Crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate and its herbicidal synergistic effects

Abstract

The present invention relates to crystalline forms of (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylic acid methyl ester (I) in two isomeric forms: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib), methods for preparing the crystalline forms, use of the crystalline forms in preparing stable agrochemical formulations, and use of the crystalline forms in controlling harmful plants in the agricultural field. #imgabs0#

Description

[0001] The present invention relates to crystalline forms of (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester (I) existing in two isomeric forms: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib), methods for preparing the crystalline forms, use of the crystalline forms in preparing stable agricultural chemical formulations, and use of the crystalline forms for controlling harmful plants in the agricultural field.

[0002]

[0003] (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester (I) is a herbicide disclosed in WO2018 / 228985.

[0004] Solid formulations in which the active ingredient is present in solid form are of great economic relevance because they have very good storage stability. These are, for example, granules, encapsulated granules, tablets, water-dispersible granules, water-dispersible tablets, water-dispersible powders or water-dispersible powders for seed treatment, dusts, formulations in which the active ingredient is present in dispersed form, for example: suspension concentrates (SC), oil-based suspension concentrates, suspoemulsions or suspension concentrates for seed treatment.

[0005] However, this type of formulation is only applicable if the active ingredient is present in solid form, most preferably in the most thermodynamically stable modified form.

[0006] Due to the constantly increasing ecological and economic demands placed on modern crop protection agents, for example with regard to activity spectrum, activity and application rate, it is desirable to obtain crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) which have their own advantages compared to the known forms in at least some areas or which can provide an activity in solid formulations which has advantages in at least some areas.

[0007] Surprisingly, new crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) have now been found which avoid the above-mentioned disadvantages of storage stability, since they can be provided in solid formulations and have improved herbicidal activity compared to the active substances disclosed in the prior art and improved herbicidal activity of the stereoisomer combinations.

[0008] The present invention relates to crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) in two isomeric forms: methyl (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylate of formula (Ia) and methyl (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (Ib).

[0009] After crystallization, methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) was separated into two stereoisomers by chromatography. The crystalline materials of the two stereoisomers were first characterized.

[0010] For the crystalline form of the compound of formula (Ia), the following reflections [peak maximum in °2θ] were measured using CuKα radiation (X-ray powder diffraction) at 25°C (Table 1).

[0011] For the crystalline form of the compound of formula (Ib), the following reflections [peak maximum in °2θ] were measured using CuKα radiation (X-ray powder diffraction) at 25°C (Table 1).

[0012] Table 1

[0013]

[0014]

[0015]

[0016] The crystalline form of the compound of formula (Ia) is characterized in that the X-ray powder diffraction pattern using CuKα radiation at 25°C has at least the following reflections: 16,9; 4,6 and 20,9, preferably at least the following reflections: 16,9; 4,6; 20,9; 17,6 and 16,5, more preferably at least the following reflections: 16,9; 4,6; 20,9; 17,6; 16,5; 28,0 and 14,5, most preferably at least the following reflections: 16,9; 4,6; 20,9; 17,6; 16,5; 28,0; 14,5; 22,0; 23,6 and 19,6, each quoted as a 2θ value ±0.2°.

[0017] The crystalline form of the compound of formula (Ib) is characterized in that the X-ray powder diffraction pattern using CuKα radiation at 25°C has at least the following reflections: 7,1; 11,1 and 23,7, preferably at least the following reflections: 7,1; 11,1; 23,7; 24,0 and 17,1, more preferably at least the following reflections: 7,1; 11,1; 23,7; 24,0; 17,1; 17,7 and 21,6, most preferably at least the following reflections: 7,1; 11,1; 23,7; 24,0; 17,1; 17,7; 21,6; 20,8; 24,6 and 19,3, each quoted as a 2θ value ±0.2°.

[0018] The crystalline form of the compound of formula (Ia) is particularly preferably characterized in that the X-ray powder diffraction pattern at 25° C. using CuKα radiation corresponds essentially to the diffraction pattern represented in FIG. 1 .

