HERBICIDAL COMPOUNDS
20230312478 · 2023-10-05
Assignee
Inventors
Cpc classification
C07D403/04
CHEMISTRY; METALLURGY
C07D231/12
CHEMISTRY; METALLURGY
International classification
C07D231/12
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates novel di- and tri-substituted pyrazolo-lactam/thiolactam-carboxamide compounds, methods for their production, and intermediates for use in such methods. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions in controlling undesirable plant growth: in particular, the use in controlling weeds in crops of useful plants.
##STR00001##
Claims
1. A compound of formula (I) or an N-oxide or salt thereof ##STR00159## wherein; X is O or S; Y is H, methyl, or methoxy; R.sup.1 is 1-difluoromethyl-pyrazol-3-yl or 1-difluoromethyl-pyrazol-4-yl ring, substituted on one or both free ring carbon atom(s) by R.sup.2, each R.sup.2 is independently halogen, C.sub.1-C.sub.3fluoroalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3alkyl; R.sup.3 is a phenyl, pyridinyl, or thienyl ring system, optionally substituted by 1, 2, or 3 R.sup.4 substituents; and each R.sup.4 is independently halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, cyano, nitro, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, or C.sub.1-C.sub.6alkylsulfonyl.
2. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of R.sup.1-1, R.sup.1-2, R.sup.1-3, and R.sup.1-4, ##STR00160## ##STR00161## ##STR00162## and ##STR00163## and wherein each R.sup.2 is as defined in claim 1, n is an integer of 1 or 2, and the jagged line denotes the point of attachment to the rest of the molecule.
3. The compound according to claim 1, wherein Y is H or methyl.
4. The compound according to claim 1 wherein X is S.
5. The compound according to claim 1 wherein X is O.
6. The compound according to claim 1, wherein R.sup.3 is selected from the group consisting of R.sup.3-1, R.sup.3-2, R.sup.3-3, R.sup.3-4, R.sup.3-5, and R.sup.3- 6 ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## wherein p is an integer of 0, 1, 2, or 3, R.sup.4 is as defined in claim 1, and the jagged line represents the point of attachment to the rest of the molecule.
7. The compound according to claim 1 wherein each R.sup.4 is independently halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3haloalkoxy.
8. The compound according to claim 1, which is selected from the group of compounds shown in the table below: TABLE-US-00012 Cmpd. No. Name Structure 9 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(3-fluoro-2-methyl-phenyl)-1-methyl-2-oxo-pyrrolidine-3-carboxamide
9. An agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) as defined in claim 1 and an agrochemically-acceptable diluent or carrier.
10. The agrochemical composition according to claim 9, comprising at least one further pesticide.
11. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 1, to the unwanted plants or to the locus thereof.
12. Use of a compound of formula (I) as defined in claim 1, as a herbicide.
13. A process for the production of a compound of formula (I) as defined in claim 4, said process comprising: (i) reacting a compound of formula (A) with ethyl acrylate, under palladium catalysis to give a compound of formula (B) ##STR00188## wherein R2.sup.a halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1- C.sub.3alkyl; and, Hal is halogen; (ii) reacting the compound of formula (B) from step (i) with a compound of formula (C), wherein Y is methyl. in a cycloaddition reaction to yield a mixture of compounds of formula (D) and (E) ##STR00189## (iii) reacting the compound of formula (D) with a hydroxide base in a water/ether mixed solvent system to give the compound of formula (X) ##STR00190## wherein R .sup.2a, R.sup.2b, and Y are as defined in steps (i) and (ii) above; (iv) reacting the compound of formula (X) from step (iii) with an aniline of formula (G) using propanephosphonic acid anhydride in a suitable solvent, with a suitable base, ##STR00191## afford the compound of formula (I), wherein R .sup.3 is a phenyl, pyridinyl, or thienyl ring system, optionally substituted by 1, 2, or 3 R.sup.4 substituents, and each R.sup.4 is independently halogen, C.sub.1—C.sub.6alkyl, C.sub.1—C.sub.6haloalkyl, C.sub.1—C.sub.6alkoxy, C.sub.1—C.sub.6haloalkoxy, cyano, nitro, C.sub.1—C.sub.6alkylthio, C.sub.1—C.sub.6alkylsulfinyl, or C.sub.1—C.sub.6alkylsulfonyl.
