Amino acid derivatives and their use as pesticides

0001The invention relates to new amino acid derivatives, a process for their preparation and their use as pesticides, in particular as fungicides and as intermediates for the preparation of known, fungicidally substituted amino acid derivatives.

0002It is already known that certain substituted amino acid derivatives have fungicidal properties and are obtained by reacting substituted amino acids with corresponding amines (cf. EP-A 0 472 995).

0003Furthermore, certain amines of substituted amino acids are known (cf. EP-A 0 587 110).

0004New compounds of the general formula (I)<chemistry id="chem0001" num="0001"><img file="EP0911318A2_D0001.tif" /></chemistry> in which<dl id="dl0001"><dt>A</dt><dd>represents straight-chain or branched alkylene</dd><dt>X</dt><dd>represents unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl, and</dd><dt>R</dt><dd>represents straight-chain, branched or cyclic alkyl, or their salts, with the exception of the compounds N¹- [1- (5-Cyano-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (5-Chloro-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (5-Fluoro-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (3-methyl-2-benzothiophenyl) ethyl-L-valinamide,</dd></dl> found

0005In the following, aryl preferably represents unsubstituted or substituted phenyl, benzothiophene or benzofuran, halogen, cyano, alkyl, haloalkyl, alkoxy and haloalkoxy being preferred as substituents.

0006In the following, alkyl preferably represents straight-chain or branched alkyl having 1 to 6, in particular 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, n-, i-, t-butyl and in particular i-propyl and s-butyl, and also cyclic Alkyl of 3 to 6 carbon atoms, such as in particular cyclopentyl.

0007In the following, alkylene preferably represents straight-chain or branched alkylene having 1 to 6, preferably 1-4 carbon atoms, such as in particular 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1-methyl-1,2-ethylene, 2-methyl-1,2-ethylene, 1,1-dimethylmethylene.

0008Compounds of the formula (I) are preferred<chemistry id="chem0002" num="0002"><img file="EP0911318A2_D0002.tif" /></chemistry> in which<dl id="dl0002"><dt>A</dt><dd>represents 1,1-ethylene or 1,2-ethylene,</dd><dt>X</dt><dd>represents in each case unsubstituted or substituted phenyl, benzothiophene or benzofuran, halogen, cyano, alkyl, haloalkyl, alkoxy and haloalkoxy being mentioned as substituents, and</dd><dt>R</dt><dd>represents i-propyl, s-butyl or cyclopentyl, or their salts, with the exception of the compounds N¹- [1- (5-Cyano-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (5-Chloro-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (5-Fluoro-2-benzofuranyl) ethyl] -L-valinamide, N¹- [1- (3-Methyl-2-benzothiophenyl) ethyl-L-valinamide.</dd></dl>

0009Compounds of the formula (I) are particularly preferred in which<dl id="dl0003"><dt>R</dt><dd>represents 1,1-ethylene or 1,2-ethylene,</dd><dt>X</dt><dd>represents phenyl, 2-benzothiophene or 2-benzofuran, which are optionally monosubstituted to triple in the phenyl ring by methyl, methoxy, triflourmethyl, trifluoromethoxy, ethyl, ethoxy, fluorine, chlorine and / or cyano and</dd><dt>R</dt><dd>represents i-propyl or s-butyl, or their salts, except for the compounds mentioned above.</dd></dl>

0010Compounds of the formula (Ia) are very particularly preferred<chemistry id="chem0003" num="0003"><img file="EP0911318A2_D0003.tif" /></chemistry> in which<dl id="dl0004" compact="compact"><dt>R¹</dt><dd>represents chlorine, methyl, ethyl or methoxy,</dd></dl> or their salts.

0011The compounds of the formula (I) contain two centers of chirality and can therefore be present in different mixtures of enantiomers and diastereomers, which can optionally be separated in a customary manner. Both the pure enantiomers and diastereomers and the mixtures are claimed according to the invention.

