AU671389B2 - Process for the formation of intermediates and intermediates useful for the preparation of fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives - Google Patents
Process for the formation of intermediates and intermediates useful for the preparation of fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives Download PDFInfo
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- AU671389B2 AU671389B2 AU74499/94A AU7449994A AU671389B2 AU 671389 B2 AU671389 B2 AU 671389B2 AU 74499/94 A AU74499/94 A AU 74499/94A AU 7449994 A AU7449994 A AU 7449994A AU 671389 B2 AU671389 B2 AU 671389B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/20—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C333/14—Dithiocarbamic acids; Derivatives thereof
- C07C333/18—Esters of dithiocarbamic acids
- C07C333/20—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
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- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
Regulation 32
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
(ORIGINAL)
r
I
r r r
I
r r o Name of Applicant: Address for Service: Rhone-Poulenc Agrochimie DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.
Invention Title: "Process for the formation of intermediates and intermediates useful for the preparation of fungicidal and derivatives" The following statement is a full description of this invention, including the best method of performing it known to us: -1 941007,p:\oper\ee,331div.flI I la- The present application is a divisional application of Australian Patent Application No. 30310/92, the entire disclosure of which is incorporated herein by reference.
AU 30310/92 relates to new imidazolinone or imidazolinthione compounds 15 for use in plant protection. The present application relates to the processes for the preparation of intermediates and to the products which can optionally be used as intermediates in the preparation processes for the imidazolinone and imidazolinthione compounds.
20 AU 30310/92 claims 2-imidazolin-5-one or 2-imidazoline-5-thione derivatives of general formula (I) N A-R 3 n -R 4
W
in which: 941007,p:\oper\ee,651O21rho.div,1 I II 1 W is a sulphur or oxygen atom or an S=O group A represents 0 or S n 0 or 1 B represents NRs or 0 or S or CR,R 6 or SO2 or C=0.
R, and R 2 which are identical or different, represent: H, provided that one of the 2 groups is different from H, or an alkyl or haloalkyl radical containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, alkylsulphonylalkyl, monoalkylaminoalkyl, alkenyl or alkynyl radical containing 2 to 6 carbon atoms or a dialkylaminoalkyl or cycloalkyl radical 15 containing 3 to 7 carbon atoms or an aryl radical preferably phenyl, naphthyl, thienyl, furyl, pyridyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, or methylenedioxyphenyl, optionally substituted by 1 to 3 groups chosen from R 7 20 or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or RI and R 2 can form, with the carbon to which they are bonded on the ring, a carbocycle or a heterocycle having from 5 to 7 atoms, it being possible for these rings to be fused to a phenyl, optionally substituted by 1 to 3 groups chosen from R,; 3
R
3 represents: an alkyl group containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, alkylsulphonylalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl, oxoalkyl, alkenyl or alkynyl group containing 2 to 6 carbon atoms or a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl group containing 3 to 6 carbon atoms or a N,N-dialkylcarbamoylalkyl group containing 4 to 8 carbon atoms or an arylalkyl group, the alkyl part being a radical containing 1 to 6 carbon atoms and the aryl part is phenyl, naphthyl, thienyl, furyl or pyridyl, 15 optionally substituted by 1 to 3 groups chosen from R,;
R
4 represents: a hydrogen atom when n is equal to 1 or an alkyl group containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, haloalkyl, 20 cyanoalkyl, thiocyanatoalkyl, alkenyl or alkynyl group containiig 2 to 6 carbon atoms or a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl group containing 3 to 6 carbon atoms or a N,N-dialkylcarbamoylalkyl group containing 4 to 8 carbon atoms or an aryl radical, preferably phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, 11-- 9117 -Ppyrazinyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl, optionally substituted by 1 to 3 groups chosen from R7 or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or an amino group disubstituted by ient.cal or different groups chosen from: an alkyl radical containing 1 to 6 carbon atoms an alkoxyalkyl, alkenyl or alkynyl radical containing 3 to 6 carbon atoms a cycloalkyl radical containing 3 to 7 carbon atoms an arylalkyl, phenyl or naphthyl radical, optionally substituted by 1 to 3 groups chosen from R 7 or a thienylmethyl or furfuryl radical a pyrrolidino, piperidino, morpholino or piperazino group, optionally substituted by alkyl containing 1 to 3 carbon atoms; R, represents: H, except when R, is H, or an alkyl, haloalkyl, alkylsulphonyl or haloalkylsulphonyl radical containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alkynyl, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsuiphonyl or cyanoalkylsuiphonyl radical containing 2 to 6 carbon atoms or an alkoxyalkoxycarbonyl, alkyithicalkoxycarbonyl or cyanoalkoxycarbonyl radical containing 3 to 6 carbon atoms or a formyl radical or a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl or alkynylcarbonyl radical containing 3 to 6 carbon atoms or a cycloalkylcarbonyl radical containing 4 to 8 carbon atoms or a phenyl; arylalkylcarbonyl, preferably phenylacetyl and phenyipropionyl; arylcarbonyl, preferably benzoyl, optionally substituted by 1 to 3 groups from
R
7 thienylcarbonyl; furylcarbonyl; pyridylcarbonyl; benzyloxycarbonyl; furfuryloxycarbonyl; tetrahydrofurfuryloxycarbonyl; thienylmethoxycarbonyl; pyridylmethoxycarbonyl; phenoxycarbonyl or (phenylthio)carbonyl, the phenyl being itself optionally substituted by 1 to 3 groups from R 7 (alkylthio)carbonyl; (haloalkylthio)carbonyl; (alkoxyalkylthio)carbonyl; (cyanoalkylthio)carbonyl; (benzylthio)carbonyl; (furfurylthio)carbonyl; (tetrahydrofurfurylthio)carbonyl; (thienylmethylthio)carbonyl; (pyridylmethylthio)carbonyl; or arylsulphonyl radical or a carbamoyl radical, optionally mono- or disubstituted by ~lllsr _II IIIIL I -L dL ~1 an alkyl or haloalkyl group containing 1 to 6 carbon atoms or a cycjoalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3
R
7 groups; a sulphamoyl group, optionally mono- or disubstituted by an alkyl or haloalkyl group containing 1 to r e 2 e o 6 carbon atoms or a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3 R, groups; an alkylthioalkylsulphonyl group containing 3 to 8 carbon atoms or a cycloalkylsulphonyl group containing 3 to 7 carbon atoms;
R
6 represents: a hydrogen atom or a cyano group or an alkyl group containing 1 to 6 carbon atoms or a cycloaicyl group containing 3 to 7 carbon atoms or an acyl or alkoxycarbonyl group containing 2 to 6 carb-n atoms or
L-
a benzoyl group, optionally substituted by 1 to 3 R 7 groups;
R
7 represents: a halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or alkylsulphonyl radical containing 1 to 6 carbon atoms or a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio radical containing 3 to 6 carbon atoms or a nitro or cyano group or an amino radical, optionally mono- or disubstituted by an alkyl or acyl radical containing 1 Sto 6 carbon atoms or an alkoxycarbonyl radical 15 containing 2 to 6 carbon atoms a phenyl, phenoxy or pyridyloxy radical, these radicals optionally being substituted; and their salts.
Certain specific compounds of the formula I, 20 of formula Ia, are known
SR
*N I Ia R N n-R4 W
R
6 in which W, R
I
to R. and n have the same L I meaning as in formula I.
Denoted S-alkylated derivatives of 5,5-diphenyl-2-thiohydantoin and of hydantoin, they have been especially studied for their pharmacological properties: a) Zejc, Dissertationes Pharmaceuticae et pharmacologicae, Warsaw, 20 507-524 and 525-537 (1968) b) Lucka-Sobstel, B. and Zejc, A., Dissertationes Pharmaceuticae et pharmacologicae, 22 13-19 (1970) c) Fetter, Harsanyi, Nyitrai, J. and Lempert, Acta Chemica (Budapest), 78 325-333 (1973).
ooeA 15 o20 o« o 20 No agricultural fungicidal activity has been described for these compounds.
