CRYSTAL FORMS OF METHYL(2R*,4R*)-4-[[(5S)-3-(3,5-DIFLUOROPHENYL)-5-VINYL-4H-ISOXAZOLE-5-CARBONYL]AMINO]TETRAHYDROFURAN-2-CARBOXYLATE AND THEIR HERBICIDAL SYNERGISTIC EFFECTS

Abstract

The present invention relates to the crystal forms of methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) existing in the form of two stereoisomers: 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-difluoro-phenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (Ib), to a method for preparing the crystal forms, to the use for preparing stable agrochemical formulations, and to the use in the field of agriculture for controlling harmful plants.

Claims

1. A 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) in respective crystallized form, wherein the X-ray powder diffractogram using Cu Kα radiation at 25° C. has at least 3 of the following 2θ (2 theta) values: TABLE-US-00007 Reflections (Peak maxima) Reflections (Peak maxima) [°2 Theta] Compound [°2 Theta] Compound of formula (Ia) of formula (Ib) 16.9 7.1 4.6 11.1 20.9 23.7 17.6 24.0 16.5 17.1 28.0 17.7 14.5 21.6 22.0 20.8 23.6 24.6 19.6 19.3

2. The methyl(2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl) 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) according to claim 1, wherein the X-ray powder diffractogram using Cu Kα radiation at 25° C. has at least 4, optionally at least 6, optionally all of the 2θ (2 theta) values.

3. The 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) in respective crystallized form according to claim 1 in which the ratio between (Ia) and (Ib) varies between 1.5 to 0.5 and 0.5 to 1.5.

4. 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 (Ia) and methyl(2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylate of formula (Ib) in respective crystallized form according to claim 1.

5. The plant protection agent according to claim 4, which further comprises one or more agriculturally acceptable additives customary for formulation of one or more plant protection agents.

6. A product comprising 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) vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran-2-carboxylate of formula (Ib) in respective crystallized form according to claim 1 or a plant protection agent comprising said methyl(2R,4R)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]-tetrahydrofuran 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) in respective crystallized form for combatting undesired plant growth.

7. The product according to claim 6, wherein the unwanted plant growth is in one or more crops of one or more useful plants.

8. The product according to claim 7, wherein the useful plants are transgenic plants.

9. A method for combating undesired plant growth, comprising applying 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) in respective crystallized form according to claim 1 or a plant protection agent comprising said 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) in respective crystallized form to one or more plants or a site of unwanted vegetation.

Description

EXAMPLES

1. Preparation

[0051] ##STR00002##

Preparation of Compound of Formula (I), (Ia) and (Ib)

Step 1: (5S)-3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazol-5-carbonylchloride

[0052] To 2.70 g (10.6 mmol) (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazol-5-carboxylic acid suspended in 45 mL dichloromethane three drops of dimethylformamide (DMF) were added. Then 2.03 g (15.9 mmol) oxalylchloride were added dropwise. Evolution of gas was observed. The mixture was stirred for 6 h at room temperature and afterwards volatile components were removed under vacuum. The crude product was used in the next step without further purification.

Step 2: Methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2-carboxylate (compound of formula (I))

[0053] To 262 mg (1.44 mmol) methyl-cis-4-aminotetrahydrofuran-2-carboxylicacid hydrochloride suspended in 5 ml dichloromethane were added 292 mg (2.88 mmol) triethylamine. To this reaction mixture a solution of 250 mg (0.96 mmol) (5S)-3-(3,5-difluorphenyl)-5-vinyl-4H-isoxazol-5-carbonylchloride dis-solved in 6 ml dichloromethane was added at 0° C. After warming up to room temperature the reaction mixture was stirred for 6 h. For workup water was added, the organic layer was separated, dried with Na.sub.2SO.sub.4 filtered and evaporated under vacuum. The crude product was purified by chromatography using silicagel as stationary phase followed by evaporation of the solvent. N-heptane was added to the residue and the resulting crystals were filtered off. Yield 75 mg (21%).

[0054] .sup.1H-NMR (400.0 MHz, CDCl.sub.3):

[0055] 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); 50.544 (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)

[0056] The preparation of methyl-cis-4-aminotetrahydrofuran-2-carboxylicacid hydrochloride is known from G. R. Ott et al.; Bioorg. Med. Chem. Lett. 2008, 694-699.

[0057] The product methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate) (I) was separated into 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) applying standard chromatography. After evaporating the solvent compound of formula (Ia) and (Ib) are received as crystalline material.

[0058] NMR Data of Compound of Formula (Ia)

[0059] .sup.1H-NMR (400.6 MHz, CDCl.sub.3):

[0060] 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); 4.597 (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); 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)

[0061] NMR Data of Compound of Formula (Ib)

[0062] .sup.1H-NMR (400.6 MHz, CDCl.sub.3):

[0063] 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); 6.152 (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); 2.573 (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)

[0064] The ratio between (Ia) and (Ib) in (I) varies between 1.5 to 0.5 and 0.5 to 1.5.