0012For the sake of simplicity, the following always refers to compounds of the formula (I), although both the pure compounds and the mixtures are meant with different proportions of isomeric, enantiomeric and diastereomeric compounds.

0013The same applies to the following compounds of the formulas (III) and (IV).

0014It has also been found that the compounds of the formula (I)<chemistry id="chem0004" num="0004"><img file="EP0911318A2_D0004.tif" /></chemistry> in which<dl id="dl0005"><dt>A</dt><dd>represents straight-chain or branched alkylene</dd><dt>X</dt><dd>represents unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl, and</dd><dt>R</dt><dd>represents straight-chain, branched or cyclic alkyl, or their salts, in surprisingly good yield, if oxazolidinediones of the formula (II)<chemistry id="chem0005" num="0005"><img file="EP0911318A2_D0005.tif" /></chemistry></dd></dl> in which<dl id="dl0006" compact="compact"><dt>R</dt><dd>has the meaning given above,</dd></dl> with amines of the general formula (III)         H₂NAX (III) in which<dl id="dl0007" compact="compact"><dt>A and X</dt><dd>have the meanings given above,</dd></dl> in the presence of a diluent and, if appropriate, in the presence of a reaction auxiliary.

0015It has also been found that the new amino acid derivatives of the formula (I) can be used as pesticides.

0016Preferred compounds of the formula (I) are those in which the underlying amino acid is the compound having the L configuration and the amine of the formula (III) used is either racemic or the R configuration or the S- Has configuration at the asymmetric carbon atom.

0017The oxazolidinediones of the formula (II) to be used as starting material for carrying out the process according to the invention are known (cf. Angew. Chem. <u>93</u>, 793 (1981)) and can be obtained by the process described therein by reacting the corresponding amino acids in a conventional manner with phosgene.

0018Formula (III) provides a general definition of the amines also to be used as starting materials for carrying out the process according to the invention.

0019The amines of the formula (III) are generally known compounds of organic chemistry.

0020Inert organic solvents such as: ketones such as acetone or ethyl methyl ketone are used as diluents for the process according to the invention; Esters such as ethyl or methyl acetate; Amides such as dimethylformamide; Nitriles such as acetonitrile; Chlorinated hydrocarbons, such as methylene chloride or carbon tetrachloride, hydrocarbons, such as toluene or ether, such as tetrahydrofuran and, if appropriate, water and mixtures thereof.

0021The process according to the invention is optionally carried out in the presence of a buffer as a reaction auxiliary. All conventional buffer systems can be used here, in particular sodium boranate / boric acid.

0022The temperatures can be varied within a substantial range when carrying out the process according to the invention. In general, temperatures from -100 to + 150 ° C, preferably from -60 to + 100 ° C.

0023When carrying out the process according to the invention, 1 to 10 mol, preferably 1 to 5 mol, of amine of the formula (III) are generally employed per mol of oxazolidinone of the formula (II).

0024In a special embodiment of the process according to the invention, the amine of the formula (III) is also used simultaneously as a diluent.

0025The compounds are worked up and isolated by generally customary and known methods.

0026The invention encompasses both the pure isomers and the mixtures of the compounds of the formula (I). These mixtures can be separated into the components by customary methods, for example selective crystallization from suitable solvents or chromatography on silica gel or aluminum oxide. Racemates can be separated into the individual enantiomers by customary methods, for example by salt formation with optically active acids such as camphorsulfonic acid or dibenzoyl tartaric acid and selective crystallization or by derivatization with suitable, optically active reagents, separation of the diastereomeric derivatives and cleavage or separation on optically active column material.

0027The compounds of the formula (I) according to the invention have a strong microbicidal action and can be used practically to combat unwanted microorganisms. The active ingredients are suitable for use as crop protection agents, in particular as fungicides.

0028When applied in appropriate amounts, the compounds according to the invention also have a herbicidal or insecticidal action.

