Carboxamide compounds

Abstract

Compounds of the formula (I), in which the substituents are as defined in claim 1, are suitable for use as nematicides. ##STR00001##

Claims

1. A compound of the formula I ##STR00063## wherein Y is C—H, C—F, C—Cl or N, A1, A2, A4 and A5 are, independently of each other, N, CH or CR6, where the number of N atoms in the ring containing A1, A2, A4 and A5 is 0, 1 or 2, R6 is, independently of each other, selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy, R1 and R2 are each methyl, or R1 and R2 form together with the carbon atom, to which they are attached, a cyclopropyl or cyclobutyl ring, R3 is, independently of each other, selected from halogen, cyano, R9, O—R9, NO2, COOR9, CONHR9, CONR9aR9, NHR9, NR9aR9, and NHCOR9, R8 is, independently of each other, selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy, R9 and R9a are, independently of each other, selected from C1-C4-alkyl, which is unsubstituted or substituted by one or more R10, C2-C6-alkenyl, which is unsubstituted or substituted by one or more R10, C2-C6-alkynyl, which is unsubstituted or substituted by one or more R10, aryl, which is unsubstituted or substituted by one or more R10, or heteroaryl, which is unsubstituted or substituted by one or more R10, R10 is, independently of each other, selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy, p is 0 to 4, m is 0 to 3, or a tautomer, an isomer, a diastereomer, or an enantiomer of one of these compounds.

2. The compound according to claim 1 wherein R1 and R2 are each methyl, or R1 and R2 form together with the carbon atom, to which they are attached, a cyclopropyl or cyclobutyl ring.

3. The compound according to claim 1 wherein Y is C—H or N.

4. The compound according to claim 1, wherein R3 is, independently of each other, selected from a halogen, cyano, C1-C2-alkyl and C1-C2-haloalkyl.

5. The compound according to claim 1, wherein R8 is, independently selected from, a halogen, cyano, C1-C2-alkyl, or C1-C2-haloalkyl.

6. The compound according to claim 1, wherein p is 0, 1 or 2.

7. The compound according to claim 1, wherein m is 0 or 1.

8. A compound of claim 1 of the formula IA ##STR00064## where R6a, R6b, R6d and R6e are independently selected from, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

9. A compound of claim 1 of the formula IB ##STR00065## where R6a, R6b, and R6d are, independently selected from, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

10. A compound of claim 1 of the formula IC ##STR00066## where R6a, R6b, and R6e are, independently selected from, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

11. A pesticidal composition, which, in addition to comprising formulation adjuvants, comprises a nematicidal effective amount of a compound according to claim 1.

12. A composition according to claim 11, which further comprises one or more insecticidally, acaricidally, nematicidally and/or fungicidally active agents.

13. A pharmaceutical composition for the control of helminths, arachnids or arthropodal endo- or ectoparasites which comprises a compound of formula (I) as defined in claim 1, a physiologically tolerable carrier and one or more customary formulation auxiliaries.

14. A pharmaceutical composition comprising a compound defined in claim 1, a physiologically tolerable carrier, and one or more customary formulation auxiliaries for controlling infection with diseases transmitted through helminths, arachnids or arthropodal endo- or ectoparasites.

15. The composition according to claim 13 further comprising one or more other biologically active compounds.

16. A method of controlling damage and/or yield loss caused by a pest and/or fungi which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest and/or fungi or to a plant propagation material an effective amount of a compound of formula (I) as defined in claim 1.

17. A method for the protecting plant propagation material from damage and/or yield loss caused by a pest and/or fungi which comprises applying to the propagation material or the site, where the propagation material is planted, an effective amount of a compound of formula (I) as defined in claim 1.

18. The method according to claim 16 wherein the damage or loss is caused by a nematode pest.

19. A method of controlling endo- and ectoparasitic nematode infestations and infections in warm-blooded animals, which comprises injecting, topically applying or orally administering a composition according to claim 13.