14. A process for the production of a compound of formula (I) as defined in claim 5 and further comprising (v) oxidatively hydrolysing the compound of formula (I) from step (iv), with hydrogen peroxide solution and a suitable acid, to yield a compound of formula (I) as defined in claim 5.
15. A process for the production of a compound of formula (I) as defined in claim 5 and further comprising (iv) oxidatively hydrolysing the compound of formula (X) from step (iii), with hydrogen peroxide solution and a suitable acid, to yield a compound of formula ##STR00192## wherein R2.sup.a halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1— C.sub.3alkyl; and Y is methyl; (v) reacting the compound of formula (J) from step (iv) with an aniline of formula (G) using propanephosphonic acid anhydride in a suitable solvent, with a suitable base, ##STR00193## to afford the compound of formula (I), wherein R .sup.3 is a phenyl, pyridinyl, or thienyl ring system, optionally substituted by 1, 2, or 3 R.sup.4 substituents, and each R.sup.4 is independently halogen, C.sub.1—C.sub.6alkyl, C.sub.1—C.sub.6haloalkyl, C.sub.1—C.sub.6alkoxy, C.sub.1—C.sub.6haloalkoxy, cyano, nitro, C.sub.1—C.sub.6alkylthio, C.sub.1—C.sub.6alkylsulfinyl, or C.sub.1—C.sub.6alkylsulfonyl.
16. A compound of formula (A) ##STR00194## wherein R is methyl or ethyl.
17. A compound of formula (B) ##STR00195## wherein, R2.sup.a halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1— C.sub.3alkyl; and Y is methyl.
18. A compound of formula (D) ##STR00196## wherein, R2.sup.a halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1— C.sub.3alkyl; and Y is methyl.
19. A compound of formula (E) ##STR00197## wherein: R2.sup.a halogen, C.sub.1—C.sub.3fluoroalky1, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalkyl, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1— C.sub.3alkyl; and Y is methyl.
20. A compound of formula (J) ##STR00198## wherein: R2.sup.a halogen, C.sub.1—C.sub.3fluoroalkyl, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalkyl, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1— C.sub.3alkyl; and Y is H, methyl, or methoxy.
21. A compound of formula (X) ##STR00199## R2.sup.a halogen, C.sub.1—C.sub.3fluoroalkyl, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.2b is hydrogen, halogen, C.sub.1—C.sub.3fluoroalkyl, C.sub.1—C.sub.3haloalkoxy, C.sub.1—C.sub.3alkoxy, or C.sub.1—C.sub.3alkyl; R.sup.Q1 and R.sup.Q4 are each hydrogen; and R.sup.Q2 and R.sup.Q3 together with the carbon atoms to which they are joined form ring Q, which is an optionally substituted 5-membered thio-lactam ring.
22. The compound of claim 21 wherein ring Q is Q1 or Q2 ##STR00200## ##STR00201## wherein Y is H, methyl or methoxy, ‘a’ denotes the point of attachment to the pyrazole moiety, and ‘c’ denotes the point of attachment to the carboxylate moiety.
23. (canceled)
24. Use of a compound of formula (A) as defined in claim 16 in the manufacture of a herbicide.
25. Use of a compound of formula (B) as defined in claim 17 in the manufacture of a herbicide.
26. Use of a compound of formula (D) as defined in claim 18 in the manufacture of a herbicide.
27. Use of a compound of formula (E) as defined in claim 19 in the manufacture of a herbicide.
28. Use of a compound of formula (J) as defined in claim 20 in the manufacture of a herbicide.
29. Use of a compound of formula (X) as defined in claim 21 in the manufacture of a herbicide.
30. Use of a compound of formula (X) as defined in claim 22 in the manufacture of a herbicide.
Description
EXAMPLES
Formulation Examples
[0120] TABLE-US-00002 Wettable powders a) b) c) active ingredients 25% 50% 75% sodium lignosulfonate 5% 5% - sodium lauryl sulfate 3% - 5% sodium diisobutylnaphthalenesulfonate - 6% 10% phenol polyethylene glycol ether - 2% - (7-8 mol of ethylene oxide) - - - highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% -
[0121] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
TABLE-US-00003 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone 30% xylene mixture 50%
[0122] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
TABLE-US-00004 Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% - - Kaolin - 94 % - mineral filler - 96%
[0123] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.
TABLE-US-00005 Extruder granules Active ingredients 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
[0124] The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
TABLE-US-00006 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
[0125] The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
TABLE-US-00007 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75 % emulsion in water) 1% Water 32%
[0126] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.