Other specific compounds of formula I have been described by Bbhme, Martin and Strahl in Archiv der Pharmazie, 313, 10-15 (1980) (ref. They are the 3 following compounds: N _SCH3 NR CH01 0 CH3 R=H, CH 3 phenyl These compounds are thus included in the compounds of formula Ib, which form part of the invention:
M
I,
9 R2
N
SR
3 N- R 4 Ib R N N' 4 W R in which W and R, to R, have the same meaning as in formula I.
The compounds of formula Ia can be prepared according to the processes known per se described in the abovementioned references and in the following references: e) Biltz, Chemische Berichte 42, 1792- 1801 (1909) f) Chattelain, M. and Cabrier, Bulletin de la Societ6 Chimique de France, 14 (1947), 639-642 g) Carrington, C.H. and Warring, W.S., Journal of the Chemical Society, (1950) 354-365 h) Lampert, Breuer, J. and Lemper- 15 Streter, Chemische Berichte, 92, 235-239 (1959) i) Shalaby, A. and Daboun, Journal fur Praktische Chemie, 313 1031-1038 (1971) j) Simig, Lemper, K. and Tamas, J., Tetrahedron, 29 3571-3578 (1973) k) Schmidt, Heimgartner, H. and Schmidt, Helvetica Chemica Acta, 62 (1979), 160-170 1) Muraoka, Journal of the Chemical Society, Perkin Transactions I, (1990), 3003-3007 I or according to one of the processes A, B, C or D described below.
The compounds of formula Ib can be obtained according to the process described by Bbhme, Martin and Strahl in Archiv der Pharmazie, 313, 10-15 (1980) (reference d) or according to one of the processes described below.
Process A: Process for the preparation of the compounds of formula The preparation of the compounds of formula by S-alkylation of the 2-thiohydantoins (II) is carried out according to the reaction scheme:
H
R
2 N Sa
)W
in which X represents a chlorine, bromine or iodine atom or a sulphate group, or an alkylsulphonyloxy or arylsulphonyloxy group, alkyl and aryl being as defined above for R and R 2 It is possible to use, as base, an alkoxide, for example potassium tert-butoxide, an alkali metal or alkalineearth metal hydroxide, an alkali metal carbonate or a tertiary amine. It is possible to use, as solvent, ethers, cyclic ethers, alkyl esters, acetonitrile, ethers, cyclic ethers, alkyl esters, acetonitrile, ~sl alcohols containing 1 to 3 carbon atoms, or aromatic polvents, for example tetrahydrofuran, at a temperature of between -5"C and This process is suitable for the compounds in which W represents a sulphur or oxygen atom.
The 2-thiohydantoins of formula (II) can be obtained according to the processes described in the literature such as, for example, in the following references: e) Biltz, Chemische Berichte, 42, 1792- 1801 (1909) n) Eberly and Dains, Journal of the American Chemical Society, 58, (1936), 2544-2547 o) Carrington, Journal of the Chemical 15 Society, (1947), 681-686 g) Carrington, C.H. and Warring, W.S., Journal of the Chemical Society, (1950), 354-365 h) Lampert, Breuer, J. and Lemper- Streter, Chemische Berichte, 92, 235-239 (1959) i) Koltai, Nyitrai, Lempert, K. and Burics, Chemische Berichte, 104, 290-300 (1971) or alternatively according to one of processes E or F described below and which form part of the invention.
Process B: Preparation of the compounds Ic.
The preparation of the 2-methylthio-2of formula (Ic) by cyclisation of the iminodithiocarbonates of formula is carried out according to the overall scheme: R, C0 2
H
CS
2 2
CH.
3 1 Base b).R 2 C SCH 3
R
4 -(B)n-NH 2
~SCH
3 R, CO 2
H
GfM)
CH
3 0
MV
R <C-NH-(B)n-R4 0
MV
R
2
SCH
3 R, N 'Bn 0 GOc a) The iminodithiocarbonates (III) can be prepared by carrying out the preparation according to the conditions described in the literature for analogous compounds: C. Alvarez Ibarra et Tetrahedron Letters, 26 243-246 (1985) E. Melendez et Synthesis, 1981, 961 according to:
R
2
><NH
2 R, C0 2
H
CS
2 2
CH
3
I
Base 1- (UD b) The compounds of formula are obtained L I ,1 I by condensing the compounds of formula (III) with amines or hydrazines of formula To carry out the condensation, the acid (III) must be activated in the acid chloride form, in the dicyclohexylisourea form using dicyclohexylcarbodiimide or in the imidazolide form using carbonyldiimidazole. Condensation is carried out under the usual conditions for this type of reaction.
c) Cyclisation of the compounds is carried out by simple heating in an aromatic solvent at reflux. It is possible to use, as solvent, especially xylene, chlorobenzene or dichlorobenzene.
Process C: Derivatisation of the compounds and Process Cl: Preparation of the co1i.-,i.ds Ib by N-derivatisation of the compounds Ib'.
The compounds of formula (compounds (Ib) in which R 5 is a hydrogen atom) can be alkylated, acylated, alkoxycarbonylated, carbamoylated or 20 sulphamoylated according to the following general scheme: a o r ft r
R
2 N Y SR 3 W
H
Base Solvent
R
5
X
R
2 YN- R 3
N"
W
R, represents h0,re an alkyl, alkoxycarbonyl, acyl, arylcarbonyl, alkylsulphonyl, arylsulphonyl, parbamoyl or sulphamoyl group, such as defined above.
X represents a halogen, a sulphate group or an optionally substituted phenoxy, or an alkylsulphonyl-oxy or arylsulphonyloxy group, or a group RsO, when R 5 is acyl.
It is possible to use, as base, alkali metal hydrides, alkoxides or a tertiary amine. The reaction can be carried out at a temperature of between and +50 0 C. It is possible to use, as solvent, for example ethers, cyclic ethers, dimethylformamide, dimethyl sulphoxide or aromatic solvents.
Carbamoylation of the compounds can be carried out by reacting with isocyanates or isothiocyanates according to the scheme:
S
.R
2 R N R 3
R
2 N SR 3 .R Rs 5 -N=C=Y 1 SNR4 R N 'R4 W Ib'H NHR The reaction is carried out under the same conditons as those described above, it being possible for the base, however, to be used in catalytic quantity.
Process C2: Preparation of the compounds Id.
The compounds Id' (compounds Id in which R 2 is a hydrogen atom, can be alkylated in position 4 according to the scheme: y R 2 X R SiN(B)n-R, solvent (B)n-R4 01r 0 0 Id X represents a chlorine, bromine or iodine atom. It is possible to use, as base, an alkoxide, a metal hydride or an amide. The reaction can be carried out at a temperature of between -30"C and +80 0 C. It is possible to use, as solvent, ethers, cyclic ethers, dimethylformamide, dimethyl sulphoxide or aromatic solvents.
Process D: Preparation of the S-oxidised derivatives of the The compounds of formula in which W represents a S=O group are obtained by oxidising the 2imidazoline-5-thiones according to the scheme: .o
S
It is possible to use peroxides, especially peracids, as oxidising agent. The oxidising agent must SB)n-R^ S S It is possible to use peroxides, especial'y peracids, as oxidising agent. The oxidising agent must be used in a stoichiometric quantity. Oxidation is carried out in chloroform or in methylene chloride at a 16 temperature of between -20"C and Process E: Preparation of the dithiohydantoins of formula (VI).
The dithiohydantoins of formula (VI) can be obtained by trapping the alpha anions of the isothiocyanates with isothiocyanates which cannot form anions according to the scheme:
H
R Base Rz N S RI-CH-N=C=S R 4 -N=C=S Y solvent
NR
4
S
.v.s 1 At least one of the groups R, or R 2 must be electron-withdrawing (aryl, substituted aryl, alkoxy- 10 carbonyl, and the like). The isothiocyanate R 4 -NCS must not be able to form an anion; aryl isothiocyanates can be used in particular in this reaction.
It is possible to use, as base, potassium tert-butoxide, lithium or sodium bis(trimethylsilyl)- 15 amide or alkali metal hydrides. It is possible to use ethers or cyclic ethers as solvent. The reaction is carried out at a temperature below -60°C. The anion must be trapped as it is formed. To achieve this, the mixture of the 2 isothiocyanates is run onto the base in solution at a temperature below Process F: Preparation of the 2-thiohydantoins of formula (VII).