20. A treated plant propagation material, wherein adhered to the plant propagation material is an effective amount of a compound of formula (I) as defined in claim 1.

21. A process for the preparation of compounds according to claim 1 by the acylation of an organometallic compound of formula III in which R3, p, R8, m and Y are as defined under formula I in claim 1, and M(a) is a metal, with a carboxylic acid derivative of formula II in which A1, A2, A4, A5, R1 and R2 are defined in claim 1, and X(a) is a C1-C6 alkoxy, a hetero-substituted —C1-C6 alkoxy or a heteroatom-substituted dialkylaminyl, in a solvent for between 10 minutes and 5 hours and between −80° C. to 25° C. ##STR00067##

Description

EXAMPLES

Preparation Examples

(1) Temperatures are given in degrees Celsius; mixing ratios of solvents are given in parts by volume.

(2) The following abbreviations were used in this section: DMF: dimethylformamide; THF: tetrahydrofuran; EtOAc: ethyl acetate; s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point; RT=retention time, [M+H].sup.+=molecular mass of the protonated cation, [M−H].sup.−=molecular mass of the molecular anion.

(3) Method A:

(4) MS ZQ Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, Extractor: 2.00 V, source temperature (° C.) 100, desolvation temperature (° C.) 250, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 100 to 900 Da. LC 1100er Series HPLC from Agilent: quaternary pump, heated column compartment and diode-array detector. Column: Phenomenex Gemini C18, 3 □m, 30×3 mm, Temp: 60° C.; DAD Wavelength range (nm): 210 to 500 Solvent gradient: A=H.sub.2O+5% MeOH+0.05% HCOOH B=Acetonitril+0.05% HCOOH

(5) TABLE-US-00013 Time (min) Time (min) Time (min) Time (min) 0.00 0.00 0.00 0.00 2.00 2.00 2.00 2.00 2.80 2.80 2.80 2.80 2.90 2.90 2.90 2.90
Method B: MS ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer) Ionisation method: Electrospray Polarity: positive ions Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700 Mass range: 100 to 800 Da DAD Wavelength range (nm): 210 to 400 LC Method Waters ACQUITY UPLC with the following HPLC gradient conditions (Solvent A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid)

(6) TABLE-US-00014 Time (min) A % B % Flow (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75
Method C: MS ZMD Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.80, cone (V) 30.00, extractor (V) 3.00, source temperature (° C.) 150, desolvation temperature (° C.) 350, cone gas flow (L/Hr) off, desolvation gas flow (L/Hr) 600, mass range: 100 to 900 Da. LC 1100er Series HPLC from Agilent: quaternary pump, heated column compartment and diode-array detector. Column: Phenomenex Gemini C18, 3 □m, 30×3 mm, Temp: 60° C.; DAD Wavelength range (nm): 200 to 500 Solvent gradient: A=H.sub.2O+5% MeOH+0.05% HCOOH B=Acetonitril+0.05% HCOOH

(7) TABLE-US-00015 Time (min) A % B % Flow (ml/min) 0.00 100 0.0 1.700 2.00 0 100 1.700 2.80 0 100 1.700 2.90 100 0 1.700 3.00 100 0 1.700
Method D: MS Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) LC Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 □m, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85

Example P1: Preparation of N-[1,1-dimethyl-2-oxo-2-[4-[trans-2-(trifluoromethyl)-1-cyclopropyl]phenyl]ethyl]-2,6-difluoro-benzamide (19.003)

Step a. Preparation of 1-bromo-4-[2-trans-(trifluoromethyl)-1-cyclopropyl]benzene