Slow Release Capsule Suspension
[0127] 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
[0128] The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
[0129] The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Preparative Examples
General Experimental
[0130] Chiral HPLC was recorded on the columns below with the solvents and gradients stated. Column: [0131] Regis Whelk O1 (s,s) 4.6 × 100 mm, 3.5 .Math.m [0132] Chiralpak IC 4.6 × 100 mm, 3.0 .Math.m
[0133] Solvents: [0134] A: iso-Hexane + 0.1% glacial Acetic Acid (v/v) [0135] B: Ethanol + 0.1% glacial Acetic Acid (v/v)
TABLE-US-00008 Gradient Time (mins): Flow (mL/min): %A: %B: 0.0 1.0 85 15 1.0 1.0 85 15 7.0 1.0 50 50 15.0 1.0 40 60
Example P1 Synthesis of 1-(difluoromethyl)-3-iodo-5-methyl-pyrazole - Compound (A1)
[0136] ##STR00134##
Step 1: Synthesis of Compound (A1- 2)
[0137] Chlorodifluoromethane was bubbled into a mixture of compound (A1-1) (6.3 g, 50 mmol) and KOH (8.5 g, 150 mmol) in 50 ml of dioxane and 30 ml of water at 50° C. for about 2 h. After cooling to room temperature, the resulting mixture was poured into water, and the mixture was extracted three times with diethyl ether. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to give the compound (A1-2) (3.9 g, 45% yield) as a light yellow solid.
[0138] .sup.1H NMR (400 Mz, CDCl.sub.3): δ 2.53 (s, 3H), 6.76 (s, 1H), 7.22 (t, J=58.2 Hz, 1H); .sup.19F NMR (282 MHz, CDCl.sub.3): δ -95.2(d, J=58.3 Hz, 2F).
Step 2: Synthesis of Compound (A1-3)
[0139] A mixture of compound A1-2 (1.77 g, 20 mmol) and 10% of Pd/C (500 mg) in 30 ml MeOH was hydrogenated at room temperature for about 3 h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the compound (A1-3) (0.95 g, 65% yield) as a yellow oil.
[0140] .sup.1H NMR (400 Mz, CDCl.sub.3): δ 2.33 (s, 3H), 3.96 (br s, 2H), 5.56 (s, 1H), 6.92 (t, J=59.7 Hz, 1H); .sup.19F NMR (282 MHz, CDCl.sub.3): δ -92.5(d, J=59.8 Hz, 2F).
Step 3: Synthesis of Compound (A1)
[0141] Sodium nitrite (0.83 g, 12 mmol) dissolved in 5 ml of water was added dropwise to a mixture of compound 3 (1.47 g, 10 mmol) and 4N hydrochloric acid (50 ml) at 0° C. After the addition was complete, the resulting mixture was stirred for one hour at the same temperature. Then, a solution of potassium iodide (3.32 g, 20 mmol) in 10 ml of water was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for another one hour. The mixture was extracted three times with ethyl acetate, and the combined organics were washed with a saturated aqueous solution of sodium thiosulfate, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether) to give the compound(A1) (1 g, 40% yield) as a light yellow solid.
[0142] .sup.1H NMR (400 Mz, CDCl.sub.3): δ 2.43 (s, 3H), 6.29 (s, 1H), 7.16 (t, J=58.8 Hz, 1H); .sup.19F NMR (282 MHz, CDCl.sub.3): δ -94.8(d, J=58.6 Hz, 2F).
Example P2 Synthesis of 1-(difluoromethyl)-3-iodo-5-ethyl-pyrazole - Compound (A2)
[0143] ##STR00135##
Step 1: Synthesis of Compound (A2-2)
[0144] 30% H.sub.2O.sub.2 (10 g, 90 mmol) was added dropwise to a mixture of compound (A2-1) (3.33 g, 30 mmol) and Na.sub.2WO.sub.4 (1.98 g, 6 mmol) in 30 ml of DMF and 10 ml of water at 50° C. After the addition, the mixture was stirred at 50° C. for 4 hour. After cooling to room temperature, the resulting mixture was poured into water, and the mixture was extracted three times with diethyl ether. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the compound (A2-2) (105 g, 25% yield) as a yellow solid. .sup.1H NMR (400 Mz, DMSO-d.sub.6): δ 1.18 (t, J=6.8 Hz, 3H), 2.63 (q, J=7.2 Hz, 2H), 6.79 (s, 1H), 13.67 (br s, 1H).