[0019] The crystalline form of the compound of formula (Ib) is particularly preferably characterized in that the X-ray powder diffraction pattern at 25° C. using CuKα radiation corresponds essentially to the diffraction pattern represented in FIG. 2 .

[0020] The crystalline form of the compound of formula (Ia) and the crystalline form of the compound of formula (Ib) are characterized by Raman spectra based on the corresponding spectra, which were recorded at 25° C. and with a laser wavelength of 1064 nm and 2 cm -1 The crystalline form of the invention exhibits at least 3, generally at least 5, in particular at least 7, and especially all of the spectral bands cited below as peak maxima (Table 2):

[0021] Table 2:

[0022]

[0023]

[0024]

[0025]

[0026] The crystalline form of the compound of formula (Ia) is characterized by the following spectral bands: 1002, 1611 and 1621, preferably at least the following spectral bands: 96, 1004, 1622, 1601 and 1578, more preferably at least the following spectral bands: 96, 1004, 1622, 1601, 1578, 1375 and 267, most preferably at least the following spectral bands: 96, 1004, 1622, 1601, 1578, 1375, 267 2952, 3015 and 3096.

[0027] The Raman spectrum is shown in Figure 3.

[0028] The crystalline form of the compound of formula (Ib) is characterized by the following spectral bands: 96, 1004 and 1622, preferably at least the following spectral bands: 1002, 1611, 1621, 1374 and 261, more preferably at least the following spectral bands: 1002, 1611, 1621, 1374, 261, 1296 and 1212, and most preferably at least the following spectral bands: 1002, 1611, 1621, 1374, 261, 1296, 1212, 2957, 1968 and 2941.

[0029] The Raman spectrum is shown in Figure 4.

[0030] Thermal microscopy of the compound of formula (Ia) revealed two metastable modifications, one with a melting point of 130°C and the other with a melting point of 152°C.

[0031] Stereoisomers often exhibit differences in biological activity. Two isolated crystalline stereoisomers: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib) exhibit, as already described, differences in herbicidal activity. (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) has superior herbicidal activity to that of (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib) (see Table 3-6).

[0032] Comparative testing of crystalline compounds of formula (I), (Ia) and (Ib) unexpectedly showed that the physical mixture consisting of (Ia) and (Ib), i.e., (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester, was more herbicidal than the physical mixture of (2R,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia). The herbicidal activity of (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) is superior to that of (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib). The physical mixture composed of (Ia) and (Ib), i.e., (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester (I), showed a synergistic effect (see Table 3-6).

[0033] The compounds (I), (Ia) and (Ib) of the present invention have excellent herbicidal activity against a broad spectrum of economically important harmful monocotyledonous and dicotyledonous plants.

[0034] In particular, some representative examples of the monocotyledonous and dicotyledonous weed flora which can be controlled by (I), (Ia) and (Ib) according to the present invention may be mentioned, without the species being limited thereto.

[0035] In this context, reference may be made to the growth stages according to the BBCH monograph “Growth stages of mono- and dicotyledonous plants”, 2nd edition, 2001, ed. Uwe Meier, Federal Biological Research Centre for Agriculture and Forestry (Biologische Bundesanstalt für Land und Forstwirtschaft).

[0036] Examples of monocotyledonous harmful plants on which (I), (Ia) and (Ib) of the present invention are effectively effective are selected from the following genera: Hordeum spp., Echinochloa spp., Poa spp., Bromus spp., Digitaria spp., Eriochloa spp., Setaria spp., Pennisetum spp., Eleusine spp., Eragrostis spp., Panicum spp., Lolium spp., Alopecurus spp., Apera spp., Brachiaria spp., Leptochloa spp. spp.), Avena spp., Cyperus spp., Axonopris spp., Sorghum spp., and Melinus spp.