(8) ##STR00044##

(9) 4-bromostyrene (48 ml, 67.5 g, 369 mmol) and Fe(TPP)Cl (7.79 g, 11.1 mmol) was stirred with a solution of 2,2,2-trifluoroethylamine hydrochloride (102 g, 738 mmol) in 600 ml water. The mixture was stirred rapidly with a mechanical stirrer and an ice/water bath used to cool the reaction flask. When the temperature of the reaction vessel sank to 15° C., addition of a solution of sodium nitrite (61.1 g, 885 mmol) in 50 ml of water was started and a portion was added. An exothermic reaction started with evolution of nitrogen. The temperature rose to 20° C. and sank again. The nitrite solution was added in portions keeping the temperature between 15° C. and 22° C. After complete addition the cooling bath was removed and the mixture stirred for a further 3 hours. NMR of a sample showed complete conversion. The reaction mixture was stirred with ca 200 ml cyclohexane and filtered through celite washing with hexane. The layers were separated and the organic layer washed with NH.sub.4Cl (5M, aq) and twice with water. The organic phase was put through a column of silica (height 15 cm, diameter 10 cm) eluting further with hexane. The solvent was evaporated yielding of 1-bromo-4[2-trans-(trifluoromethyl)-1-cyclopropyl]benzene (70 g).

(10) .sup.1H-NMR (CDCl3) 1.13 (1H, m, cPr); 1.38 (1H, m, cPr); 1.77 (1H, m, cPr); 2.32 (1H, m, cPr); 6.99 (2H, Ar); 7.41 (2H, Ar).

Step b. Preparation of 2-(2,6-difluorophenyl)-4,4-dimethyl-oxazol-5-one

(11) ##STR00045##

(12) 2,6-difluorobenzoyl chloride (20 ml, 159.84 mmol) was added to a suspension of alpha-aminoisobutyric acid (7.417 g, 71.93 mmol) in pyridine (140 ml) under stirring at 0° C. The mixture was allowed to warm to room temperature and stirred for six days. The solvent was evaporated and the crude product mixture shaken between ether/hexane 1:4 and water. The organic phase was washed twice with HCl (1M), once with NaHCO.sub.3 (1M), dried over Na.sub.2SO.sub.4, and evaporated to yield the product (14.3 g) as light yellow solid. M.p. 36-39° C.

(13) .sup.1H-NMR (CDCl3, 400 MHz) 1.58 (6H, s, 2×Me); 7.03 (2H, dd, J=9, Ar); 7.50 (1H, m, Ar).

Step c. Preparation of 2,6-difluoro-N-[2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]benzamide

(14) ##STR00046##

(15) A mixture of 2-(2,6-difluoro-phenyl)-4,4-dimethyl-4H-oxazol-5-one (1.90 g, 8.44 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10.1 mmol), pyridine (0.80 ml, 10.1 mmol, 1.2 eq.), and methylene chloride (28 ml) was stirred at room temperature for 24 hours. Methylene chloride was removed by evaporation under reduced pressure. The resulting mixture was diluted with ethyl acetate (150 ml), washed with twice with 5% of aq. HCl (50 mL) and saturated aqueous NaHCO.sub.3 (50 ml) and dried over Na.sub.2SO.sub.4, Removal of the solvent afforded the crude product N-[2-(4-cyclopropyl-phenyl)-1,1-dimethyl-2-oxo-ethyl]-2,6-difluoro-benzamide as yellow solid, which was submitted in the next step without further purification.

Step d. Preparation of N-[1,1-dimethyl-2-oxo-2-[4-[trans-2-(trifluoromethyl)-1-cyclopropyl]phenyl]ethyl]-2,6-difluoro-benzamide (19.003)

