KR20010085897A - Substituted pyrrolidinone, thiazolidinone or oxazolidinone as herbicides - Google Patents

Abstract

The present invention relates to a compound of formula (1).

[Formula 1]

[Wherein Y is O, S or CH ₂ ; R ¹ is an optionally substituted aryl or heteroaromatic ring wherein the optional substituents are selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or C ₁ -C ₄ -haloalkoxy; R ² and R ³ are independently selected from hydrogen or halogen; R ⁴ and R ⁵ are independently selected from halogen.

This compound is useful as a herbicide.

Description

Substituted pyrrolidinone, thiazolidinone or oxazolidinone as herbicide {SUBSTITUTED PYRROLIDINONE, THIAZOLIDINONE OR OXAZOLIDINONE AS HERBICIDES}

The present invention relates to chemical compounds useful as herbicides, methods of making them and herbicide compositions and methods of using them.

WO 95/33719 describes various herbicide compounds based on heterocycles containing N-aryl substituted nitrogen.

Applicants have found particularly a group of compounds with special substitution patterns active as herbicides.

Thus, the compound of formula (1) is provided.

[Wherein Y is O, S or CH ₂ ; R ¹ is an optionally substituted aryl or heteroaromatic ring wherein the optional substituents are selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or C ₁ -C ₄ -haloalkoxy; R ² and R ³ are independently selected from hydrogen or halogen; R ⁴ and R ⁵ are independently selected from halogen.

The expression "alkyl" refers to a fully saturated straight or branched chain hydrocarbon having 1-6 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl and hexyl. Expressions such as "alkoxy" and "haloalkoxy" should be understood accordingly.

"Aryl" and "aromatic ring system" in the context of the present specification refers to a ring system that may be mono-, di-, or tricyclic. Examples of such rings include phenyl, naphthelenyl, anthracenyl or phenanthrenyl. Also, "heteroaromatic ring" or "heteroaromatic ring system" refers to an aromatic ring system containing one or more heteroatoms and consisting of a single ring or two or more fused rings. Preferably, the single ring will contain up to three heteroatoms, and the bicyclic system will contain up to four heteroatoms, preferably selected from nitrogen, oxygen and sulfur. Examples of such groups include furyl, thienyl, pyrroyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothia Zolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadia Zolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 1,2,3 -Thiazinyl, 1,2,4-thiazinyl, 1,3,5-thiazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothia Zolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cynolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, Benzotriazinyl, furinyl, putridinyl and indolizinyl. Preferred examples of heteroaromatic radicals include pyridyl, pyrimidyl, triazinyl, thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl.

As used herein, "halogen" includes fluorine, chlorine, bromine and iodine.

Preferred group R ¹ is optionally substituted phenyl or optionally substituted thienyl, preferably 2-thienyl. When R ¹ is substituted phenyl, the substituents are suitably arranged in 3-, 3,4-, 3,5- or 3,4,5- position and when R ¹ is substituted 2-thienyl, the substituents are Suitably in the 5-, 3,5- or 4,5-position.

Preferred substituents for group R ¹ are trifluoromethyl, trichloromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, fluoromethoxy, chloromethoxy, trichloroethoxy, trifluoro Roethoxy, dichloroethoxy, difluoroethoxy, fluoroethoxy, ethoxy, methoxy, fluoro, chloro, bromo, iodo and methyl. If there is more than one substituent, the substituents may be the same or different.

More preferably R ¹ is substituted with trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluoro, chloro, bromo and methyl.

Suitable groups for R ² and R ³ are hydrogen or chlorine. Preferred compounds include those in which both R ² and R ³ are identical.

Suitably halogen groups R ⁴ and R ⁵ are both the same and especially chlorine.

Y is preferably S or CH ₂ , most preferably CH ₂ .

Formula (1) described above is incapable or common isomer of a freely rotating molecular moiety with respect to other moieties, for example, in different ways to rearrange the molecules in the crystal lattice or known as "rotamer forms" or "rotamers". Or modifications of physically distinguishable compounds that may occur due to intermolecular or intramolecular hydrogen bonding and the like, as well as tautomeric forms of the structure.

The compounds of the present invention may exist in enantiomer forms and some may exist in both enantiomer and diastereomer forms. The present invention includes all individual forms and mixtures thereof in all proportions.

Specific examples of the compound of formula (1) are listed in Tables 1, 2 and 3 below. In Table 1 and throughout the specification, Me represents methyl, Et represents ethyl, Pr represents propyl, Ph represents phenyl, Bz represents benzyl, and Ac represents acetyl. Many of the compounds of the present invention may exist in two diastereomeric forms, which are generally in the form of a mixture of 1: 1 unless otherwise indicated, and A or B forms refer to separate diastereomers.

Compounds of formula (1) are suitably prepared by a variety of methods as described, for example, in WO 95/33719 and WO 96/37483.

For example, a compound of formula (1) may be prepared by reacting a compound of formula (2) with a compound of formula (3) and then modifying the substituents on group R ¹ if desired.

[Wherein, R ¹ and Y are as defined for Formula (1).

[Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined for formula (1) and X is a leaving group.

Preferred leaving group X is halogen, in particular chlorine.

The reaction may be carried out in an organic solvent such as chloroform, dichloromethane or toluene at 0-50 ° C., preferably at room temperature. The reaction is generally most preferred to proceed in the presence of a base and suitable bases include amines such as 4-N, Ndimethylaminopyridine (DMAP) or triethylamine or combinations thereof.

Modification of the substituents on group R ¹ may be carried out using conventional chemistry. For example, when R ¹ is an optionally substituted phenyl or thienyl group, the substituents or further substituents, in particular halogen substituents, are subsequently introduced by reacting with a halogenating agent such as N-succinimide as described below, for example. You can do it.

Alternatively or additionally, substituents such as bromine or iodine may be substituted by C _1-4 -alkyl such as methyl by reacting with a reagent such as tetramethyl tin in the presence of a catalyst such as Pd (O) as described below, for example. have.

Compounds of formula (2) are suitably prepared by reacting a compound of formula (4) with methylamine.

[Wherein R ¹ and Y are as defined for formula (1) and X ¹ is a leaving group such as halogen, mesylate or tosylate, in particular iodine.

When Y is CH ₂ , X ¹ is preferably bromine, iodine, mesylate or tosylate, most preferably iodine. When Y is S or O, X ¹ may be bromine, iodine, mesylate or tosylate as well as chlorine. The reaction is suitably carried out in the presence of an organic solvent such as tetrahydrofuran at a high temperature of 0-100 ° C. The compounds of the preferred formula (4), X ¹ is iodine is a compound of suitably of the formula (4) X ¹ is different leaving group, in an organic solvent such as acetonitrile or acetone may be prepared by reaction with iodide salt.

Compounds of formula (4) wherein Y is CH ₂ are suitably prepared by reacting a compound of formula (5) with a compound of formula (6) or a salt thereof, such as an acid addition salt, such as hydrobromide salt.

[Wherein X ² , X ³ and X ⁴ are independently selected from leaving groups and in particular halogen such as bromine or chlorine.

R ¹ -NH ₂

[Wherein, R ¹ is as defined for the formula (1).

The reaction is suitably carried out in the presence of a base and an organic solvent as listed above for the reaction between the compounds of formulas (2) and (3). The reaction may be carried out at a temperature of 0-50 ° C., preferably at room temperature.

Particularly preferred compound of formula (5) is 2,4-dibromobutanoyl chloride.

Alternatively, the compound of formula (4) wherein Y is CH ₂ is reacted with a compound of formula (7) by reacting the compound of formula (6) at high temperature, for example 100-180 ° C, preferably 150-160 ° C. It will be possible to manufacture.

Compounds of formula (4), wherein Y is sulfur, may be prepared, for example, using known chemical reactions according to the following scheme.

Compounds of formula (4), wherein Y is oxygen, may be prepared by other methods. For example, the compounds of formula (4) will be obtained by halogenation, mesylation or tosylation of compounds of formula (8).

[Wherein, R ¹ is as defined for the formula (1).

For example, when reacting a compound of formula (8) with a halogenating agent such as oxalyl chloride, a compound of formula (4) is obtained wherein X is a halogen leaving group. The compound of formula (8) is suitably It is prepared using the scheme.

In the above schemes, reagents such as bases, solvents, salts and the like are given by way of example only. Alternatives to this will be apparent to those skilled in the art.

When R ¹ is substituted thiophene and Y is CH ₂ , a compound of Formula 8 may be prepared by using one of the following methods.

In this scheme, X ⁵ is chlorine or bromine and NMP is N-methylpyrrolidin-2-one.

When R ¹ is other than mono-bromo substituted thiophene, the compound of formula (1) suitably comprises an acid addition salt, in particular a hydrobromide salt of the compound of formula (6) as defined above. Prepared by reacting with a compound. In this example, the preferred scheme for preparing the hydrobromide salt of formula (6) is as follows.

In this scheme, DPPA is diphenylphosphoryl azide and X ⁶ and X ⁷ are suitably independently selected from halogen, hydrogen or alkyl other than bromine. In particular X ⁶ is chlorine and X ⁷ is hydrogen or methyl.

Various cosolvents and butanol can be arbitrarily used in the modification of (14)-(20). If the amount of t-butanol does not fall below 1 molar equivalent relative to (14), for example, 1,4-dioxane, diglyme or monoglyme may be used in the mixture. Various combinations of these cosolvents may be used in several different ratios and any cosolvent (s) used need not necessarily be limited to those mentioned above. One particularly preferred procedure for this modification is to slowly adjust the DPPA reagent to the mixture of solvent and other reaction components that are heated. As a result, the material containing azide, which may be harmful in the reaction vessel, can be kept at a low concentration throughout the reaction, thereby increasing the safety of the process.

Compounds of formula (3) are suitably prepared by reacting a compound of formula (22) with a halogenating agent such as thionyl chloride or oxalyl chloride.

[Wherein, R ² , R ³ , R ⁴ and R ⁵ are as defined for Formula (1).

The reaction is carried out in an organic solvent such as dichloromethane containing a small amount of dimethylformamide at a moderate temperature of 0-50 ° C., conveniently at ambient temperature.

As discussed above, the compounds of the present invention may exist in the form of enantiomers. Some may also exist in both enantiomer and diastereomer forms. If desired, compounds in dissolved form may be prepared by techniques known to those skilled in the art. For example, chiral starting materials such as pure compounds of formula (22) as enantiomers can be used in the reaction outlined above. By way of example, a compound of formula (22) pure as an enantiomer suitably reacts the racemic compound with a suitable chiral base, such as cinconine, in a suitable solvent such as a mixture of ethanol and water so that both diastereomer salts can be formed. Can be prepared. One enantiomer salt can then be separated by crystallization. Other enantiomers recover the acid by acidifying the mother liquor and extracting with a suitable solvent such as ethyl acetate or dichloromethane.

Compounds of formulas (5), (6), (7), (8), (13), (14), (17), (19) and (22) are known compounds or compounds known by known methods It can be prepared from. For example, a compound of formula (14) in which R ² , R ³ , R ⁴ and R ⁵ are all halogen can be prepared by halogenation of the corresponding dihalo compound, as illustrated later. In particular, compounds in which R ² , R ³ , R ⁴ and R ⁵ are all chlorine may be prepared by adding dichlorocarbene to an ester of the corresponding 2,2-dichloro-1-methyl propenoic acid and then hydrolyzing with acid (14). Can be. Compounds in which R ⁴ and R ⁵ are fluorine are described by Gassen and Baasner in J. fluorine Chem ., 1990, 49, 127-139, while similar compounds in which R ⁴ and R ⁵ are bromine are JCS Perkin by Baird and Baster. Trans. 1 , p2317-2325 (1979).

Since the compound of formula (1) is active as a herbicide, the present invention provides, in another aspect, an undesired plant comprising applying a herbicidally effective amount of the compound of formula (1) to a plant or plant growth medium. Provides a way to severely damage or kill them. Compounds of formula (1) are active against a broad range of weed species, including monocotyledonous and dicotyledonous species. They show some selectivity for certain species and may be used, for example, as selective herbicides in soybean, corn and especially rice crops. Compounds of formula (1) may be applied directly to unwanted plants (post-applied) or applied to soil before unwanted plants appear (pre-applied). When the compound of the formula (1) is applied to rice, it is preferable to add them in an overflowing state, that is, in a bed plate state. The compound of formula (1) may be used by itself to kill or severely damage the plant, but is preferably used in the form of a composition comprising the compound of formula (1) together with a carrier comprising a solid or liquid diluent. .

Compositions comprising a compound of formula (1) include both ready-to-use diluent compositions and concentrated compositions that normally have to be diluted with water before use. Preferably the composition contains 0.01-90% by weight of active ingredient. The dilution composition ready for use preferably contains 0.01-2% of the active ingredient, while the concentrated composition will usually contain 20-70% but preferably 20-90% of the active ingredient.

Solid compositions may be in the form of granules or dust powders in which the active ingredient is mixed with finely divided solid diluents such as kaolin, bentonite, kijel-gur, dolomide, calcium carbonate, talc, powdered magnesia, soil of Fuller and gypsum Could be. They may also be in the form of dispersible powders or granules comprising a humectant to facilitate dispersion of the powder or granules in the liquid. The solid composition in powder form may be added as leaf flour.

The liquid composition may optionally include a dispersion or solution of the active ingredient in a water immiscible organic solvent that contains a dispersion or solution of the active ingredient in water containing a surfactant or is dispersed in water.

The surfactant may be of cationic, anionic or nonionic type or mixtures thereof. Cationic agents are for example quaternary ammonium compounds (eg cetyltrimethylammonium bromide). Suitable anionic agents include soaps; Salts of aliphatic monoesters of sulfuric acid, such as sodium lauryl sulfate; And salts of sulfonated aromatic compounds such as sodium dodecylbenzenesulfonate, sodium, calcium and ammonium lignosulfonate, butylnaphthalene sulfonate and sodium salts of diisopropyl and triisopropylnaphthalenesulfonic acid. Suitable nonionic agents are condensation products of ethylene oxide with alkylphenols such as fatty acid alcohols such as oleyl alcohol and cetyl alcohol or octyl- or nonyl-phenols (eg Agral 90 ™) or octyl-cresol. Other nonionic agents include partial esters derived from long chain fatty acids and hexitol anhydrides such as sorbitan monolaurate; Partial esters with ethylene oxide; lecithin; And silicone surfactants (eg water soluble surfactants having a backbone comprising siloxane chains such as Silwet L77 ™). A mixture in a suitable mineral oil is Atplus 411F ™.

Aqueous solutions or dispersions may be prepared by dispersing the active ingredient in water or an organic solvent, optionally containing a wetting or dispersing agent (s), and then optionally adding the mixture obtained above to water containing a wetting or dispersing agent (s), if an organic solvent is used. It will be possible to manufacture. Suitable organic solvents include, for example, ethylene di-chloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methylnaphthalene, xylene and trichloroethylene.