[0037] Specific examples of the monocotyledonous harmful plant species on which (I), (Ia) and (Ib) of the present invention are effectively effective are selected from the following species: Hordeum murinum, Echinochloa crus-galli, Poa annua, Bromus rubens L., Bromus rigidus, Bromus secalinus L., Digitaria insularis, Digitaria sanguinalis, Eriochloa gracilis, Setaria faberi, Setaria viridis, Pennisetum glaucum, Eleusine indica, Eragrostispectinacea, Panicum miliaceum, Lolium sp.), Brachiaria platyphylla, Leptochloa fusca, Avena fatua, Cyperus compressus, Cyperus esculentes, Axonopris offinis, Sorghum halapense, Alopecurus myosuroides, Apera spica-venti, and Melinus repens.

[0038] Examples of dicotyledonous harmful plants against which the methods (I), (Ia) and (Ib) of the present invention are effective are selected from the following genera: Amaranthus spp., Polygonum spp., Medicago spp., Molluscous spp., Cyclospermum spp., Stellaria spp., Gnaphalium spp., Taraxacum spp., Oenothera spp., Amsinckia spp., Erodium spp., Erigeron spp., Senecio spp., Lamium spp., Kochia spp. spp.), Chenopodium spp., Lactuca spp., Malva spp., Ipomoea spp., Brassica spp., Sinapis spp., Urtica spp., Sida spp., Portulaca spp., Richardia spp., Ambrosia spp., Calandrinia spp., Sisymbrium spp., Sesbania spp., Capsella spp., Sonchus spp., Euphorbia spp., Helianthus spp., Coronopus spp.), Salsola spp., Abutilon spp., Vicia spp., Epilobium spp., Cardamine spp., Picris spp., Trifolium spp., Galinsoga spp., Epimedium spp., Marchantia spp., Solanum spp., Oxalis spp., Metricaria spp., Plantago spp., Tribulus spp.), Cenchrus spp., Bidens spp., Veronica spp., and Hypochaeris spp.

[0039] Specific examples of dicotyledonous harmful plant species on which (I), (Ia) and (Ib) of the present invention are effectively effective are selected from the following species: Amaranthus spinosus, Amaranthus palmer, Amaranthus rudis, Polygonum convolvulus, Medicago polymorpha, Mollugo verticillata, Cyclospermum leptophyllum, Stellaria media, Gnaphalium purpureum, Taraxacum officinale, Oenothera laciniata, Amsinckia intermedia, Erodium cicutarium, Erodium moschatum, Erigeron bonariensis), European groundsel (Senecio vulgaris), wild sesame (Lamium sp.), Canada fleabane (Erigeroncanadensis), Polygonum aviculare, Kochia scoparia, Chenopodium album, Lactuca serriola, Malva parviflora, Malvaneglecta, Ipomoea hederacea, Ipomoea lacunose, Black mustard (Brassica nigra), Sinapis arvensis, Urtica dioica, Amaranthus blitoides, Amaranthus retroflexus, Amaranthus hybridus, Amaranthus lividus, Sida spinosa, Portulaca oleracea, and Richardia scabra), Ambrosia artemisiifolia, Calandrinia caulescens, Sisymbrium irio, Sesbania exaltata, Capsella bursa-pastoris, Sonchus oleraceus, Euphorbia maculate, Helianthus annuus, Coronopus didymus, Salsolatragus, Abutilon theophrasti, Vicia benghalensis L., Epilobium paniculatum, Cardamine spp., Picris echioides, Trifolium spp., Galinsoga spp., Epimedium spp., Marchantia spp.), Solanum spp., Oxalis spp., Matricaria chamomilla, Plantago spp.), Tribulus terrestris, Salsola kali, Cenchrus spp., Bidens bipinnata, Veronica sp., Galium aparine L., Papaver rhoeas, Viola arvense, Centaurea cyanus, and Hypochaeris radicata.

[0040] (I), (Ia) and (Ib) used in the present invention are applied once, twice or thrice according to the Gregorian calendar year, that is, once, twice or thrice per year according to the Gregorian calendar.

[0041] In a preferred embodiment, the present invention relates to the use of crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) in two isomeric forms: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylate of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (Ib) for controlling harmful plants in agriculture and for combating unwanted vegetation in crops of beneficial plants.

[0042] In another preferred embodiment, the present invention relates to the use of crystalline forms of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) in two isomeric forms: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylate of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (Ib) for combating unwanted vegetation in crops of beneficial plants.