(16) ##STR00047##

(17) A solution of phenyl lithium in Bu.sub.2O (1.8M, 30.2 mmol, 17 ml) was added slowly to a solution of 2,6-difluoro-N-[2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]benzamide (8.64 g, 30.2 mmol in 100 ml THF) at −70° C. In a separate flask nBuLi in hexanes (19 ml, 1.6M, 30.2 mmol) was added slowly to a solution of 1-bromo-4[2-trans-(trifluoromethyl)-1-cyclopropyl]benzene from step 1 (8.00 g, 30.2 mmol) in THF (50 ml) at −70° C. After 15 minutes this new aryl lithium solution was added by cannula to the solution described above. After 1 hour at −70° C. NH.sub.4Cl (5M, 50 ml) was added, the mixture warmed to RT, and tBuOMe (150 ml) and water (100 ml) was added. The phases were separated, the organic layer washed with NaHCO.sub.3 (1M, 50 ml) and NaCl (satd, 50 ml), dried over MgSO.sub.4 and the solvent evaporated to yield the crude product (16.97 g) as a yellow oil still containing Bu.sub.2O. This reaction was repeated on a 240 mmol scale following the procedure above but quenching the reaction with 58 g of acetic acid instead of NH4Cl (5M). This afforded a crude yield of 112 g of the product containing Bu.sub.2O. This was chromatographed together with the 16.95 g from the first reaction. Chromatography was performed with 1.5 kg of silica using an EtOAc/heptanes gradient to yield 67.5 g of the product, which was crystallised from Et2O/hexane m.p. 65-80° C.

(18) LCMS (method A). RT 2.11 min [M+H].sup.+ 412.

(19) .sup.1H-NMR (CDCl3, 400 MHz) 1.22 (1H, m, cPr); 1.43 (1H, m, cPr); 1.80 (6H, s, Me2); 1.84 (1H, m, cPr); 2.48 (1H, m, cPr); 6.89 (2H, t, Ar); 6.92 (1H, br s, NH); 7.16 (2H, d); 7.33 (IH, m, Ar); 7.98 (2H, d, Ar)

Example P2: N-[1,1-dimethyl-2-oxo-2-[4-[2,2-dichlorocyclopropyl]phenyl]ethyl]-2,6-difluoro-benzamide (19.002)

Step a: N-[1,1-dimethyl-2-oxo-2-(4-vinylphenyl)ethyl]-2,6-difluoro-benzamide

(20) ##STR00048##

(21) Tributylvinyltin (912 mg) was added to a solution of N-[1,1-dimethyl-2-oxo-2-(4-bromophenyl)ethyl]-2,6-difluoro-benzamide (1 g) in toluene (50 ml). The solution was degassed and flushed with argon. Palladium(tetrakis(triphenylphosphine)) (302 mg) was added and the solution was stirred at 90° C. overnight then cooled to room temperature and quenched by addition of saturated aqueous sodium carbonate solution and stirred 4 hours at room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with 5% aqueous ammonia solution, dried over sodium sulphate and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (ethyl acetate/cyclohexane) to afford the title product as a dark yellow gum (1.42 g).

(22) LCMS (method A). RT 1.74 min [M+H].sup.+ 330.

(23) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 1.82 (s, 6H), 5.38 (d, 1H), 5.85 (d, 1H), 6.21 (dd, 1H), 6.90-7.00 (m, 3H), 7.25 (m, 1H), 7.45 (d, 2H), 8.00 (d, 2H).

Step b: N-[1,1-dimethyl-2-oxo-2-[4-[2,2-dichlorocyclopropyl]phenyl]ethyl]-2,6-difluoro-benzamide (19.002)

(24) ##STR00049##

(25) To a stirred solution of N-[1,1-dimethyl-2-oxo-2-(4-vinylphenyl)ethyl]-2,6-difluoro-benzamide (200 mg), potassium hydroxide (170 mg) and tetrabutylammonium bromide (39 mg) in dichloromethane (3 ml) at 40° C. was added chloroform (362 mg) dropwise. Addition of chloroform was repeated until all starting material was consumed, as assessed by LCMS analysis. The crude residue was purified by flash chromatography (ethyl acetate/heptanes) to afford the title product as a yellow oil (137 mg).

(26) LCMS (method A). RT 1.87 min [M+H].sup.+ 412/414.