The preparation of the 2-thiohydantoins (VII) from the isothiocyanates derived from the amino acids (VIII) is carried out according to the reaction:
H
R2 R, N S
R
1 -C R 4 OzR R N C0 2 R R (B)n-R 4 Cn) Cyclisation can be carried out in two ways: thermally: in this case, 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 or the chlorobenzenes; in basic medium: the cyclisation is carried 10 out in the presence of one equivalent of a base such as an alkali metal alkoxide, an alkali metal hydroxide or a tertiary amine. Under these conditions, cyclisation takes place at a temperature of between -10 and +80 0
C.
It is possible to use ethers, cyclic ethers, alcohols, esters, DMF, DMSO and the like as solvent.
The isothiocyanates can be prepared according to one of the processes mentioned in SulZur Reports, Volume 8 pages 327-375 (1989).
Process G: Preparation of the compounds of formula I in a single stage.
During cyclisation of the 2-thiohydantoins according to process F, if the cyclisation is carried out in basic medium, the thiohydantoin is in the thiolate form at the end of the reaction and can be reacted directly with an alkyl halide or alkyl sulphate
R
3 X or with R 3 X in which X is an alkylsulphonyloxy or aryl-sulphonyloxy to form Processes A and F are thus linked together according to the scheme: RI-C.N R 4
-NT
2
CO
2
R
R
3 X R .YSR
!R
2
S
flR4 R,\0)I
R
S
S
Process Preparation of the compounds of formula le, in which (B)n is a sulphur atom.
These compounds can be obtained by reacting a suiphuryl chloride RSC1 with an imidazolinone of formula IX according to the scheme:
SS.S
R
2
SR
3
R
1
NH
0 4SIBase R N
S-R
3 R S I s lventR 1 T
R
0 (IE) 19- The reaction is carried out at a temperature of between -20°C and +30 0 C, in the presence of one molar equivalent of a base. As solvent, it is possible to use alkali metal hydrides, alkali metal alkoxides or tertiary amines as a base. As a solvent, it is possible to use polar solvents, for example, ethers, cyclic ethers, dimethylformamide, dimethyl sulphoxide or aromatic solvents. The imidazolinones (IX) can be prepared by processes analogous to process A.
Some of the intermediates used in the preparation of the compounds of general formula of the present invention and the processes for their preparation are novel per se.
According to one aspect of the present invention there is provided a process for the preparation of compounds of formula wherein an imino dithiocarbonate of formula (III) is condensed with an amine or a hydrazine of formula (IV) according to the scheme: SCH, R 4 1
-NH
2
CH
2 NXc-- S (IV) K N -SCH Ri C OH R C-N H---(B)T-R4 (MI) (V) in which: n=0or 1 20 B represents NR, or O or S or CRR 6 or SO 2 or C=O R, and R 2 which are identical or different, represent: *e:i H, provided that one of the 2 groups is different from H, or an alkyl or haloalkyl radical conta'i:ing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, alkylsulphonylalkyl, monoalkylaminoalkyl, 25 alkenyl or alkynyl radical containing 2 to 6 carbon atoms or S C a dialkylaminoalkyl or cycloalkyl radical containing 3 to 7 carbon atoms or an aryl radical preferably phenyl, naphthyl, thienyl, furyl, pyridyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, or methylenedioxyphenyl, optionally substituted by 1 to 3 groups chosen from R 7 or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or R, and R 2 can form, with the carbon to which they are bonded on the ring, a carbocycle or a heterocycle having from 5 to 7 atoms, it being possible for these rings 960207,p:\opcr\dab.74499.spe,19 19a sc r r to be fused to a phenyl, optionally substituted by 1 to 3 groups chosen from R,;
R
4 represents: a hydrogen atom when n is equal to 1 or an alkyl group containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl, alkenyl or alkynyl group containing 2 to 6 carbon atoms or a dialk!ylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl group containing 3 to 6 carbon atoms or a N,N-dialkylcarbamoylalkyl group containing 4 to 8 carbon atoms or an aryl radical, preferably phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, beuzofuryl, quinolyl, isoquinolyl or methylenedioxyphenS optionally substituted by 1 to 3 groups chosen from R, or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or an amino group disubstituted by 2 identical or different groups chosen from: an alkyl radical containing 1 to 6 carbon atoms an alkoxyalkyl, alkenyl or alkynyl radical containing 3 to 6 carbon atoms a cycloalkyl radical containing 3 to 7 carbon atoms an arylalkyl, phenyl or naphthyl radical, optionally substituted by 1 to 3 groups chosen from R, or a thienylmethyl or furfuryl radical a pyrrolidino, piperidino, morpholino or piperazino group, optionally substituted by alkyl containing 1 to 3 carbon atoms; R, represents: H, expect when R 4 is H, or an alkyl, haloalkyl, alkylsulphonyl or haloalkylsulphonyl radical containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alkynyl, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulphone or cyanoalkylsulphonyl radical containing 2 to 6 carbon atoms or an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl or cyanoalkoxycarbonyl radical containing 3 to 6 carbon atoms or a formyl radical or 960207,p:\pcr'ihb,74499spcp, 19 *4.
r
__I
19b a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl or alkynylcarbonyl radical containing 3 to 6 carbon atoms or a cycloalkylcarbonyl radical containing 4 to 8 carbon atoms or a phenyl; arylalkylcarbonyl, preferably phenylacetyl or phenylpropionyl; arylcarbonyl, preferably benzoyl, optionally substituted by 1 tu 3 groups from R,; thienylcarbonyl;furylcarbonyl;pyridylcarbonyl;benzyloxycarbonyl;furfuryloxycarbonyl; tetrahydrofurfuryloxycarbonyl; thienylmethoxycarbonyl; pyridylmethoxycarbonyl; phenoxycarbonyl or (phenylthio)carbonyl, the phenyl being itself optionally substituted by 1 to 3 groups from (alkylthio)carbonyl; (haloalkylthio)carbonyl; (alkoxyalkylthio)carbonyl; (cyanoalkylthio)carbonyl; (benzylthio)carbonyl; (furfurylthio)carbonyl; (tetrahydrofurfuryithio)carbonyl; (thienylmethylthio)carbonyl; (pyridylmethylthio)carbonyl; or arylsulphonyl radical or a carbamoyl radical, optionally mono- or disubstituted by an alkyl or haloalkyl group containing 1 to 6 carbon atoms or a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3 R 7 groups; a sulphamoyl group, optionally mono- or disubstituted by an alkyl or haloalkyl group containing 1 to 6 carbon atoms or a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3 R, groups; an alkylthioalkylbulphonyl group containing 3 to 8 carbon atoms or a cycloalkylsulphonyl group containing 3 to 7 carbon atoms; R represents: a hydrogen atom or a cyano group or an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing AN 960207,pAopcrLab,74499.spe, 19 'i T 19c 3 to 7 carbon atoms or an acyl or alkoxycarbonyl group containing 2 to 6 carbon atoms or a benzoyl group, optionally substituted by 1 to 3 R 7 groups;
R
7 represents: a halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or alkylsulphonyl radical containing 1 to 6 carbon atoms or a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio radical containing 3 to 6 carbon atoms or a nitro or cyano group or 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 a phenyl, phenoxy or pyridyloxy radical, these radicals optionally being substituted; it being necessary for the acid (III) to be activated for this condensation in the acid chloride form, in the dicyclohexylisourea form using dicyclohexylcarbodiimide, or in the imidazolide form using carbonyldiimidazole.
According to another aspect of the present invention there is provided a process for the preparation of dithiohydantoins of formula (VI) (process E):
H
R: R,
R
25
(VI)
in which R 2 and R 4 have the same meaning as defined above with at least one of R, or R 2 being electron-withdrawing, characterised in that two isothiocyanates, of formulae R 1
R
2 CHNCS and R 4 NCS in which R 4 NCS is unable to form an anion, are reacted in the presence of a base, in a solvent and at a temperature below The present invention also provides a process for the preparation of the 2thiohydantoins of formula (VII) (process F): 960207,p:\opr'dab,74499,spc, 19 19d
H
Ri
R
4
(VII)
characterised in that, before cyclising, a compound of formula (IV) (R(B)nNH 2 is reacted with isothiocyanates derived from the amino acids of formula (VIII):
R
2 R -N=C==S O2,R
(VIII)
in which R R 2 R4, B and n have the same meaning as defined above and R is
C
14 alkyl or a benzyl group.
The present invention further provides compounds having the formulae II, III, IV, V, VI, VII and VIII
H
R2 S
SC
v N N(B C=S sulphur or oxygen atom or an S=O group.
