOCH2)	MeS	Ph	164	I
58	0	4-(3-Cl-PhOCH2)	MeS Ph	149	I
59	0	4-(2-Cl-PhOCH2)	MeS	Ph	102	I
60	0	4-(4-F-PhOCH2)	MeS	Pb	132	I

ΑΡ/Ρ/ 9 5 / 0 0 7 22

AP. Ο 05Ϊ 1

61	0	4-<3-F-PhOCH2)	MeS	Ph	147	I
62	0	4-<2-MeO-PhOCH2)	MeS	Ph	156
63	0	3-<PhCH2O)	MeO	Ph	56
84	0	3-<PhCH2O)	OMe	Ph	56	C
85	0	4-(2-F-PhOCH2)	SMe	Ph	153	I
86	0	4-PhSO	Et	Ph	honey	D
87	0	4-PI1SO2	Et	Ph	194	D
88	0	4-(4-F-PhC(O))	SMe	Ph	163	E
89	0	4-{4-MeO-Ph)OCH2	SMe	Ph	151	I
90	0	4-<3-MeO-Ph)OCH2	SMe	Ph	131	I
91	0	4-{4-CF3-Ph>OCH2	SMe	Ph	173	I
92	0	4-<3-MeO-PhCH2O)	SMe	Ph	126	G
93	0	4-<2-F-PhOCH2)	OMe	Ph	165	C
94	0	4-{4-Cl-PhCO2CH2)	SMe	Ph	129	K
95	0	4-PhSO	OMe	Ph	honey	c
96	0	4-<4-Cl-Ph)CH20	SMe	Ph	187	G
98	0	4-PhCH(0H)	SMe	Ph	honey	E
99	0	4-(4-MeO-PhCH2O)	SMe	Ph	156	G“
100	0	4-(4-NC-PhCH2O)	SMe	Ph	209	G
101	0	4-PhOCH2	OMe	Ph	158	c
102	0	4-(3-01^00¼)	OMe	Ph	147	c
103	0	4-(3-F-PhOCH2)	OMe	Ph	179	c
104	0	4-(4-F-PhOCH2)	OMe	Ph	141	c
’05	0	4-(4-CF5-PtOCH-)	OMe	Ph	143	c
106	0	4-PbCH(Cl)	SMe	Ph	153	M
107	0	4-PhCH(0Me)	SMe	Ph	161	L

7. 7, / Ο Ο / c. « zj/

AP. ' 0 5 8 1

108	0	4-PhCH(0Me)	OMe	Ph	136	c
109	0	4-PhS	SMe	2,5-<liF-Ph	104	Ti *
110	0	4-PhCO	SMe	Ph	162
111	0	4-{2-CN-PhCH2O)	SMe	Ph	174	G
112	0	4-PhCO	OMe	Ph	83	c
113	0	3-<4-Cl-PhCOOCH2)	SMe	Ph	156	K
114	0	3-<4-Cl-PhCOOCH2)	OMe	Ph	105	c
115	0	4-PhS	SMe	2,3-diF-Ph	113	B
116	0	4-{3-CN-PhCH2O)	SMe	Ph	171	G
117	0	3-<4-CF3-PhOCH2)	SMe	Ph	127	I
118	0	3-<PhCO)	SMe	Ph	149	ε
119	0	3-<4-Cl-PhCH(OH))	SMe	Ph	156	ε
120	0	3-(4-014^00¾)	SMe	Ph	112	I
121	0	3-(4-CF3-PhOCH2)	OMe	Ph	102	c
122	0	3-<PhCH(OMe))	OMe	Ph	120	c
123	0	3<4-Cl-PhCH(OMe))	OMe	Ph	120	c
124	0	3-<4-O-Ph0CH2)	OMe	Ph	honey	c
125	0	3-<4-Me-PliOCH2)	SMe	Ph	87	Γ
126	0	3-(4-F-PhOCH2)	OMe	Ph	136	c
127	0	3-(4-F-PbCH(OH))	SMe	Ph	128	E
128	0	3-(4-CF3-PfaCH(OH))	SMe	Ph	145	ε
129	0	3-(4-OMe-PbCH(OH))	SMe	Ph	114	ε
130	0	3-(4-F-PhCH(OMe))	OMe	Ph	131	c
131	0	3-{PhCH2O)	SMe	Ph	132	I
132	0	3-(PhCO)	SMe	Ph	honey	E
133	0	3-(PhOCH2)	OMe	Ph	honey	C

AP/P/ 95/00722

AP.00581

134	0	4-{4-FPhCH2O)	OMe	Ph	171	G
135	0	4-[(2-Bcnzothiazolyl)O]	SMe	Ph	144

(II)

Ν’	At2	R	M-p-CC)	PlOCCH
64	4-F-Ph	NOj	171	F
65	Ph	NOj	148	F
66	2-F-Ph	NOj	115	F
67	3-F-Ph	NOj	112	F
68	4-Cl-Ph	NOj	146	F
69	3-Cl-Ph	NO2	103	F
70	2-Cl-Ph	NO2	93	F
71	2-Naphthyl	NO2	131	F
72	2-HO-Ph	NO2	97	F
73	4-HOPh	NOj	145	F
74	4-MeOPh	NO2	134	F
75	3-MeOPh	NO2	165	F

AF/P/ 95/00722

AP. 00561

76	4-MePh	no2	115	F
77	2-MePh	no2	120	F
1 78	3-MePh	no2	113	f
1 79	Ph	cf3	166	r
I 80	4-Me-Ph	cf3	149	F
81	4-MeO-Ph	cf3	151	F
82	4-Cl-Ph	cf3	149	f I
83	3-F-Ph	cf3	143	F |