Example P3: Preparation of N-[2-(4-cyclopropylphenyl)-1,1-dimethyl-2-oxo-ethyl]-2,6-difluoro-benzamide (19.001)

(27) ##STR00050##

(28) N-[1,1-dimethyl-2-oxo-2-(4-chlorophenyl)ethyl]-2,6-difluoro-benzamide (26 g) was dissolved in toluene (520 ml). Cyclopropyl boronic acid (10 g), tricyclohexylphosphine (2.16 g), potassium phosphate (57.2 g) and water (31 ml) were added followed by palladium acetate (0.86 g) and the solution was stirred at 100° C. overnight then cooled to room temperature and partitioned between water and ethyl acetate. The combined organic layers were washed with brine and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (ethyl acetate/cyclohexane) to afford the title product as a dark yellow gum (48 g).

(29) LCMS (method B). RT 1.73 min [M+H].sup.+ 344.

(30) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 0.75 (m, 2H), 1.02 (m, 2H), 1.82 (s, 6H), 1.91 (m, 1H), 6.90 (t, 2H), 7.09 (d, 2H), 7.12 (br s, 1H), 7.32 (m, 1H), 7.92 (d, 2H).

Example P4: Alternative Synthesis of N-[2-(4-cyclopropylphenyl)-1,1-dimethyl-2-oxo-ethyl]-2,6-difluoro-benzamide (19.001)

(31) ##STR00051##

(32) To a solution of 2-(2,6-difluorophenyl)-4,4-dimethyl-oxazol-5-one (0.5 g) in cyclopropylbenzene (5.47 ml) at 0° C. was added aluminium trichloride (0.83 g) and the reaction mixture was stirred 30 min at 0° C. It was then allowed to warm up to room temperature and the reaction mixture was decomposed by addition of ice and 2N hydrochloric acid. The organic layer was washed with sodium bicarbonate, dried over sodium sulphate and the solvents evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate/cyclohexane) to afford the title product as an off-white gum (0.36 g).

(33) LCMS (method C). RT 1.77 min [M+H].sup.+ 344.

(34) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 0.75 (m, 2H), 1.02 (m, 2H), 1.82 (s, 6H), 1.91 (m, 1H), 6.90 (t, 2H), 7.09 (d, 2H), 7.12 (br s, 1H), 7.32 (m, 1H), 7.92 (d, 2H).

Example P5: Alternative Synthesis of N-[2-(4-cyclopropylphenyl)-1,1-dimethyl-2-oxo-ethyl]-2,6-difluoro-benzamide (19.001)

(35) ##STR00052##

(36) A solution of 1-bromo-4-cyclopropyl-benzene (300 mg, 1.52 mmol) in dry THF (4 ml) at −78° C. under argon was treated dropwise over a period of 20 minutes with BuLi (1.6N in hexanes, 1.00 ml, 1.60 mmol) To the resulting mixture at −78° C. was added dropwise over a period of 15 minutes a solution of 2-(2,6-difluoro-phenyl)-4,4-dimethyl-4H-oxazol-5-one (0.196 g, 0.685 mmol) in dry THF (1.5 ml). The reaction mixture was stirred for 15 min at −78° C. and for one hour at room temperature. The reaction was quenched by the addition of saturated aqueous NH.sub.4Cl. Ethylacetate (10 ml) was added and the layers were separated. The aqueous phase was extracted twice with ethylacetate (20 ml). The organic layers were combined, washed with aqueous saturated NaCl, dried over Na.sub.2SO.sub.4. Removal of the solvent afforded the crude product as a yellow oil. The crude product was purified by flash-chromatography on a silica gel column eluted with heptanes/ethalyacetate 2/1 to afford N-[2-(4-Cyclopropyl-phenyl)-1,1-dimethyl-2-oxo-ethyl]-2,6-difluoro-benzamide (94 mg) as a colorless solid.