0029Some pathogens of fungal diseases that fall under the generic names listed above may be mentioned as examples, but not by way of limitation:<ul id="ul0001" list-style="none" compact="compact"><li>Pythium species, such as, for example, Pythium ultimum;</li><li>Phytophthora species, such as, for example, Phytophthora infestans;</li><li>Pseudoperonospora species, such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubense;</li><li>Plasmopara species, such as, for example, Plasmopara viticola;</li><li>Peronospora species, such as, for example, Peronospora pisi or Peronospora brassicae;</li><li>Erysiphe antennas, such as Erysiphe graminis;</li><li>Sphaerotheca species, such as, for example, Sphaerotheca fuliginea;</li><li>Podosphaera species, such as, for example, Podosphaera leucotricha;</li><li>Venturia species, such as, for example, Venturia inaequalis;</li><li>Pyrenophora species, such as, for example, Pyrenophora teres or Pyrenophora graminea (conidial form: Drechslera, synonym: Helminthosporium);</li><li>Cochliobolus species, such as, for example, Cochliobolus sativus (conidial form: Drechslera, synonym: Helminthosporium);</li><li>Uromyces species, such as, for example, Uromyces appendiculatus;</li><li>Puccinia species, such as, for example, Puccinia recondita;</li><li>Til letia species, such as, for example, Tilletia caries;</li><li>Ustilago species, such as, for example, Ustilago nuda or Ustilago avenae;</li><li>Pellicularia species, such as, for example, Pellicularia sasakii;</li><li>Pyricularia species, such as, for example, Pyricularia oryzae;</li><li>Fusarium species, such as, for example, Fusarium culmorum;</li><li>Botrytis species, such as, for example, Botrytis cinerea;</li><li>Septoria species, such as, for example, Septoria nodorum;</li><li>Leptosphaeria species, such as, for example, Leptosphaeria nodorum;</li><li>Cercospora species, such as, for example, Cercospora canescens;</li><li>Alternaria species, such as, for example, Alternaria brassicae;</li><li>Pseudocercosporella species, such as, for example, Pseudocercosporella herpotrichoides.</li></ul>

0030The fact that the active compounds are well tolerated by plants in the concentrations required to combat plant diseases enables treatment of above-ground parts of plants, of propagation stock and seeds and of the soil. Depending on their respective physical and / or chemical properties, the active ingredients can be converted into customary formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, very fine encapsulations in polymeric substances and in coating compositions for seeds, and ULV Cold and warm mist formulations.

0031These formulations are prepared in a known manner, for example by mixing the active ingredients with extenders, that is to say liquid solvents, pressurized liquefied gases and / or solid carriers, optionally using surface-active agents, that is to say emulsifiers and / or dispersants and / or foam-generating agents. In the case of the use of water as an extender, for example organic solvents can also be used as auxiliary solvents. The following are essentially suitable as liquid solvents: aromatics, such as xylene, toluene, alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chlorethylenes, or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example Petroleum fractions, alcohols, such as butanol or glycol, and their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, highly polar solvents, such as dimethylformamide or dimethyl sulfoxide, and water; Liquefied gaseous extenders or carriers mean liquids which are gaseous at normal temperature and under normal pressure, for example Aerosol propellants, such as halogenated hydrocarbons and butane, propane, nitrogen and carbon dioxide; Solid carrier materials are suitable: for example natural rock powders such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth and synthetic rock powders such as highly disperse silica, aluminum oxide and silicates; Solid carrier substances for granules are: eg broken and fractionated natural rocks such as calcite, marble, pumice, sepiolite, dolomite and synthetic granules from inorganic and organic flours and granules from organic material such as sawdust, coconut shells, corn cobs and tobacco stalks; Suitable emulsifying and / or foam-generating agents are: for example nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example Alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and protein hydrolyzates; The following may be used as dispersants: for example lignin sulfite waste liquor and methyl cellulose.

0032Adhesives such as carboxymethyl cellulose, natural and synthetic, powdery, granular or latex-shaped polymers, such as gum arabic, polyvinyl alcohol, polyvinyl acetate, and natural phospholipids, such as cephalins and lecithins and synthetic phospholipids, can be used in the formulations. Other additives can be mineral and vegetable oils. Dyes such as inorganic pigments, for example Iron oxide, titanium oxide, ferrocyan blue and organic dyes such as alizarin, azo and metal phthalocyanine dyes and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc can be used.