Certain compounds described above as intermediates, namely the compounds of formulae IZIa, nib, IV, VII, XIII, XIX, XX, XXII, XXIV and XXVII in vhich the substituents have the meaning defined above also constitute a feature of the invention. As vith the compounds defined by the general formula (I) of the invention, these compounds can exist in one or a number of isomeric forms depending on the number of asymmetric centres in the molecule. The invention therefore also relates both to the optical isomers of the compounds vhich can be used as intermediates and to their corresponding racemic mixtures and diastereoisomers, separate or as a mixture, and especially to the enantiomers of the compounds comprising the asymmetric carbon carrying R,. Separation of the optical isomers and/or of the diastereoisomers from the racemic mixtures can be carried out according to methods known per se. Enantiomers of the intermediates comprising the

AP/P/ 95/00722 /,η . <·> c 5 θ 1 asymmetric carbon carrying R_x can also be prepared, according to processes known per se or according to the processes described above, from chiral starting materials and especially from chiral a-amino acidsr**o£ formula (IX), that is to say from the compounds of formula (IX) in which the carbon attached to R_x is an asymmetric carbon.

The invention also relates to a process for the treatment of cultivated plants affected or capable of being affected by fungal diseases, characterized in that an effective dose of a compound according to the formula (I) is applied on the aerial parte of these plants. Effective dose is understood to mean an amount sufficient to make possible control and destruction of the fungi present on these cultivated plant·. The use doses can, however, vary within wide limits depending on the fungus to he controlled, type of crop, the weather conditions and depending on the compound used.

In practice, the compounds are advantageously applied at doeee of 0.002 to 5 kg/ha and preferably of

0.005 to 1 kg/ha.

Fungal dieeases ie understood to mean the diseases caused by phytopathogenic fungi and especially those of the family of the Oomycetes, Ascomycetee and

Easidicmycetes.

Mention may be made, among the crops which can form the subject of a fungicidal treatment using a comoound according to the invention, of rice, cereals,

AP/P/ 95/00722 especially wheat and barley, and vegetable plants. Rice is a preferred crop for fungicidal treatments using a compound according to the invention. — ·

The examples which follow illustrate th<_good fungicidal activity of the compounds according to the invention.

Example Bl: In vivo test on Plricularla oryzae responsible for piriculariosis in rice:

An aqueous suspension of the active material to he tested, having the following composition, is prepared, hy fine milling:

- active material: 60 sig

- acetone: 5 ml

- surface-active agent (oleate of polyoxyethylenated derivative of sorbitan) diluted to 10% in water: 0.3 ml

- made up to 60 ml with water.

This aqueous suspension is then diluted with .water to obtain the desired concentration of active^ material.

AP/P/ 9 5 / 0 0 7 2 2

Rice, seeded in email pots in a 50/50 mixture of enriched peat and pozzolana, is treated at the approximately 10 cm-high stage (which corresponds to the 2-3 leaf stage) by epraying with the above aqueous suspension.

After 24 hours, an aqueous suspension of spores of Plricularla orvzae, which spores are obtained from a 15-day culture and subsequently suspended at a

AP.00581 concentration of 100,000 per cm³, is applied to the leaves.

The rice seedlings are incubated for 24--hours (25*C, 100% relative humidity) and are then put inram observation cell, under the same conditions, for 5 days.

Reading is carried out 6 days after infection.

Under these conditions, at a dose of 1 g/1, a 10 good (at least 75%) or total protection is observed with the following compounds: 9, 11, 15, 16, 23, 27 to 29, 31 to 33, 35 to 37, 42, 67, 68, 84, 92, 94, 95, 96, 102, 104, 105, 108, 109, 112, 114 and 121.

Example B2: In vivo test on Pucciaia 15 recondite responsible for brown rust of wheat:

An aqueous suspension of the active material to be tested, having the following composition, is prepared, by fine stilling:

o - active material: 60 mg _

- acetone: 5 ml

- surface-active agent Tween 80 (oleate of polyoxyethyleneted derivative of sorbitan) diluted to 10% in water: 0.3 ml

- made up to 60 ml with water.

This aqueous suspension is then diluted with water to obtain the desired concentration of active material.

AP/P/ 9 5 / 0 0 7 2 2

Wheat, seeded on a 50/50 peat/pczzolana

AP.0 0 5 8 1 substrate in a small pot and maintained at 12°C, ia treated at the 10 cm-high stage by spraying with the above aqueous suspension. =. <

After 24 hours, en aqueous suspension of— spores (100,000 sp/cm³) is sprayed on the wheat; this suspension was obtained from infected seedlings. The wheat is then placed for 24 hours in an incubation cell, at approximately 20°C and at 100% relative humidity, and then for 7 to 14 days at €0% relative humidity.

Monitoring of the condition of the seedlings is carried out between the 8th and 15th day after infection, by comparison with an untreated control.

Under these conditions, at a dose of 1 g/1, a good (at least 75%) or total protection is observed with the following compounds: 4, 8 to 13, 15 to 18, 20 to 28, 31 to 33, 35, 36, 38, 40 to 43, 48, 49, 73, 79, 81, 84, 85, 89, 90, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 115, 116,

3V* ¹²⁰ ·“<* ¹²¹ · __ example B3: In vivo test on Septoria tritici responsible for septoria disease of wheat:

An aqueous suspension, with a concentration of 1 g/1, of the active material tested is obtained by milling 60 mg of the latter in the following mixture:

- acetone: 5 ml

- surface-active agent (oleate of polyoxyethylenated derivative of sorbitan) diluted to 10%: 0.3 ml

AP/P/ a 5 / 0 0 / 2 2

AP . 0 0 5 8 1 ©

r 20 and then the volume is adjusted to 60 ml with water.

This aqueous suspension is then diluted_with water to obtain the'desired concentration of active material.

Wheat seedlings (variety Darius), seeded on a 50/50 peat/pozzolana substrate and grown under glass at a temperature of 10-12°C, are treated at the 1-leaf stage (size of approximately 10 cm) by spraying with the active material suspension described above.