Example P6: tert-butyl N-[2-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropyl]carbamate (19.062)

Step a: tert-Butyl (E)-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]prop-2-enoate

(37) ##STR00053##

(38) Dichloromethane (200 ml) was placed in a dry flask and degassed by introducing argon for 10 min. The catalyst (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene) dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs catalyst, 2.sup.nd generation, 1.03 g, 1.22 mmol) was added at RT followed by tert-butyl propenoate (9.28 ml, 64.0 mmol) and N-[1,1-dimethyl-2-oxo-2-(4-vinylphenyl)ethyl]-2,6-difluoro-benzamide (10.8 g, 32.8 mmol). The solution was heated at 40° C. overnight. After cooling, the mixture was filtered off and the mother liquor was evaporated. The residue was submitted to flash chromatography to give 5.35 g of the title compound as a white solid. Mp: 161-2° C.

(39) LCMS (method D): 1.10 min, 430 (M+1).sup.+.

Step b: trans-tert-Butyl-2-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropanecarboxylate (19.060)

(40) ##STR00054##

(41) To a solution of trimethylsulfoxonium iodide (13.9 g, 61.7 mmol) in DMSO (50 ml), sodium hydride (2.47 g; 61.7 mmol) was added and the mixture was stirred 1 h at RT. tert-Butyl (E)-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]prop-2-enoate (5.30 g, 12.3 mmol) dissolved in THF (30 ml) was added dropwise over 10 min and the reaction was stirred overnight at RT. After quenching with water and brine, the solution was extracted with ethyl acetate. The organic phase was separated and dried over MgSO4. After evaporation, the residue was purified by flash-chromatography to give the title compound as a white solid.

(42) LC-MS (method D): 1.09 min, 444, (M+1).sup.+.

Step c: trans-2-[4-[2-[(2,6-Difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropane carboxylic acid (19.061)

(43) ##STR00055##

(44) To a solution of tert-butyl-2-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropanecarboxylate (685 mg, 1.55 mmol) in dichloromethane was added thiophenol (0.18 ml, 1.70 mmol) and trifluoroacetic acid (5 ml). After 2 h, the reaction was quenched with a saturated solution of NaHCO.sub.3 and extracted with ethyl acetate. The organic phase was separated and dried over MgSO.sub.4. After evaporation, the residue was purified by flash-chromatography to give the title compound (501 mg) as white crystals.

(45) LCMS (method D): 0.82 min, 386 (M+1).sup.+.

(46) Step d: trans-tert-Butyl N-[2-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropyl]carbamate (19.062)

(47) ##STR00056##

(48) 2-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]cyclopropane carboxylic acid (360 mg, 0.93 mmol) was solved in tert-butanol. Triethylamine (0.39 ml, 2.80 mmol) was added and after 30 min diphenylphosphoryl azide (dppa, 0.22 ml, 1.12 mmol). The solution was heated at reflux overnight. After cooling, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was washed with water and brine and dried over MgSO4. After evaporation, the residue was purified by flash-chromatography to give the title compound (130 mg) as white crystals.

(49) LCMS (method D): 1.00 min, 459 (M+1).sup.+.

(50) .sup.1H NMR (CDCl.sub.3, 400 MHz): 1.10-1.29 (m, 2H), 1.76 (s, 9H), 2.09 (m, 1H), 2.78 (m, 1H), 5.32 (b, 1H), 6.72 (m, 2H), 6.89 (b, 1H), 7.09 (m, 2H), 7.29 (m, 1H), 7.88 (s, 1H), 7.89 (s, 1H).

Example P7: Ethyl 1-cyano-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]-2,2-dimethyl-cyclopropanecarboxylate (20.001)

Step a: 2,6-Difluoro-N-[2-(4-formylphenyl)-1,1-dimethyl-2-oxo-ethyl]benzamide

(51) ##STR00057##

(52) N-[1,1-Dimethyl-2-oxo-2-(4-vinylphenyl)ethyl]-2,6-difluoro-benzamide (10.0 g, 30.4 mmol) was dissolved in CH.sub.2Cl.sub.2 under argon. The solution was cooled to −78° C. and ozone was blown through it, until it turned blue (˜2 h). The reaction was quenched with dimethyl disulphide (0.1 ml) and warm up to RT overnight. Triphenylphosphine (1.0 g, 3.77 mmol) was then added to completely reduce the intermediate ozonide. Insoluble material was filtered off and the remaining solution was evaporated. The residue was purified by flash chromatography to give the title compound (5.67 g) as white crystals.