0033The formulations generally contain between 0.1 and 95 percent by weight, preferably between 0.5 and 90%, of active ingredient.

0034The active compounds according to the invention, as such or in their formulations, can also be used in a mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, in order to broaden the spectrum of action, for example, or to prevent the development of resistance. For the mixtures, for example:

Fungicides:

0035<ul id="ul0002" list-style="none" compact="compact"><li>2-aminobutane; 2-anilino-4-methyl-6-cyclopropyl-pyrimidine; 2 ', 6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoromethyl-1,3-thiazole-5-carboxanilide; 2,6-dichloro-N- (4-trifluoromethylbenzyl) benzamide; (E) -2-methoxyimino-N-methyl-2- (2-phenoxyphenyl) acetamide; 8-hydroxyquinoline sulfate; Methyl- (E) -2- {2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy] phenyl} -3-methoxyacrylate; Methyl (E) methoximino [alpha- (o-tolyloxy) -o-tolyl] acetate; 2-phenylphenol (OPP), aldimorph, ampropylfos, anilazine, azaconazole,</li><li>Benalaxyl, Benodanil, Benomyl, Binapacryl, Biphenyl, Bitertanol, Blasticidin-S, Bromuconazole, Bupirimate, Buthiobate,</li><li>Calcium polysulfide, captafol, captan, carbendazim, carboxin, quinomethionate (quinomethionate), chloroneb, chloropicrin, chlorothalonil, chlozolinate, cufraneb, cymoxanil, cyproconazole, cyprofuram,</li><li>Dichlorophen, diclobutrazole, diclofluanid, diclomezin, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, dinocap, diphenylamine, dipyrithione, ditalimfos, dithianon, dodine, drazoxolone,</li><li>Edifenphos, epoxyconazole, ethirimol, etridiazole,</li><li>Fenarimol, Fenbuconazole, Fenfuram, Fenitropan, Fenpiclonil, Fenpropidin, Fenpropimorph, Fentinacetate, Fentinhydroxyd, Ferbam, Ferimzone, Fluazinam, Fludioxonil, Fluoromide, Fluquinconazole, Flusilazole, Flusulfamide, Flutolanyl, Futrianolide, Futrianol, Futin Furmecyclox,</li><li>Guazatine,</li><li>Hexachlorobenzene, hexaconazole, hymexazole,</li><li>Imazalil, Imibenconazol, Iminoctadin, Iprobefos (IBP), Iprodione, Isoprothiolan,</li><li>Kasugamycin, copper preparations, such as: copper hydroxide, copper naphthenate, copper oxychloride, copper sulfate, copper oxide, oxine-copper and Bordeaux mixture,</li><li>Mancopper, Mancozeb, Maneb, Mepanipyrim, Mepronil, Metalaxyl, Metconazol, Methasulfocarb, Methfuroxam, Metiram, Metsulfovax, Myclobutanil,</li><li>Nickel dimethyldithiocarbamate, nitrothal isopropyl, nuarimol,</li><li>Ofurace, oxadixyl, oxamocarb, oxycarboxin,</li><li>Pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, probenazole, prochloraz, procymidon, propamocarb, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil, pyroquilon,</li><li>Quintozen (PCNB),</li><li>Sulfur and sulfur preparations,</li><li>Tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, Thicyofen, thiophanate-methyl, thiram, Tolclophos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, Trichlamid, tricyclazole, tridemorph, triflumizole, triforine, triticonazole,</li><li>Validamycin A, vinclozolin,</li><li>Zineb, ziram</li></ul>

Bactericides:

0036<ul id="ul0003" list-style="none" compact="compact"><li>Bronopol, dichlorophene, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furan carboxylic acid, oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulfate and other copper preparations.</li></ul>