Step 2: Synthesis of Compound (A2-3)
[0145] Chlorodifluoromethane was bubbled into a mixture of compound (A2-2) (1.41 g, 10 mmol) and KOH (1.71 g, 30 mmol) in 20 ml of dioxane and 10 ml of water at 50° C. for about 4 h. After cooling to room temperature, the resulting mixture was poured into water, and the mixture was extracted three times with diethyl ether. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to give the compound (A2-3) (1.06 g, 56% yield) as a light yellow solid.
[0146] .sup.1H NMR (400 Mz, CDCl.sub.3): δ1.35 (t, J=7.6 Hz, 3H), 2.92 (q, J=7.6 Hz, 2H), 6.81 (s, 1H), 7.22 (t, J=57.6 Hz, 1H); .sup.19F NMR (282 MHz, CDCl.sub.3): δ -94.5(d, J=57.8 Hz, 2F).
Step 3: Synthesis of Compound (A2-4)
[0147] A mixture of compound (A2-3) (1.91 g, 10 mmol) and 10% of Pd/C (500 mg) in 30 ml MeOH was hydrogenated at room temperature for about 3 h. The reaction mixture was filtered and the solvent was removed under vacuum give a crude compound (A2-4) (1.12 g, 70% yield) as a yellow oil, which was used for the next step without further purification.
Step 4: Synthesis of Compound (A2)
[0148] Sodium nitrite (0.58 g, 8.4 mmol) dissolved in 5 ml of water was added dropwise to a mixture of compound (A2-4) (1.12 g, 7 mmol) and 4N hydrochloric acid (40 ml) at 0° C. After the addition was complete, the resulting mixture was stirred for one hour at the same temperature. Then, a solution of potassium iodide (2.32 g, 14 mmol) in 10 ml of water was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for another one hour. The mixture was extracted three times with ethyl acetate, and the combined organics were washed with a saturated aqueous solution of sodium thiosulfate, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether) to give the compound (A2) (0.93 g, 49% yield) as a light yellow solid.
[0149] .sup.1H NMR (400 Mz, CDCl.sub.3).. δ1.28 (t, J=7.6 Hz, 3H), 2.83 (q, J=7.6 Hz, 2H), 6.33 (s, 1H), 7.16 (t, J=59.2 Hz, 1H); .sup.19F NMR (282 MHz, CDCl.sub.3): δ -94.1 (d, J=57.8 Hz, 2F).
Example p3: Synthesis of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-n-(2,3-difluorophenyl)-1-methyl-2-thioxo-pyrrolidine-3-carboxamide (Compound No. 37) and 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-n-(2,3-difluorophenyl)-1-methyl-2-oxo-pyrrolidine-3-carboxamide (Compound No33)
Step 1: Synthesis of Ethyl (E)-3-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]prop-2-enoate
[0150] ##STR00136##
[0151] 1-(Difluoromethyl)-3-iodo-5-methyl-pyrazole (0.20 g, 0.78 mmol) was dissolved in acetonitrile (2.7 mL) in a microwave vial, and ethyl acrylate (0.25 mL, 2.3 mmol) was added followed by triethylamine (0.11 mL, 0.78 mmol), tri-ortho-tolylphoshine (0.024 g, 0.078 mmol) and palladium acetate (0.017 g, 0.078 mmol). The vial was flushed with nitrogen, sealed and heated at 100oC under microwave irradiation for 30 minutes.The reaction mixture was filtered, rinsing through with small portions of EtOAc, and the combined filtrate and washings were concentrated to remove the bulk of solvent. The crude product was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The organic extracts were then combined, washed with water (2 x 10 mL), passed through a phase separation cartridge and the collected organics concentrated giving a light brown oil. Purification by chromatography with an EtOAc/iso-hexane gradient elution, afforded the desired product, ethyl (E)-3-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]prop-2-enoate, as light brown liquid (144 mg).