(53) LCMS (method D): 0.84 min, 332 (M+1).sup.+.

Step b: Ethyl 2-cyano-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]prop-2-enoate

(54) ##STR00058##

(55) 2,6-Difluoro-N-[2-(4-formylphenyl)-1,1-dimethyl-2-oxo-ethyl]benzamide (300 mg, 0.91 mmol) was solved in CH.sub.2Cl.sub.2 (5 ml). To this solution were added magnesium sulfate (0.13 g, 1.07 mmol), ammonium acetate (0.09 g, 1.11 mg) and methyl 2-cyanoacetate (0.11 g, 0.01 mmol). After stirring 4 h at RT, 0.11 g methyl 2-cyanoacetate (1.07 mmol) and 5 ml ethylene dichloride were added. After overnight at reflux temperature, the mixture was poured into water and extracted with CH.sub.2Cl.sub.2. The organic phase was dried over MgSO4. After evaporation, the residue was purified by flash-chromatography to give the title compound (90 mg) as an oil.

(56) LCMS (method D): 0.98 min, 433 (M+1).sup.+.

Step c: Ethyl 1-cyano-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]-2,2-dimethyl-cyclopropanecarboxylate (20.001)

(57) ##STR00059##

(58) According to literature (e.g. D. J. Du Bois et al. WO2009/043784, Hoffmann-La Roche), to a solution of ethyl 2-cyano-3-[4-[2-[(2,6-difluorobenzoyl)amino]-2-methyl-propanoyl]phenyl]prop-2-enoate (150 mg, 0.36 mmol) in ethanol (10 ml) was added 2-nitropropane (0.034 ml, 0.36 mmol) and K.sub.2CO.sub.3 (0.05 g, 0.36 mmol) and the suspension was heated at reflux for 4 h. The mixture was poured into brine and extracted with ethyl acetate. The organic phase was dried over MgSO4. After evaporation, the residue was purified by flash-chromatography to give the title compound (31 mg) as an oil.

(59) LCMS (method D): 1.03 min, 469 (M+1).sup.+.

(60) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 1.38 (t, 3H), 1.49 (s, 3H), 1.58 (s, 3H), 1.81 (s, 6H), 3.29 (s, 1H), 4.32 (q, 2H), 6.81 (s, b, 1H), 6.90 (m, 2H), 7.34 (m, 3H), 7.99 (s, 1H), 8.0 (s, 1H).

(61) Tables 19: Characterising Data

(62) Table 19 shows selected melting point, selected HPLC-MS, and selected NMR data for compounds of the present invention. CDCl.sub.3 was used as the solvent for NMR measurements, unless otherwise stated. No attempt is made to list all characterising data in all cases.

(63) In Table 19 and throughout the description that follows, temperatures are given in degrees Celsius; “NMR” means nuclear magnetic resonance spectrum; HPLC is high pressure liquid chromatography; MS stands for mass spectrum; “%” is percent by weight, unless corresponding concentrations are indicated in other units. The following abbreviations are used throughout this description:

(64) TABLE-US-00016 m.p. = melting point [° C.] b.p. = boiling point. S = singlet br = Broad d = doublet dd = doublet of doublets t = triplet q = quartet m = multiplet ppm = parts per million
Table 19 below is a list of characterised compounds of the formula IE.