The compounds which are preferred for their better fimgicidal activity and/or for their ease of synthesis are: j -r (m popr\dab74499.sp19 Sthe compounds of formula Ib, oC' vi) (v) Z 3 960207,p:\operlab,74499.sp,19 19e- 2) the compounds of formula I, in particular Ib, in which R, is a hydrogen atom, 3) the compounds in which R, and R 2 are different from H, 4) the compounds in which R 2 represents an alkvl group containing 1 to 3 carbon atoms, the compounds in which R, represents a phenyl ring, optionally substituted by R 7 6) the compounds in which R 3 represents an alkyl group containing 1 to 3 carbon atoms, 7) the compounds in which R 4 represents a phenyl ring, optionally substituted by R,, 8) the compounds in which R 3 represents a methyl group.
The examples below are given by way of *i e e 960207p:opcr\dab,74499.spc, 19 illustration of the compounds according to the invention, of the processes for their preparation and of their antifungal properties.
The structures of all the products were established by at least 1 of the following spectral techniques: proton NMR spectrometry, carbon-13 NMR spectrometry, infrared spectrometry and mass spectrometry.
In the tables below, the methyl and phenyl radicals are represented respectively by Me and Ph, and Cst means a physical constant, that is to say either a melting point or the refractive index Example 1: Preparation of compound No. 34 according to process A.
0.9 g (3 mmol) of 3-benzyl-5-methyl-5-phenyl- 2-thiohydantoin is dissolved in 30 ml of anhydrous tetrahydrofuran. The mixture is cooled to O'C and then 0.34 g (3 mmol) of potassium tert-butoxide is added.
The mixture is left to react for 10 min at 0°C and then 20 0.46 g (3.3 mmol) of methyl iodide is run in dropwise at this temperature: potassium iodide is observed to precipitate. The temperature of the mixture is allowed to return to room temperature. The mixture is diluted with 100 ml of ethyl acetate. The solution is washed 2 25 times with 100 ml of water on each occasion. The solution is dried over sodium sulphate and is then treated with active charcoal. The solution is concentrated under reduced pressure: 0.6 g of 1-benzyl-4 -methyl-2-methylthio-4 -phenyl-2-imidazolin-5 one (compound No. 34) is recovered in the form of a pale-yellkw solid melting at 68*C.
The compounds described below were prepared in the same way:
R
2 N SR 3 NNR4 o0'1 a.
*aa.
o. R 2
R
3 R, R 5 W Cst 1 Me Me Ph H S 127*C 3 Me 2-oxopropyl Ph H S 1300C 9 Me Me Ph H 0 M.p.=_149 0
C
Me Me meta-tolyl H 0 124 0
C
11 Me Me para-tolyl H 0 150 0
C
12 Me Et Ph H 0 1180C 13 Me Me 4-fluoroPh H 0 144 0
C
14 Me allyl Ph H 0 92 0
C
Me Me ortho-tolyl H 0 92C 16 Me Me 3-chioroPh H 0 120 0
C
17 Me iso-propyl I Ph H 0 95 0
C
18 Me Me 4-chioroPh H 0 149 0
C
19 Me Me tert-butyl H 0 73 0
C
Me Me 2-chloroPh H 0 134C 22 Me Me Ph Me 0 124 0
C
23 Me Me Ph acetyl 0 132*C 24 Me Me 4-methoxyPh H 0 138C Me n-propyl Ph H 0 Me Me 2-methoxyPh H 0 110*C 41 Me Me acetyl H 0
_L
No. R 2 I R3 R, R5 W Cst 43 Mef Me 4-N0 2 -Ph H 0 133*C 44 Me Me 2-pyridyl H S 114C Me Me 2-pyridyl H 0 147C 46 Me Me 3-pyridyl H 0 140C 47 Me Me 3-pyridyl H S 176*C 54 Me Me 2,6-Me 2 Ph H S 146*C 73 Me Me 2-thia- Me 0 116*C IMe CHF 2 Ph H 0 82 Me Me 4-Me- H 0 130C S02-Ph s r s Ir No. R 2 R3 R, n R5 W Cst 26 Me Me Ph 0 S 123C 27 Ph Me Ph 0 S 120*C 28 Me Me Me 0 S Mp. 29 Ph Me Me 0 I S 144C No. R 2
R
3 R4 n R 5 W Cst Me Me Ph0 -0 31 Me Me Me 0 0 58C 32 Ph Me Me 0 0 M.P.1700C 33 H me Ph 0 -0 MP=250 0
C
34 Me Me Ph 1 H 68*C me Me 2-thienyl 1 jH 0 760C 36 Me Me TMe 1 Me 0 n~ 0 1.553 37 Me Me 2-furyl 1 H 10 "honey-like I consistency" 38 Me Me 3-pyridyl 0 0 "honey-like ____I,consistency" Ph MeS IMe 10 H I M.p.=144 0
C
52 Me MeS Ph 1 CO 2 Me 0 "honey-like _____consistency" 57 Me MeS 2-MePh 0 101"honey-like 10_ consistency"i 0~*c
__II_
The following were also prepared: 4-(3-pyridyl)-4-methyl-l-(N-phenylamino)- 2 (compound 51: M.p.
156*C); 4-phenyl-4-methyl-l-(benzyloxy)- 2 (compound 56: honey-like consistency).
Example 2: Preparation of compound No. 7 according to process B.
a) N-[bis(methylthio)methylene]-2-phenylglycine (compound (III) with R, phenyl and R 2
H):
100 g (0.66 mol) of phenylglycine are dissolved at +5"C in 335 g of 22 aqueous potassium hydroxide (1.3 mol). 55.3 g of carbon disulphide are added while stirring the mixture vigorously: a precipitate appears and the mixture turns orange in colour. The mixture is left to react for 3 h at room temperature and then 103 g (0.73 mol) of methyl iodide are run in while keeping the temperature of the mixture 20 below 30*C. The mixture is left to react for 0.5 h and S' then 74 g (0.66 mol) of a 50 potassium hydroxide solution are added. The mixture is left to react for 0.5 h and then 103 g of methyl iodide are again run in and left to react for 1 h. The mixture is diluted with 25 300 ml of water. The mixture is acidified to pH 4 with IN hydrochloric acid. The product is extracted with 500 ml of ethyl acetate. The solution is dried over magnesium sulphate and then concentrated under 26 reduced pressure. 49.5 g of N-[bis(methylthio)methylene]-2-phenylglycine (yield 31 are recovered in the form of a yellow solid melting at 112°C.
b) 2'-(metachlorophenyl)[N-(bis(methylthio)methylene)-2-phenylglycyl]hydrazide (compound V with R, phenyl, R 2 H, R 4 metachlorophenyl, n 1, B NH): 3.38 g (16.4 mmol) of dicyclohexylcarbodiimide are added to a solution of 2.95 g (16.4 mmol) of N-[bis(methylthio)methylene]-2-phenylglycine in methylene chloride (40 ml), and the mixture is then left to react for 0.5 h at room temperature. 2.34 g (16.4 mmol) of metachlorophenylhydrazine are added. The mixture is heated for 0.5 h at 30"C. The insoluble material is filtered off. The filtrate is washed with 2 times 30 ml of water on each occasion. The solution is concentrated: a honey-like product is obtained which is purified by chromatography on a silica column. After purification, 2.5 g of 2'-(metachlorophenyl)[N- (bis(methylthio)methylene)-2-phenylglycyl]hydrazide are 20 recovered in the form of a pinkish powder melting at 146°C.
c) l-Metachlorophenylamino-2-methylthio-4-phenyl- 2-imidazolin-5-one (compound No. 7): 1.92 g (5 mmol) of 2'-(metachlorophenyl)[N- 25 (bis(methylthio)methylene)-2-phenylglycyl]hydrazide is dissolved in 30 ml of xylene. The reaction mixture is heated for 4 h at reflux. The mixture is concentrated under reduced pressure. The resulting honey-like 27 product is triturated with 10 ml of ether: the product crystallises. The precipitate is filtered and the product is dried in a desiccator under vacuum. Compound No. 7 is thus obtained, with a yield of 56 in the form of a yellow powder melting at 196 0
C.