Compositions used in the form of aqueous solutions or dispersions are generally supplied in the form of concentrates containing a high proportion of active ingredient and then the feed is diluted with water before use. Concentrates need to be able to be aqueous preparations that are typically homogeneous for sufficient time to withstand long term storage and to be diluted with water after such storage and supplied to conventional spraying devices. The concentrate conveniently contains 20-90% by weight, preferably 20-70% by weight of active ingredient (s). Diluted preparations ready for use may contain the active ingredient (s) in varying amounts depending on the intended purpose, usually 0.01-10.0% by weight, preferably 0.1-2% by weight of the active ingredient (s). do.

A concentrated composition of the preferred form comprises the active ingredient finely divided and dispersed in water in the presence of a surfactant and suspending agent. Suitable suspending agents are hydrophobic colloids and include, for example, polyvinylpyrrolidone and sodium carboxymethylcellulose and vegetable rubbers such as acacia rubber and cragacant rubber. Preferred suspensions are those which impart thixotropy to the concentrate or increase the viscosity of the concentrate. Examples of preferred suspending agents include hydrated colloidal mineral silicates such as montmorillonite, Weidelite, nontronite, hectorite, saponite and socorrite. Bentonite is particularly preferred. Other suspending agents include cellulose derivatives and polyvinyl alcohols.

The rate of application of the compounds of the present invention will depend on a number of factors including, for example, the compound selected for use, the plant whose growth is inhibited, the composition selected for use and whether the compound is added by mouth absorption or by root absorption. However, as a general guideline, an application rate of 0.001-20 kilograms per hectare may be appropriate and 0.025-10 kilograms per hectare may be desirable.

The composition of the present invention may include one or more compounds of the present invention in addition to one or more compounds of the present invention, but not one of the compounds of the present invention but having biological activity. Accordingly, another embodiment of the present invention provides a herbicidal composition comprising at least one herbicidal compound of formula (1) as described above and at least one other herbicide mixture.

Other herbicides may be some herbicides that do not have formula (1). This will generally be a herbicide that complements the particular application. Examples of useful complementary herbicides include:

1,2,4-triazine-5-one, such as metamitrone and metrizin

2 Dimethylpyrazoles such as benzophenad, pyrazolate (pyrazolate) and pyrazoxifen

Acylanilides such as 3 propanyl

Amide herbicides, such as benfluamide, bromobutide, carbamide, flufenacet, isoxaben, naproanilide, napropamide, naphthalam, propizamide and tebutam

5 amino acids and salts and esters thereof, such as bialaphos and salts and esters thereof, glufosinate salts and esters thereof, glyphosate and salts and esters and sulfosate thereof

6 aryloxypropionate, optionally including active isomers thereof, such as clodinapop-propargyl, cyclohalo-butyl, diclopop and esters thereof such as methyl esters, phenoxaprop and esters thereof such as ethyl Esters, fluazippopt-butyl, haloxypops and esters thereof, propaquizapops, quazolopops and esters and quazolopop-p-tefuryl

7 arylanilides such as diflufenican, flamprop, flamprop-M and esters thereof

8 arylureas, such as chlorbromuron, chlorotoluron, cumyluron, dimuron (dimeron), dimefuron, diuron, phenuron, fluoromethuron, isoproturon, isourone, linuron, metabenzthiazuron , Methyldimeron, metobromuron, methoxuron, monolinuron, neburon and tebutiuuron

9 Benzo-2,1,3-thiadiazin-4-one-dioxide, such as bentazone

10 benzoic acid, such as 2,3,6-trichlorobenzoic acid, chlorambene and dicamba

11 bipyridylium such as diquat and salts thereof and paraquat and salts thereof

12 Carbamate, such as chlorprofam and profam, and phenoxycarbamoyloxyphenyl carbamate, such as desmedape and penmedamfam

13 acetamides, such as acetochlor, alachlor, butachlor, dimethachlor, dimethenamid and its isomers, metazachlor, metolachlor and isomers, pretilachlor, propachlor, propisochlor and tenylchlor

14 cyclohexanedione, such as alkoxydim and its salts, butoxydim, cletodim, cycloxydim, cetoxydim, tetraproxydim and tralcoxysid

15 dihalobenzonitrile such as diclobenyl

Dinitrophenols such as 16 dinoterb and dintro ortho-cresol (DNOC)

17 diphenyl ethers such as aciflurofen and salts and esters thereof, acloniphene, biphenox, clomethoxyphene, chlornitrofen, fluroglycopene or salts or esters thereof, pomessafen, lactofen and oxyfluorfen

18 dinitroaniline such as dinitramin, etafluralin, fluchlorine, oryzaline, pendimethalin, prodiamine and trifluralin

19 haloalkano herbicides such as dalapon and trichloroacetic acid and salts thereof

20 Hydroxybenzonitrile (HBN) herbicides such as bromoxynil and oxynyl and HBN precursors such as bromophenoxime

21 hormone herbicides such as 2,4,5-trichlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, 2,4-dichlorophenoxybutyric acid, clopyralide, dichlorprop and dichlorprop-p, Fluoroxypyr, 4-chloro-2-methoxyacetic acid (MCPA), MCPA-thioethyl, 4- (4-chloro-2-methylphenoxy) butyric acid (MCPB), mecoprop and mecoprop-p, Piccloram, Tiazopyr and Triclopyr

22 Imidazolinones such as imazapic, imazamox, imazamethabenz-methyl, imazapyr and isopropylammonium salts thereof, imazaquin and imazetapyr

23 methyl isothiocyanate precursors such as benzometh

24 Ammonium Sulphate, Asulam, Azaphenidine, Benazolin, Benzobicyclon / Benbiclone, Cynmethylene, Clomazone, Defenquat and its salts, such as Methyl Sulfate Salt, Diflufenzopyr-Sodium (SAN-835H), Dimethipine, Dimexiflom, Diphenamide, Dithiopyr, Epoprodan, Etofumesate, Etobenzanide, Fluazolate, Pentrazamide, Flukabazone, Flumiclo Lac-pentyl, flumioxazine, flupoxam, flurenol-butyl, flulochloridone, flutamone, fluthiacet-methyl, hexazinone, mefenacet, oxadione, oxazilomepon, pentoxazone, pyraflu Phen-ethyl, pyridatol / pyridafol, pyridate, isoxachlortol, isoxaplutol and sodium chlorate. Organoarsen herbicides such as disodium methylarsonate (DSMA) and monosodium methylarsonate (MSMA).

26 Organic Phosphorus Herbicides such as Anilophos and Posamine-Sodium

27 phosphorothioates such as butamifos, bensulfide and piperophos

28 pyridazinones such as chloridazone and norflurazon

29 Pyridones such as fluidone

30 pymidinyloxybenzoic acid and salts thereof and esters thereof such as pyrithiobac-sodium, bispyribac-sodium, pyriminobac-methyl and pyribenzoxime.

31 Quinorinecarboxylic acids, such as quinomerac and quinclorac

32 herbicide detoxifiers, such as benoxacor, cloquintocet-mexyl, dichlormide, fenchlorazole-ethyl, fenchlorim, fluxofenim, furylazole, naphthalic anhydride, oxaventriyl, mefenpyr-di Ethyl, N- (dichloroacetyl) -1-oxa-4-azaspirobicyclo- (4,5) -decane (AD-67), 3-dichloroacetyl-2,2,5-trimethyloxazolidine (R -29148) and 2-dichloromethyl-2-methyl-1,3-dioxalan (MG-191).

Sulfamoylureas such as 33 cyclosulfamuron

34 sulfonanilides such as chloransullam-methyl, diclosulam, flulasulam, flumetsulam, and metosulam

35 sulfonylureas such as amidosulfuron, azimsulfuron, bensulfuron and esters thereof, chlorimuron and esters such as ethyl esters, chlorsulfuron, cynosulfuron, etamethsulfuron-methyl, plazasulfuron, Flupyrsulfuron and salts thereof, halosulfuron-methyl, ethoxysulfuron, imazosulfuron, iodosulfuron, metsulfuron and esters thereof, nicosulfuron, oxasulfuron, prisulfuron and esters thereof Methyl Ester, Prosulfuron, Pyrazulfuron-ethyl, Rimsulfuron, Sulfomethuron-methyl, Sulfosulfuron, Thifensulfuron-methyl, Triasulfuron, Tribenuron, Tribenuron-methyl and Triplelusulfuron- methyl

36 thiocarbamates, such as butyrate, cycloate, dimeperperate, ethyl dipropylthiocarbomate, esprocarb, molinate, orbencarb, pebulate, prosulfocarb, thiobencarb, thiocarbazil, Tri-allate and vernolate.

37 triazine herbicides such as amethrin, atrazine, cyanazine, dimethatrin, promethone, promethrin, propazine, simazine, cymetrin, terbutylazine, terbutrin and triethazine.

38 Triazole herbicides such as amitrol.

39 triazolinones such as carpentrazole-ethyl and sulfentrazone.

40 Triketones such as mesotrione and sulfotion

41 uracils, such as bromacil, lenacil, and tubacil.

Particularly suitable supplement herbicides for use in mixtures containing the compound of formula (1) are dimethyl pyrazoles such as pyrazolates, amide herbicides such as bromobutide and naproanilide, triketones such as sulfotion, cumylurone and Sulfonylureas such as arylurea and ethoxysulfuron. Some of these mixtures may show synergistic or other useful effects.

The invention is illustrated by the following examples. (The preparation of the intermediate is described in the preliminary example). Abbreviations used in the examples have the following meanings:

NMR spectrum: Nuclear magnetic resonance spectrum recorded at 270 or 400 MHz. (This refers to the quantum magnetic resonance spectrum unless otherwise indicated). In the NMR spectrum, abbreviations such as s (single), d (double), t (triple), q (quad), quin (fold), m (multi; br (wide)) are used to represent the peak multiplicity.

IR spectrum: infrared absorption spectrum

MS: mass spectrum

GC: Gas Chromatography TLC: Thin Layer Chromatography

m.p .: melting point b.p .: boiling point

Manufacture 1

Preparation of 3-bromo-5-fluoro-4-methyl aniline

2-fluoro-4-nitrotoluene (15.5 g) was heated to 80 ° C. Iron powder (0.2 g) (reduced with hydrogen) was added in portions followed by bromine (6.1 g) dropwise over 10 minutes. The reaction was then heated to reflux for 4.5 hours and then allowed to cool. To the solution of sodium metabisulfate (200 ml) was added the reaction mixture and stirred for 30 minutes. The product was extracted into dichloromethane, washed with water, dried (MgSO ₄ ) and concentrated to give a dark oil (21.9 g). Crude nitrotoluene was reduced directly. Nitrotoluene solution in ethanol (100 ml) was added to a flask containing iron powder (20.2 g) in ethanol (120 ml) and water (80 ml) and concentrated hydrochloric acid (1.7 ml). The reaction was heated to reflux for 3.25 hours and then sodium hydroxide solution (2M) was added to make it basic. The solution was then filtered through hyflo to high temperature and washed with hot ethanol and water. The solvent was concentrated to about 25% by volume and then extracted with dichloromethane. The organic layer was washed with water, then dried (MgSO ₄ ) and concentrated to give an orange oil. Column chromatography (diethyl ether / hexane 1: 1) with the eluent gave aniline (2.89 g) as a yellow oil.

Manufacture 2

Preparation of 3-bromo-4,5-dimethyl nitrobenzene

3,4-dimethyl ditrobenzene (15 g) was stirred with iron powder (0.2 g reduced with hydrogen) and heated to 77 ° C. Bromine (6.1 ml) was added dropwise over 20 minutes while maintaining the temperature at 75-80 ° C. The heating was continued for another 1.5 hours and the reaction was allowed to cool. The solid material was added to sodium hydroxide solution (10% w / v, 150 ml) and stirred for 1.5 hours. The liquid was decanted and dissolved in hot glacial acetic acid (50 ml). It was cooled on ice to give a solid precipitate. The solid was filtered again and added to 1% aqueous sodium hydroxide and heated to 90 ° C. After cooling on ice the solid was filtered and dried in vacuo to yield a light brown solid. Yield 16.98 g, 74%. Melting point 95-97 ° C.

Manufacture 3

Preparation of 3-bromo-4,5-dimethyl aniline

3-bromo-4,5-dimethyl nitrobenzene (16.1 g) was dissolved in ethanol (150 ml) at 50 ° C. Iron powder (reduced with hydrogen, 14.1 g) was added followed by water (56 ml) and concentrated hydrochloric acid (1.2 ml). The reaction was heated to reflux for 2 hours. Upon cooling sodium hydroxide (1.2 g in 2 ml water) was added. The reaction mixture was filtered through hyflo and hyflo was washed with ethanol. The solution was then concentrated in vacuo to give a white solid. It was dissolved in diethyl ether, washed with brine, dried (MgSO ₄ ) and concentrated to yield an off-white solid. Melting point 72-74 ° C.

Manufacture 4

Preparation of 3-chloro-5-fluoro-4-methyl aniline

2-fluoro-4-nitrotoluene (2.5 g) was dissolved in carbon tetrachloride (25 ml). Iron powder (0.05 g, reduced with hydrogen) was added and chlorine gas was bubbled through the reaction mixture for 20 minutes. The reaction flask was wrapped in aluminum foil to protect it from light. After stirring at room temperature for 1.5 hours, additional iron powder was added and chlorine gas was bubbled again for 15 minutes. The solution was then decanted and diluted with dichloromethane and washed with sodium thiosulfate (10% w / v) solution and water. Then dichloromethane was dried (MgSO ₄ ) and concentrated to give a pale yellow liquid.

The entire procedure was repeated for the material of the second batch using the above procedure. The batches were collected and put together.

The crude nitrotoluene solution in collected ethanol (25 ml) was added dropwise to a suspension of iron powder (6.06 g) in ethanol (75 ml) / water (50 ml) / concentrated hydrochloric acid (0.5 ml) at 70 ° C. The reaction was again heated to reflux for 1.5 hours. A solution of sodium hydroxide (0.28 g in 1 ml water) was added and the reaction mixture was filtered through hyflo at high temperature. The residue was washed with ethanol and water and the collected solution was concentrated in vacuo to about 25% of the volume. The product was extracted into dichloromethane, washed with water, dried (MgSO ₄ ) and concentrated to give a pale yellow liquid.

The crude oil was eluted with diethyl ether / hexane (1: 1) and separated by column chromatography to give aniline as a yellow oil. Yield 0.49 g.

Manufacture 5

Preparation of pure 2,2-dichloro-1-methyl cyclopropane carboxylic acid as enantiomer

The following procedure was repeated until the optical rotation was constant and the non-rotation was measured using an OpticalActivity AA100 photometer with 2dm cells at room temperature in ethanol.