[0043] In another preferred embodiment, the present invention relates to a plant protection agent comprising a crystalline form of methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) in two isomeric forms: (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylate of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (Ib), the plant protection agent further comprising one or more agriculturally acceptable additives commonly used for formulating plant protection agents.

[0044] The compounds of formula (I), (Ia) and (Ib) of the present invention can be formulated in various ways, depending on the prevailing biological and / or chemico-physical parameters. The following are generally possible examples of formulations.

[0045] Wettable powders (WP), water-soluble powders (SP), water-soluble concentrates, sprayable solutions, suspension concentrates (SC), oil-based or water-based dispersions, oil-miscible solutions, capsule suspensions (CS), dusting products (DP), seed dressing products, granules for broadcasting and soil application, granules in microgranular form (GR), spray granules, coated granules and adsorbent granules, water-dispersible granules (WG), water-soluble granules (SG), ULV preparations, microcapsules and waxes.

[0046] Preference is given to solid formulations (wherein the active ingredient is present in solid form), for example, granules, encapsulated granules, tablets, water-dispersible granules, water-dispersible tablets, water-dispersible powders or water-dispersible powders for treating seed, dusts, formulations where the active ingredient is present in dispersed form, for example: suspension concentrates (SC), oil-based suspension concentrates, suspoemulsions or suspension concentrates for treating seed.

[0047] These individual formulation types are known in principle and are described, for example, in: Winnacker-Küchler, "Chemische Technologie" [Chemical Technology], Volume 7, C. Hanser Verlag Munich, 4th edition, 1986; Wade van Valkenburg, "Pesticide Formulations", Marcel Dekker, NY, 1973; K. Martens, "Spray Drying" Handbook, 3rd edition, 1979, G. Goodwin Ltd. London.

[0048] The required formulation auxiliaries, such as inert materials, surfactants, solvents and further additives are likewise known and are described, for example, in: Watkins, "Handbook of Insecticide Dust Diluents and Carriers", 2nd edition, Darland Books, Caldwell NJ; HvOlphen, "Introduction to Clay Colloid Chemistry", 2nd edition, J. Wiley & Sons, NY; C. Marsden, "Solvents Guide", 2nd edition, Interscience, NY 1963; McCutcheon's "Detergents and Emulsifiers Annual", MCPubl.Corp., Ridgewood NJ; Sisley and Wood, "Encyclopedia of Surface Active Agents", Chem.Publ.Co.Inc., NY 1964; [Interface-active Ethylene Oxide Adducts], Wiss. Verlagsgesellschaft, Stuttgart 1976; Winnacker-Küchler, "ChemischeTechnologie" [Chemical Technology], volume 7, C. Hanser Verlag Munich, 4th edition, 1986.

[0049] Wettable powders are formulations that can be uniformly dispersed in water and contain, in addition to the active ingredient and a diluent or inert substance, ionic and / or nonionic surfactants (wetting agents, dispersants), such as polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates, alkanesulfonates, alkylbenzenesulfonates, sodium ligninsulfonate, sodium 2,2'-dinaphthomethane-6,6'-disulfonate, sodium dibutylnaphthalenesulfonate, or sodium oleoylmethyltaurate. To prepare wettable powders, the herbicidal active ingredient is finely ground, for example, in conventional equipment such as hammer mills, blower mills, and jet mills, and simultaneously or subsequently mixed with formulation adjuvants.

[0050] Dusts are prepared by grinding the active compound with finely divided solid substances, for example talc, natural clays such as kaolin, bentonite and pyrophyllite, or diatomaceous earth.

[0051] Suspension concentrates may be water-based or oil-based. They may be prepared, for example, by wet grinding using a commercially available ball mill, optionally with the addition of surfactants as described above, for example, in the other formulations.

[0052] Granules can be prepared by spraying the active ingredient onto an adsorbable granular inert material, or by applying an active compound concentrate to the surface of a carrier, such as sand, kaolin, or a granular inert material, using a binder such as polyvinyl alcohol, sodium polyacrylate, or mineral oil. Suitable active ingredients can also be granulated in the conventional manner for preparing fertilizer granules—if desired, as a mixture with a fertilizer.