By carrying out the preparation in a similar way, the compounds which appear in the following table were prepared: *ft 28 R2 N Y SR 3 N
N-~R
4 3w
R,
No. R2 R 3 W Cst 4 f H Me 2-chloroPh H 0 130*C H Me Ph H 0 1900C 6 H Me 4-chloroPh H 0 162 aC 7 H Me J3-chioroPh H 0 196'C 8 H Me meta-tolyl H 0 182 0
C
59 H MeS 2, 4 -(CH 3 2 Ph H 0 64 0
C
61 H MeS 2,5-(CH 3 2 Ph H 0 162 0
C
63 H MeS 2-EtPh H 0 126 0
C
69 H MeS 2, 5- (Cl) 2 Ph H 0 144 0
C
71 HIMeS I3,5-(C1) 2 Ph IH 0 146*C 4-Phenyl--(N-phenylamino) -2-moethylthio-2- (compound 120) was also prepared.
Example 3: Preparation of 4-methyl-1-(N- -,ethyl-N-phenylamino) -2-methylthio-'4-phenyl-2- (coripound No. 22) by alkylation (methylation) according to process C1.
0.4 g (3.5 minol) of potassium tert-butoxide is added to a solution of 4-methyl-l-phenylamino-2- 29 methylthio-4-p~enyl-2-imidazolin-5-one (compound No. 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to O'C. The mixture is left to react for 0.5 h at 0°C. 0.5 g (3.5 mmol) of methyl iodide is then added and then the mixture is left to react for h at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether, Tho ethereal solution is dried over magnesium sulphate and then concentrated. The product crystallises when triturated in 10 ml of diisopropyl ether. It is filtered and then dried under vacuum. 0.73 g (yield: 70 of compound 22 is thus obtained in the form of a pale-yellow powder melting at 124 0
C.
Example 4: Preparation of 4-methyl-l-(Nacetyl-N-phenylamino)-2-methylthio-4-phenyl-2imidazolin-5-one (compound No. 23) by acylation (acetylation) according to process C1.
0.4 g (3.5 mmol) of potassium tert-butoxide 20 is added to a solution of 4-methyl-l-phenylamino-2a* thylthio-4-phenyl-2-imidazolin-5-one (compound No. 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0°C. The mixture is left to react for 0.5 h at 0°C. 0.25 g (3.5 mmol) of acetyl chloride 25 is then added and the mixture is left to react for h at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The ,so ution is dried over magnesium sulphate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallises from diisopropyl ether.
0.25 g of compound No. 23 is obtained in the form of a white powder melting at 132 0
C.
By carrying out the preparation in the same way, compounds No. 39 and 42 were obtained.
R
2 N Y. SR 3 NNR4 aW R No. R 2
R
3 R4R 5 W Cst
S*
S.
S
1 C 23 Me IMe Ph acetyl 0 132*C 39 Me Me Ph formyl 0 "honey-like cons. -stency" 2 Me Me Ph tBuOCO 0 hnylk F ____consistency" Example 5: Preparation of 4-ethyl-2methylthio-4-phenyl- 1-phenylamino-2-imidazolin-5-one (compound 48) according to process C2.
0.55 g of potassium tert-butoxide is added to a solution of 1.5 g (5.05 mmol) of 2-methylthio-4phenyl-1-phenylamino.-2-imidazolin-5-one (compound No. 5) in 50 ml of anhydrous tetrahydrofuran. The mixture is left to react for 30 min at room temperature and then 0.8 g (5.05 mmol) of ethyl iodide is added.
The mixture is left to react for 1 h at room temperature. The mixture is diluted with 150 ml of ethyl acetate. The solution is washed with water and then concentrated under reduced pressure. The product is purified by chromatography on a silica column (Merck silica; eluent: 25 ethyl acetate/75 heptane).
0.65 g of compound No. 48 is obtained in the form of a beige powder melting at 147 0
C.
By carrying out the preparation in the same way, compound No. 49 was obtained.
*1I*I e* e o
R
2 N-Y SR 3 W
K
No. R2 W Cst 5 48 Et Me Ph H 0 147 0
C
49 iso-Pr Me Ph H 0 135*C Me MeS 2, 4 2 Ph H 0 -honey-like 62 Me [MeS 2,5-(Me),Ph H 0 160*C 64 Me JMeS 2-EtPh H 0"honey-like ______consistency" Me MeS 2,4-(Cl) 2 Ph H 0 66 Me MeS 1-naphthyl H 0 174 0
C
70 Me MeS 2, 5- (Cl) 2 Ph H 0 180 0
C
72 Me MeS 3,5-(Cl) 2 Ph H 0 200*C 74 CHF 2 MeS Ph H 0 124*C 79 Me MeS 2-CF3--Ph H 0 91*C 4-Methyl-2-methylthio-4-(4-fluorophenyl) -1- (compound 68) was also prepared.
Example 6: Preparation of compound 2 according to process D.
1.7 g (5.2 mmol) of 4-methyl-2-methylthio-4- (compound No. 1) is dissolved in 20 ml of chloroform. The solution is cooled to -10 0 C and then a solution of 1.35 g (5.5 mmol) of metachloroperbenzoic acid and ml of chloroform is added over 10 min. On completion of addition, the temperature is allowed to return to room temperature. The mixture is washed with a saturated aqueous sodium bicarbonate solution and then with distilled water. The organic phase is treated with active charcoal and then concentrated. The resulting honey-like product is taken up in 20 ml of ether: the product dissolves and then a beige solid precipitates.
The precipitate is filtered. The product is dried under reduced pressure. 0.4 g (yield: 25 of compound No. 2 is thus obtained in the form of a beige powder melting at 150°C.
20 No. R R3 R4 R, W Cst 2 Me Me Ph H S=O M.p.= Example 7: Preparation of 3,5-diphenyl-5- Smethyldithiohydantoin according to process E.
15.1 g (122 mmol) of potassium terr-butoxide are dissolved in 200 ml of tetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under a dry argon I 1_1 atmosphere. The solution is cooled to -70 0 C. A solution containing 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g (122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is run in dropwise while keeping the temperature of the mixture below -60"C. On completion of addition, the mixture is held for 0.5 h at -70C and then is left to return to room temperature. The mixture is poured into 500 ml of water. The mixture is acidified to pH 1 by addition of N hydrochloric acid. The product is extracted with ethyl acetate (2 extractions, each with 150 ml of solvent). The solution is dried over magnesium sulphate. The solution is concentrated under reduced pressure. The product is crystallised from 50 ml of ether. The precipitate is filtered. 21 g (yield: 58 of 3,5-diphenyl-5-methyldithiohydantoin are thus obtained, a yellow powder melting at 157°C.
Example 8: Preparation of 3,5-diphenyl-5 methyl-2-thiohydantoin according to process F.
20 4.7 g (20 mmol) of ethyl 2-isothiocyanato-2- S* phenylpropionate are dissolved in 40 ml of xylene.
2.16 g (20 mmol) of phenylhydrazine are added and the mixture is heated for 4 h at reflux. The mixture is cooled to room temperature and a beige solid 25 precipitates. The precipitate is filtered, washed with ml of diisopropyl ether and then dried under vacuum.
4.6 g (yield 77 of 3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of a beige powder melting at 164°C.
Example 9: Preparation of 3-(2-pyridylamino)-2-thiohydantoin according to process F.
2 g (9 mmol) of methyl 2-isothiocyanato-2phenylpropionate are dissolved in 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: the temperature of the mixture rises from 20 to 30°C and a solid precipitates. The mixture is allowed to react for h at 30"C and then is cooled to 5°C. A solution containing 1 g of potassium tert-butoxide and 10 ml of tetrahydrofuran is then added: the mixture becomes violet in colour. The mixture is left to return to room temperature and is left to react for 2 h. The mixture is poured into 150 ml of water. The mixture is neutralised with acetic acid. The product is extracted with 150 ml of ethyl acetate. The solution is washed with water, dried over magnesium sulphate and then 20 treated with active charcoal. The solution is 0*O* 0. concentrated and the product is crystallised from 20 ml of diethyl ether. The abovementioned product is *fee filtered and is dried under vacuum. 1.6 g (yield: 60 of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin 25 is obtained, a pale-yellow solid melting at *oro The compounds of formula (VII) collated in the following table, which are intermediates of the compounds of formula I and are numbered from number 1001, were prepared according to this process:
H
R,
N\ (B)n--R 4
(VDI)
R, methyl and R. phenyl.
r u r o o No. n B R 4 Yield M.p.