Cinkronine (8 g) was suspended in 95: 5 ethanol: water (30 ml) to give a soft suspension (no solid lump). 2,2-dichloro-1-methyl cyclopropane carboxylic acid (5 g) was added in one batch. The mixture was stirred with heating until complete solution was obtained. Crystallization started after 15 minutes on cooling. The liquid was then poured out to leave a crystal of acid salt (6 g, 0.013 M). These crystals were acidified with 2.0 M HCl (1.5 eq, 0.0195 M, 9.75 ml) and extracted with ethyl acetate (3 × 30 ml). The organic layer was collected, washed once with 0.5 M HCl, then twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo to leave a liquid (2.13 g, non-rotating = -27.2).

The process was repeated to rotate the liquid at -40 ° C. The acid was rotated further -38.4 ° C.

NMR analysis of the sample using (R)-(-)-2,2,2-trifluoro-1- (9-antryl) ethanol as the resolution in CDCl ₃ without further purification of the acid in this final step To confirm the optical purity.

Racemic + (R)-(-)-2,2,2-trifluoro-1- (9-antryl) ethanol: 2.25d, d

Resolved sample + (R)-(-)-2,2,2-trifluoro-1- (9-antryl) ethanol: 2.18d, which means that the sample purity exceeds 99%.

Example 1

3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one (Compound 31 in Table 1) Preparation of Diastereomers

Step 1

Preparation of 2- (difluoromethoxy) -1-methyl-4-nitrobenzene

2-Methyl-5-nitrophenyl (15.3 g) was partially dissolved in dichloromethane (120 ml) and tetrabutylphosphonium bromide (3.4 g) was added and the mixture was stirred at room temperature. This suspension was then added in portions over 1 hour to sodium hydroxide (20 g) dissolved in water (50 ml) using overhead stirring. During this addition, the internal temperature rose slightly to give a dark red solution containing an orange precipitate which was stirred for another 75 minutes at room temperature. The apparatus was then equipped with a CO 2 / acetone condenser and bubbled chlorodifluoromethane into the reaction mixture for 1 hour to give a dark red emulsion (39 g of chlorodifluoromethane was used for this process, as judged by the weight loss of the cylinder). . The reaction mixture was allowed to come to room temperature (introduction of gas led to a drop in reaction mixture temperature) and allowed to stand overnight at room temperature. The reaction mixture was diluted with dichloromethane (120 ml) and poured into water. After shaking in a separatory funnel, the organic layer was separated, washed twice with water, and dried (MgSO ₄ ). After filtration to remove the desiccant, the solution was evaporated to dryness under reduced pressure to give a beige semisolid (23 g). The product contained some residual tetrabutylphosphonium salt and was judged pure enough for use in the next reaction.

δ (CDC1 ₃ ): inter alia 2.4 (3H, s), 6.63 (1H, t), 7.4 (1H, d), 8.0 (2H, m)

Step 2

Preparation of 3- (difluoromethoxy) -4-methylaniline

5% palladium (0.5 g) on carbon was suspended in water (20 ml) and stirred under nitrogen. Sodium borohydride (4.0 g) was dissolved in water (20 ml) and added to the palladium suspension over 30 minutes. Crude 2- (difluoromethoxy) -1-methyl-4-nitrobenzene (10 g) (prepared above) was dissolved in some methanol (50 ml) and added in portions to palladium / sodium borohydride over 2 hours. . (The above addition bath was used to maintain the temperature of the reaction mixture at 25-35 ° C.). After addition was continued stirring for a while and the reaction mixture was allowed to stand at room temperature overnight. Filtration was carried out using celite to remove the catalyst to give a two-phase system comprising a thick yellow oil in the lower layer. The upper (aqueous) layer was decanted from the yellow oil and extracted three times with ether. This ether extraction then collected the yellow oil originally precipitated and the solution was washed with water (x3) and finally with brine (x1). The ether was dried and evaporated to dryness (MgSO ₄ ) to afford the title compound as an orange oil (5.6 g). (This was judged pure enough for use in the next reaction).

δ (CDC1 ₃ ): 2.18 (3H, s), 3.65 (2H, broad s), 6.42 (1H, t), 6.43 (2H, m), 6.98 (1H, d)

Step 3

Preparation of 3- (methylamino) -1- (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one

3- (difluoromethoxy) -4-methylaniline (4.57 g) was dissolved in anhydrous dichloromethane (100 ml) and stirred with cooling in an ice bath. A solution of 2,4-dibromobutanoyl chloride (7.92) in dichloromethane (15 ml) was added dropwise to give a creamy suspension. Triethylamine (7.7 g) was then introduced to give a yellow solution and the reaction mixture was allowed to rise to room temperature. After brief stirring the reaction mixture was allowed to stand at room temperature overnight. The mixture was then diluted with dichloromethane (100 ml), washed three times with water, dried (MgSO ₄ ), filtered and evaporated to afford dark brown oil (8 g). This material was purified by chromatography on silica gel using ethyl acetate / hexane (2: 3) as eluent to give 3-bromo-1- (3-difluoromethoxy-4-methylphenyl) pyrrolidine-2- A mixture (6.4 g) of one and 3-chloro-1- (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one was obtained. This material was then dissolved with sodium iodide (3.5 g) in acetonitrile (30 ml) and the solution was refluxed moderately for 2.5 hours. The reaction mixture was then left to cool to room temperature and left overnight, at which time a yellow solid separated. The reaction mixture was concentrated on a rotary evaporator and partitioned between dichloromethane and water. The organic layer was washed thoroughly with water, dried (MgSO ₄ ), filtered and evaporated to afford 3-iodo-1- (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one as a brown semisolid (6.5 g). ) A portion (3 g) of this material was then stirred at 20 ° C. in anhydrous THF (30 ml) and bubbled methylamine gas into the solution for a total of two hours (temperature constantly rose to 33 ° C. and then dropped to 25 ° C.). The reaction mixture was concentrated on a rotary evaporator to afford the title compound as an orange oil (1.75 g), which was judged pure enough for the next reaction.

δ (CDC1 ₃ ): inter alia 1.95 (1H, m), 2.0 (1H, broad s), 2.27 (3H, s), 2.45 (1H, m), 2.52 (3H, s), 3.5 (1H, m) , 3.75 (2H, m), 6.53 (1H, t) 7.25 (2H, m), 7.57 (1H, s).

Step 4

Preparation of diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one

3- (methylamino) -1- (3-difluoromethoxy-4-methylphenyl) pyrrolidin-2-one (0.5 g) was dissolved in anhydrous dichloromethane (20 ml) and stirred with cooling in an ice-bath. . 2,2-dichloro-1-methylcyclopropyl carbonyl chloride (0.5 g) (prepared as described in Example 7 below) was added, and 20 minutes later, another drop of triethylamine (0.5 g) was added over 20 minutes. Thickly added. The reaction mixture was allowed to come to room temperature and then left to stand at room temperature for 2 days. The reaction mixture was diluted with dichloromethane (30 ml) and washed with water (× 3) followed by 1 M hydrochloric acid, water and brine. The solution was dried (MgSO ₄ ), filtered and evaporated to afford dark brown oil (0.9 g), which was chromatographed on silica gel with ethyl acetate / hexanes (2: 3) to give the title compound 1: 1 diastereomer mixture. Obtained as (0.5 g).

δ (CDC1 ₃ ): inter alia 1.62 (s), 1.65 (s), 1.66 (s) -cyclopropyl-1-methyl resonance; 2.91 (s), 3.17 (s), 3.28 (s) -N-methyl resonance; 7.25 (2 H, m), 7.6 (1 H, m).

Example 2

3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (4-bromo-3-trifluoromethoxyphenyl) pyrrolidin-2-one (compound of Table 1) Preparation of Diastereomer of 37)

(Prepared as described in Example 7 below) 3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine- 2-one (1 g) was stirred in anhydrous DMF (25 mL) and N-bromosuccinimide (0.4 g) was added The reaction mixture was stirred at rt for 1 h and then left overnight. The reaction mixture was heated for 2 h at 60 ° C. N-bromosuccinimide (0.9 g in total) was added two more times and the reaction mixture was again heated at 60 ° C. for 2 h. The product was extracted with ether (x3) and the collected layers were washed with water, dried (MgSO ₄ ), filtered and evaporated to give an orange oil which was ethyl acetate / hexane (2 as eluent). Purification by chromatography on silica gel using 1: 1 after: 3) The title compound (0.55 g) was obtained in a 1: 1 diestereomeric mixture.

δ (CDC1 ₃ ): inetr alia 1.6-1.7 cyclopropyl-1-methyl resonance; 2.91 (s), 3.18 (s), 3.29 (s) -N-methyl resonance; 7.55-7.85 (3H, m)

Example 3

3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (3-trifluoromethoxy-4-methylphenyl) pyrrolidin-2-one (compound 36 in Table 1) Preparation of Diastereomers

(Prepared in Example 2 above) 3 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -1 (4-bromo-3-trifluoromethoxyphenyl) pyrrolidine 2-one (0.25 g) was dissolved in N-methylpyrrolidinone (1 ml), after which tetramethyltin (0.1 ml) was added followed by tetrakis (triphenylphosphine) palladium (O) (0.58 g). The mixture was stirred and heated to 100 ° C. to moderate reflux of the tetramethyl tin, which was continued to heat for 3 hours when GLC analysis showed about 33% conversion to the title compound. An additional amount of tetrakis (triphenylphosphine) palladium (O) (0.58 g) and further addition of pin) palladium (O) and tetramethyltin followed by further reflux for 2 hours. Tetramethyltin (0.1 ml) was added and refluxed again for 2 hours, then the reaction mixture was poured into water (30 ml) and extracted with ether. Washing the Termini phase with water (x3), brine, dried (MgSO _4), filtered and evaporated to give a pale yellow oil. The crude material with ethyl acetate / hexane (2: 3). Purification by chromatography on silica gel using The title compound was obtained as pale yellow oil (0.12 g).

δ (CDC1 ₃ ): inetr alia 1.63-1.68 cyclopropyl-1-methyl resonance; 2.91 (s), 3.17 (s), 3.28 (s) -N-methyl resonance; 7.20-7.70 (3H, m)

Example 4

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2) pyrrolidin-2-one (compound 51 in Table 2) Manufacture

Step 1

Preparation of 2-t-butoxycarbonylamino-5-chlorothiophene

5-chlorothiophene-2-carboxylic acid (64.8 g) was dissolved in anhydrous 1,4-dioxane (320 ml) and stirred at room temperature. Anhydrous t-butanol (35.7 g) was added and the solution was treated with triethylamine (44.44 g) to exothermic to 30 ° C. The solution was heated to moderate reflux (97 ° C. internal temperature, 120 ° C. oil bath temperature). Droplet of diphenylphosphoryl azide (DPPA) (86.2 ml) using a nitrogen pressurized bottle / teflon line over 5 hours, measuring the volume of nitrogen released from the reactants by collecting the gas in a large cylinder aqueous phase replacement Was added. (This monitoring was done to control DPPA addition so that in no case was more than 18-20 mmol of azide containing components present in the reaction mixture). When the addition was complete, the reaction mixture was refluxed again for 30 minutes and then left at room temperature overnight. The next day the reaction mixture was stirred and refluxed for 3 hours to allow to cool to room temperature. Then poured slowly into cold water (4 liters) and stirred for a while. The precipitated solids were collected in a sinter funnel and aspirated as dry as possible. The material was then resuspended in cold water and allowed to stand overnight at room temperature. The brown solid was collected by pump, washed well with water, dried aspirated and transferred to a round bottom flask when the last trace of water was removed on a 40 ° C. rotary evaporator.

δ (CDC1 ₃ ): 1.52 (9H, s), 6.22 (1H, d), 6.62 (1H, d), 7.21 (1H, broad s).

Step 2

Preparation of 3-bromo-1 (5-chlorothien-2-yl) pyrrolidin-2-one

To an ice cooled flask equipped with a stir bar was added 2-t-butoxycarbonylamino-5-chloro-thiophene (6 g) and slowly stirring 45% hydrobromic acid in cold acetic acid (45 ml). Upon addition was accompanied by vigorous bubbling and a beige suspension was produced. After 1 h anhydrous ether (250 ml) was added under nitrogen and the reaction mixture was stirred for 1 h at which time the light beige suspension was filtered and the residue was washed with additional anhydrous ether free of acetic acid. The collected solid (2-amino-5-chlorothiophene. Hydrobromic acid salt) was quickly dissolved in anhydrous dichloromethane (150 ml) and stirred under nitrogen while cooling in an ice-bath. 2,4-Dibromobutanoyl chloride (8 g) was added followed by triethylamine (5.4 g) dropwise and the reaction mixture was allowed to rise to room temperature over 2 hours. The reaction mixture was then poured into 2M hydrochloric acid (150 ml) and the organic layer was separated and the aqueous layer was extracted with dichloromethane. The collected dichloromethane layer was washed with water (x3), dried (MgSO ₄ ), filtered and evaporated to afford a dark brown solid. This was recrystallized from ethyl acetate / hexane (2/3) to give the title compound as a beige solid (2.5 g).

δ (CDC1 ₃ ): 2.53 (1H, m), 2.83 (1H, m), 3.85 (1H, m), 3.98 (1H, m), 4.61 (1H, m), 6.35 (1H, d), 6.75 ( 1H, d).

Step 3

Preparation of 3- (methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one

3-bromo-1 (5-chlorothien-2-yl) pyrrolidin-2-one (0.9 g) was dissolved in anhydrous THF (35 ml) and stirred at room temperature. The suspension resulting from the active bubbling of the methylamine gas into the solution became very cloudy and there was some exotherm after 1 hour. After 3 hours tlc showed no starting material and the volatile components of the reaction mixture were removed on a rotary evaporator. The residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, then dried (MgSO ₄ ), filtered and evaporated to afford the title compound as a beige solid (0.5 g). This material was pure enough to be used without further purification.

δ (CDC1 ₃ ): 1.85 (1H, broad s), 2.05 (1H, m), 2.52 (3H, s), 2.53 (1H, m), 3.56-3.75 (2H, m), 3.85 (1H, m) , 6.25 (1H, d), 6.61 (1H, d)

Step 4

Preparation of diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one

3- (methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one (3.45 g) was partially dissolved in anhydrous dichloromethane (50 ml) and stirred at room temperature. Dichloro-1-methylcyclopropyl carbonyl chloride (3.07 g) (prepared as described in Example 7 below) was added dropwise to obtain a milky suspension. Triethylamine was then added dropwise, then the reaction mixture was stirred at room temperature for 3 hours and allowed to stand overnight. The suspension was concentrated on a rotary evaporator and ethyl acetate and water were added and the mixture was transferred to a separatory funnel. The aqueous layer was separated and the organic layer washed with water and brine. The cloudy organic layer was dried (MgSO ₄ ), filtered through a pad of celite and concentrated on a rotary evaporator. On this evaporation the title compound began to precipitate as a cream solid which was collected under reduced pressure (2.3 g).