[0053] Water-dispersible granules can be prepared by conventional methods such as spray drying, fluidized bed granulation, pan granulation, mixing using a high-speed mixer, and extrusion without using a solid inert substance.

[0054] For the preparation of disk granules, fluidized bed granules, extruded granules and spray granules, see, for example, "Spray-Drying Handbook", 3rd edition, 1979, G. Goodwin Ltd., London; J. E. Browning, "Agglomeration", Chemical and Engineering 1967, p. 147; "Perry's Chemical Engineer's Handbook", 5th edition, McGraw-Hill, New York 1973, pp. 8-57.

[0055] For more details on the formulation of crop protection compositions, see, for example, "Weed Control as a Science", John Wiley and Sons, Inc., New York, 1961, pp. 81-96 and JD Freyer, SA Evans, "Weed Control Handbook", 5th edition.

[0056] Therefore, the present invention also provides a method for controlling harmful plants and / or regulating plant growth, characterized in that an effective amount of

[0057] - a crystalline form of a compound of formula (I), (Ia), (Ib) or any mixture thereof,

[0058] or

[0059] - an agrochemical formulation according to the invention as defined above,

[0060] Apply to plants, plant seeds, soil where plants are growing, or areas where they are grown. Example

[0061] 1. Preparation

[0062]

[0063] Preparation of compounds of formula (I), (Ia), (Ib)

[0064] Step 1 :(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl chloride

[0065] To a suspension of 2.70 g (10.6 mmol) of (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid in 45 mL of dichloromethane was added three drops of dimethylformamide (DMF). 2.03 g (15.9 mmol) of oxalyl chloride was then added dropwise. Gas evolution was observed. The mixture was stirred at room temperature for 6 hours, and then the volatile components were removed under vacuum. The crude product was used in the next step without further purification.

[0066] Step 2 :(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylic acid methyl ester (compound of formula (I))

[0067] To 262 mg (1.44 mmol) of methyl-cis-4-aminotetrahydrofuran-2-carboxylic acid hydrochloride suspended in 5 ml of dichloromethane was added 292 mg (2.88 mmol) of triethylamine. To the reaction mixture was added a solution of 250 mg (0.96 mmol) (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl chloride dissolved in 6 mL of dichloromethane at 0°C. After warming to room temperature, the reaction mixture was stirred for 6 hours. Water was added for post-treatment, the organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by chromatography using silica gel as the stationary phase and then the solvent was evaporated. n-heptane was added to the residue and the resulting crystals were filtered out. Yield 75 mg (21%).

[0068] 1 H-NMR (400.0 MHz, CDCl3):

[0069] δ=7.262(28.6);7.180(2.2);7.174(2.6);7.171(1.5);7.163(1.5);7.160(2.6);7.154(2.1);6.903(0.8);6.887(0.9);6.882(1.6);6.876(0.8);6.860(0.8);6.176(2.0);6.150(2.3);6.133(2.4);6.106(2.5);5.560(1.8);5.558(1.8);5.544(1.7);5.543(1.7);5.517(1.5);5 .515(1.5);5.501(1.5);5.500(1.4);5.357(1.6);5.356(1.6);5.343(1.5);5.342(1.5);5.330(1.5);5.329(1.5);5.316(1.4);5.315(1.4);5.299(9.2);4.603(0.5);4.596(0.6);4.591(0.6);4.585(0.6);4.579(0.6);4.574(1.1);4.565(1.2);4.558(1.1);4.550(1.4);4.542 (0.9);4.534(0.9);4.525(0.8);4.056(0.8);4.043(0.9);4.041(0.9);4.033(1.3);4.028(0.8);4.020(1.3);4.017(1.4);4.004(1.1);3.950(0.7);3.946(0.7);3.944(0.7);3.929(1.1);3.922(2.7);3.905(0.5);3.899(2.3);3.878(2.2);3.856(2.2);3.814(15.9);3.800(16 .0);3.322(1.9);3.313(1.9);3.279(1.6);3.270(1.7);2.566(0.5);2.564(0.5);2.555(0.6);2.549(0.5);2.546(0.5);2.540(0.6);2.538(0.6);2.531(0.6);2.529(0.6);2.514(0.5);2.511(0.6);2.094(0.6);2.060(0.5);2.052(0.5);2.044(0.6);1.577(5.9);0.000(11.4)

[0070] The preparation of methyl-cis-4-aminotetrahydrofuran-2-carboxylic acid hydrochloride is known from GROtt et al.; Bioorg. Med. Chem. Lett. 2008, 694-699.