[0152] 1H NMR: (400 MHz, CDCl3) δ = 7.56 (d, J = 16.1 Hz, 1H), 7.33 - 7.04 (t, 1H), 6.40 (d, 1H), 6.36 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H)
Step 2: Synthesis of Ethyl-8-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-6-methyl-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate
[0153] ##STR00137##
[0154] To a suspension of cesium fluoride (0.370 g, 2.43 mmol) in tetrahydrofuran (1.8 mL) stirred at -50° C., under a nitrogen atmosphere was added a solution of ethyl (E)-3-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]prop-2-enoate (0.140 g, 0.608 mmol) and 1,3-dithiolan-2-ylidene-methyl-(trimethylsilylmethyl)ammonium;trifluoromethanesulfonate (0.338 g, 0.912 mmol) in tetrahydrofuran (1.82 mL) drop-wise over 10 minutes, whilst keeping the reaction temperature below -45° C. The resulting pale amber suspension was allowed to warm to room temperature gradually. After 16 hours the reaction mixture was diluted with dichloromethane and filtered. Purification by chromatography with an EtOAc/iso-hexane gradient elution afforded ethyl-8-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-6-methyl-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate as a yellow oil, (94 mg)
[0155] 1H NMR: (400 MHz, CDCl3)δ = 7.27 - 6.97 (t, 1H), 6.02 (s, 1H), 4.31 - 4.17 (m, 2H), 3.87 (d, 1H), 3.78 (q, J = 8.4 Hz, 1H), 3.31 - 3.05 (m, 5H), 2.94 (dd, J = 7.5, 9.3 Hz, 1H), 2.46 (s, 3H), 2.40 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H)
Step 3: Synthesis of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-1-methyl-2-thioxo-pyrrolidine-3-carboxylic Acid
[0156] ##STR00138##
[0157] To a solution of ethyl-8-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-6-methyl-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate (0.094 g, 0.25 mmol,) in 1,4-dioxane (6 mL) and water (2 mL,) was added lithium hydroxide (0.060 g, 2.5 mmol,) and the stirred mixture heated to 60° C. under a nitrogen atmosphere. After 45 mins the reaction mixture was allowed to cool and concentrated to remove the bulk of dioxane. The residual mixture was diluted with water (10 mL), acidified with dilute HCl to pH3, then extracted with DCM (3 × 8 mL). The organic extracts were combined, washed with water (5 mL), separated then passed through a phase separation cartridge. The collected organics were concentrated to give a colourless gum which crystallised to an off-white solid, 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid (73 mg).
[0158] 1H NMR: (400 MHz, CDCl3) δ = 7.24 - 6.95 (t, 1H), 6.22 (s, 1H), 4.17 - 4.02 (m, 4H), 3.33 (s, 3H), 2.43 (s, 3H)
Step 4: Synthesis of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(2,3-difluorophenyl)-1-methyl-2-thioxo-pyrrolidine-3-carboxamide (Compound No. 37)
[0159] ##STR00139##
[0160] To a solution of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid (0.073 g, 0.25 mmol,) in dichloromethane (1.8 mL) was added 2,3-difluoroaniline (0.026 mL, 0.25 mmol). The propylphosphonic anhydride (50 mass% in ethyl acetate) (0.26 mL, 0.43 mmol,) was added, followed by N,N-diisopropylethylamine (0.13 mL, 0.76 mmol). The reaction mixture was stirred at room temperature for 2 hours then left to stand at room temp overnight.
[0161] The reaction mixture was quenched by the addition of water (2 mL), with stirring, transferred to a phase separation cartridge and the organics collected and the collected and purified by chromatography with an EtOAc/iso-hexane gradient elution to afford 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(2,3-difluorophenyl)-1-methyl-2-thioxo-pyrrolidine-3-carboxamide as a colourless gum (62 mg).