δ (CDC1 ₃ ): inetr alia 1.62 (s), 1.64 (s), 1.68 (s), cyclopropyl-1-methyl resonance; 2.85 (s), 3.14 (s), 3.28 (s) -N-methyl resonance; 6.25-6.78 (2H, m).

Example 5

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one (compound of Table 2) Preparation of Diastereomer of 53)

Step 1

Preparation of 2-chloro-3-methylthiophene

Sulfuryl chloride (36 g) was added dropwise over 30 minutes to stirred, moderately refluxing 3-methylthiophene (25 g). The reaction mixture was again refluxed for 2 hours and then distilled at atmospheric pressure. The title compound (22 g) was collected by fractional distillation at 152-157 ° C.

δ (CDC1 ₃ ): 2.14 (3H, s), 6.72 (1H, d), 6.94 (1H, d).

Step 2

Preparation of 5-chloro-4-methylthiophene-2-carboxylic acid

To anhydrous ether (20 ml) n-butyllithium (20 ml of 1.6 M solution in hexane) was added and the mixture was stirred under nitrogen. The solution was then treated with 2-chloro-3-methylthiophene (4.2 g) and dissolved in ether (5 ml) over 30 minutes at which time the solution became relatively hot. The reaction mixture was stirred and heated at reflux for 2 hours and then left overnight at room temperature under nitrogen. The reaction mixture was cooled to -78 ° C and poured into a solid carbon dioxide and ether mixture with hand stirring. Carbon dioxide was evaporated and the ether solution was extracted thoroughly with water (60 ml, x3). The aqueous layer was extracted with ether and the aqueous solution was acidified with 2M hydrochloric acid to give the title compound as a pale yellow precipitate. It was collected by filtration, washed well with water and dried under reduced pressure. (This procedure gave 1.8 g of the title compound).

δ (CDC1 ₃ ): 2.23 (3H, s), 6.5-7.5 (1H, very broad s), 7.58 (1H, s).

Step 3

Preparation of 2-t-butoxycarbonylamino-5-chloro-4-methylthiophene

5-Chloro-4-methylthiophene-2-carboxylic acid (7.04 g) was mixed with anhydrous t-butanol (40 ml) and the solution / suspension was stirred at room temperature. Triethylamine (4.04 g) was then added dropwise to obtain a homogeneous brown solution, which was again treated dropwise with diphenylphosphoryl azide (8.62 ml). After stirring for 30 minutes at room temperature the reaction mixture was refluxed moderately for 3 hours and then left at room temperature overnight. The reaction mixture was again refluxed moderately for 3 hours, cooled and slowly poured into an ice / water mixture. Semisolid precipitated but it could not be collected by filtration and the aqueous mixture was extracted with ether (x3) and the collected organic layers were washed with water and brine. The black tar obtained by drying the ether (MgSO ₄ ), filtration and evaporation was redissolved in ether and passed through a pad of silica. The solution was allowed to stand overnight with small bleached charcoal, filtered through celite and evaporated to afford the title compound as a brown oil which solidified on standing (5.8 g). The product was pure enough to be used without further purification.

δ (CDC1 ₃ ): 1.5 (9H, s), 2.08 (3H, s), 6.17 (1H, s), 6.92 (1H, broad-s)

Step 4

Preparation of 3-iodo-1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one

2-t-butoxycarbonylamino-5-chloro-4-methylthiophene (5.2 g) was stirred in the flask under nitrogen atmosphere with ice-bath cooling. 48% of hydrogen bromide / acetic acid was added dropwise over 20 minutes at which time gas was released. After stirring again for 30 minutes, anhydrous ether (250ml) was slowly added, and the resulting dark green suspension was quickly filtered off with nitrogen, washed with anhydrous ether, and dried with suction. The yield of 2-amino-5-chloro-4-methylthiophene.hydrobromide obtained is 4.8 g and the material is quickly transferred to a flask and suspended in anhydrous dichloromethane (140 ml) under a nitrogen atmosphere. Cool and add 2,4-dibromobutanoyl chloride (8 g) dropwise. After 30 minutes, triethylamine (6.75 g) was added dropwise to dissolve the suspension, and the resulting black solution was allowed to stand at room temperature for 2 days. The reaction was then diluted with dichloromethane (100 ml), washed with water (× ₃ ), dried (MgSO ₄ ), filtered and evaporated to afford a dark brown viscous solid. The crude material was purified by chromatography on silica gel using ethyl acetate / hexanes (2: 3) to give a viscous beige solid. This material was titrated with hexane / ether (9/1) to give 3-bromo-1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one and 3-chloro-1 (5- Obtain a brown solid comprising a mixture of chloro-4-methylthien-2-yl) pyrrolidin-2-one and drop it over 30 minutes into a solution of sodium iodide (2 g) in anhydrous acetonitrile (30 ml). Thickly added. The reaction mixture was refluxed moderately with stirring for 3 hours and left overnight at room temperature. The solvent was then removed under reduced pressure and the residue was partitioned between dichloromethane and water and the organic phase was washed with water and then dried (MgSO ₄ ), filtered and evaporated to give a brown solid. This material was titrated with ether to give the title compound as a brown solid (2.35 g) which was pure enough to be used for the next synthetic step.

δ (CDC1 ₃ ): 2.15 (3H, s), 2.43 (1H, m), 2.73 (1H, m), 3.78 (2H, m), 4.73 (1H, m), 6.27 (1H, s)

Step 5

Preparation of 3- (methylamino) -1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one

3-Iodo-1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one (2.15 g) was dissolved in anhydrous THF (40 ml) and stirred at room temperature (21 ° C.). The methylamine gas was bubbled at vigorous rate and the internal temperature rose to 36 ° C. After 15 minutes the temperature was slowly lowered back to 21 ° C. (total reaction time 1 hour). The solution was then evaporated and the soft dark brown solid obtained by titration with ether was partitioned between ethyl acetate and water. The organic layer was dried (MgSO ₄ ), filtered and evaporated to afford the title compound as a solid (0.9 g).

δ (CDC1 ₃ ): 1.92-2.1 (2H, broad singlet superimposed on a multiplet), 2.15 (3H, s), 2.53 (3H, s), 2.53 (1H, m), 3.55-3.72 (2H, m), 3.82 (1 H, m), 6.28 (1 H, s)

Step 6

Of the diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one Produce

3- (methylamino) -1 (5-chloro-4-methylthien-2-yl) pyrroli instead of 3- (methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one Except for using din-2-one, the title compound was obtained as a 1: 1 diastereomer mixture and separated as a solid.

δ (CDC1 ₃ ): inter alia 1.62 (s), 1.64 (s), 1.68 (s)-cyclopropyl-1 -methyl resonance; 2.85 (s), 3.14 (s), 3.29 (s) -N-methyl resonance; 6.25-6.80 (2H, m).

Example 6

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino-1 (4-chloro-5-methylthien-2-yl) pyrrolidin-2-one (Compound 54 in Table 2) Of diastereomer)

Step 1

Preparation of 2-acetyl-4-chloro-5-methylthiophene

In a dried 250 ml three-necked flask, aluminum chloride (55 g) was stirred and 2-acetyl-5-methylthiophene (23.5 g) was added dropwise to slightly exotherm. Chlorine gas was passed over the slurry from the wide inlet tube for 4 hours, the mixture becoming dark brown; The reaction mixture was then stopped and left overnight at room temperature. The reaction mixture was slowly added to the excess ice and concentrated hydrochloric acid (50 ml) mixture and stirring continued until the ice melted. The mixture was extracted with ether and the ether was washed with water (x3) and brine. The brown oil (16.5 g) obtained as the title compound by drying (MgSO ₄ ), filtration and evaporation of the ether extract was then solidified.

δ (CDC1 ₃ ): 2.44 (3H, s), 2.50 (3H, s), 7.45 (1H, s).

Step 2

Preparation of 4-chloro-5-methyl-thiophene-2-carboxylic acid

Sodium hydroxide (4.2 g) was dissolved in sodium hypochlorite solution ('Haychlor Agricultural' sodium hypochlorite, label:> 5% <16% usable chlorine ') (100 ml) with stirring at 60 ° C and 30 A small amount of 2-acetyl-4-chloro-4-methylthiophene (10.87 g) was added over minutes. After another 30 minutes, sodium hypochlorite solution (110 ml) was further added, and the reaction mixture was stirred and heated at 70 ° C. for 90 minutes. After cooling to room temperature until sodium hypochlorite is consumed (this is measured by testing a small sample from the reaction mixture with aqueous potassium iodide solution until iodine is no longer released) sodium metabisulfite (total 5 g) was added in portions. The creamy precipitate obtained by acidifying the solution with concentrated hydrochloric acid was then collected by filtration and washed well with water. The solid was washed well with a small amount of ether and hexanes and dried to afford the title compound (6.5 g).

δ (CDC1 ₃ ): inter alia 2.45 (3H, s), 7.64 (1H, s), 8,5-9.5 (1H, very broad s).

Step 3

Preparation of 2-t-butoxycarbonylamino-4-chloro-5-methylthiophene

The title compound in a similar manner as described in Example 5, Step 3, except that 4-chloro-5-methyl-thiophene-2-carboxylic acid is used instead of 5-chloro-4-methyl-thiophene-2-carboxylic acid Was obtained as a beige solid.

δ (CDC1 ₃ ): 1.40 (9H, s), 2.19 (3H, s), 6.20 (1H, s), 7.13 (1H, broad s)

Step 4

Preparation of 3-iodo-1 (4-chloro-5-methylthien-2-yl) pyrrolidin-2-one

Example 5, step, except that 2-t-butoxycarbonylamino-4-chloro-5-methylthiophene is used instead of 2-t-butoxycarbonylamino-5-chloro-4-methylthiophene In the same manner as described for 4, the title compound was obtained as a solid.

δ (CDC1 ₃ ): 2.31 (3H, s), 2.43 (1H, m), 2.75 (1H, m), 3.80 (2H, m), 4.73 (1H, m), 6.38 (1H, s).

Step 5

Preparation of 3- (methylamino) -1 (4-chloro-5-methylthien-2-yl) pyrrolidin-2-one

3-Iodo-1 (4-chloro-5-methylthien-2-yl) pyrroli instead of 3-iodo-1 (5-chloro-4-methylthien-2-yl) pyrrolidin-2-one The title compound was obtained as a beige solid in a similar manner as described in Example 5, step 5 except using din-2-one.

δ (CDC1 ₃ ): 2.05 (1H, m), 2.13 (1H, broad s), 2.30 (3H, s), 2.51 (1H, m), 2.53 (3H, s), 3.55-3.73 (2H, m) , 3.80 (1 H, m), 6.29 (1 H, s).

Step 6

Of a diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4-chloro-5-methylthien-2-yl) pyrrolidin-2-one Produce

3- (methylamino) -1 (4-chloro-5-methylthien-2-yl) pyrroli instead of 3- (methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one The title compound was obtained as a 1: 1 diastereomer mixture separated as off-white solid in a similar manner as described in Example 4, Step 4 except using din-2-one.

δ (CDC1 ₃ ): inter alia 1.62 (s), 1.65 (s), 1.69 (s)-cyclopropyl-1 -methyl resonance; 2.85 (s), 3.15 (s), 3.27 (s) -N-methyl resonance; 6.30-6.41 (1H, 3s).

Example 7

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one (Compound 2 in Table 1)

A solution of 2,2-dichloro-1-methylcyclopropyl carbonyl chloride was prepared as follows: A stirred solution of 2,2-dichloro-1-methylcyclopropyl carboxylic acid (0.12 g) in dichloromethane (5 ml) was jade. Treated with salyl chloride (0.10 g) followed by dimethylformamide (1 drop) and the resulting solution was stirred at room temperature for 6 hours. 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one (0.20 g; prepared as described in WO95 / 33719), triethylamine (0.15 g) and dichloromethane A stirred solution of 4-dimethylaminopyridine (0.003 g) in (15 ml) was cooled in an ice bath and a solution of 2,2-dichloro-1-methylcyclopropyl carbonyl chloride was added dropwise. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h again. The mixture was diluted with dichloromethane then washed with 2M hydrochloric acid, saturated with aqueous sodium hydrogen carbonate and dried (MgSO ₄ ). After removal of the desiccant by filtration, the solution was evaporated to dryness under reduced pressure and the residue was purified by chromatography on silica-gel (eluted with ethyl acetate / hexane mixture) to give the title compound as a rubber (0.24 g). Obtained in a 1: 1 mixture.

δ (CDC1 ₃ ): inter alia 1.61 (s), 1.64 (s), 1.68 (s)-cyclopropyl-1 -methyl resonance; 2.91 (s), 3.18 (s), 3.30 (s) -N-methyl resonance; 4.43 (t), 4.85 (dd), 5.36 (dd)-pyrrolidone 3-H resonance.

Example 8

Step 1

Preparation of 3-hydroxy-1 (3,4-dichlorophenyl) pyrrolidin-2-one

3,4-Dichloroaniline (78.3 g) and α-hydroxybutyrolactone (40.84 g) were heated at 150 ° C. (bath temperature) for 72 hours. The mixture was then cooled and diluted with dichloromethane and carefully poured into 10M aqueous sodium hydroxide solution (120 ml). The resulting precipitate was filtered off, washed with dichloromethane and the filtrate was betul. The solid was suspended in dichloromethane and acidified with 2M hydrochloric acid. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The collected dichloromethane extracts were washed with water and brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to leave the title compound. Yield 71.06 g.

δ (CDC1 ₃ ): 2.11 (1H, m), 2.61 (1H, m), 3.66-3.82 (2H, m), 3.90 (1H, broad s), 4.50 (1H, t), 7.40 (1H, d) , 7.52 (1H, dd), 7.80 (1H, d)

Step 2

Preparation of 3 (methanesulfonyloxy) -1 (3,4-dichlorophenyl) pyrrolidin-2-one

A stirred solution of triethylamine (26.51 g) and 3-hydroxy-1 (3,4-dichlorophenyl) pyrrolidin-2-one (51.18 g) in dichloromethane (1000 ml) was cooled to about 5 ° C. and Treatment with methanesulfonyl chloride solution in dichloromethane over 1 hour. After addition the mixture was allowed to rise to room temperature and left overnight. Aqueous hydrochloric acid (2M) was added and a small amount of insoluble material was filtered off, the dichloromethane layer was separated, washed with brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to leave the title compound.

δ (CDC1 ₃ ): 2.41 (1H, m), 2.73 (1H, m), 3.31 (3H, s), 3.79-3.95 (2H, m), 5.34 (1H, t), 7.41-7.58 (2H, m ), 7.82 (1 H, d).