Seedlings, used as controls, are treated by spraying with an aqueous solution which does not contain the active material.

hours after treatment, the seedlings are infected by spraying with an aqueous suspension of spores (500,000 sp/ml) harvested from a 7-day old culture.

After infection, the seedlings are placed at 18*C in a humid atmosphere. Assessment is carried out 20 days after infection, by comparison with the control seedlings.

Under these conditions, at a dose of 1 g/1, a good (at least 75%) or total protection ia observed with the compounds: 9, 15, 21, 23, 32, 36, 49, 73, 88, 89, 90, 93, 94, 95, 98, 104, 105, 108, 112, 114, 117, 118, 120 and 121.

Another subject of the present invention is ccr.positions, which can be used as fungicidal agents,

AP/P/ 95/00 7.22

AP. C Ο 5 8 1 containing, ae active material(a), one (or a number of) compound according to the formula (I), as described earlier, mixed with solid or liquid vehicles which are acceptable in agriculture and surface-active agents which ere also acceptable in agriculture. In particular, inert and conventional vehicles and conventional surface-active agents can be used.

These compositions can also contain all kinds of other ingredients euch as, for example, protective colloids, adhesives, thickening agents, thixotropic agents, penetration agents, stabilizing agents, sequestering agents end the like. More generally, the compounds used in the invention can be used in combination with any of the solid or liquid additives which correspond to the usual formulating techniques.

Generally, the compositions according to the invention usually contain from 0.05 to approximately 95% (by weight) of a compound according to the invention (subsequently called active material), ons or more solid or liquid vehicles and, optionally, one or more surface-active agents.

The term vehicle*, in the present account, means a natural or synthetic, organic or inorganic material with which the compound is combined in order to facilitate its application to the plant, to seeds or to the soil. This vehicle is therefore generally inert and it has to be acceptable in agriculture, especially to the treated plant. The vehicle can. be solid (claye,

AP/P/ 95/00 7 22

AP . Ο Ο 5 β 1 ©

Γ 20 natural or synthetic silicates, silica, resins, waxes, solid fertilizers, and the like) or liquid (water, alcohols, especially butanol, and the like). <

The surface-active agent can be an (— emulsifying, dispersing or wetting agent of ionic or nonionic type or a mixture of such surface-active agents. There may be cited, for example, salts of poly(acrylic acids), salts of lignosulphonic acids, salts of phenolsulphonic or naphthalenesulphonic acids, polycondensates of ethylene oxide with fatty alcohols or fatty acids or fatty amines, substituted phenols (especially alkylphenols or arylphenols), salts of •stars of sulphosuccinic acids, derivatives of taurine (especially alkyltaurates), phosphoric esters of polyoxyethylene ted alcohols or phenols, esters of fatty acids and of polyols, and the derivatives of the above compounds having a sulphate, sulphonate or phosphate functional group. The presence of at least one surfaceactive agent is generally indispensable where the_ compound and/or the inert vehicle are not Soluble, in water and where the vector agent of the application is water.

Thus, the compositions for agricultural use according to the invention can contain the active materials according to the invention within very wide limits, ranging from 0.05% to 95% (by weight). Their surface-active agent content is advantageously between 5% and 40% by weight.

AP/P/ 95/00722 e

Γ 20 z\P . 0^581

These compositions according to the invention are themselves in fairly diverse, solid or liquid forms. — «

Thera may be mentioned, as solid composition forms, powders for dusting (containing the compound at a content of up to 100%) and granules, especially those obtained by extrusion, by compacting, by impregnation of a granulated vehicle, or by granulation from a powder (the content of the compound in these granules being between 0.5 and 80% for the latter cases), tablets or effervescent tablets.

The compounds of formula (X) can also be used in the form of powders for dusting; it is also possible to use a composition comprising 50 g of active material and 950 g of talc; it is also possible to use a composition comprising 20 g of active material, 10 g of finely divided silica and 970 g of talc; these constituents are mixed and milled and the mixture is .applied by dusting. _

As composition forms which are liquid or intended to constitute liquid compositions during application, there may be mentioned solutions, in particular water-soluble concentrates, emulsifiable concentrates, emulsions, suspension concentrates, aerosols, wettable powders (or errayable powder), pastes or gels.

The emulsifiable or soluble concentrates most often comprise 10 to 80% of active material, while the

AP/P/ 95/00722

AP. Ο Ο 58 1 ready-to-apply solutions or emulsions contain 0.001 to

20% of active material.

In addition to the solvent, the emulsifiable concentrates can contain, when this ie necessary,—2 to 5 20% of suitable additives such as the stabilizing agents, surface-active agents, penetration agents, corrosion inhibitors, dyes or adhesives mentioned above.

It is possible, hy diluting these 10 concentrates with water, to obtain emulsions of any desired concentration which are particularly suitable for application to crops.

By way of example, the composition of several emulsifiable concentrates will now be given:

BC Example 1

400 g/1 24 g/1

1« ail 200 g/1 litre concentrate

- active material

- alkaline dodecyibenzenesulphonate

- oxyethylenated nonylphenol containing 10 molecules of ethylene oxide

- cyclohexanone

- aromatic solvent qs

According to another emulsifiable formula, there are used:

EC Example 2

- active material

- epoxidized vegetable oil

- mixture of alkylarylsulphonate and

250 g g

of ether of polyglycol and fatty alcohols

100 g

AP . Ο Ο 5 8 1

- dimethylformamide 50 g

- xylene 575 g

The suspension concentrates, which can Also be applied by «praying, are prepared eo a· to produce a stable fluid product which does not settle out and they generally contain from 10 to 75% of active material, from 0.5 to 15% of surface-active agents, from 0.1 to 10% of thixotropic agents, from 0 to 10% of suitable additives, such as antifoaming agents, corrosion inhibitors, stabilizing agents, penetration agents and ¹ adhesives and, as vehicle, water or an organic liquid in which the active material has little or no solubility: certain solid organic materials or inorganic salts can be dissolved in the vehicle to help in preventing sedimentation or as antifreeze for the water.