1001 1 NH Ph 66 164*C 1002 1 NH meta-tolyl 62 17400 1003 1 CH 2 Ph 46 12500 1004 1 1 NH para-tolyl 13 162"C 1005 1 CH 2 2-thienyl 49.5 134 0
C
1006 1 NH 4-fluoroPh 30 162"C 1007 1 NH ortho-tolyl 38 16200 1008 0 iso-propyl 60.5 14600 1009 1 INH 3-chloroPh 32 7800 1010 1 NH tert-butyl 18 120"C 1011 1 NH 4-chioroPh 24 196 0
C
1012 1 NH 2-chloroPh 69 17200 1013 0 piperidino 32 206*C 1014 1 NH 4-methox'yPh 27 1460C 1015 1 NH 2-ethoxyPh 29 214 0
C
1016 1 CH 2 2-furyl 39 10500 1017 1 NH aceyl 42 20000 1018 1 NH 4-N0 2 -Ph 41 23400 1019 1 NH 2-pyridy. 60 8000 1020 1 NH 3-pyridyl 17 r Example 10: Preparation of compound 9 according to process G.
11.1 g (50 mmol) of methyl 2-isothiocyanato- 2-phenylpropionate are dissolved in 150 ml of anhydrous tetrahydrofuran. A solution containing 5.4 g (50 mmol) of phenylhydrazine and 50 ml of anhydrous tetrahydrofuran is added progressively over 10 min: the temperature of the mixture rises to 35"C. On completion of addition, the mixture is left to react for 0.5 h at 30"C and the mixture is then cooled to A solution containing 5.6 g (50 mmol) of potassium tert-butoxide and 50 ml of anhydrous tetrahydrofuran is added at this temperature: the mixture turns violet in colour and then a precipitate forms. The mixture is left to react 15 for 0.5 h at 0°C and then 8.5 g (60 mmol) of methyl iodide are added. The mixture is left to react for 1 h at room temperature. The mixture is diluted with 200 ml of ethyl acetate. The mixture is washed 2 times with 150 ml of water on each occasion. The solution is dried 20 over magnesium sulphate and then treated with active charcoal. The solution is concentrated: a purplishbrown honey-like prodw t is obtained which is crystallised from 50 ml of ether. The precipitate is washed and then dried under vacuum. A second crop of product is recovered after concentrating the mother liquors and taking up the residual honey-like product in 50 ml of diisopropyl ether. 12 g (yield 77 of 4-methyl-2-methylthio-4-phenyl-l-phenylamino-2- I 38 (compound 9) are thus obtained in the form of a beige powder melting at 149"C.
By carrying out the preparations as above, the following compounds were obtained:
R
2 N S-CH 3
R'
1 0 R4 e *ee No. R 2 B R, M.p.
58 Me MeS NH I 2,3-(Me) 2 Ph 116*C 67 Me MeS (CE 2 2 Ph honeylike cons istency 7 6- L*.l MeS I CE 2 I 3-pyridyl 67*C 77 -Me MeS CE 2 2 -pyridyl honeylike consistency 78 M- 1 e L MeS N PhCH= 95 0
C
83 4-Me Me j MeS NH Ph 179 0
C
84 I- Me MeS NH 13-Me-2-pyridyl 1480C 4-Cl Me MeS NH Ph {_173 0
C
86 13,4-(MeO), 2 Me MeS NH Ph 165 0
C
87 I3,4-(MeO) 2 1 Me MeS NH I 2-Me-Ph 151 0
C
88 14-Me Me MeS NH 2-Me-Ph 52 0
C
89 1 4-PhO _Me MeSNH Ph 146 0
C
1 4-Cl I Me MeS NH 13-Me-2-pyridyl 13 3 0
C
91 14-Cl Me MeS Ni 2-pyridyl 172 92* 1 R, PhCH 2 J Me MeS NH Ph 166 0
C
93 1 4-Pho Me MeS NH 2-Me-Ph 130*C 94 1 4-F Me MeS NH 2-Me-Ph 120 0
C
96 4-Cl Me MeS NH J_2-Cl-Ph 145*C 971 -(CE 2 3 MeS NH J Ph I158C 98 (CE 2 2 MeS NH Ph 85 0
C
99 4-Cl H MeS NH 4-Cl-Ph 163 0
C
100 4-Cl Me MeSi NH 4-Cl-Ph 1720C oo o r tR' 1 R f R 3 B R, M.P.
101 4-cl Me jMeS NH 4-F-Ph 170'C 102 4-Cl Me MeS NH 3-Cl-Ph 146*C 103 14-Cl Me MeS NH 4-Me-Ph 178 0
C
104- CH 2 3 _MeS 1 NH 2-Cl-Ph 168*C 105 t4-Cl Me MeS I NH 2-Me-Ph 124"C 106 J4-C1 Me MeS NH 3-Me-Ph 136*C 107 1 4-F Ime MeS NH 3-Me-Ph 121aC 108 K Me MeS NH 3-F-Ph 163 0
C
109 Me MeS NH 2,5-F 2 -Ph 141 0
C
110 14-Me Me MeS NH 4-Cl-Ph 168 0
C
111 14-Me Me MeS NH 2-Cl-Ph 168 0
C
112 i(CT2) 3 MeS NH 4-Cl-Ph 191 0
C
113K 1
(CH
2 3 MeS NH 2-Me-Ph 1740C 15 114 14-Me Me 1_MeS NH 3-Cl-Ph 184-C 115 1 4-F Me MeS NH 3-Cl-Ph 124- 0
C
116 14-Me Me MeS NH 4-F-Ph 186 0
C
117 4-Me Me MeS NH 4-Me-Ph 157*C 118 4-F Me MeS NH 4-Me-Ph 158 0
C
119 4-Me Me MeS NH 3-Me-Ph 178*C 121 4-F Me MeS NH 4-Cl-Ph 159*C 122 Me MeS NH 2,4-(Me) 2 -Ph 63*C 123 Me MeS NH 3-Cl-2-Pyr 1270C 124 1 4-C1 Me MeS NH 2-F-Ph 120"C 125 4-F Me MeS NH 2-F-Ph 112 0
C
126 4-Me Me MeS NH 2-F-Ph 156*C
S..
a..
a..
40a These compounds have the following formulae: Compound 97: Ny S-CH 3
'NHQ
Compound 98: /S -CH3 Compound 104: Compound 112: CH3 N~HQ
CI
Compound 113: PCl
CH
3 940427,p:koperee,331rbo-5C,40 40b Compound 92: Q N- S-CH3
CH
3 0 N ~NH Q This compound does not follow the general formula on page 38.
94O42,p:\opr\ct,331rOsmC4O Example 11: Preparation of 4-phenyl-4-methyl- 1-(phenylthio) -2-methylthio-2-imidazolin-5-one (compound 95: M.p. 112"C).
0.6 g (2.7 mmol) of 2-methylthio-4-methyl-4phenyl-2-imidazolin-5-one in solution in 50 ml of anhydrous tetrahydrofuran (THF) is charged to a 100 ml, three-necked, round-bottomed flask under an inert atmosphere. The solution is stirred with a magnetic stirrer and is cooled to O'C (ice bath acetone).
0.30 g (1 molar equivalent) of potassium tert-butoxide is added and the mixture is stirred for 10 min at 0OC.
A solution containing 0.40 g of phenylsulphenyl chloride and 10 ml of anhydrous THF is then run in. The mixture is then left to return to room temperature for 15 one hour. The reaction mixture is run into 100 ml of water. Extraction is carried out with 100 ml of ethyl acetate. The organic phase is washed 4 times with water and dried over sodium sulphate.
The organic phase is concentrated under vacuum. A yellow honey-like product is obtained which crystallises from isopropyl ether after purification on silica with a yield of 68% (melting point: 112"C).
B)n-R4
R
2 SR 3 (C)n -R,
R
2 NS SR 3 RI N_ IR 4 w
R
2 IN-. SR 3
WH
R, S- SCHJ R1, 0 (B
-R
R, N--cSCH3 R,>CO.H SCH3 1
CO
2
R
4
-NH-,
TEV)
(M)
R, NC IS CH3 H-(B)n 0
(V)
R2 R 'CB)n-PR 4 0 mVT RI-C-N~c~s CO2
R
(VfII.