Step 3

Preparation of 3 (methylamino) -1 (3,4-dichlorophenyl) pyrrolidin-2-one

A stirred solution of 3 (methanesulfonyloxy) -1 (3,4-dichlorophenyl) pyrrolidin-2-one (5 g) in tetrahydrofuran (200 ml) was treated with potassium iodide (2.54 g) The mixture was heated to 60 ° C. (bath temperature) and methylamine was bubbled through the mixture for 3 hours. The reaction mixture was cooled down and left for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was separated, washed with dichloromethane and then the collected dichloromethane extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to afford the remaining crude title compound still with a slight amount of 3 (methylamino) -1 (3). , 4-dichlorophenyl) pyrrolidin-2-one. The crude product thus obtained was dissolved in dichloromethane, extracted into aqueous hydrochloric acid (2M) and the dichloromethane layer was discharged. The acid extract was made basic with 2M aqueous sodium hydroxide solution and then extracted with dichloromethane. The dichloromethane extract was dried (MgSO ₄ ), filtered and evaporated under reduced pressure to leave the title compound.

δ (CDC1 ₃ ): 1.91 (1H, broad), 1.95 (1H, m), 2.48 (1H, m), 3.52 (1H, dd), 3.69-3.82 (2H, m) 7.41 (1H, d), 7.55 (1H, dd), 7.80 (1H, d)

Step 4

Preparation of 3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3,4-dichlorophenyl) pyrrolidin-2-one

Example 7 except using 2,2-difluoro-1-methylcyclopropyl carboxylic acid (prepared by Gassen and Baasner as described in J. Fluorine Chem., 1990, 49, 127-139) In a similar manner as described above, the title compound was obtained as a 1: 1 diastereomer mixture separated as a white solid.

δ (CDC1 ₃ ): inter alia 1.48-1.57 (complex) -cyclopropyl-1-methyl resonance; 2.87 (s), 3.09 (s), 3.18 (s) -N-methyl resonance; 4.56 (t), 4.73 (dd), 5.22 (dd) -pyrrolidone 3-H resonances.

Example 9

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-difluoromethoxyphenyl) pyrrolidin-2-one (Compound No. 5 in Table 1)

3- (methylamino) -1 (3-difluoromethoxyphenyl) pyrrolidine-2- scaled with 3- (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a 1: 1 diastereomer mixture separated by pale yellow rubber in a similar manner as described in Example 7 except using On (prepared as described in WO95 / 33719).

δ (CDC1 ₃ ): inter alia 1.62 (s), 1.63 (s), 1.67 (s) -cyclopropyl-methyl resonance; 2.92 (s), 3.18 (s), 3.29 (s) -N-methyl resonance; 4.45 (t), 4.84 (dd), 5.34 (dd)-pyrrolidone 3-H resonance.

Example 10

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one (compound 6 in Table 1)

3- (methylamino) -1 (prepared as described in WO95 / 33719) scaled with 3- (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a rubber separated 1: 1 diastereomer mixture in a similar manner as described in Example 7 except using 3-trifluoromethylphenyl) pyrrolidin-2-one.

δ (CDC1 ₃ ): inter alia 1.62 (s), 1.63 (s), 1.67 (s) -cyclopropyl-methyl resonance; 2.92 (s), 3.18 (s), 3.29 (s) -N-methyl resonance; 4.45 (t), 4.84 (dd), 5.34 (dd)-pyrrolidone 3-H resonance.

Example 11

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one (compound 9 in Table 1)

The title compound was prepared in rubber in a similar manner as described in Example 7, except that 2,2-difluoro-1-methylcyclopropyl carboxylic acid scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid was used. A separated 1: 1 diastereomer mixture was obtained.

δ (CDC1 ₃ ): inter alia 1.48-1.64 (complex) -cyclopropyl-methyl resonance; 2.89 (s), 3.10 (s), 3.19 (s) -N-methyl resonance; 4.61 (t), 4.76 (dd), 5.31 (dd)-pyrrolidone 3-H resonance.

Example 12

Of 3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3,5-dichlorophenyl ) pyrrolidin-2-one (compound 12 in Table 1) Produce

Step 1

Preparation of 3 (methylamino) -1 (3,5-dichlorophenyl) pyrrolidin-2-one

The title compound was obtained as a solid by a procedure similar to that described in Example 8, Step 1-3, except that 3,5-dichloroaniline was used instead of 3,4-dichloroaniline.

δ (CDC1 ₃ ): 1.80 (1H, s), 1.97 (1H, m), 2.48 (1H, m), 2.51 (3H, s), 3.51 (1H, dd), 3.65-3.81 (2H, m), 7.12 (1 H, t), 7.61 (2 H, d)

Step 2

Preparation of 3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3,5-dichlorophenyl) pyrrolidin-2-one

2,2-difluoro-1-methylcyclopropyl carboxylic acid and 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine-scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid The title compound was converted to pale yellow rubber in a similar manner as described in Example 7 except using 3 (methylamino) -1 (3,5-dichlorophenyl) pyrrolidin-2-one scaled to 2-one. A separated 1: 1 diastereomer mixture was obtained.

δ (CDC1 ₃ ): inter alia 1.50-1.60 (complex) -cyclopropyl-methyl resonance; 2.88 (s), 3.09 (s), 3.19 (s) -N-methyl resonance; 4.51 (t), 4.72 (dd), 5.23 (dd)-pyrrolidone 3-H resonance.

Example 13

Of 3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-difluoromethoxyphenyl) pyrrolidin-2-one (compound 13 in Table 1) Produce

2,2-difluoro-1-methylcyclopropyl carboxylic acid and 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine-scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid The title compound was prepared in a similar manner to that described in Example 7 except for using 3 (methylamino) -1 (3-difluoromethoxyphenyl) pyrrolidin-2-one scaled to 2-one. Obtained as a 1: 1 diastereomer mixture separated by.

δ (CDC1 ₃ ): inter alia 1.48-1.60 (complex) -cyclopropyl-methyl resonance; 2.89 (s), 3.08 (s), 3.18 (s) -N-methyl resonance; 4.61 (t), 4.73 (dd), 5.32 (dd) -pyrrolidone 3-H resonances.

Example 14

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3,5-dichlorophenyl) pyrrolidin-2-one (compound 3 in Table 1)

3 (methylamino) -1 (3,5-dichlorophenyl) pyrrolidin-2-one scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained in a 1: 1 diastereomer mixture separated by pale yellow rubber in a similar manner as described in Example 7.

δ (CDC1 ₃ ): inter alia 1.61 (s), 1.65 (s), 1.67 (s) -cyclopropyl-methyl resonance; 2.91 (s), 3.17 (s), 3.30 (s) -N-methyl resonance; 4.37 (t), 4.83 (dd), 5.29 (dd)-pyrrolidone 3-H resonance.

Example 15

3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (4-chloro-3-fluorophenyl) pyrrolidin-2-one (Compound 16 in Table 1) Manufacturing

2,2-difluoro-1-methylcyclopropyl carboxylic acid and 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine-scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid Except using 3- (methylamino) -1 (4-chloro-3-fluorophenoxy) pyrrolidin-2-one (prepared as described in heading 95/33719) scaled to 2-one And in a similar manner as described in Example 7, the title compound was obtained as a 1: 1 diastereomer mixture separated as a white solid.

δ (CDC1 ₃ ): inter alia 1.48-1.56 (complex) -cyclopropyl-methyl resonance; 2.89 (s), 3.08 (s), 3.18 (s) -N-methyl resonance; 4.54 (t), 4.72 (dd), 5.23 (dd)-pyrrolidone 3-H resonance.

Example 16

5 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -3 (3-trifluoromethoxyphenyl) -1,3-oxazolidin-4-one (Table 1 Preparation of Compound 4)

5 (methylamino) -3 (3-trifluoromethoxyphenyl) -1,3-oxazolidine scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a 1: 1 diastereomer mixture separated as a white solid in a similar manner as described in Example 7 except using 4-one (prepared as described in WO96 / 37483). .

δ (CDC1 ₃ ): inter alia 1.60-1.72 (complex) -cyclopropyl-methyl resonance; 2.88 (s), 2.92 (s), 3.21 (s), 3.22 (s) -N-methyl resonance; 5.98 (d), 6.14 (s)-oxazolidinone 5-H resonance.

Example 17

3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-chloro-4-methylphenyl) pyrrolidin-2-one (Diar of Compound 27 in Table 1 Preparation of Stereomer Forms A and B)

Step 1

Preparation of 3 (methylamino) -1 (3-chloro-4-methylphenyl) pyrrolidin-2-one

The intended compound was prepared in a similar manner as described in Example 1, Step 3, except that 3-chloro-4-methyl aniline was used instead of 3- (difluoromethoxy) -4-methylaniline.

M.P. = 76-77 ℃

1.89-2.03 (m, 1 H); 2.36 (s, 3 H); 2.41-2.53 (m, 1 H); 3.48-3.54 (m, 1 H); 3.72-3.80 (m, 2 H); 7.18-7.22 (d, 1 H); 7.45-7.49 (m, 1 H); 7.64-7.66 (m, 1 H).

Step 2

2,2-difluoro-1-methylcyclopropyl carboxylic acid and 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine-scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid Silica-gel eluted with ethyl acetate / hexanes (7: 3) using 3 (methylamino) -1 (3-chloro-4-methylphenyl) pyrrolidin-2-one from step 1 instead of 2-one The diastereomer of the following title compound was obtained in a similar manner as described in Example 7 except that the crude product mixture was further separated by high performance liquid chromatography in phase:

Diastereomer A: δ (CDC1 ₃ ): 1,29 (1H, m), 1.54 (3H, d), 1.94 (1H, m), 2.11 (1H, m), 2.35 (3H, s), 2.47 ( 1H, m), 3.09 (1H, m), 4.71-4.89 (2H, m), 5.32 (1H, dd), 7.21 (1H, d), 7.44 (1H, dd), 7.70 (1H, d)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.20-1.38 (1H, m), 1.83-1.97 (1H, m), 2.17-2.33 (1H, m), 2.31 & 2.34 (3H, 2 xs ), 2.35-2.58 (1H, m), 2.88 & 3.18 (3H, 2 xs), 3.69-3.91 (2H, m), 4.59-4.78 (1H, m), 7.14-7.27 (1H, m), 7.40- 7.49 (1 H, m), 7.65-7.73 (1 H, m)

Example 18

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4,6-dimethylpyridin-2-yl) pyrrolidin-2-one (of Compound 60 in Table 3 Preparation of Diastereomer Forms A and B)

Step 1

Preparation of 3 (methylamino) -1 (4,6-dimethylpyridin-2-yl) pyrrolidin-2-one

A stirred solution of triethylamine (12.41 g) and 4,6-dimethylpyridine (5.00 g) in dichloromethane (200 ml) was cooled in an ice bath and 2,4-dibromobutanoyl chloride in dichloromethane (50 ml) 12.54 g) was added dropwise. After the addition was completed, the mixture was allowed to warm to room temperature and again stirred at room temperature for 24 hours and then left to stand for about 60 hours. Water was added and the mixture extracted with dichloromethane (x3). The collected extracts were washed with brine, dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure. The remaining dark rubber was washed with 3-bromo- and 3-chloro-1 (4,6-dimethylpyridin-2-yl). It consisted of rollidin-2-one and N (4,6-dimethylpyridin-2-yl) 2,4-dibromobutanamide. The mixture was dissolved in tetrahydrofuran and sodium hydride (700 mg) was added to complete cyclization of pyrrolidinone of dibromobutanamide. The reaction was stirred for 3 hours and then left for 20 hours. Water was added and the mixture extracted with ethyl acetate (x3). The organic rubber was washed with brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to give 3-bromo-1 (4,6-dimethylpyridin-2-yl) pyrrolidine-2. It was found to be about a 1: 1 mixture of -one and 3-chloro-1 (4,6-dimethylpyridin-2-yl) pyrrolidin-2-one. This rubber was dissolved in tetrahydrofuran (250 ml) and potassium iodide (2.50 g) was added. The stirred mixture was then heated to 65 ° C. (bath temperature) and methylamine was bubbled into the mixture for 2 days. The reaction mixture was cooled down and water was added and the mixture was extracted (x3) with ethyl acetate.

The collected extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to afford crude 3 (methylamino) -1 (4,6-dimethylpyridin-2-yl) pyrrolidin-2-one (3.70 g )

δ (CDC1 ₃ ): 1.88 (1H, m), 2.31 (3H, s), 2.41 (3H, s), 2.42 (1H, m), 2.52 (3H, s), 2.79 (1H, d), 3.54 ( 1H, dd), 3.82 (1H, m), 4.20 (1H, m), 6.74 (1H, s), 7.99 (1H, s).

Step 2

Preparation of diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4,6-dimethylpyridin-2-yl) pyrrolidin-2-one

3 (methylamino) -1 (4,6-dimethylpyridin-2-yl) pyrrolidine-2 scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one Of the title compound in a manner similar to that described in Example 7 except that the crude product mixture is further separated by high performance liquid chromatography on silica-gel using -one and eluting with ethyl acetate / hexanes (1: 1). The diastereomer was obtained:

Diastereomer A: δ (CDC1 ₃ ): 1,41 (1H, d), 1.67 (3H, s), 2.08 (1H, m), 2.12 (1H, d), 2.32 (3H, s), 2.39 ( 1H, m), 2.42 (3H, s), 3.13 (3H, s), 3.82 (1H, m), 4.31 (1H, m), 5.44 (1H, dd), 6.76 (1H, s), 8.02 (1H , s)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.38-1.48 (1H, m), 3.63 & 3.68 (3H, 2 xs), 2.05-2.18 (1H, 2 xd), 2.22-2.78 (2H, m), 2.28 & 2.33 (3H, 2 xs), 2.40-2.48 (3H, 2 xs), 2.90 & 3.25 (3H, 2 xs), 3.81-4.02 (1H, m), 4.22-4.35 (1H, m) , 4.72 & 4.87 (t + dd), 6.72 & 6.81 (1H, 2 xs), 8.00 & 8.03 (1H, 2 xs)

Compound 59 in Table 3 was prepared in a similar manner.