By way of example, the composition of a suspension concentrate will now he given:

20 - active material	500 .	9
- polyethoxylated tristyrylphenyl phosphate	50	9
- polyethoxylated alkylphenol	50	9
- sodium polycarboxylate	20	9
- ethylene glycol	50	9
2 5 - organopolysiloxane oil (antifoam)	1	9
- polysaccharide	1.5	9
- water	316.5	9
The wettable powders (or sprayable	powders)

AP/P/ 9 5 / 0 0 7 2 2 are generally prepared so that they contain 20 to 95% of active material, and they generally contain, in addition to the solid vehicle, from 0 to 30% of a_ < wetting agent, from’3 to 20% of a dispersing agent—and, when necessary, from 0.1 to 10% of one or more stabilizing agents and/or other additives, such as penetration agents, adhesives, or anticaking agents, dyes, and the like.

In order to obtain the sprayable powders or 10 wettable powders, the active materials are intimately mixed in suitable mixers with the additional substances and the mixture is milled in mills or other suitable grinders. Sprayable powders are thereby obtained whose wettability and suspenaihility are advantageous; they can be suspended in water at any desired concentration and these suspensions can be used very advantageously in particular for application to plant leaves.

Instead of wettable powders, it is possible ,pp produce pastes. The conditions and methods for _ producing and using these pastes are similar to those for the wettable powders or sprayable powders.

By way of example, various wettable powder (or sprayable powder) compositions will now be given:

WP Example 1

- active material 50 %

- ethoxylated fatty alcohol (wetting agent) 2.5%

- ethoxylated phenylethylphenol (dispersing agent) 5 %

AP/P/ 9 5 / 0 0 7 2 2

A ⁿ η Γ, 5 8 1

- chalk (inert vehicle)

WP Example 2

- active material ” ^C13 branched-type Synthetic oxo alcohol ethoxylated with 8 to 10 ethylene oxide (wetting agent)

- neutral calcium lignoeulphonate (dispersing agent)

- calcium carbonate (inert filler) qs

WP Example 3:

This wettable powder contains the ingredients as in the above example, in the below t

- active material

- wetting agent

- dispersing agent

- calcium carbonate (inert filler) qs

WP Example 4:

_^>ctive material • ethoxylated fatty alcohol (wetting agent) * ethoxylated phenylethylphenol (dispersing agent)

WP Example 5:

- active material

- mixture of anionic and nonionic surface-active agents (wetting agent)

- sodium lignoeulphonate (dispersing

42.5%

Ms .

0.75% % 100. '% same proportions %

1.50% %

100 %

SO %

% %

2.5 %

AP/P/ 95/00722

AP.00581 agent) 5 %

- kaolin clay (inert vehicle) 42.5 %

The aqueous dispersions and emulsions, for example the composition· obtained by diluting a ~~ wettable powder or an emulsifiable concentrate according to the invention using water, are included within the general scope of the present invention. The emulsions can be of water-in-oil or oil-in-water type and they can have a thick consistency like that of a mayonnaise.

The compounds according to the invention can be formulated in the form of water-diaperaible granules also included in the scope of the invention.

These dispersible granules, with an apparent 15 density generally of between approximately 0.3 and 0.6, have a particle size generally between approximately 150 and 2,000 and preferably between 300 and 1,500 microns.

___ The active materiel content of these granges is generally between approximately 1% and 90%, and preferably between 25% and 90%.

The remainder of the granule is essentially composed of a solid filler and optionally of surface-active adjuvants which confer water25 dispersibility properties on the granule. These granules can be essentially of two distinct types depending upon whether the filler used is soluble or insoluble in water. When the filler is water-soluble,

AP/P/ 9 5 / 0 0 7 2 2

ΛΡ 00581 it can be inorganic or, preferably, organic. Excellent results have been obtained with urea. In the case of an insoluble filler, the latter is preferably inorganic^, such as, for example, - kaolin or bentonite. Zt is^then advantageously accompanied hy surface-active agents (at an amount of 2 to 20% by weight of the granule) of which more than half consists, for example, of at least one essentially anionic dispersing agent such as an alkali metal or alkaline-earth metal polynaphthalene sulphonate or an alkali metal or alkaline-earth metal lignosulphonate, the remainder consisting of nonionic or anionic wetting agents such as an alkali metal or alkaline-earth metal alkylnaphthalene sulphonate.

Moreover, although this is not indispensable, it is possible to add other adjuvants such as antifoaming agents.

The granule according to the invention can be prepared by mixing the required ingredients and then .granulating according to several techniques known _τ per se (pelletizer, fluid bed, atomizer, extrusion, and the like). Generally, the preparation is completed hy crushing followed by sieving to the particle size chosen within the abovementioned limits. It is alternatively possible to use granules obtained as above and then impregnated with a composition containing the active material.

Preferably, it is obtained by extrusion, the preparation being carried out as shown in the

AP ,?058Ί so examples below.

DG Example 1; Dispersible granules

90% by weight of active materiel and 10% ef urea in the pearl fora are mixed ia a mixer. The~— mixture is then milled in a pin mill, λ powder is obtained which is moistened with approximately 8% by weight of water. The damp powder is extruded in a perforated-cylinder extruder, λ granule is obtained which is dried and then crushed and sieved so as to retain only the granules with a size of between 150 and ( 2,000 microns respectively.

DG Example 2: Dispersible granules

The following constituents are mixed in a mixer:

- active material 75%

- wetting agent (sodium alkylnaphthalene sulphonate) 2%

- dispersing agent (sodium polynaphthalene e ^sulphonate) _

- water-insoluble inert filler (kaolin) . 15%

This mixture is granulated in a fluid bed, in the presence of water, and is then dried, crushed and sieved so as to produce granules of between 0.15 and

0.80 oa in size.