[0071] The product (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester (I) was separated into (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib) using standard chromatography. After evaporation of the solvent, the carboxylic acid methyl esters of compounds of formula (Ia) and (Ib) were collected as crystalline materials.

[0072] NMR data of compound of formula (Ia)

[0073] 1 H-NMR (400.6 MHz, CDCl3):

[0074] δ=7.494(0.6); 7.474(0.6); 7.278(0.9); 7.184(1.5); 7.178(2.0); 7.176(1.4); 7.167(1.3); 7. 164(2.0);7.159(1.7);6.906(0.6);6.890(0.7);6.884(1.3);6.879(0.7);6.863(0.6);6.180( 1.1); 6.153(1.2); 6.137(1.4); 6.110(1.4); 5.560(2.2); 5.559(2.2); 5.516(1.9); 5.516(1.9); 5.358(2.1); 5.331(2.0); 4.622(0.5); 4.615(0.6); 4.611(0.6); 4.608(0.6); 4.602(0.6); 4.59 7(0.6); 4.562(1.0); 4.553(1.2); 4.539(1.2); 4.530(1.1); 4.060(0.9); 4.047(1.0); 4.036(1.5); 4.023(1.4); 3.955(1.1); 3.951(1.2); 3.928(2.9); 3.885(2.5); 3.801(16.0); 3.322(2.3); .279(2.0); 2.569(0.5); 2.551(0.6); 2.546(0.6); 2.534(0.7); 2.528(0.6); 2.517(0.7); 2.511(0.7); 2.493(0.6); 2.056(0.5); 2.050(0.8); 2.043(0.6); 2.015(0.8); 2.009(0.5); 0.000(0.8)

[0075] NMR data of compound of formula (Ib)

[0076] 1 H-NMR (400.6 MHz, CDCl3):

[0077] δ=7.461(0.7); 7.442(0.7); 7.278(0.9); 7.184(1.6); 7.178(2.0); 7.164(2.1); 7.159( 1.6);6.907(0.6);6.891(0.8);6.885(1.3);6.880(0.7);6.864(0.7);6.179(1.1);6.15 2(1.3); 6.136(1.4); 6.109(1.4); 5.543(2.3); 5.500(2.0); 5.344(2.2); 5.317(2.1); 4.593(0.6); 4.587(0.7); 4.579(1.6); 4.570(1.8); 4.563(0.6); 4.555(1.5); 4.546(1.2) ;4.043(1.0);4.030(1.0);4.019(1.6);4.006(1.4);3.935(1.2);3.930(1.2);3.905(3.0);3.862(2.6);3.814(16.0);3.331(2.4);3.288(2.1);2.596(0.5);2.579(0.6);2.57 3(0.6); 2.562(0.7); 2.555(0.6); 2.544(0.7); 2.538(0.7); 2.521(0.6); 2.107(0.6); 2.101(0.9); 2.095(0.6); 2.073(0.5); 2.067(0.8); 2.060(0.5); 1.257(0.5); 0.000(0.8)

[0078] The ratio of (Ia) to (Ib) in (I) varies between 1.5 and 0.5 and between 0.5 and 1.5.

[0079] The difference between the (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester disclosed in WO 2018 / 228985 and the (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylic acid methyl ester (I) of the present invention is the crystallinity. This is the first publication in which n-heptane was used for the crude product (see step 2 of its preparation). The separated stereoisomers were also published as crystalline products for the first time.