Example 19

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-bromo-5-chlorothien-2-yl) pyrrolidin-2-one (of Table 1 Preparation of Diastereomers A and B) of Compound 56

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one in anhydrous dichloromethane (3 ml) (above A stirred solution of (200 mg) was treated dropwise with a bromine (84 mg) solution in dichloromethane (1 ml), similarly to the method described in Example 1. After the addition, the colorless solution was dried under reduced pressure until drying. The crude product obtained by evaporation was eluted with ethyl acetate / hexanes (2: 3) and separated by high performance liquid chromatography on silica-gel to give a diastereomer of the following title compound:

Diastereomer A: δ (CDC1 ₃ ): 1,41 (1H, d), 1.62 (3H, s), 2.11 (1H, d), 2.15 (1H, m), 2.49 (1H, m), 3.17 ( 3H, s), 3.78-3.96 (2H, m), 5.26 (1H, dd), 6.78 (1H, s)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.39 & 1.45 (1H, 2 xd), 1.60 & 1.68 (3H, 2 xs), 2.07-2.15 (1H, 2 xd), 2.22-2.83 (2H , m), 2.91 & 3.28 (3H, 2 xs), 3.81-3.99 (2H, m), 4.39 & 4.81 (1H, dd + t), 6.76 & 6.82 (1H, 2 xs)

Example 20

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3,5-dichlorothien-2-yl) pyrrolidin-2-one (of Compound 57 in Table 1 Preparation of Diastereomers A and B)

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one (200mg) in anhydrous dichloromethane (4ml) ) Was stirred dropwise with sulfuryl chloride (0.042 ml) After the addition, the colorless solution was evaporated to dryness under reduced pressure to elute with ethyl acetate / hexane (2: 3). Separation by high performance liquid chromatography on silica-gel afforded the diastereomer of the following title compound:

Diastereomer A: δ (CDC1 ₃ ): 1,40 (1H, d), 1.62 (3H, s), 2.12 (1H, d), 2.16 (1H, m), 2.50 (1H, m), 3.15 ( 3H, s), 3.82-4.06 (2H, m), 5.27 (1H, dd), 6.72 (1H, s)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.39 & 1.46 (1H, 2 xd), 1.60 & 1.67 (3H, 2 xs), 2.07 & 2.14 (1H, 2 xd), 2.23-2.85 (2H , m), 2.89 & 3.28 (3H, 2 xs), 3.82-4.09 (2H, m), 4.38 & 4.81 (1H, dd + t), 6.68 & 6.77 (1H, 2 xs)

Example 21

3 ((N (2,2-difluoro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-bromo-4-methylphenyl) pyrrolidin-2-one (of Compound 50 in Table 1 Preparation of Diastereomer)

Step 1

3 (methylamino) -1 (3-bromo-4-methylphenyl) pyrrolidin-2-one

The title compound was prepared from 3-bromo-4-methyl aniline using a method similar to that described in WO95 / 33719.

M.P. = 83-84 ℃

1.89-2.03 (m, 1 H); 2.36 (s, 3 H); 2.40-2.53 (m, 1 H); 2.52 (s, 3 H); 3.48-3.54 (m, 1 H); 3.68-3.80 (m, 2 H); 7.19-7.23 (d, 1 H); 7.52-7.56 (m, 1 H); 7.78-7.80 (m, 1 H).

Step 2

2,2-difluoro-1-methylcyclopropyl carboxylic acid and 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidine-scaled with 2,2-dichloro-1-methylcyclopropyl carboxylic acid Use 3- (methylamino) -1 (3-bromo-4-methylphenyl) pyrrolidin-2-one (from step 1) scaled to 2-one with ethyl acetate / hexanes (7: 3) A diastereomer of the following title compound was obtained in a similar manner as described in Example 7 except that the crude product mixture was further separated by high performance liquid chromatography on silica-gel by eluting:

Diastereomer A: δ (CDC1 ₃ ): 1,28 (1H, m), 1.51-1.54 (3H, m), 1.93 (1H, m), 2.11 (1H, m), 2.37 (3H, d), 2.45 (1H, m), 3.09 (3H, s), 3.71-3.88 (2H, m), 5.32 (1H, dd), 7.22 (1H, d), 7.50 (1H, dd), 7.88 (1H, d)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.20-1.38 (1H, m), 1.48-1.57 (3H, m), 1.83-1.99 (1H, m), 2.10-2.60 (5H, m) , 2.88 & 3.17 (3H, 2 xs), 3.69-3.91 (2H, m), 4.60-4.77 (1H, m), 7.15-7.28 (1H, m), 7.46-7.54 (1H, m), 7.82-7.91 (1H, m)

Example 22

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chloro-3-fluorothien-2-yl) pyrrolidin-2-one (of Table 1 Preparation of Diastereomers A and B) of Compound 58

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one in anhydrous tetrahydrofuran (5 ml) 200 mg) and a stirred solution of N-fluorobenzenesulfonimide (330 mg) were heated under reflux for 6 hours, then cooled to room temperature and left for 16 hours The crude product obtained by evaporating the resulting solution to dryness under reduced pressure Elution with ethyl acetate / hexanes (1: 1) and separation by high performance liquid chromatography on silica-gel gave the diastereomer of the following title compound:

Diastereomer A: δ (CDC1 ₃ ): 1,41 (1H, d), 1.63 (3H, s), 2.11 (1H, d), 2.15 (1H, m), 2.52 (1H, m), 3.12 ( 3H, s), 3.91 (1H, m), 4.11 (1H, m), 5.26 (1H, t),

6.63 (1 H, s)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.38 & 1.45 (1H, 2 xd), 1.61 & 1.69 (3H, 2 xs), 2.07 & 2.13 (1H, 2 xd), 2.20-2.84 (2H , m), 2.85 & 3.28 (3H, 2 xs), 3.88-4.20 (2H, m), 4.36 & 4.82 (1H, dd + t), 6.70 & 6.78 (1H, 2 xs)

Example 23

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethyl-4-methylphenyl) pyrrolidin-2-one (of Compound 32 in Table 1 Preparation of Diastereomers A and B)

Step 1

Preparation of 3 (methylamino) -1 (3-trifluoromethyl-4-methylphenyl) pyrrolidin-2-one

The title compound was obtained as a solid in a similar manner as described in Example 18 Step 1, except that 3-trifluoromethyl-4-methylaniline was used instead of 4,6-dimethyl-2-aminopyridine (Chemical Abstracts 122 See: 265013).

δ (CDC1 ₃ ): 1.73 (1H, board), 1.99 (1H, m), 2.43 (3H, d), 2.47 (1H, m) 2.51 (3H, s), 3.52 (1H, dd), 4.79 (1H , m), 7.28 (1H, m), 7.75-7.82 (2H, m)

Step 2

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethyl-4-methylphenyl) pyrrolidin-2-one

3 (methylamino) -1 (3-trifluoromethyl-4-methylphenyl) pyrrolidine-2 scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one Of the following title compound in a similar manner as described in Example 7 except that the crude product mixture was further separated by high performance liquid chromatography on silica-gel by using -one and eluting with ethyl acetate / hexanes (7: 3). The diastereomer was obtained:

Diastereomer A: δ (CDC1 ₃ ): 1,41 (1H, d), 1.67 (3H, s), 2.11 (1H, d), 2.15 (1H, m), 2.46 (3H, d), 2.50 ( 1H, m), 3.18 (3H, s), 3.76-3.92 (2H, m), 5.34 (1H, dd), 7.29 (1H, dd), 7.76 (1H, dd), (7.87 (1H, d)

Diastereomer B: δ (CDC1 ₃ ; Rotamer Mixture): 1.39 & 1.45 (1H, 2 xd), 1.61 & 1.67 (3H, 2 xs), 2.08 & 2.17 (1H, 2 xd), 2.23-2.83 (5H) , m), 2.91 & 3.28 (3H, 2 xs), 3.73-3.98 (2H, m), 4.45 & 4.85 (1H, 2 xt), 7.21-7.37 (1H, m), 7.74-7.94 (2H, m)

Example 24

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4-methylpyridin-2-yl) pyrrolidin-2-one (Compound 59 in Table 1)

Except for purification of the final product by chromatography on silica-gel using 2-amino-4-methylpyridine scaled with 2-amino-4,6-dimethylpyridine and eluting with ethyl acetate / hexanes (1: 1) The title compound was obtained in a 1: 1 mixture of diastereomers.

δ (CDC1 ₃ ): inter alia 1.60 (s), 1.64 (s), 1.67 (s)-cyclopropyl-1 -methyl resonance; 2.91 (s), 3.17 (s), 3.27 (s) -N-methyl resonance; 4.67 (t), 4.89 (t), 5.42 (dd)-pyrrolidone 3-H resonance.

Example 25

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one (compound of Table 1) Isolation of 51 Diastereomers A and B)

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one (206 g) was diluted with ethyl acetate / hexane ( Eluting with 1: 1) and separating by high performance liquid chromatography on silica-gel to obtain the following diastereomers:

Diastereomer A: mp 192.5-193 ° C .; δ (CDC1 ₃ ): 1.41 (1H, d), 1.64 (3H, s), 2.13 (1H, d), 2.15 (1H, m), 2.59 (1H, m), 3.12 (3H, m), 3.76 ( 1H, m), 3.91 (1H, m), 5.37 (1H, t), 6.30 (1H, d), 6.72 (1H, d)

Diastereomer B: mp 171-173 ° C .; δ (CDC1 ₃ ): 1.38 & 1.44 (1H, 2 xd), 1.58 & 1.62 (3H, 2 xs), 2.06 & 2.14 (1H, 2 xd), 2.25-2.91 (2H, m), 2.85 & 3.29 (3H , 2 xs), 3.66-4.00 (2H, m), 4.43 & 4.90 (1H, dd + t), 6.26 & 6.36 (1H, 2 xd), 6.68 & 6.75 (1H, 2 xd)

Example 26

3 ((N (2,2,3,3-tetrachloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one (compound of Table 1) Manufacture of 30)

Manufacture 1

Preparation of 2,2,3,3-tetrachloro-1-methylcyclopropyl carboxylic acid

Ethyl 2,2-dichloro-1-methylpropenoate (1.02 g) was heated to 145 ° C. (bath temperature) and sodium trichloroacetate (excess) was added in portions. The reaction was cooled to rt and left for 16 h. The mixture was then again heated to 145 ° C. (bath temperature) and further (very excess) sodium trichloroacetate was added over 7 hours. The reaction was cooled to room temperature, left for 16 hours, then heated to 145 ° C. (bath temperature) and further added (very excess) sodium trichloroacetate over 4 hours. The mixture was cooled down and water was added. The mixture was then extracted with ethyl acetate (x3) and the collected extracts were dried (MgSO ₄ ), filtered and evaporated under reduced pressure to afford ethyl 2,2,3,3-tetrachloro-1-methylcyclopropyl carboxylate and unreacted 2 The mixture of, 2-dichloro-1-methylpropenoate remained rubber. This mixture (226 mg) was dissolved in ethanol (5 ml) and sodium hydroxide (95 mg) was added. The resulting solution was stirred at room temperature for 2 hours and then left overnight. The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (x3) to drain the extract. The aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate (x3). The collected extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to give 2,2,3,3-tetramethyl-1-methylcyclopropyl carboxylic acid [δ (CDCl ₃ ): 1.80 (3H, s) -methyl signal] and 2,2-dichloro-1-methylpropenoic acid [δ (CDCl ₃ ): 2.14 (3H, s) -methyl signal]. This mixture was used for the next step.

Manufacture 2

Preparation of 3 ((N (2,2,3,3-tetrachloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one

The debris of step 1 was heated at reflux in thionyl for 2 hours. It was evaporated under reduced pressure and then the residue was dissolved in dichloromethane. This acid chloride solution was reacted with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one as described in Example 1 to silica-gel chromatography (ethyl acetate / hexane mixtures). Eluting with (1: 2)) to afford the title compound.

Electron impact MS: m / e 493 (MH ⁺ ) [limited quantum nmr spectrum with limited rotation]

Example 27

3 ((N (2,2,3,3-tetrachloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one (of Table 1 Preparation of Compound 52)

Use 3 (methylamino) -1 (5-chlorothien-2-yl) pyrrolidin-2-one instead of 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a clear rubber in a similar manner as described in Example 26.

Electron impact MS: m / e 493 (MH ⁺ ) [limited quantum nmr spectrum with limited rotation]

Example 28

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-fluoro-4-methylphenyl) pyrrolidin-2-one (compound of Table 1) Separation of 23 Diastereomers A and B)

3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-fluoro-4-methylphenyl) pyrrolidin-2-one in ethyl acetate / hexane (65:35 Was eluted with) and separated by high performance liquid chromatography on silica-gel to give the following diastereomer:

Diastereomer A: δ (CDC1 ₃ ): 1.41 (1H, d), 1.67 (3H, s), 2.10 (1H, m), 2.11 (1H, d), 2.26 (3H, d), 2.48 (1H, m), 3.15 (3H, s), 3.70-3.88 (2H, m), 5.35 (1H, dd), 7.17 (1H, t), 7.23 (1H, d), 7.50 (1H, d)

Diastereomer B: δ (CDC1 ₃ ): 1.39 & 1.43 (1H, 2 xd), 1.58 & 1.62 (3H, 2 xs), 2.08 & 2.14 (1H, 2 xd), 2.21-2.26 (3H, 2 xd) , 2.25-2.80 (2H, m), 2.90 & 3.28 (3H, 2 xs), 3.74 (1H, m), 3.88 (1H, m), 4.50 & 4.82 (1H, t + dd), 7.08-7.32 (2H , m), 7.43-7.54 (1H, m)

Example 29

Of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-chloro-5-methoxyphenyl) pyrrolidin-2-one (compound 35 in Table 1) Produce

Step 1

Preparation of 3 (methylamino) -1 (3-chloro-5-methoxyphenyl) pyrrolidin-2-one

The title compound was obtained as a rubber in a similar manner as described in Example 18, step 1 except using 3-chloro-5-methoxyaniline instead of 4,6-dimethyl-2-aminopyridine.

δ (CDC1 ₃ ): 1.95 (1H, m), 2.46 (1H, m), 2.51 (3H, s), 3.51 (1H, dd), 3.66-3.82 (2H, m), 3.80 (3H, s), 6.69 (1 H, m), 7.17 (1 H, m), 7.29 (1 H, m)

Step 2

Preparation of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-chloro-5-methoxyphenyl) pyrrolidin-2-one

3 (methylamino) -1 (3-chloro-5-methoxyphenyl) pyrrolidine-2- scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a rubber separated 1: 1 diastereomer mixture in a similar manner as described in Example 1 except for using On.

δ (CDC1 ₃ ): inter alia 1.58 (s), 1.62 (s), 1.68 (s)-cyclopropyl-1 -methyl resonance; 2.90 (s), 3.17 (s), 3.29 (s) -N-methyl resonance; 4.47 (t), 4.83 (dd), 5.35 (dd)-pyrrolidone 3 -H resonance

Example 30

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-bromothien-2-yl) pyrrolidin-2-one (see Table 2 Preparation of Diastereomers A and B) of Compound 55

Step 1

Preparation of 1 (5-bromothien-2-yl) pyrrolidin-2-one

2,5-dibromothiophene (50 g), pyrrolidin-2-one (17.6 g), copper (I) oxide (28.8 g) and N-methylpyrrolidin-2-one (10 ml) mixed together Then heated at 150 ° C. for 6 h under a nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate, filtered through celite and concentrated under pressure to give a dark oil. The material was partitioned between dichloromethane and water, the organic layer was separated, washed with brine, dried (MgSO ₄ ), filtered and evaporated to give a brown solid. This material was triturated with ether to give a beige solid (6.3 g). (The solvent was evaporated in the first mill and the residue was triturated again with ether to give the second material (1.4 g)).

m.p. = 141-143 ° C

δ (CDC1 ₃ ): 2.22 (2H, quintet), 2.59 (2H, t), 3.79 (2H, t), 6.19 (1H, d), 6.81 (1H, d).