These granules can be used alone or in solution or dispersion in water so as to produce the required dose. They can also be used to prepare combinations with other active materials, especially

AP/P/ 9 5 / 0 0 7 2 2

ΑΓ . ί' V 5 S 1 fungicides, the latter being in the form of wettable powders or of granules or aqueous suspensions.

As regards the compositions which are =_ · suitable for storing and transporting, they more -— advantageously contain from 0.5 to 95% (by weight) of active substance.

AP/F/ 95/00722

Claims (25)

1. 2-Imidazolin-5-one derivatives of the the general formula (I):

in which:

5 - R, represents a hydrogen atom or a vinyl or allyl group or an alkyl or haloalkyl radical, each containing 1 to 3 carbon atoms;

or alternatively, R₁ and Arj-X-Ar, can additionally fora, with the carbon to which they are bonded on the

10 inidasolinone ring, the following unit:

77/00/56 ,1/dV in which the dot in bold type represents the carbon of the imidazolinone ring of the formula (I) to which the R, and Ar^X-Ar, radicals are bonded, and m is equal to 2, 3 or 4;

AP . Ο Ο 5 8 1

- η Ο or 1;

- ¥ represents an oxygen or sulphur atom;

- R₂ represents: — ’

- a hydrogen atom when n is equal to 0 or .27

5 - an alkyl or haloalkyl group, each containing 1 to 3 carbon atoms, or a cyclopropyl group;

- Rj represents an aryl or heteroaryl radical comprising phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, benzothienyl,

10 benzofuryl, quinolyl, ieoquinolyl, benzothiazolyl or methylenedioxyphenyl, each of theee radicals optionally being substituted by 1 to 7 groups, preferably from 1 to 3 groups, chosen from the meanings of R_s defined hereinbelow;

15 - R₄ represents a hydrogen atom, a formyl or aroyl radical, an acyl radical containing 2 to 6 carbon atoms, an alkoxycarbonyl radical containing 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulphonyl .xadieal, an alkylsulphonyl radical containing 1

20 6 carbon atoms or an alkyloxalyl or alkoxyoxalyl radical containing 3 to 6 carbon atoms;

- represents:

- a halogen atom or a hydroxyl, mercapto, nitro, SP₅, cyano, thiocyanato or azido group; or

25 - an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, alkylsulphinyl, alkylsulphonyl, haloalkylsulphinyl or haloalkylsulphonyl radical,

7 7 / η n / C fi MZ4V each containing 1 to 6 carbon atoms; or

- a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio radical, each containing 3 to 6 carbon atoms; or

5 - an amino radical, optionally mono- or disubstituted by an alkyl or acyl radical containing 1 to 6 carbon atoms or an alkoxycarbonyl radical containing 2 to 6 carbon atoms; or

10 - an alkoxycarbonyl group containing 2 to 7 carbon atoms; or

- an N-alkylcarbamoyl group containing 2 to 7 carbon atoms; or

- an Μ,Μ-dialkylcarbamoyl group containing 3 to

15 13 carbon atoms;

- w represents O, 8 or 80;

- Ar₁ is a divalent radical vhich derives from an aryl or heteroaryl radical comprising phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl,

20 benzofuryl, indolyl, quinolyl, ieoquinolyl or methylenedioxyphenyl radicals, each of these radicals optionally being substituted by 1 to 6 groups, preferably by 1 to 3 groups, chosen from the meanings of R,;

25 - Xr₂ represents a mono- or bicyclic system containing 5 to 10 atoms, vhich is aromatic, saturated or unsaturated, and vhich is either a carbocyclic system or a heterocyclic system containing from l to 4 hetero >

.

(O cr

PC rc

ΔΡ 00581 atoms chosen from O, 8 or N and which comprises phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indanyl, indolyl, quinolyl, isoquinolyl,

S methylenedioxyphenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, benzimidazolyl, indazolyl, bsnzoxazolyl, bsnzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,

10 triazinyl, naphthyridyl, quinoxazolyl, quinazolyl, cinnolyl or phthalazinyl radicals, each of these radical* optionally being substituted by 1 to 7 groups, preferably by 1 to 3 groups, chosen from the meaning* of 1^;

15 - X represents a linkage of general formula:

in which: - j and k, which are identical or different, are equal to 0 or 1?

20 - R end R*, which are identical or different, represent a saturated or unsaturated hydrocarbon chain which contains from 1 to ί carbon atoms, optionally substituted by 1 to 12 groups, preferably by 1 to 3 groups, chosen from R₇ defined hereinbelow; and in which one or a number of carbon atoms can be replaced by O, 8 or N(R₆),

22/00/56 Zd/dV z 2 / ο n / c fi Mi_rnt

AP.'531

7 carbon atoms or a sulphamoyl radical (optionally substituted by one or two alkyl radicals) containing l to 6 carbon atoms; or 5 - an aroyl or arylsulphonyl radical; or - an alkyloxalyl or alkoxyoxalyl radical, each containing 3 to 8 carbon atoms; or - an oxamoyl radical (optionally substituted by one or two alkyl radicals) containing 2 to 8 carbon atoms 10 - R₇ represents a halogen atom or a cyano, thiocyanato, hydroxycarbonyl, alkoxycarbonyl, amino (optionally substituted), hydroxyl, oxo, (' alkoxy, haloalkoxy, alkoxyalkoxy, mercapto, alkylthio, haioalkylthio, alkoxyalkylthio, 15 acyloxy, alkyl, haioalkyl, alkoxyalkyl, 20 alkylidene, aroyloxy, heteroaroyloxy, arylacyloxy, cycloalkylcarbonyloxy, acylthio, aroylthio, heteroaroylthio, arylacylthio, cyeloalkylcarbonylthio, carbamoyloxy (optionally substituted), carbamoylthio (optionally • 25 substituted), thiocarbamoyloxy (optionally substituted), thiocarbamoylthio, (optionally substituted), acylamino, cycloalkylcarbonylamino, aroylamino, ureido (optionally substituted), thioureido, alkoxycarbonylamino, 30 aryloxycarbonylamino, alkylsulphonylamino, arylsulphonylamino or aminosulphonylamino (optionally substituted) group, it being understood that optionally substituted groups within the definition of R₇ are optionally substituted by one or two alkyl groups, each aliphatic hydrocarbon radical having from 1 to 4 carbon atoms and each cycloalkyl radical having from 3 to 7 carbon atoms; 35 - Rj and R'_a, which are identical or different,