-43- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but nor the exclusion of any other integer or group of integers.
ee *ee 941007,p:\oper\e,651021rho.div,43
Claims (3)
1. A process for the preparation of compounds of formula wherein an imino dithiocarbonate of formula (III) is condensed with an amine or a hydrazine of formula (IV) according to the scheme: R SCH3 R 4 -(B)n-NH2 S CH3 R N SCH 3 U R2 -S CH R 1 COzH R, C-NH-(B)n-R 4 0 (V) in which: n 0or B represents NR s or O or S or CRsR 6 or SO 2 or C=O R, and R 2 which are identical or different, represent: H, provided that one of the 2 groups is different from H, or an alkyl or haloalkyl radical containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, alkylsulphonylalkyl, monoalkylaminoalkyl, alkenyl or alkynyl radical containing 2 to 6 carbon atoms or 20 a dialkylaminoalkyl or cycloalkyl radical containing 3 to 7 carbon atoms or an aryl radical preferably phenyl, naphthyl, thienyl, furyl, pyridyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, or methylenedioxyphenyl, optionally substituted by 1 to 3 groups chosen from R 7 or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or 25 R, and R 2 can form, with the carbon to which they are bonded on the ring, a carbocycle or a heterocycle having from 5 to 7 atoms, it being possible for these rings to be fused to a phenyl, optionally substituted by 1 to 3 groups chosen from Ry; R 4 represents: a hydrogen atom when n is equal to 1 or an alkyl group containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl, alkenyl or alkynyl group containing 2 to 6 carbon atoms or 941007,p:\opcr\ce,651 2rh.div,44 a dialkylaminoalkyl, alkoxycarbonylalkyl or N-alkylcarbamoylalkyl group containing 3 to 6 carbon atoms or a N,N-dialkylcarbamoylalkyl group containing 4 to 8 carbon atoms or an aryl radical, preferably phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl or methylenedioxyphenyl, optionally substituted by 1 to 3 groups chosen from R, or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulphonylalkyl radical, or an amino group disubstituted by 2 identical or different groups chosen from: an alkyl radical containing 1 to 6 carbon atoms an alkoxyalkyl, alkenyl or alkynyl radical containing 3 to 6 carbon atoms a cycloalkyl radical containing 3 to 7 carbon atoms an arylalkyl, phenyl or naphthyl radical, optionally substituted by 1 to 3 groups chosen from R, or a thienylmethyl or furfuryl radical a pyrrolidino, piperidino, morpholino or piperazino group, optionally substituted by alkyl containing 1 to 3 carbon atoms; R, represents: H, except when R 4 is H, or an alkyl, haloalkyl, alkylsulphonyl or haloalkylsulphonyl radical containing 1 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl, acyl, alkenyl, alt ynyl, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulphone or cyanoalkylsulphonyl radical containing 2 to 6 carbon atoms or an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl or cyanoalkoxycarbonyl radical containing 3 to 6 carbon atoms or a formyl radical or a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl or alkynylcarbonyl radical containing 3 to 6 carbon atoms or a cycloalkylcarbonyl radical containing 4 to 8 carbon atoms or a phenyl; arylalkylcarbonyl, preferably phenylacetyl or phenylpropionyl; arylcarbonyl, preferably benzoyl, optionally substituted by 1 to 3 groups from R,; thienylcarbonyl;furylcarbonyl;pyridylcarbonyl;benzyloxycarbonyi;furfuryloxycarbonyl; S S.. S 0, 960207,p:\oper\dab,74499.spe,45 -46- tetrahydrofurfuryloxycarbonyl; thienylmrnetb.jcarbonyl; pyridylmethoxyacrbnnyl; phenoxycarbonyl or (phenylthio)carbonyl, the phenyl being itself optionally substituted by 1 to 3 groups from (alkylthio)carbonyl; (haloalkylthio)carbonyl; (alkoxyalkylthio)carbonyl; (cyanoalkylthio)carbonyl; (benzylthio)carbonyl; (furfurylthio)carbonyl; (tetrahydrofurfurylthio)carbonyl; (thienylmethylthio)carbonyl; (pyridylmethylthio)carbonyl; or arylsulphonyl radical or a carbamoyl radical, optionally mono- or disubstituted by an alkyl or haloalkyl group containing 1 to 6 carbon atoms or a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3 R, groups; a sulphamoyl group, optionally mono- or disubstituted by an alkyl or haloalkyl group containing 1 to 6 carbon atoms or a cycloalkyl, alkenyl or alkynyl group containing 3 to 6 carbon atoms or an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing 2 to 6 carbon atoms or a phenyl, optionally substituted by 1 to 3 R, groups; an alkylthioalkylsulphonyl group containing 3 to 8 carbon atoms or a cycloalkylsulphonyl group containing 3 to 7 carbon atoms; R 6 represents: a hydrogen atom or a cyano group or an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms or an acyl or alkoxycarbonyl group containing 2 to 6 carbon atoms or a benzoyl group, optionally substituted by 1 to 3 R, groups; R, represents: a halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or alkylsulphonyl radical containing 1 to 6 carbon atoms or
9. 0** a. a a.. -V.A 960207,p;\opcr\dab,74499.spc,46 -47 a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio radical containing 3 to 6 carbon atoms or a nitro or cyano group or 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 a phenyl, phenoxy or pyridyloxy radical, these radicals optionally being substituted; it being necessary for the acid (III) to be activated for this condensation in the acid chloride form, in the dicyclohexylisourea form using dicyclohexylcarbodiimide, or in the imidazolide form using carbonyldiimidazole. 2. A process for the preparation of dithiohydantoins of formula (VI) (process E): H R, N R S(VI) in which R 2 and R 4 have the same meaning as in Claim 1 with at least one 20 of R, or R 2 being electron-withdrawing, characterised in that two isothiocyanates, of formulae RR 2 CHNCS and R 4 NCS in which R 4 NCS is unable to form an anion, are reacted in the presence of a base, in a solvent and at a temperature below -60 0 C. 3. A process according to claim 2, characterised in that the base is chosen from 25 potassium tert-butoxide, sodium or lithium bis(trimethylsilyl)-amide and/or alkali metal hydrides and the solvent is chosen from ethers and cyclic ethers. 4. A process according to claim 2 or claim 3, characterised in that R, and/or R 2 is an aryl or substituted aryl. A process according to any one of claims 2 to 4 characterised in that the .isothiocyanate R 4 NCS is an aryl isothiocyanate. 960207,pAopcr\dab,74499.spc,47 48 6. A process for the preparation of the 2-thiohydantoins of formula (VII) (process F): H R, N S N R R N(B)-R4 0 (VII) characterised in that, before cyclising, a compound of formula (IV) (R 4 (B)nNH 2 is reacted with isothiocyanates derived from the amino acids of formula (VIII): R 2 R-C-N=C=S COR (VIII) in which R 1 R 2 R 4 B and n have the same meaning as in claim 1 and R is C 4 alkyl or a benzyl group. 7. A process according to claim 6, characterised in that the cyclisation is carried out thermally by heating the mixture of the reactants at a temperature of between 110 and So. 180°C in an aromatic solvent preferably toluene, xylene or the chlorobenzenes. 8. A process according to claim 6, characterised in that cyclisation is carried out 25 with one equivalent of base, in a solvent and at a temperature of between -10 and 0 C, the mixture being subsequently neutralised at room temperature. 0ee 9. A process according to claim 8, characterised in that the base is chosen from the group comprising an alkali metal alkoxide, an alkali metal hydroxide or a tertiary amine; the solvent is chosen from the group comprising ethers, cyclic ethers, alcohols, esters, DMF and DMSO. 960207,p:\oper\dab,74499.spe,48 PA:OI'SRM07C4499-94AT 1619 49 Compounds having the formulae 11, 111, IV, V, VI, VII and Vill (MID R 2 N=ecK 0V. R< 'SCN 0 MB~R o. *S* S S S S S R 1 4 -N--C=S LO2R (Yin) (MII in which R 2 B, n and R 4 have the same meaning as in clairn 1, W is a sulphur or oxygen atom or an S =O group and R is C,4 alkyl.