Step 2

Preparation of 1 (5-bromothien-2-yl) -3-hydroxypyrrolidin-2-one

A stirred solution of 1 (5-bromothien-2-yl) pyrrolidin-2-one (10.0 g) in tetrafuran (250 ml) was cooled to −70 ° C. under nitrogen atmosphere and lithium hexamethyl disilazide (tetra A solution of 1.0 M in furan; 85.4 ml) was added dropwise. The dark solution was partially treated with 2-p-toluenesulfonyl-3-phenyloxaziridine (13.4 g). The mixture was slowly heated to 0 ° C. and then quenched with 1 M aqueous hydrochloric acid solution and added at a rate not exceeding 3 ° C. The mixture was extracted with ethyl acetate (2x200 ml) and the collected extracts were washed with brine and dried (MgSO ₄ ). The solvent was evaporated under reduced pressure so that the dark crystallized partially by standing the dark rubber. It was triturated with diethyl ether and ethyl acetate mixture and the solid was filtered off. This solid was eluted with an ethyl acetate / hexanes (4: 1) mixture and purified by silica-gel chromatography to give the title compound as a white solid. Yield 2.3 g

δ (CDC1 ₃ ): 1.82 (1H, m), 2.41 (1H, m), 3.59 (1H, m), 3.78 (1H, m), 4.33 (1H, m), 5.80 (1H, d), 6.43 ( 1H, d), 6.99 (1H, m)

Step 3

Preparation of 1 (5-bromothien-2-yl) -3-methanesulfonyloxypyrrolidin-2-one

Use of 1 (5-bromothien-2-yl) -3-hydroxypyrrolidin-2-one instead of 3-hydroxy-1 (3,4-dichlorophenyl) pyrrolidin-2-one The title compound was obtained as a solid in a similar manner as described in Example 8 Step 2 except.

δ (CDC1 ₃ ): 2.47 (1H, m), 2.80 (1H, m), 3.31 (3H, s), 3.80 (1H, m), 4.96 (1H, m), 5.40 (1H, dd), 6.33 (1H, d), 6.89 (1H, d)

Step 4

Preparation of 1 (5-bromothien-2-yl) -3 (methylamino) pyrrolidin-2-one

1 (5-bromothien-2-yl) -3-methanesulfonyloxypyrrolidin-2-one instead of 3-methanesulfonyloxy-1 (3,4-dichlorophenyl) pyrrolidin-2-one The title compound was obtained as a solid in a similar manner as described in Example 8 Step 3 except using.

δ (CDC1 ₃ ): 1.78 (1H, broad s), 2.03 (1H, m), 2.51 (3H, s), 2.53 (1H, m), 3.59 (1H, m), 3.71 (1H, m), 3.83 (1H, m), 6.26 (1H, m), 6.85 (1H, m)

Step 5

Preparation of Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (5-bromothien-2-yl) pyrrolidin-2-one

1 (5-bromothien-2-yl) -3- (methylamino) pyrrolidin-2-one instead of 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The title compound was obtained as a solid in a similar manner as described in Example 7 except for using. It was eluted with ethyl acetate / hexanes (1: 1) and separated by high performance liquid chromatography on silica-gel to give the following diastereomers:

Diastereomer A: mp 173-174 ° C .; δ (CDC1 ₃ ): 1.40 (1H, d), 1.63 (3H, s), 2.11 (1H, d), 2.15 (1H, m), 2.58 (1H, m), 3.12 (3H, s), 3.76 ( 1H, m), 5.35 (1H, t), 6.30 (1H, d), 6.87 (1H, d)

Diastereomer B: mp 185-183 ° C .; δ (CDC1 ₃ ): 1.38 & 1.44 (1H, 2 xd), 1.60 & 1.69 (3H, 2 xs), 2.05 & 2.14 (1H, 2 xd), 2.28-2.90 (2H, m), 2.86 & 3.28 (3H , 2 xs), 3.68-3.99 (2H, m), 4.44 & 4.90 (1H, dd + t), 6.26 & 6.37 (1H, 2 xd), 6.81 & 6.90 (1H, 2 xd)

Example 31

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4-chloro-3-methylphenyl) pyrrolidin-2-one (Compound 34 in Table 2) Preparation of Diastereomers A and B)

Step 1

Preparation of 3 (methylamino) -1 (4-chloro-3-methylphenyl) pyrrolidin-2-one

The title compound was obtained as a solid in a similar manner as described in Example 18 Step 1 except that 4-chloro-3-methylaniline was used instead of 4,6-dimethyl-2-aminopyridine.

δ (CDC1 ₃ ): 2.01 (1H, m), 2.38 (3H, s), 2.48 (1H, m), 2.53 (3H, s), 2.70 (1H, d), 3.58 (1H, dd), 3.69- 3.80 (2H, m), 7.29 (1H, d), 7.38 (1H, dd), 7.52 (1H, d)

Step 2

Preparation of diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (4-chloro-3-methylphenyl) pyrrolidin-2-one

3 (methylamino) -1 (4-chloro-3-methylphenyl) pyrrolidin-2-one scaled with 3 (methylamino) -1 (3-trifluoromethoxyphenyl) pyrrolidin-2-one The diastereomer of the following title compound was obtained by a similar method as described in Example 7 except that the crude product mixture was further chromatographed on silica-gel by eluting with ethyl acetate / hexanes (1: 2). :

Diastereomer A: δ (CDC1 ₃ ): 1.40 (1H, d), 1.66 (3H, s), 2.10 (1H, m), 2.10 (1H, m), 2.12 (1H, d), 2.38 (3H, s), 2.45 (1H, m), 3.15 (3H, s), 3.73-3.88 (1H, dd), 7.32 (1H, d), 7.38 (1H, dd), 7.70 (1H, d)

Diastereomer B: δ (CDC1 ₃ ): 1.40 & 1.46 (1H, 2 xd), 1.61 & 1.67 (3H, 2 xs), 2.09 & 2.17 (1H, 2 xd), 2.20-2.80 (2H, m), 2.36 & 2.40 (3H, 2 xs), 2.90-3.29 (3H, 2 xs), 3.71-3.93 (2H, m), 4.45 & 4.82 (1H, 2 xt), 7.23-7.42 (2H, m), 7.59- 7.68 (1 H, m)

Example 32

Diastereomer of 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-chloro-4-methylphenyl) pyrrolidin-2-one (Compound 20 in Table 1) Preparation of Diastereomers A and B)

Elution with ethyl acetate / hexanes (75:25) was performed by high performance liquid chromatography on silica-gel 3 ((N (2,2-dichloro-1-methylcyclopropyl carbonyl) methylamino) -1 (3-chloro- 4-methylphenyl) pyrrolidin-2-one was isolated to give the following diastereomer:

Diastereomer A: δ (CDC1 ₃ ): 1.41 (1H, d), 1.64 (3H, s), 2.09 (1H, m), 2.12 (1H, m), 2.36 (3H, s), 2.48 (1H, m), 3.18 (3H, s), 3.72-3.90 (2H, m), 5.33 (1H, dd), 7.22 (1H, d), 7.44 (1H, dd), 7.70 (1H, d)

Diastereomer B: δ (CDC1 ₃ ): 1.39 & 1.43 (1H, 2 xd), 1.61 & 1.67 (3H, 2 xs), 2.08 & 2.16 (1H, 2 xd), 2.21-2.80 (2H, m), 2.31 & 2.36 (3H, 2 xs), 2.89 & 3.28 (3H, 2 xs), 3.69-3.95 (2H, m), 4.48 & 4.82 (1H, t + dd), 7.15-7.28 (1H, m), 7.41 7.50 (1 H, m), 7.66-7.78 (1 H, m)

Example 33

Table 1 Preparation of Compound 1

Step 1

Preparation of 2- (methylthio) -N- (3-chloro, 4-fluorophenyl) acetamide

Potassium t-butoxide (56 8 gms, 0.507 mol) was dissolved in anhydrous tetrahydrofuran (200 ml) with water bath cooling and stirred at 20 ° C. for 15 minutes. A 3-chloro-4-fluoroaniline (70.0 gms, 0.48 mol) solution in anhydrous tetrahydrofuran (150 ml) was added over 20 minutes and the dark purple solution was stirred at 20 ° C. for 45 minutes. Ethyl (methylthio) acetate solution (64.8 gm, 0.48 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise while cooling to about 20 ° C. and the resulting solution / slurry was stirred at 20 ° C. for 2 hours.

The mixture was then poured into ice water (300 ml), acidified to pH 6 with dilute hydrochloric acid and extracted with ethyl acetate (500 ml). The separated organic phase was washed twice with brine, 1M hydrochloric acid and finally with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a pale brown oil which was left to solidify (103 gm).

δ (CDC1 ₂ ) = 7.75 (1H, m); 7.4 (H, m); 7.2 (1H, doublet of double); 3.35 (2H, s); 2.2 (3H, s)

Step 2

Preparation of N- (ethoxymethyl) -N- (3-chloro-4-fluorophenyl) -2- (methylthio) acetamide

Dissolve sodium hydroxide pellets (86 gm) in water (80 ml) with stirring and cooling in an ice bath and slowly add the solution in acetamide (102.8 gm, 0.43 mol) from step 1 in dichloromethane (260 ml) at about 10 ° C. (Ice bath cooling). Benzyltrimethylammonium chloride (1.0 gm of catalyst) was added at a rate not exceeding 16 ° C., followed by chloromethylethyl ether (100 gm, 2.2 eq). When the addition was complete, stirring was continued for another 2.5 hours. The solution was diluted with water (500 ml) and saturated brine (20 ml) and additional amount of dichloromethane (100 ml). The organic phase was separated, washed with brine and dried over magnesium sulfate, filtered and evaporated under reduced pressure to dryness to give a brown oil (124 gm).

delta (CDC13): 7.4 (1H, doublet), 7.2 (2Hdd), 5.0 μH, s; 3 65 (2H, q); 3.0 (2H, s); 2.2 (3H, s); 1.2 (3H, t)

Step 3

Preparation of 5-hydroxy-3- (3-chloro-4-fluorophenyl) -oxazolidin-4-one

Sodium periodate solution (101 gm, 0.46 mol) in water (650 ml) was slowly added to a step 2 product stirred solution (124 gm) in ethanol (700 ml) at a rate capable of maintaining the internal temperature below 24 ° C. (bath cooling). . The solid suspension was stirred overnight at ambient temperature.

The slurry was then evaporated to almost dryness, ethyl acetate (500 ml) was added, the inorganic solids were filtered off, the organic phase was washed with brine (500 ml), ethyl acetate was dried over magnesium sulfate, filtered and evaporated to dryness to 131.2 g of the product brown. Obtained as an oil, it was passed through silica to decolorize and used directly in the next step.

The sulfoxide (76.9 gm, 0.25 mol) in the resulting tetrahydrofuran (300 ml) was cooled to about 17 ° C. in an ice bath and the trifluoroacetic anhydride solution (63 gm, 42.3 ml) in anhydrous tetrahydrofuran (70 ml) was quenched. It was added over 20 minutes. After stirring for another 30 minutes, a solution of sodium hydrogen carbonate (52 gm) in water (420 ml) was added in portions over about 20 minutes and then stirred overnight under a slow nitrogen stream at ambient temperature to remove sulfite by-products.

Further water (500 ml) and dichloromethane (500 ml) were added followed by the organic phase washed twice with water (2 × 500 ml), dried over magnesium sulphate and evaporated to dryness.

The crude hydrated aldehyde product of the Pummer reaction (72.5 g) was divided into two equal parts and each 36 g of alicoat dissolved in cooling about 4 ° C. hydrogen chloride (about 80 g) in an ice bath was separately dissolved in dioxane (350 ml). The temperature was slowly raised to 20 ° C. and stirring continued for 4 hours. After standing overnight at room temperature, a solution of potassium carbonate (80 g) in water (200 ml) was slowly added while keeping the internal temperature below 10 ° C. in an ice / salt bath. The pH of the solution was then about 4 with saturated aqueous sodium bicarbonate and the product was extracted with ethyl acetate. The separated organic phase was washed twice with water and dried over magnesium sulphate. The brown oil obtained by evaporating the solvent was triturated with hexane and a small volume of diethyl ether to give a pale brown solid. In this way 21.0 g of product of acceptable purity were obtained.

delta (CDC1 ₃ ): 7.7 (IH, m), 7.35 (IH, m); 7.15 (1 H, t); 5.65 (1 H, d); 5.6 (1 H, m); 5.4 (1H, d).

Step 4

Preparation of 5- (methylamino) -3- (3-chloro-4-fluorophenyl) -oxazolidin-4-one

The hydroxy-oxazolidinone (7.0 g, 0.0302 mol) obtained in step 3 was dissolved in anhydrous dichloromethane (50 ml) and two drops of dimethylformamide were added. Oxalyl chloride (4.2 g, 1.1 eq) was slowly added by syringe and the solution stirred for 4 hours at room temperature at which time degassing stopped. The solution was evaporated to dryness to afford 5-chlorooxazolidin-4-one as a light brown oil (7.7 g).

It was dissolved in anhydrous tetrahydrofuran (50 ml) and stirred at about 16 ° C. under nitrogen. Methylamine (2.0 mol in tetrahydrofuran, 33.4 ml: 2.2eq) was added dropwise over 15 minutes at which time a white solid was produced and the temperature was maintained at 22 ° C. or lower. After stirring for 2 hours at room temperature, the reaction was refrigerated overnight.

The amine hydrochloride was then filtered, washed with ethyl acetate and the collected filtrate and washes were evaporated to dryness and the yellow solid obtained was triturated with diethyl ether to give a white solid (4.2 g).

Step 5

Preparation of 5 ((N (2,2-dichloro-11-methylcyclopropylcarbonyl) methylamino) -2 (3-chloro-4-fluorophenyl) -oxazolidin-2-one (compound 1)

A 2,2-chloro-1-methylcyclopropyl carbonyl chloride solution (310 mg) in anhydrous dichloromethane (10 ml) was prepared and cooled to about 5 ° C. (ice bath). A portion of methylamino oxazolidinone (367 mg-0.0015 mol) obtained in step 4 was added and the solution was stirred for 10 minutes. Pyridine (120 mg) was added and the solution was stirred at rt for 3 h.

The reaction was evaporated to dryness and the product was partitioned between water and ethyl acetate and the organic phase was washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and then evaporated to dryness to obtain a wax product. Elution with diethyl ether and chromatography on silica gave the purified product as a colorless oil that foamed into a fluffy solid upon vacuum treatment. The yield was 351 mg as a diastereomer mixture.

δ (CDC1 ₃ ): inter alia 1.61 (s); 1.64 (s); 1.68 (s)-diastereomer and rotamer-1 -methyl group for cyclopropyl peak; 2.92 (s); 3.22 (s)-N-methyl resonance; 5.4-5.6 (2H, m) -oxazolidinone methylene quantum resonance.