AP/P/ 95/00/ΖΖ

AP . ο Ο 5 a 1 represent:

- an alkyl radical containing 1 to β carbon atoms; or

- a cycloalkyl radical containing 3 to

5 7 carbon atoms; or

- an alkenyl or alkynyl radical containing 2 to 6 carbon atoms; or

- an arylalkyl, preferably benzyl, radical or an aryl radical which is optionally

10 substituted, preferably phenyl optionally substituted by 1 to 5 groups, preferably by 1 to 3 groups, chosen from the meanings of R*;

- R, represents:

- a hydrogen atom or a morpholino,

15 piperidino, pyrrolidino or pipsrazino group;

or

- an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio or cyanoalkylthio radical, saeh

20 containing 1 to 6 carbon atoms, or a dialkylamino radical containing 2 to β carbon atoms;

- 9* and R'_1O, which are identical or different, represent a hydrogen atom, an alkoxy group

25 containing 1 to C carbon atoms, or an R^ group;

- R₁₁ and R'_n, which are identical or different, represent a hydrogen atom or a halogen or an alkyl group containing l to 3 carbon atoms;

as well as the salts and the enantiomers and <.

c c

c

x.

AP. 00581 stereoisomers of these compounds, especially the 2 enantiomers of each of these compounds which correspond to the asymmetric carbon of the imidazolinone ring carrying R,;

5 and with the exception of the compounds in which:

- when (Y)_n-Rj represents a methyl thio, a methyl or an ethyl, Ar₂-X-Ar, represents an optionally substituted phenoxyphenyl group;

- when (¥)_n-Rj represents a methoxy, when R₁ 10 is a methyl, when Rj represents a phenyl or pyridyl radical optionally substituted by a fluorine atom or a methyl group, when R₄ is a hydrogen and when W represents an oxygen atom, then Ar_?-X-Ar₁ represents either a 4-phenoxyphenyl group, optionally substituted

15 on its phenoxy part hy 1 or 2 fluorine atoms, or a

3-phenoxyphenyl group;

and with the exception of the compound of formula:

©

2. Compounds according to claim l, wherein:

20 - Ar₁ represents a divalent radical derived from e phenyl, naphthyl, thienyl, pyridyl, benzothienyl or quinolyl, each of these radicals optionally being substituted by 1 to 3 groups chosen from the meanings

AP/P/ 95/00722

AP . ΰ C 5 8 1

100 of R,;

• Xr₂ represents a phenyl, naphthyl, thienyl, pyridyl, benzothienyl, thiazolyl, benzothiazolyl or pyrimidinyl radical, each of these radicals optionally

5 being substituted by 1 to 3 groups chosen from the meanings of Rj.

3. Compounds according to one of claims 1 and 2, wherein:

- Ar, represents a divalent radical derived 10 from a phenyl, thienyl or pyridyl vhich is optionally substituted by 1 to 3 groups chosen from a halogen atom or an alkyl or haloalkyl radical;

- Ar₂ represents a phenyl, naphthyl, pyridyl or bensothiasolyl radical which is optionally

15 substituted by 1 to 3 groups chosen from a halogen atom or an alkyl or haloalkyl radical;

- X represents the linkage of general formula:

-(R**,j-A-(R*,_k20 in which:

f

- R and R', vhich are identical or different, represent a carbon chain containing 1 to 3 carbon atoms, preferably a methylene group, in which a carbon atom is optionally replaced by 0 or NH, and

25 vhich is optionally substituted by 1 to 3 groups chosen from a halogen atom, a hydroxyl or oxo group or a alkyl radical;

AP/P/ 9 5 / 0 0 7 2 2

AP Ο Ο 5 At

101

- A is Ο, S, so, so₂, CO, c(R₁₀) (R'_1O), —C=C— or in vhich:

- r₁₀ and R'₁₀z vhich are identical or different, are a hydrogen or halogen atom or a

5 hydroxyl, C,-^ alkyl or σ,-Cj alkoxy radical;

- Z represents Ο or C(R_n> (R'_n), where R_n and R'_n, vhich are identical or different, are a hydrogen or chlorine atom.

4. Compounds according to any one of claims 10 1 to 3 of the formula (X) in vhich, simultaneously:

IS

- R, is a methyl radical;

- Rj is a methyl or ethyl radical;

- Rj represents a phenyl or pyridyl radical;

- R_t is a hydrogen atom or a formyl radical;

- R, is a halogen atom or a Ο,-Cj alkyl cr

C^Cj haloalkyl radical; and

- w is an oxygen atom.

5. Process for the preparation of the

AP/P/ 9 5 / 0 0 7 2 2 compounds of formula (X) according to claim 1, in vhich 20 R₄ is other than a hydrogen atom, hy reaction of the compounds of formula (Xa) vith a compound of formula R₄L', in the presence of a base and in a solvent medium, according to the scheme:

AP. η π 58 1

103 an aromatic solvent.