[0065] The difference between Methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate published in WO2018/228985 and Methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) according to the present invention is its crystallinity which is published for the first time when applying N-heptane to the crude product (see step 2 of its preparation). The separated stereoisomers are also published as crystalline product for the first time.

2. NMR Peak Lists Procedure

[0066] .sup.1H-NMR data of selected examples are written in form of .sup.1H-NMR peak lists. δ-Values in ppm and the signal intensity in round brackets are listed to each signal peak. Semicolons are depicted as delimiters between the δ-value—signal intensity pairs.

[0067] Therefore the Peak List of an Example has the Form:

[0068] δ.sub.1 (intensity.sub.1); δ.sub.2 (intensity.sub.2); . . . ; δ.sub.i (intensity.sub.i); . . . ; δ.sub.n (intensity.sub.n)

[0069] The intensity of sharp signals correlates with the height of the signals in a printed view of a .sup.1H-NMR spectrum in cm and shows the real relations of signal intensities. Several peaks from broad signals or the middle of the signal and their relative intensity in comparison to the most intensive signal in the spectrum can be shown.

[0070] Tetramethylsilane or the chemical shift of the solvent in cases where the sample does not contain tetramethylsilane is used for a calibration of the chemical shift for .sup.1H spectra. Therefore the tetramethylsilane peak can occur in .sup.1H-NMR peak lists, but not necessarily.

[0071] .sup.1H-NMR peak lists are equivalent to classical .sup.1H-NMR prints and contain usually all peaks, which are also listed at classical .sup.1H-NMR-interpretations.

[0072] In addition, they can show signals of solvents, stereoisomers of the compounds which are optionally object of the invention, and/or peaks of impurities, like classical .sup.1H-NMR prints.

[0073] .sup.1H-NMR solvent signals, the tetramethylsilane signal and the water signal in the corresponding solvent are excluded from the relative intensity calibration as they have very high intensity values.

[0074] On average, the peaks of stereoisomers of the compounds according to the invention and/or peaks of impurities have usually a lower intensity than the peaks of compounds according to the invention (for example with a purity >90%).

[0075] Such stereoisomers and/or impurities can be typical for the specific preparation process. Thus, the corresponding peaks can help to recognize the reproduction of the preparation process via “side-products-fingerprints”.

[0076] An expert, who calculates the peaks of the target compounds with known methods (MestreC, ACD-simulation, but also with empirically evaluated expectation values), can assign the peaks of the target compounds as needed, optionally using additional intensity filters. This assignment would be similar to the usual peak picking at classical .sup.1H-NMR interpretations.

[0077] The used solvent can be extracted from the JCAMP file with the parameter “solvent”, the spectrometer frequency with “observe frequency” and the spectrometer type with “spectrometer/data system”.

[0078] .sup.13C-NMR data are displayed analogous to .sup.1H-NMR data as peak lists from broadband decoupled .sup.13C-NMR spectra. .sup.13C-NMR solvent signals and tetramethylsilane are excluded from the relative intensity calibration as these signals can have very high intensities.

[0079] Further details of NMR-data description with peak lists are disclosed in the publication “Citation of NMR Peaklist Data within patent applications” of the Research Disclosure Database Number 564025.

3. Characterization of Crystal Forms

[0080] Methods [0081] All data which is part of the present application has been prepared according to the methods described below unless otherwise indicated. The samples used for measurement were directly used and did not undergo any further sample preparation.

[0082] XRPD [0083] X-Ray diffraction patterns were recorded at room temperature using XRD-diffractometers X'Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 Å). All X-Ray reflections are quoted as °2θ (theta) values (peak maxima) with a resolution of ±0.2°.

[0084] Raman [0085] Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS 100 and MultiRam) from Bruker. Resolution was 2 cm.sup.−1. Measurements were performed in glass vials or aluminium discs.

[0086] Thermomicroscopy [0087] Axio Scope.A1 and Axioskop 40 (Zeiss) Enlargement: 100× Light: Polarized and normal transmitted light

4. Biological Testing

[0088] Methodology of Post-Emergence Treatments [0089] Seeds of grass and broadleaf weeds were sown in pots (diameter: 7 cm) filled with a sandy loam soil. Following germination the plants were grown under optimal conditions up to a growth stage of BBCH 11 to 14 depending on species. [0090] The applications were performed by post emergence treatments on the planted pots using a spray volume of 300 L water per hectare. The herbicides were applied alone and in combination as described. [0091] The trial was conducted in the greenhouse ensuring optimal growing conditions. [0092] The herbicidal effects were assessed 21 days following application by visual ratings comparing treated and untreated plants (0%=no effect to 100%=complete die-off). [0093] The compounds of the formula (Ia), (Ib) and (I) were formulated as WP (wettable powder) formulation.