[0080] 2. NMR Peak List Program

[0081] Selected embodiments 1 H-NMR data were 1Write the H-NMR peak list. For each peak, list the delta value in ppm and the signal intensity in parentheses. Separate delta value–signal intensity pairs with a semicolon.

[0082] Therefore, the peak list of the embodiment has the following form:

[0083] δ1(intensity 1); δ1(intensity 2); ...; δ1(intensity i );……;δ n (strength n )

[0084] The intensity of the spike signal is related to 1 The signal heights in cm in the printed view of the H-NMR spectrum are correlated and show the true relationship of the signal intensities. In the case of broad signals, several peak values ​​or medians of the signal can be shown, along with their relative intensities compared to the strongest signal in the spectrum.

[0085] 1 The chemical shift of the H spectrum is calibrated using the chemical shift of tetramethylsilane or the solvent (if the sample does not contain tetramethylsilane). Therefore, the tetramethylsilane peak can appear at 1 H-NMR peak list is included, but not required.

[0086] 1 H-NMR peak list is equivalent to the classical 1 H-NMR diagrams, and are usually included in the classic 1 All peaks listed in H-NMR interpretation.

[0087] Furthermore, they may show signals of solvents, signals of stereoisomers of the compounds which are optional objects of the present invention, and / or peaks of impurities, such as the classical 1 H-NMR printout.

[0088] Exclude the corresponding solvent from the relative intensity calibration 1 H-NMR solvent signal, tetramethylsilane signal, and water signal because they have very high intensity values.

[0089] On average, the peaks of the stereoisomers and / or impurity peaks of the compounds of the invention are generally less intense than the peaks of the compounds of the invention (eg, purity >90%).

[0090] Such stereoisomers and / or impurities may be typical for a particular preparation process. The corresponding peaks may therefore help to identify the reproducibility of the preparation process by means of a "by-product fingerprint".

[0091] Experts who calculate the peaks of target compounds using known methods (MestreC, ACD simulation, and empirically estimated expectation values) can optionally use additional intensity filters to separate the peaks of target compounds. This separation is similar to that in classical 1 Peak picking in H-NMR interpretation is similar.

[0092] The solvent used can be extracted from the JCAMP file with the parameter "Solvent", the spectrometer frequency as "Observation frequency" and the spectrometer type as "Spectrometer / Data System".

[0093] 13 C-NMR data and 1 H-NMR data are similar and appear to be derived from broadband decoupling. 13 Peak list for C-NMR spectra. Excluded from relative intensity calibration 13 C-NMR solvent signals and tetramethylsilane, as these signals can have very high intensities.

[0094] Further details of NMR data documentation with peak lists are disclosed in the publication "Citation of NMR Peaklist Data within Patent Applications" in Research Disclosure Database Number 564025.

[0095] 3. Characterization of Crystalline Form

[0096] method

[0097] Unless otherwise stated, all data forming part of this application were prepared according to the methods described below. The samples used for the measurements were used directly without any further sample preparation.

[0098] XRPD

[0099] XRD-diffractometers X`Pert PRO (PANalytical) and STOE STADI-P (radiation Cu Kα1, wavelength ) X-ray diffraction patterns were recorded at room temperature. All X-ray reflections are quoted as °2θ (theta) values ​​(peak maximum) with a resolution of ±0.2°.

[0100] Raman

[0101] Raman spectra were recorded at room temperature using a FT-Raman spectrophotometer from Bruker (models RFS 100 and MultiRam) with a resolution of 2 cm -1 . The measurements were performed in glass vials or aluminum pans.

[0102] Thermal microscopy

[0103] Axio Scope.A1 and Axioskop 40 (Zeiss) Magnification: 100x Light: polarized and normal transmitted light.

[0104] 4. Biological testing

[0105] Post-emergence treatment methods

[0106] Seeds of grasses and broadleaf weeds were sown in pots (diameter: 7 cm) filled with sandy loam soil. After germination, the plants were grown under optimal conditions until the growth stage of BBCH11 to 14, depending on the species.

[0107] Applications were made on planted pots via post-emergence treatment using a spray volume of 300 L of water per hectare. The herbicides were applied individually and in combination as described.