7. Process for the preparation of the compounds of formula (II) by S-alkylation of the 2-thiohydantoins of formula (XXX), la the presence of a base and in a solvent, according to the scheme:

V »

Ατ,-Χ-ΑτΓγ^ ''NH—Rj

W (ΙΠ)

Λ-l

Bass

S-Ri — r, a,,-_X-*,<Yⁿ'nh-r, w

(Π) in which R,, Rj, Rj, Ar,, hr₂ and X are defined according to claim X, V represents 8 or O and X. represents a group chosen from a halogen atom (preferably chlorine, bromine or iodine) or an alkyl sulphate,

XO alkyl sulphonyl oxy or arylsulphonyloxy group.

8. Process for the preparation of the compounds of formula (XXa), characterised in that the compound of formula (VII, is suoeessively reacted, in the presence of a solvent, vith a hydrazine of formula

15 Rj-NH-NHj, then vith a base of formula BM* and, finally, vith an alkylating agent of formula RjL, according to the scheme:

AP/P,' 95/00722 .* Ci ii 1

104

N=C=S *R,—NH-NH, Afj—X—Af, >-ORE

O (VII)

RJ —Rj ^RiL . o ^N=/ ^RQ\ N

Ar,—X-Ar/jjf' ^XNH-R, (Ha) in which It,, Rj, Rj, Ar,, Ar₂ and X are defined according to claim 1, with the proviso that Rj is other than hydrogen, Rg represents a Ο,-Cj alkyl radical and Lisa halogen atom or an alkyl sulphate, alkylsulphonyloxy or

5 arylsulphonyloxy group.

9. Process according to claim 8, characterised in that the base is chosen from an alkali metal or alkaline-earth metal alkoxide, an alkali metal or alkaline-earth metal hydroxide or a tertiary amine

10 and in that the reaction is carried out at a temperature of between -10 and +80*C and in a solvent chosen especially from a cyclic or non-cyclic ether, an alcohol, an ester, DMT, DMSO, acetonitrile or from an aromatic.

15 10. Process for the preparation of the compounds of formula (XI), characterized in that the 2-alkylthio-2-imidazolin-5-ones of formula (II) are reacted in a solvent with an alcohol R₂OH in the presence of a strong base, according to the scheme:

AP/P/ 9 3 / 0 u / fir ^Γ' 5 9 1

105 \V· ^Χ-Ar ‘ >4H — R

W (II)

Base » R, jolven, Arj-X-Ar/yN^^

W (XI) in which R'₂ represents an alkyl group comprising from 1 to 3 carbon atoms and the other groups are defined according to claim 1.

11. Process according to claim 10, characterized in that the reaction is carried out in the alcohol R₂OH, as solvent, and by using the sodium alkoxide RjO’Na* as base and in that the reaction ia carried out at a temperature of between 20 and 80 *C.

12. Proceaa for the preparation of the compounds of formula (XIX):

^R|vⁿ*t^xRj (ΧΠ) characterized in that a hydrazine of formula Rj-NH-NB^ ia reacted with an azalactone of formula (XIII), according to the scheme:

^r‘V^S!t^xRi

Ati-X-Ar/y-e

OCIII) r₃nhnh₂ ch₃cooh

CHjCOONa ^Riv^l,csr^xRj

ΑΤ₅-Χ-Α,<Υ-^Ν^_Ή __R 0 (XII) in which R_x, R₂, R₃, Ar_x,

Ar- and X are defined

106 according to claim 1, by heating the mixture of the reactants in acetic acid at reflux, in the presence of sodium acetate as catalyst.

13. Process for the preparation of the 5 compounds of formula (Ia):

by condensation of an organometallic derivative of formula (XV) with an electrophilic radical Ar₂-X'*, according to the scheme:

(XV) (Ia) in vhich:

10 * R,, Rj, R,, T, Ar,, Ar₂, V and n are defined according to claim it

M, represents a metal chosen from lithium, sodium, magnesium, sine, titanium, tin, copper, boron or silicon and is preferably lithium;

15 * Ar₂-X' is an electrophilic radical generated by a compound chosen especially from:

- an aralkyl compound of formula Ar₂-R₁₂-L in which:

AP/P/ 9 5 I 0 V > <AP/P/ 9 5 / 0 0 7 2 2

108

- a sulphonyl halide of formula:

O

II

Ar₂—(FMp—S—Hal O in vhich Hal represents a halogen atom, preferably a chlorine atom;

- an epoxide of formula:

in vhich R,„ and »'n> arc defined according to claim 1;

X has the same meaning as X*.

ς

Ί3 co cn

14. Process for the preparation of the compounds of formula (Zb) by reacting an imidazolinona of formula (XVX) vith a nucleophile of formula (XVZXX) according to the scheme:»

-r₂ ^2-^' I2)P-ZH (XVUI) ‘'x'V'*'^{2 R}'y^N^

Π*¹ ~^A'l Ar2-(R 12)p — 2— Λη ^/y-^N^N__f

W * W I __^H H

-R₂ w <xvo w

(h>)

AP/P/ 95/00722 in vhich R,, Rj, Rj, Ar,, Ar₂, Y, n are as defined in claim 1, p=0 or 1, Z represents O or C(R,,) (R^#,,), where R_n and R'„ vhich are identical or different, are a hydrogen or chlorine atom and R'₁₂ represents a saturated or unsaturated linear or branched, aliphatic chain containing 1 to 6 carbon atoms.

110 wherein R_1# Rj, Rj, Y, n, and W are as defined in claim 1, ^R,12 ^and P ^{are as} defined in claim 14 and 2' represents an oxygen or sulphur atom or an N-R_u group in which A,* represents a hydrogen atom or a C,-C₆ alkyl

5 group.