[0094] The Following Abbreviations were Used: [0095] BBCH=the BBCH code provides information about the morphological development stage of a plant. Officially, the abbreviation denotes the Biologische Bundesanstalt, Bundessortenamt and Chemische Industrie [Federal Biological Institute for Agriculture and Forestry, Federal Office for Crop Plant Varieties and Chemical Industry]. The range of BBCH 00-10 denotes the germination stages of the seeds until surface penetration. The range of BBCH 11-25 denotes the leaf development stages until stocking (corresponding to the number of tillers or side-shoots).

[0096] In the Trials, the Following Biotypes of Broad-Leaved Weeds and Weed Grasses were Used: [0097] ALOMY—sensitive (Alopecurus myosuroides) sensitive to customary herbicidally active compounds. [0098] ALOMY_R (resistant) (Alopecurus myosuroides) resistant to herbicidally active compounds of the HRAC groups A and B; population mixture of field origin having increased metabolic resistance (IMR) and some target site resistance (TSR). [0099] LOLRI—sensitive (Lolium rigidum) sensitive to customary herbicidally active compounds. [0100] LOLRI_R (resistant) (Lolium rigidum) resistant to herbicidally active compounds of the HRAC groups A and B; population mixture of field origin having increased metabolic resistance (IMR) and some target site resistance (TSR). [0101] AMAPA_R (resistant) (Amaranthus palmeri) resistant to herbicidally active compounds of the HRAC groups A and B; population mixture of field origin having increased metabolic resistance (IMR) and some target site resistance (TSR). [0102] CHRVI (Chloris virgate) feather finger grass [0103] KCHSC (Kochia scoparia) Mexican burning bush [0104] MATIN (Matricaria inodora) false chamomile [0105] POLCO (Polygonum convolvulus) black knotweed [0106] ABUTH (Abutilon theophrasti) china jute [0107] AMAPA (Amaranthus palmeri) palmer amaranth [0108] BIDPI (Bidens pilosa) common blackjack [0109] CHEAL (Chenopodium album) common lambsquarters [0110] EPHHL (Euphorbia heterophylla) wild spurge [0111] XANST (Xanthium strumarium) large cocklebur [0112] EMEAU (Emex australis) —Cathead [0113] GALAP (Gallium aparine) —Cleaver

[0114] The synergistic herbicidal activity was calculated using Colby's formula (cf. S. R. Colby; Weeds 15 (1967), 20-22):

[0115] According to Colby synergistic effects of herbicidal active ingredients are indicated if the measured efficacy is higher than the expected one calculated according to his formula for 2-way mixtures

E.sup.C=A+B−(A×B)/100

[0116] The Results are Shown in Tables 3 to 6 Below:

TABLE-US-00003 TABLE 3 g/ha g/ha CHRVI EMEAU Compound (Ia) (Ib) Observed Expected Synergism Observed Expected Synergism (Ia) 50  0 80 25  0 12, 5  0 35  6, 25  0 (Ib)  0 50 45  0 25  0 12, 5 20  0  6, 25 (I) 50 25 12,5 95 48 47 97 89 8  6,25 g/ha g/ha KCHSC LOLRI Compound (Ia) (Ib) Observed Expected Synergism Observed Expected Synergism (Ia) 50  0 25  0 12, 5  0 70 90  6, 25  0 20 (Ib)  0 50  0 25  0 12, 5 40 0  0  6, 25 0 50 25 12,5 95 82 13 95 90 5  6,25 75 20 55

TABLE-US-00004 TABLE 4 g/ha g/ha LOLRI_R GALAP Compound (Ia) (Ib) Observed Expected Synergism Observed Expected Synergism (Ia) 50  0 75 25  0 30 12, 5  0 20  6, 25  0 15 (Ib)  0 50 35  0 25 0  0 12, 5 0  0  6, 25 0 (I) 50 90 84 6 25 40 30 10 12, 5 40 20 20  6, 25 30 15 15 g/ha g/ha MATIN POLCO Compound (Ia) (Ib) Observed Expected Synergism Observed Expected Synergism (Ia) 50  0 0 25  0 0 12, 5  0 0 85  6, 25  0 (Ib)  0 50 0  0 25 0  0 12, 5 0 40  0  6, 25 50 20 0 20 25 15 0 15 12, 5 15 0 15 95 91 4  6, 25

TABLE-US-00005 TABLE 5 g/ha g/ha ABUTH AMAPA-R BID PI Compound (Ia) (Ib) Observed Expected synerg. Observed Expected synerg. Observed Expected synerg. (Ia) 100  0  50  0 60  25  0 45 35 30 (Ib)  0 100  0  50 20  0  25 10 25 10 (I) 100 100  50  50 75 68 7  25  25 75 51 25 65 51 14 65 37 28

TABLE-US-00006 TABLE 6 g/ha g/ha CHEAL EPHHL XANST Compound (Ia) (Ib) Observed Expected synerg. Observed Expected synerg. Observed Expected synerg. (Ia) 100  0 20  50  0 35 20  25  0 70 30 0 (Ib)  0 100 20  0  50 60 35 10  0  25 20 35 0 (I) 100 100 65 36 29  50  50 70 58 12 35 28 7  25  25 95 76 19 65 55 11 35 0 35