Insecticides / acaricides / nematicides:

0037<ul id="ul0004" list-style="none" compact="compact"><li>Abamectin, Abamectin, Acephat, Acrinathrin, Alanycarb, Aldicarb, Alphamethrin, Amitraz, Avermectin, AZ 60541, Azadirachtin, Azinphos A, Azinphos M, Azocyclotin,</li><li>Bacillus thuringiensis, 4-bromo-2- (4-chlorophenyl) -1- (ethoxymethyl) -5- (trifluoromethyl) -1H-pyrrole-3-carbonitrile, bendiocarb, benfuracarb, bensultap, betacyluthrin, bifenthrin, BPMC, Brofenprox, bromophos A, bufencarb, buprofezin, butocarboxin, butylpyridaben,</li><li>Cadusafos, Carbaryl, Carbofuran, Carbophenothion, Carbosulfan, Cartap, Chloethocarb, Chlorethoxyfos, Chloretoxyfos, Chlorfenvinphos, Chlorfluazuron, Chlormephos, N - [(6-Chloro-3-pyridinyl) -methyl] -N'-cyano-N-methyl-ethanimidamide , Chlorpyrifos, Chlorpyrifos M, Cis-Resmethrin, Clocythrin, Clofentezin, Cyanophos, Cycloprothrin, Cyfluthrin, Cyhalothrin, Cyhexatin, Cypermethrin, Cyromazin,</li><li>Deltamethrin, Demeton M, Demeton S, Demeton-S-methyl, Diafenthiuron, Diazinon, Dichlofenthion, Dichlorvos, Dicliphos, Dicrotophos, Diethion, Diflubenzuron, Dimethoat,</li><li>Dimethylvinphos, dioxathione, disulfoton,</li><li>Edifenphos, Emamectin, Esfenvalerat, Ethiofencarb, Ethion, Ethofenprox, Ethoprophos, Etofenprox, Etrimphos,</li><li>Fenamiphos, Fenazaquin, Fenbutatinoxid, Fenitrothion, Fenobucarb, Fenothiocarb, Fenoxycarb, Fenpropathrin, Fenpyrad, Fenpyroximat, Fenthion, Fenvalerate, Fipronil, Fluazinam, Fluazuron, Flucycloxuron, Flucythrinat, Flufenxurophone, Flufenxurophone, Flufenoxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufionxuron, Fufin</li><li>HCH, heptenophos, hexaflumuron, hexythiazox,</li><li>Imidacloprid, Iprobefos, Isazophos, Isofenphos, Isoprocarb, Isoxathion, Ivemectin,</li><li>Lamda-cyhalothrin, Lufenuron,</li><li>Malathion, Mecarbam, Mervinphos, Mesulfenphos, Metaldehyde, Methacrifos, Methamidophos, Methidathion, Methiocarb, Methomyl, Metolcarb, Milbemectin, Monocrotophos, Moxidectin,</li><li>Naled, NC 184, Nitenpyram</li><li>Omethoate, Oxamyl, Oxydemethon M, Oxydeprofos,</li><li>Parathion A, Parathion M, Permethrin, Phenthoat, Phorat, Phosalon, Phosmet, Phosphamdon, Phoxim, Pirimicarb, Pirimiphos M, Primiphos A, Profenofos, Profenophos, Promecarb, Propaphos, Propoxur, Prothiofos, Prothiophos, Prothoat, Pyroflosophroat, Pymophos, Pyroficos Pyraclophos, Pyradaphenthion, Pyresmethrin, Pyrethrum, Pyridaben, Pyrimidifen, Pyriproxifen,</li><li>Quinalphos,</li><li>Salithion, Sebufos, Silafluofen, Sulfotep, Sulprofos,</li><li>Tebufenozide, Tebufenpyrad, Tebupirimphos, Teflubenzuron, Tefluthrin, Temephos, Terbam, Terbufos, Tetrachlorvinphos, Thiafenox, Thiodicarb, Thiofanox, Thiomethon, Thionazin, Thuringiensin, Tralomenhrononium, Triomenophoniazonium, Tri</li><li>Vamidothione, XMC, xylylcarb, YI 5301/5302, zetamethrin.</li></ul>