11. A process according to any one of claims 1 to 9 or a compound according to claim substantially as hereinbefore described with reference to any one of the examples. DATED this 6th day of June, 1996 Rhone-Poulenc Agrochirnie By DAVIES COLLISON CAVE Patent Attorneys for the Applicants. A. NJ ABSTRACT The invention relates to intermediates useful in processes for preparation of fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione and processes for the preparation of said intermediates. 0 0* 941007,p\oper\e,651O2 1rho.div,49
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9116200 | 1991-12-20 | ||
| FR9116200A FR2685328B1 (en) | 1991-12-20 | 1991-12-20 | DERIVATIVES OF 2-IMIDAZOLINE-5-ONES AND 2-IMIDAZOLINE-5-THIONES FUNGICIDES. |
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|---|---|---|---|
| AU30310/92A Division AU651021B2 (en) | 1991-12-20 | 1992-12-18 | Fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives |
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| Publication Number | Publication Date |
|---|---|
| AU7449994A AU7449994A (en) | 1995-01-05 |
| AU671389B2 true AU671389B2 (en) | 1996-08-22 |
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| AU30310/92A Ceased AU651021B2 (en) | 1991-12-20 | 1992-12-18 | Fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives |
| AU74499/94A Ceased AU671389B2 (en) | 1991-12-20 | 1994-10-07 | Process for the formation of intermediates and intermediates useful for the preparation of fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives |
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| AU30310/92A Ceased AU651021B2 (en) | 1991-12-20 | 1992-12-18 | Fungicidal 2-amidazolin-5-one and 2-amidazoline-5-thione derivatives |
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| DE3931907A1 (en) * | 1989-09-25 | 1991-04-04 | Henkel Kgaa | AQUEOUS LACQUER SPRAY PROTECTIVE COATING FOR SPRAY CABINS AND METHOD FOR THE PRODUCTION THEREOF |
| FR2706455B1 (en) * | 1993-06-18 | 1995-08-04 | Rhone Poulenc Agrochimie | Optically active derivatives of 2-imidazoline-5-ones and 2-imidazoline-5-thiones fungicides. |
| US6002016A (en) * | 1991-12-20 | 1999-12-14 | Rhone-Poulenc Agrochimie | Fungicidal 2-imidazolin-5-ones and 2-imidazoline-5-thiones |
| FR2698359B1 (en) * | 1992-11-25 | 1995-10-27 | Rhone Poulenc Agrochimie | DERIVATIVES OF 2-ALKOXY 2-IMIDAZOLINE-5-ONES FUNGICIDES. |
| FR2706456B1 (en) * | 1993-06-18 | 1996-06-28 | Rhone Poulenc Agrochimie | Optically active derivatives of 2-imidazoline-5-ones and 2-imidazoline-5-thiones fungicides. |
| FR2685328B1 (en) * | 1991-12-20 | 1995-12-01 | Rhone Poulenc Agrochimie | DERIVATIVES OF 2-IMIDAZOLINE-5-ONES AND 2-IMIDAZOLINE-5-THIONES FUNGICIDES. |
| EP1008589A1 (en) * | 1992-05-22 | 2000-06-14 | E.I. Du Pont De Nemours & Company Incorporated | Fungicidal imidazolinones |
| US6008370A (en) * | 1992-11-25 | 1999-12-28 | Rhone-Poulenc Agrochimie | Fungicidal-2-alkoxy/haloalkoxy-1-(mono- or disubstituted)amino-4,4-disubstituted-2-imidazolin-5-ones |
| FR2716192B1 (en) * | 1994-02-17 | 1996-04-12 | Rhone Poulenc Agrochimie | 2-Imidazoline-5-ones fungicidal derivatives. |
| AU1892495A (en) * | 1994-03-09 | 1995-09-25 | Rhone-Poulenc Agrochimie | Pesticide substituted 2-imidazolinones |
| FR2721022B1 (en) * | 1994-06-10 | 1996-07-19 | Rhone Poulenc Agrochimie | Derivatives of 5-imino 2-imidazolines fungicides. |
| FR2722499B1 (en) * | 1994-07-13 | 1996-08-23 | Rhone Poulenc Agrochimie | NEW 2-IMIDAZOLINE-5-ONES FUNGICIDE DERIVATIVES |
| FR2722652B1 (en) * | 1994-07-22 | 1997-12-19 | Rhone Poulenc Agrochimie | FUNGICIDE COMPOSITION COMPRISING A 2-IMIDAZOLINE-5-ONE |
| EP0760239A3 (en) * | 1995-09-01 | 1999-04-14 | Pfizer Inc. | Therapeutic agents for use in cancer therapy |
| FR2751327A1 (en) | 1996-07-22 | 1998-01-23 | Rhone Poulenc Agrochimie | INTERMEDIATES FOR THE PREPARATION OF 2-IMIDAZOLINE-5-ONES |
| UA61064C2 (en) * | 1997-12-02 | 2003-11-17 | Рон-Пуленк Агро | Synergic fungicidal composition containing 2-іnidazolin-5-оn and a method of controlling the phytopathogenic fungi of crops |
| UA70327C2 (en) | 1998-06-08 | 2004-10-15 | Баєр Акціенгезельшафт | Method of combating phytopathogenic diseases on crop plants and a fungicidal composition |
| FR2783401B1 (en) * | 1998-09-21 | 2000-10-20 | Rhone Poulenc Agrochimie | NEW FUNGICIDAL COMPOSITIONS |
| EP1092712A1 (en) * | 1999-10-13 | 2001-04-18 | E.I. Du Pont De Nemours And Company | Process for preparing fungicidal oxazolidinones and imidazolinones |
| DE50312724D1 (en) | 2002-04-24 | 2010-07-01 | Basf Se | USE OF CERTAIN ALCOHOL ALKOXYLATES AS ADJUVANS FOR THE AGROTECHNICAL FIELD |
| CN101863835B (en) * | 2010-06-29 | 2012-10-10 | 渤海大学 | Synthesis method of S-substituted-5,5-diphenyl-2-thiohydantoin derivatives |
| CN103081915A (en) * | 2011-11-07 | 2013-05-08 | 深圳诺普信农化股份有限公司 | Bactericidal composition |
| EP2622961A1 (en) | 2012-02-02 | 2013-08-07 | Bayer CropScience AG | Acive compound combinations |
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| AU6458694A (en) * | 1993-06-18 | 1994-12-22 | Rhone-Poulenc Agro | Fungicidal optically active 2-imidazolin-5-one and 2-imidazoline-5-thione derivatives |
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| FR2329276A1 (en) * | 1975-10-29 | 1977-05-27 | Roussel Uclaf | NEW SUBSTITUTES IMIDAZOLIDINES, METHOD OF PREPARATION, APPLICATION AS A MEDICINAL PRODUCT AND COMPOSITIONS CONTAINING THEM |
| DE3305203A1 (en) * | 1983-02-16 | 1984-08-16 | Bayer Ag, 5090 Leverkusen | N-SULFENYLATED HYDANTOINE, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MICROBICIDE |
| DE3340595A1 (en) * | 1983-11-10 | 1985-05-23 | Hoechst Ag, 6230 Frankfurt | IMIDAZOLINONES, METHOD FOR THEIR PRODUCTION AND THEIR USE IN PLANT PROTECTION |
| JPH02502721A (en) * | 1987-03-20 | 1990-08-30 | イー・アイ・デユポン・デ・ニモアス・アンド・カンパニー | Bactericidal and fungicidal aminotriazole and aminoimidazole |
| RO111765B1 (en) * | 1989-04-21 | 1997-01-30 | Du Pont | Derivates of 4-oxazolidinone, preparation process therefor, agricultural compositions which contain it thereof and method for the fungic illnesses control at plants |
| NZ237476A (en) * | 1990-03-20 | 1994-01-26 | Sanofi Sa | N-substituted heterocyclic compounds and pharmaceutical compositions. |
| FR2671348B1 (en) * | 1991-01-09 | 1993-03-26 | Roussel Uclaf | NOVEL PHENYLIMIDAZOLIDINES, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2685328B1 (en) * | 1991-12-20 | 1995-12-01 | Rhone Poulenc Agrochimie | DERIVATIVES OF 2-IMIDAZOLINE-5-ONES AND 2-IMIDAZOLINE-5-THIONES FUNGICIDES. |
| EP1008589A1 (en) * | 1992-05-22 | 2000-06-14 | E.I. Du Pont De Nemours & Company Incorporated | Fungicidal imidazolinones |
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