17. Process for the preparation of the compounds of formula (If) by reacting a nucleophilic compound of formula Xr₂-(R*₁₂)_p-2^ZH (XVIII) with a 4(chloromethylphenyl)-2-imidazolin-5-one of formula

10 (XXIII), according to the scheme:- (XXIII)

Afj—(R’u)p-rH (XVHI)

Af,—(R* ij)p—Z-CHR (If) . Y, n, w and Ar, are as defined wherein, R₁, Rj, in claim 1, R'_u and p are as defined in claim 14, «* is as defined in claim 16 and R represents a hydrogen atom, an alkyl, haloalkyl or alkoxyalkyl radical or an 15 alkylidene radical, the alkyl or alkylidene parts of these radicals containing from 1 to 6 carbon atoms.

18. Process for the preparation of the compounds of formula (lg) by reaction of a 4(amincphenyl)-2-imidazolin-5-one of formula (XXV) with

20 an electrophilic radical formula Ar₂X'*, according to

AP/P/ 95/00/ZZ the reaction scheme:111 (XX V)

Ar₂X· * -=-►

Arj—X —NH wherein, R,, Rj, R₃, Y, n, W and Ar₂ are as defined in claim 1 and X' is as defined in claim 13.

19. Process for the preparation of a compound of formula (Xh) by reacting derivatives of

5 formula (XXVII) with an electrophilic reagent of formula Ar₂-(R'₁₂)_p-CO-Cl in the presence of a base in an inert solvent, according to the schemesHZ-CHR

Ar₂—(R’₁₂)_p-C-a 0 base, solvent

7 7 Z 0 0 / 5 θ ,’d/dV

Ar₂—(R'ljp—C—Z—CHR O

AP. Ο Π 58 1

112 wherein R,, Rj, Rj, γ, n, W and Xr₂ are as defined in claim 1, R'₁₂ and p are as defined in claim 14 and Z' and R are as defined in claim 17.

20. Process for the preparation of compounds 5 of formula (Ii) by reacting benzyl derivatives of 2imidazolin-S-ones of formula (XXVIII) with a nucleophile of formula HZ*R'₂, optionally in the presence of a base, according to the scheme:-

HZR₂’ base, solvent (XXVDI)

Is

-r₂ ft ft / q 6 ,'rVdV wherein R_v Rj, Rj, Y, n, W and Ar₂ are as defined 10 in claim 1/ R'i2 and p ere as defined in claim 14, R*₂ represents a hydrogen atom, an alkyl or haloalkyl group, each containing 1-3 carbon atoms, or a cyclopropyl group, and R is as defined in claim 17.

21. Process for the preparation of compounds 15 of formula (Ij) by halogenation of compounds of formula (XXIX):

Λ Ρ 0-58 1

113

POXj or ΡΧ, or

ΗΧ or SOO.

(Ij) wherein R,, 1^, Rj, γ, a, V end *r₂ as defined ia claia 1, R'₁₂ and p are defined in olaia 14, X represents a halogen atom and R is as defined in claim 17 to convert the grouping -CR(OH)- in the compound of formula (XXIX) into a grouping -CR(X)- wherein R ie as defined in claim 17 and X represents a halogen atom.

22. Compounds useful as intermediates in the preparation of the compounds of claim 1, of the formula ma, mb, it, vix, xiii, xix, xx, xxn, xxiv or XX7H:

AP/P/ 9 5 / 0 0 7 22 ©

fi P

114 (xm)

HZ—CHR

AP/P/ 95/00722

AP. -6581

115 in which:

- Rj is defined according to claim B,

- 2' represents an oxygen or sulphur atom or a group in vhich R_u represents a hydrogen atom or

5 a ^ci“^C6 alkyl group,

- the other groups are defined according to claim 1;

and the optical isomers of these compounds, especially the enantiomers of the compounds comprising the

10 asymmetric carbon carrying R,.

23. Fungicidal composition containing, as active material, at least one compound according to any one of claims 1 to 4 in association vith an agriculturally acceptable solid or liquid vehicle and

IS an agriculturally acceptable surface-active agent.

24. Fungicidal composition according to claim 23, containing from 0.05 to 95% (by veight) of active materiel.

25. Method for the treatment of cultivated 20 plants effected or capable of being affected hy fungal diseases, vhich comprises applying an effective dose of φ a oompound according to any one of claims 1 to 4 to the serial parte of the plants.

n

26. Method according to claim 25, wherein 25 the effective dose is between 0.002 and 5 kg/ha.

27. Method according to claim 25, vherein the effective dose is between 0.005 and 1 kg/ha.

AP/P/ 95/00722 ^Δρ Ο Γ· f β 7

116

28.

Compound according to claim 1, when prepared by a process according to any one of claims 5 to 21.

S'

117

ABSTRACT

The invention relates to 2-imidazolin-5-one derivatives of general formula (I):

in which:

- R_x is H or a vinyl or allyl group or an alkyl or haloalkyl radical, • n » 0 or 1; T i· 0 or 8;

- Rj i« an alkyl or haloalkyl group or a cyclopropyl group;

- R₃ is an optionally substituted aryl or heteroaryl radical coo$>rising especially phenyl or naphthyl,

- R₄ is a hydrogen atom and various radicals including a formyl or aroyl radical or an acyl radical containing 2 to € carbon atoms,

- R_s is especially H or a hydroxyl, mercapto, nitro, cyano, thiocyanato or azido group or an optionally substituted alkyl or cycloalkyl radical,

- W is 0, S or SO;

- Ar_x is an optionally substituted divalent radical which derives from an aryl or heteroaryl radical comprising, especially, phenyl, naphthyl or thienyl radicals,

- Ar₂ is an optionally substituted mono- or bicyclic

Ah'/Η; ό υ / c

c r

r

AP . Ο Ο 5 fi ι

118 system containing 5 to 10 atoms which is aromatic, saturated or uneaturated and which is either a carbocyclic system or a heterocyclic system containing from 1 to 4 hetero atoms chosen from O, S or N,

- X is especially -C(0)NH-, -NHC(0)NH-, -SO₂NH-, -CH₂O-, -CHjNH- or -CH₂-.

The invention also relates to the preparation of these compounds and to their use as broad-spectrum fungicides.