0038A mixture with other known active ingredients, such as herbicides or with fertilizers and growth regulators, is also possible. The active compounds can be used as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules. They are used in the usual way, e.g. by pouring, spraying, atomizing, scattering, dusting, foaming, brushing, etc. It is also possible to apply the active ingredients using the ultra-low-volume process or to inject the active ingredient preparation or the active ingredient into the soil itself. The seeds of the plants can also be treated.

0039In the treatment of parts of plants, the active compound concentrations in the use forms can be varied within a substantial range: they are generally between 1 and 0.0001% by weight, preferably between 0.5 and 0.001% by weight.

0040In the seed treatment, amounts of active ingredient of 0.001 to 50 g per kilogram of seed, preferably 0.01 to 10 g, are generally required.

0041When treating the soil, active ingredient concentrations of 0.00001 to 0.1% by weight, preferably 0.0001 to 0.02% by weight, are required at the site of action.

0042The compounds of the formula (I) and (Ia) according to the invention are also particularly suitable as intermediates for the preparation of known, fungicidally active substituted amino acid derivatives of the general formula (IV)<chemistry id="chem0006" num="0006"><img file="EP0911318A2_D0006.tif" /></chemistry> in which<dl id="dl0008"><dt>R, A and X</dt><dd>have the meanings given above and</dd><dt>Y</dt><dd>stands for aryl, aralkyl or alkyl, preferably i-propyl and s-butyl or for phenyl, benzyl or cyclopentyl optionally substituted by chlorine, methyl and / or methoxy.</dd></dl>

0043The amino acid derivatives of the formula (IV) are obtained if the compounds of the formula (I) or (Ia)<ul id="ul0005" list-style="none"><li>a) with acid derivatives of the general formula (V)         YO-CO-Z (V) in which<dl id="dl0009"><dt>Y</dt><dd>has the meaning given above and</dd><dt>Z.</dt><dd>represents halogen or the grouping -O-CO-OY, in the presence of a diluent and, if appropriate, in the presence of an acid binder and, if appropriate, in the presence of a catalyst, at temperatures between -100 and + 120 ° C .;</dd></dl> or</li><li>b) first reacted with phosgene in the presence of a diluent and, if appropriate, in the presence of an acid binder at temperatures between -100 and + 120 ° C. and then, without isolating the intermediately formed isocyanates or carbamoyl chlorides, with alcohols of the general formula (VI)         Y-OH (VI) in which<dl id="dl0010" compact="compact"><dt>Y</dt><dd>has the meaning given above,</dd></dl> implemented at temperatures between -100 and + 120 ° C.</li></ul>

0044Process variants (a) and (b) provide the compounds of the formula (IV) in almost quantitative yield.

0045Another particular advantage is the entirety of the processes, ie the direct combination of the process according to the invention for the preparation of the compounds of the formula (I) or (Ia) and their further implementation in accordance with process variants (a) and (b).

0046It is also possible to directly implement the compounds of the formula (I) or (Ia) without intermediate isolation.

0047Formula (V) provides a general definition of the acid derivatives to be used as starting materials for carrying out process variant (a) according to the invention. In this formula, Y has the meanings given above. Z preferably represents chlorine, bromine or the grouping -O-CO-OY.

0048The acid derivatives of the formula (V) are generally known compounds of organic chemistry.

0049Formula (VI) provides a general definition of the alcohols to be used as starting materials for carrying out process variant (b) according to the invention. In this formula, Y has the meanings given above.

0050The alcohols of the formula (VI) are generally known compounds of organic chemistry.

0051Inert organic solvents such as: ketones such as acetone or ethyl methyl ketone are used as diluents for process variants (a) and (b) according to the invention; Esters such as ethyl or methyl acetate; Amides such as dimethylformarnide; Nitriles such as acetonitrile; Chlorinated hydrocarbons, such as methylene chloride or carbon tetrachloride; Hydrocarbons, such as toluene or ethers, such as tetrahydrofuran and, if appropriate, water and mixtures thereof.