[0108] The experiments were carried out in a greenhouse ensuring optimal growing conditions.

[0109] 21 days after application, the herbicidal effect is assessed by visual rating comparing treated and untreated plants (0% = no effect to 100% = complete death).

[0110] The compounds of formula (Ia), (Ib) and (I) are formulated into WP (wettable powder) formulations.

[0111] The following abbreviations are used:

[0112] BBCH = The BBCH code provides information on the morphological developmental stages of a plant. Officially, the abbreviation stands for Biologische Bundesanstalt, Bundessortenamt und Chemische Industrie [Federal Institute for Agricultural and Forest Biology, Federal Office of Crop Plant Varieties and Chemical Industries]. The BBCH range of 00-10 indicates the germination stage from seed to surface penetration. The BBCH range of 11-25 indicates the leaf development stage until stocking (corresponding to the number of tillers or lateral branches).

[0113] The following biotypes of broadleaf weeds and grass weeds were used in the trials:

[0114] ALOMY-Sensitive (Alopecurus australis) is sensitive to conventional herbicidal active compounds.

[0115] ALOMY_R(resistant) (Alopecurus australis) resistant to herbicidally active compounds of HRAC groups A and B; a mixture of field-derived populations with increased metabolic resistance (IMR) and some target site resistance (TSR).

[0116] LOLRI-sensitive (Ryegrass rigidus) is sensitive to conventional herbicidally active compounds.

[0117] LOLRI_R(resistant) (Ryegrass) resistant to herbicidally active compounds of HRAC groups A and B; a mixture of field-derived populations with increased metabolic resistance (IMR) and some target site resistance (TSR).

[0118] AMAPA_R(resistant) (Palm Amaranth) resistant to herbicidally active compounds of HRAC groups A and B; a mixture of field-derived populations with increased metabolic resistance (IMR) and some target site resistance (TSR).

[0119] CHRVI (chloris virgate) Sansevieria

[0120] KCHSC (kochia scoparia)

[0121] MATIN (matricaria inodora) Chamomile

[0122] POLCO (polygonum convolvulus)

[0123] ABUTH(abutilon theophrasti)fennel

[0124] AMAPA (amaranthus palmeri)

[0125] BIDPI (bidens pilosa)

[0126] CHEAL (Chenopodium album)

[0127] EPHHL (euphorbia heterophylla) Orangutan Grass

[0128] XANST (xanthium strumarium) cocklebur

[0129] EMEAU (Emex australis) - Southern three-thorn fruit

[0130] GALAP (Gallium aparine) – Gallium spp.

[0131] The synergistic herbicidal activity was calculated using Colby's formula (see SR Colby; Weeds 15 (1967), 20-22):

[0132] According to Colby, if the measured efficacy is higher than the expected efficacy of a two-way mixture calculated according to his formula, it indicates the presence of a synergistic effect of the herbicidal active ingredients.

[0133] E C =A+B-(AxB) / 100

[0134] The results are shown in Tables 3 to 6 below:

[0135] Table 3

[0136]

[0137] Table 4:

[0138]

[0139] Table 5:

[0140]

[0141] Table 6:

[0142]

Claims

1. (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (I) containing (2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ia) and (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (Ib), characterized in that To (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (I) was added n-heptane and filtered to obtain the resulting crystals, wherein the ratio of (Ia) to (Ib) varied from 1.5 to 0.

5.

2. A plant protection agent comprising methyl (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylate of formula (I) according to claim 1 in crystalline form.

3. The plant protection agent according to claim 2, further comprising one or more agriculturally acceptable additives commonly used in formulating plant protection agents.

4. Use of (2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylic acid methyl ester of formula (I) in crystalline form according to claim 1 or a plant protection agent according to claim 2 or 3 for combating unwanted plant growth.

5. The use according to claim 4, wherein the unwanted plants are grown in crops of useful plants.

6. A method for combating unwanted plant growth, wherein (2R*,4R*)-methyl 4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylate of formula (I) according to claim 1 in crystalline form or a plant protection agent according to claim 2 or 3 is applied to the site of plants or unwanted vegetation.

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