[0162] 1H NMR: (400 MHz, CDCl3) δ = 10.21 (br s, 1H), 8.05 - 7.98 (m, 1H), 7.26 - 6.95 (t, 1H), 7.04 (ddt, J = 2.1, 5.9, 8.3 Hz, 1H), 6.95 - 6.86 (m, 1H), 6.13 (s, 1H), 4.40 - 4.33 (m, 1H), 4.19 (d, J = 6.1 Hz, 1H), 4.11 (dd, 1H), 4.02 (dd, 1H), 3.32 (s, 3H), 2.43 (d, 3H)
Step 5: Synthesis of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(2,3-difluorophenyl)-1-methyl-2-oxo-pyrrolidine-3-carboxamide (Compound No. 33)
[0163] ##STR00140##
[0164] To a solution of 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(2,3-difluorophenyl)-1-methyl-2-thioxo-pyrrolidine-3-carboxamide (0.060 g, 0.15 mmol,) in acetonitrile (1.5 mL), stirred and cooled to around 0-5° C., in an ice bath, was added hydrogen peroxide (50%) (0.18 mL). After 5 minutes hydrobromic acid (0.018 mL, 0.15 mmol) was added and the colourless solution was stirred at 5° C. for around 1 h. The reaction mixture was quenched with sodium thiosulfate solution (2 mL) and the mixture was diluted with water (2 mL) and concentrated to remove the bulk of solvent. The residual aqueous was extracted with DCM (3 × 5 mL) and the combined organic extracts passed through a phase separation cartridge. The collected organics were concentrated to give a colourless gum.The crude product was purified by chromatography with an EtOAc/iso-hexane gradient elution, affording 4-[1-(difluoromethyl)-5-methyl-pyrazol-3-yl]-N-(2,3-difluorophenyl)-1-methyl-2-oxo-pyrrolidine-3-carboxamide as a colourless gum (50 mg).
[0165] 1H NMR: (400 MHz, CDCl3) δ = 10.14 (br s, 1H), 8.08 - 8.02 (m, 1H), 7.27 - 6.98 (t, 1H), 7.02 (ddt, J = 2.1, 5.9, 8.3 Hz, 1H), 6.93 - 6.84 (m, 1H), 6.26 (s, 1H), 4.07 (q, J = 8.9 Hz, 1H), 3.76 (d, J = 9.3 Hz, 1H), 3.72 (s, 1H), 3.70 (s, 1H), 2.97 (d, 3H), 2.44 (d, 3H).
[0166] The following compounds of formula (I), shown below in Table 2, were made in an analogous manner.
TABLE-US-00009 Table 2 Compounds of formula (I) Cmpd. No. Name Structure 1HNMR (CDCl.sub.3) 82 4-[1-(difluoromethyl)-5-ethyl-pyrazol-3-yl]-N-(2,6-difluoro-3-pyridyl)-1-methyl-2-oxo-pyrrolidine-3-carboxamide
Biological Examples
Herbicidal Efficacy of Compounds of Formula (I)
[0167] Seeds of a variety of test species [Ipomoea hederacea (IPOHE); Zea mays (ZEAMX); Echinochloa crus-galli (ECHCG); Setaria faberi (SETFA); Abutilon theophrasti (ABUTH); Amaranthus retroflexus (AMARE)] were sown in standard sterilised soil in pots. After cultivation for one day (pre-emergence) or after 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65 % humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone / water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5), subsequently diluted in water, and sprayed to give the stated application rate.
[0168] The test plants were then grown under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65 % humidity) and watered twice daily.
[0169] After 13 days for pre- and post-emergence, the test was evaluated visually for percentage phytotoxicity to the plant (where 5 = total damage to plant; 0 = no damage to plant). Results are shown in Tables B1 and B2.
TABLE-US-00010 Table B1 Application pre-emergence Compound Number Rate (g/ha) SETFA ECHCG ZEAMX IPOHE AMARE ABUTH 82 250 5 5 3 3 1 1 10 250 5 5 4 2 1 2 58 250 5 5 3 1 0 0 35 250 5 5 4 1 2 2 9 250 5 5 3 1 1 1 83 250 5 5 1 0 0 0 86 250 5 5 1 0 2 1 59 250 5 5 1 0 0 1 81 250 5 5 2 2 0 0 62 250 5 5 2 0 0 0 38 250 5 5 4 2 0 0 57 250 5 5 2 1 1 1 85 250 4 4 1 0 0 0 61 250 5 5 1 0 2 0 33 250 5 5 4 1 2 1
TABLE-US-00011 Table B2 Application post-emergence Compound Number Rate (g/ha) SETFA ECHCG ZEAMX IPOHE AMARE ABUTH 82 250 4 4 4 4 1 1 10 250 4 4 4 4 1 0 58 250 4 4 2 3 1 0 35 250 4 4 4 4 2 0 9 250 4 4 3 3 3 0 83 250 3 4 4 1 1 1 86 250 4 4 3 1 1 3 59 250 4 4 3 1 1 0 81 250 4 4 4 1 2 0 62 250 4 4 1 1 1 1 38 250 4 4 3 4 1 0 57 250 4 4 2 3 1 1 85 250 2 4 1 1 1 0 61 250 3 4 2 1 1 0 33 250 4 4 3 4 2 1