0052Suitable acid binders for the process variants (a) and (b) according to the invention are customary inorganic and organic acid binders. These preferably include tertiary amines, such as triethylamine, pyridines or N-methylpiperidine, and also inorganic bases, for example metal hydroxides such as sodium and potassium hydroxide or metal carbonates such as sodium carbonate or calcium carbonate.

0053Process variant (a) according to the invention is optionally carried out in the presence of a catalyst. Examples include 4-dimethylaminopyridine, 1-hydroxy-benzotriazole or dimethylformamide.

0054The temperatures can be varied over a wide range when carrying out process variants (a) and (b). In general, temperatures from -100 to + 120 ° C, preferably from -60 to + 50 ° C.

0055When carrying out process variant (a) according to the invention, 1 to 2 mol, preferably 1 to 1.5 mol, of acid derivative of the formula (V) are generally employed per mol of the compound of the formula (I).

0056The process variant (b) according to the invention is preferably carried out in equimolar amounts. In some cases it proves advantageous to work with di- or triphosgene instead of phosgene or to use an excess of alcohol of the formula (VI).

0057The substituted amino acid derivatives of the general formula (IV) obtained according to process variants (a) and (b) can be purified by conventional methods, such as, for example, crystallization from a suitable solvent or chromatography on silica gel or aluminum oxide, and separated into the components. Racemates can be separated into the individual enantiomers by customary methods.

<b>Manufacturing examples</b>

<b>example 1</b>

L-valine-4-methylpheneth-1-yl amide

005823.6 g (0.175 mol) of 4-methylpheneth-1-yl-amine in 100 ml of acetonitrile are mixed at -10 ° C within 4 to 6 hours with 5.0 g (0.035 mol) of 4-isopropyl-2,5- added oxazolidinedione. The reaction mixture is left to stir at room temperature for about 18 hours and the solvent and excess amine are then distilled off in vacuo. The crude product obtained can be used directly for the preparation of the compound (IV-1).

0059After cleaning under high vacuum, 7.0 g (84.5% of theory) of L-valine-4-methylpheneth-1-yl-amide are obtained.<ul id="ul0006" list-style="none" compact="compact"><li>¹H-NMR (D₆-DMSO; δ = 0.74-0.87 (dm, 6H, 2xCH₃), 1.33 (d, 3H, CH₃), 1.62 (5, 2H, NH₂), 1.77-1.87 (m, H, CH), 2.26 (s, 3H, CH₃), 2.93 (d, H, CH), 4.85-4.95 (m, H, CH) 7.09-7.21 (m, 4H, Ph), 8.13 (m, H, NH).</li></ul>

0060The following compounds of the general formula (Ia) are obtained in accordance with Example 1 and in accordance with the general process instructions: <tables id="tabl0001" num="0001"><table frame="all"><title>Table 1</title><tgroup cols="3" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="52.50mm" /><colspec colnum="2" colname="col2" colwidth="52.50mm" /><colspec colnum="3" colname="col3" colwidth="52.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="center">E.g. no.</entry><entry namest="col2" nameend="col2" align="center">R¹</entry><entry namest="col3" nameend="col3" align="center">Physical data</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="right">2</entry><entry namest="col2" nameend="col2" align="left">4-cl</entry><entry namest="col3" nameend="col3" align="left">Mp 94-95 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="right">3</entry><entry namest="col2" nameend="col2" align="left">4-OCH₃</entry><entry namest="col3" nameend="col3" align="left">n<maths id="math0001" num=""><math display="inline"><mrow><mfrac linethickness="0" numalign="left" denomalign="left"><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0911318A2_D0007.tif" /></maths> = 1.4905</entry></row></tbody></tgroup></table></tables>

<b>Example 2</b>

0061<chemistry id="chem0007" num="0007"><img file="EP0911318A2_D0008.tif" /></chemistry>

L-valine-2- (3,4-dimethoxyphenyl) ethylamide

006210.2 g (0.055 mol) of 2- (3,4-dimethoxyphenyl) ethylamine in 60 ml of acetonitrile are mixed at 50 ° C. in the course of 2-3 hours with 2.0 g (0.01398 mol) of 4-isopropyl-2, 5-oxazolidinedione added. The reaction mixture is left to stir for 18 hours and then the solvent and excess amine are distilled off in vacuo.