Step 34

Preparation of 5 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -3 (3,5-dichlorophenyl) -oxazolidin-2-one (compound 7 in Table 1)

The title compound was prepared as a mixture of diastereomers in a similar manner as described in Example 33 except that 3,5-dichloroaniline was used instead of 3-chloro-4-fluoroaniline.

δ (CDC1 ₃ ): inter alia 1.60 (s); 1.62 (s), 1.67 (s)-diastereomer and rotamer peaks for cyclopropyl-1-methyl groups: 2.88 (s), 2.92 (s), 3.24 (s), 3.33 (s)-N -methyl Resonance, 5.4-5.6 (2H, m)-both oxazoline methylene.

Step 35

Preparation of 5 ((N (2,2-dichloro-1-methylcyclopropylcarbonyl) methylamino) -3 (3-chlorophenyl-oxazolidin-2-one (compound 8 in Table 1)

The title compound was prepared as a mixture of diastereomers in a similar manner as described in Example 33 except using 3-chloroaniline instead of 3-chloro-4-fluoroaniline.

δ (CDC1 ₃ ): inter alia 1.55 (s), 1.62 (s), 1.65 (s), 1.68 (s), 1.72 (s) —diastereomer and rotamer peak for cyclopropyl—1-methyl group; 2.90 (s), 3.21 (s) and 3.32 (s) -N-methyl resonance:

Step 36

Of 3 ((N (2,2-dichloro-1-methyl cyclopropyl carbonyl) methylamino) -1 (3-chloro-4- fluorophenyl) pyrrolidin-2-one (compound 17 in Table 1) Produce

3 (methylamino) -1 (3-chloro-4-fluorophenyl) pyrrolidin-2-one instead of 3- (methylamino) -1 (3-trifluoromethoxy phenyl) pyrrolidin-2-one The title compound was obtained in a 1: 1 mixture of diastereomers in a similar manner as described in Example 7 except for using (prepared as described in WO95 / 33719).

δ (CDC1 ₃ ): inter alia (1.62 (s), 1.67 (s)-cyclopropyl-1 -methyl resonance: 2.90 (s), 3.18 (s), 3.3 (s)-N-methyl resonance; 4.38 (dd ), 4.85 (dd), 5.30 (dd)-pyrrolidinone 3-H resonance.

Step 37

Preparation of 3 ((N (2,2-dichloro-1-methyl cyclopropyl carbonyl) methylamino) -1 (3,4-dichloro phenyl) pyrrolidin-2-one (compound 18 in Table 1)

3 (methylamino) -1 (3,4-dichloro) pyrrolidin-2-one (in Example 8) instead of 3- (methylamino) -1 (3-trifluoromethoxy pyrrolidin-2-one The title compound was obtained in a 1: 1 mixture of diastereomer in a similar manner as described in Example 7 except for using the same).

δ (CDC1 ₃ ): inter alia 1.60 (s), 1.62 (s), 1.65 (s)-cyclopropyl-1 -methyl resonance; 2.92 (s), 3.18 (s), 3.30 (s) -N-methyl resonance; 4.39 (dd), 4.83 (dd), 5.29 (dd)-pyrrolidinone 3-H resonance.

Step 38

Preparation of 3 ((N (2,2-dichloro-1-methyl cyclopropyl carbonyl) methylamino) -1 (3-methoxy-4-methylphenyl) pyrrolidin-2-one (compound 22 in Table 1)

Step 1

Preparation of 3-bromo-1 (3-methoxy-4-methoxyphenyl) pyrrolidin-2-one

3-methoxy-4-methylaniline (3.5 g) was dissolved in anhydrous dichloromethane (50 ml) and cooled to 5 ° C. under nitrogen (ice-water bath). Triethylamine (14.2 ml, 4eq) was added followed by 2,4-dibromobutyryl bromide (9.5 g, 1.2eq) containing 2,4-dibromobutyryl chloride in known amounts.

The reaction was stirred at room temperature for 30 minutes and then left at room temperature for 2 days. The solvent was then removed under reduced pressure and the product partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was washed with sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a brown oil (5.6 g).

δ (CDC1 ₃ ): 7 5 (1H, t); 7.1 (1H, d), 6.8 (IH, dd); 4.6 (IH, m); 3.8-4.1 (2H, m); 3.8 (3H, s); 2.4-2.8 (2H, m); 2.2 (3H, s).

Step 2

Preparation of 3-methylamino-1 (3-methoxy-4-methylphenyl) pyrrolidin-2-one

The product obtained from step 1 (3.3 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and treated with 1 equivalent of sodium iodide (1.75 g). The solution was stirred at room temperature and after a while became cloudy. After stirring for 5 minutes, methylamine (20 ml of 2M solution in tetrahydrofuran) was added and stirring continued at room temperature for 5 hours.

After standing at room temperature overnight, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to yield 1.943 g of oil product. Column chromatography (silica, 10% methanol in dichloromethane eluent) purification was carried out to give pure product (1.11 g).

δ (CDC1 ₃ ): 7 5 (1H, s); 7.1 (1H, d), 6.8 (IH, dd); 3.85 (3H, s); 3.8 (2H, m); 3.5 (IH, doublet); 2.55 (3H, s), 2.45 (IH, m); 2.2 (3H, s), 2.0 (1H, m).

Step 3

Preparation of Compound 22

The product from step 2 (158 mg) was dissolved in anhydrous dichloromethane (3 ml) and 2,2-dichloro-1-methylcyclopropyl carbonyl chloride (140 mg) was added with stirring. After 15 minutes at room temperature triethylamine (113 ml) was added and stirring continued for 3 hours, after which the reaction was allowed to stand at room temperature for 2 days. The reaction mixture was partitioned with ethyl acetate and water and the organic phase was washed successively with 2M hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated to dryness to afford the desired product as a pale yellow oil (264 mg).

δ (CDC1 ₃ ): in particular 1.62 (s), 1.63 (s), 1.67 (s), 1.70 (s) -cyclopropyl-1-methyl resonance; 2.93 (s), 3.18 (s), 3.27 (s) -N-methyl resonance; 4.59 (dd), 4.84 (dd), 5.40 (dd) -pyrrolidine 3-H resonance

Step 39

Of 3 ((N (2,2-dibromo-1-methylcyclopropyl carbonyl) methylamino) -1 (3-trifluoromethoxybenzyl) pyrrolidin-2-one (compound 26 in Table 1) Produce

2,2-dibromo-1-methylcyclopropyl carbonyl chloride (Baird and Baster described in JCS Perkin Trans. 1, p2317-2325 (1979) instead of 2,2-dichloro-1-methylcyclopropylcarbonyl chloride) The title compound was obtained in about a 1: 1 mixture of diastereomers in a similar manner as described in Example 7 except for the use as prepared).

δ (CDC1 ₃ ): in particular 1.57 (s), 1.65 (s), 1.68 (s) -cyclopropyl-1-methyl resonance; 2.93 (s), 3.21 (s), 3.34 (s) -N-methyl resonance; 4.40 (dd), 4.88 (dd), 5.38 (dd) -pyrrolidine 3-H resonance

Example 40

Preparation of Compound 24 in Table 1

3- (methylamino) -1- (3-bromo-4,5-dimethylphenyl) -pyrrolidin-2-one (0.3 g) was dissolved in dichloromethane (10 ml). Triethylamine (0.28 ml) was added at room temperature and 2,2-dichloro-1-methylcyclopropyl carbonyl chloride (prepared as described in Example 7) (0.21 g) was added in part with stirring at room temperature. The reaction was stirred overnight. The reaction was then diluted with water and the product extracted with dichloromethane. The organic phase was washed with an aqueous solution of sodium chloride and sodium carbonate, then dried (MgSO ₄ ) and concentrated under reduced pressure to give the product as a tan foam. Yield 0.415 g, 92%.

1.4 (m, 1 H); 1.6 (m, 1 H); 1.6 (s, 3 H); 2.1 (m, 1 H); 2.3 (s, 3H); 2.35 (s, 3 H), 2.4 (m, 1 H); 3.15 and 3.3 (s, 3 H); 3.8 (m, 2 H); 4.5 and 5.35 (m, 1 H); 7.5-7.7 (m, 2H)

Example 41

The following compounds were prepared using a method analogous to that described in Example 40 above.

Compound 38 in Table 1

Example 42

Preparation of Compound 62 in Table 1

3- (methylamino) -1- (3-chloro-4-methyl) -oxazolidin-2-one was dissolved in dichloromethane and cooled to 2-4 ° C. To dichloromethane was added a solution of 2,2-dichloro-1-methylcyclopropyl carbonyl chloride (prepared as in Example 7) for 1 minute. Pyridine was added and the reaction was stirred for 45 minutes at 0 ° C., followed by another 3 hours at room temperature. The reaction was washed with sodium hydroxide solution and water and then dried. The solvent was removed in vacuo to give an orange rubber. Elution with diethyl ether / hexane (3: 1) chromatographed on silica gel to give a cream solid. Trituration with hexane gave the product as a white solid. Yield 0.37 g, 32%.

Example 43

Using the same method as in Example 42, the following compounds were prepared.

Example 44

Example 4 The following compounds were prepared using a method similar to step 4.

Biological data

The herbicidal activity of the compounds was tested as follows:

Each compound was dissolved in an appropriate amount according to the volume of the final spray solution of a solvent / surfactant formulation comprising 78.2 gm / l Tween 20 and 21.8 gm / l Span80 adjusted to 1 liter using methylcyclohexanone. Was prepared. Tween20 is a registered trademark of surfactant, including a condensate of 20 mole fractions of ethylene oxide and sorbitan laurate. Span 80 is a registered trademark of surfactant, including sorbitan mono-laurate. If the chemical did not dissolve, the volume was brought to 5 cm ³ with water and glass utensils were added and the mixture was shaken to cause the chemical to dissolve or suspend and then remove the utensil. In all cases, the mixture was diluted with water to the intended spray volume. When sprayed independently a 20cm ³ were required when being sprayed with a volume of 10cm ^{3 3} and 14cm were required for the appearance before and after emergence tests respectively. The sprayed aqueous emulsion contained 4% of the initial solvent / surfactant mix and test chemistry at appropriate concentrations.

The spray composition thus prepared was sprayed on young seedlings with a spray volume of 400 liters per hectare (post-emergence test and flood condition test). Flood conditions were used for species suitable for the growth of rice crops. In this test, plant species were included in a 4 cm diameter Aqua pot that remained wet for at least 48 hours prior to spraying. After spraying, the barrel was kept wet for another 24 hours and then flooded to a depth of about 2 cm. This moisture level was maintained during the test. Compared to untreated plants, the post-emergence tests assessed plant damage in the 0-9 range after spraying 13 and 20 days after flooding conditions, with 0 being 0% damage, 1 being 1-5% damage, 2 being 6-15%. Damage, 3 is 16-25% damage, 4 is 26-35% damage, 5 is 36-59% damage, 6 is 60-69% damage, 7 is 70-79% damage, 8 is 80-89% damage 9 is 90-1005 damage.

In tests to measure herbicidal activity before emergence, sowing crop seeds (i.e. beets, cotton, rapeseeds, winter wheat, corn, rice, soybeans) to 2 cm deep, weeding seeds to 1 cm deep under the culture soil, 400 liters per hectare Up to a volume of spray composition was sprayed. After 20 days of spraying, the seedlings in the sprayed plastic trays were compared to the seedlings in the non-sprayed control trays and the damage was assessed in the 0-9 range.

The compound of formula (1) and other herbicide mixtures were further tested under flood conditions. Octo (60% sand, 26% silt, 13% mud and 7% organics) was used in these 480 cm ² bins for these tests. Weed seedlings and rice transplants were treated 12 times later. Commercially available granules were used for all meals except Compounds 5 and 51 applied as an acetone solution. Evaluation was made 33 days after application as compared to untreated plants.

The test results are shown in Tables 4, 5, 6 and 7 below.

In the following table, the following abbreviations are used for the test plants:

GM-Soybeans

ZM-Corn

OS-Rice

TA-Wheat

PC- Polygonum Convolbulus

CA- Kenopodium Alboom

GA- Gallium Apalli

AR- Amaranthus Retroflexus

BP -Vidence Philrosa

IH- Ipomenoea Hedrakea

AT- Abutylon Teoplasty

XT- Xantium Strumumium

AF- Avena Patua

AM- Allopecurus Myosuroides

SH- Sorgum Halepense

SV- Setaria Viridis

EC- Echinokloa Cruz-Gali

CD- Cyprus Deformis

SJ- Skirpus Yuncoides

SP- Scamaria Pigmaea

EO- Echinokloa Orientosades

MO- Mono Korea Baginalis

CS- Cyprus Serotos

ST- Fraudaria Tripolia

EK- Eleokaris Kuroguwai

Claims (14)

Compound of formula (1) [Formula 1] [Wherein Y is O, S or CH ₂ ; R ¹ is an optionally substituted aryl or heteroaromatic ring wherein the optional substituents are selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or C ₁ -C ₄ -haloalkoxy; R ² and R ³ are independently selected from hydrogen or halogen; R ⁴ and R ⁵ are independently selected from halogen. The compound of claim 1, wherein R ¹ is optionally substituted phenyl or optionally substituted thienyl. The compound of claim 2, wherein R ¹ is a phenyl group substituted at the 3-, 3,4-, 3,5- or 3,4,5-position on the phenyl ring. The compound of claim 2, wherein R ¹ is a 2-thienyl group substituted at the 5-, 3,5- or 4,5-position on the thienyling. The compound of claim 1, wherein R ¹ is trifluoromethyl, trichloromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, fluoromethoxy, chloromethoxy, trichloro Substituted with one or more groups selected from ethoxy, trifluoroethoxy, dichloroethoxy, difluoroethoxy, fluoroethoxy, ethoxy, methoxy, fluoro, chloro, bromo, iodo and methyl compound. The compound of claim 5, wherein R ¹ is substituted with one or more groups selected from trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluoro, chloro, bromo and methyl. The compound of any one of the preceding claims, wherein R ² and R ³ are the same and are selected from hydrogen or chlorine. The compound of any one of the preceding claims, wherein R ⁴ and R ⁵ are both chlorine. The compound of any one of the preceding clauses wherein Y is CH ₂ . The compound according to any one of the preceding claims, wherein the compound of formula (1) is in the form of enantiomer or diastereomer. A process for preparing a compound of formula (1) by reacting a compound of formula (2) with a compound of formula (3) and then modifying the substituents on group R ¹ if desired: [Formula 2] [Wherein, R ¹ and Y are as defined for Formula (1). [Formula 3] [Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined for formula (1) and X is a leaving group. A herbicidal composition comprising the compound of any one of claims 1 to 10 together with an agriculturally acceptable carrier or diluent. A method of severely damaging or killing an undesired plant, comprising applying an herbicidally effective amount of a compound of any one of claims 1 to 10 to a plant or plant growth medium. 13. The herbicidal composition of claim 12, which also contains a second herbicide that does not have formula (1).