0063The crude product obtained is 3.5 g, 90% d. Th. And can be used directly for the preparation of compound IV.

Characterization:

0064<ul id="ul0007" list-style="none" compact="compact"><li>¹H-NMR: (D₆-DMSO)</li><li>δ = 0.75 (d, 3H, CH₃), 0.84 (d, 3H, CH₃), 1.81-1.92 (m, H, CH), 2.65 (t, 2H, CH₂), 3.21-3.35 (m, 2H, CH₂), 3.45 (s, 2H, NH₂), 3.71 (s, 3H, CH₃), 3.74 (s, 3H, CH₃), 6.7-6.89 (m, 3H, aromatic protons), 7.96 (m, H, NH).</li></ul>

<b>Example 3</b>

0065<chemistry id="chem0008" num="0008"><img file="EP0911318A2_D0009.tif" /></chemistry>

00662.5 g (0.0127 mol) of 1- [2- (5-chlorobenzofuranyl)] ethylamine in 50 ml of acetonitrile are mixed at 50-55 ° C. in the course of 2-3 hours with 1.83 g (0.0127 mol) 4-isopropyl-2,5-oxazolidinedione added. The mixture is then stirred for 18 hours and then the solvent is distilled off. The product is purified by chromatography (silica gel CH₂Cl₂ : CH₃OH 10: 1). 1.7 g of 45.5% of theory are isolated of the desired product (mixture of diastereomers).<ul id="ul0008" list-style="none" compact="compact"><li>¹H-NMR (D₆-DMSO): 0.8-0.9 (dm, 6H, 2 x CH₃), 1.48 (d, 3H, CH₃), 1.78-2.0 (m, H, CH), 3.02 (d, H, DH), 5.19 (m, H, CH), 2.45 (<maths id="math0002" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>s</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP0911318A2_D0010.tif" /></maths>, 2H, NH₂), 6.73 (m, H, aromat. H), 7.24-7.68 (m, 3H, aromat. H), 8.39 (m, H, NH).</li></ul>

<b>Preparation of the compounds of the formula (IV)</b>

<b>Example (IV-1)</b>

<b>(Process variant a)</b>

00671 g (0.0043 mol) of L-valine-4-methylpheneth-1-yl-amide (see Example 1) and 0.62 g (0.0045 mol) of potassium carbonate are suspended in 50 ml of dichloromethane at -10 ° C and mixed with 0.8 g (0.0065 mol) of isopropyl chloroformate in 10 ml of methylene chloride. The reaction mixture is left to stir at room temperature for about 18 hours, poured onto ice water, the phases are separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated.

00681.35 g (98% of theory) of N- (isopropoxy-carbonyl) -L-valine-4-methylpheneth-1-yl-amide with a melting point of 160 ° C. are obtained.

<b>(Process variant b)</b>

00690.1 mol of L-valine-4-methylpheneth-1-yl-amide (cf. Example 1) and 0.1 mol of triethylamine are initially introduced at -50 ° C. into 300 ml of methylene chloride. 0.12 mol of phosgene are introduced into this solution. The reaction mixture is warmed to room temperature within 4 hours. A solution of 0.12 mol of isopropanol in 50 ml of methylene chloride is then added dropwise and the mixture is stirred at 50 ° C. for 1 hour.

0070After working up, 16.9 g of N- (isopropoxycarbonyl) -L-valine-4-methylpheneth-1-yl-amide with a melting point of 160 ° C. are obtained.