(65) ##STR00060##

(66) TABLE-US-00017 FFT 80188 RT [M + H]+ LC MS Cpd no AA Y R8a R3aa R3ab Stereo (min) (measured) Method MP/° C. 19.001 2,6-difluorophenyl C—H H H H — 1.73 344 B 121-123 19.002 2,6-difluorophenyl C—H H Cl Cl — 1.87 412/4 A 19.003 2,6-difluorophenyl C—H H CF3 H trans, rac. 65-82 19.004 2,6-difluorophenyl N F H H — 127-128 19.005 2,6-difluorophenyl C—H H CF3 H S, S 74-85 19.006 2,6-difluorophenyl C—H H CF3 H R, R 74-85 19.007 2-fluoro-6-n-butylphenyl C—H H CF3 H trans, rac. 1.18 450 D 19.008 2-chloro-pyrid-3-yl C—H H CF3 H trans, rac. 76-77 19.009 2-trifluoromethyl-pyrid-3-yl C—H H CF3 H trans, rac. 148-149 19.010 3-chloro-pyrid-2-yl C—H H CF3 H trans, rac. 76-77 19.011 2-chloro-pyrid-3-yl C—H H H H — 95-96 19.012 2-trifluoromethyl-pyrid-3-yl C—H H H H — 137-138 19.013 3-chloro-pyrid-2-yl C—H H H H — 0.97 343/5 D 19.014 3-fluoro-pyrid-2-yl C—H H H H — 0.94 327 D 19.015 3-chloro-pyrazin-2-yl C—H H H H — 121-122 19.016 2-trifluoromethyl-phenyl C—H H H H — 156-157 19.017 3-chloro-pyrazin-2-yl C—H H CF3 H trans, rac. 1 412/4 D 19.018 3-fluoro-pyrid-2-yl C—H H CF3 H trans, rac. 100-101 19.019 2-trifluoromethyl-phenyl C—H H CF3 H trans, rac. 124-125 19.020 2-methoxy-phenyl C—H H H H — 1.62   338.29 B 19.021 2-chloro-phenyl C—H H H H — 1.56 342/4 B 19.022 3-bromo-pyrid-2-yl C—H H H H — 1.49 342/4 B 19.023 2-tolyl C—H H H H — 1.56 387/9 B 19.024 2,4,6-trifluorophenyl C—H H H H — 1.56 322 B 19.025 2-fluorophenyl C—H H H H — 1.57 362 B 19.026 2-chloro, 6-fluorophenyl C—H H H H — 1.56 326 B 19.027 3-methyl-pyrid-2-yl C—H H H H — 1.57 360/2 B 19.028 2-fluoro-6-methoxyphenyl C—H H H H — 1.51 323 B 19.029 2-fluoro-6-methylphenyl C—H H H H — 1.58 356 B 19.030 2,6-dichlorophenyl C—H H H H — 1.62 339 B 19.031 3,5-dichloro-pyrid-2-yl C—H H H H — 1.68 376/8 B 19.032 2-chloro-1-oxo-pyrid-6-yl C—H H H H — 1.50 377/9 B 19.033 3-6-dichloro-pyrid-2-yl C—H H H H — 1.65  359/61 B 19.034 3-chloro-5-trifluoromethyl- C—H H H H — 1.74 377/9 B pyrid-2-yl 19.035 3-fluoro-5-chloro-pyrid-2-yl C—H H H H — 1.63  410/12 B 19.036 2-bromophenyl C—H H H H — 1.58 361/3 B 19.037 2-methyl-pyrid-3-yl C—H H H H — 1.04 386/8 B 19.038 3-methoxy-pyrid-2-yl C—H H H H — 1.33 323 B 19.039 2-trifluoromethylsulfanyl- C—H H H H — 1.76 339 B phenyl 19.040 2-fluoro-6-trifluoromethyl- C—H H H H — 1.64 394 B phenyl 19.041 2-tolyl C—H H CF3 H trans, rac. 1.70 390 B 19.042 2,4,6-trifluorophenyl C—H H CF3 H trans, rac. 1.69 430 B 19.043 2-fluorophenyl C—H H CF3 H trans, rac. 1.69 394 B 19.044 2-chloro-6-fluorophenyl C—H H CF3 H trans, rac. 1.69  428/30 B 19.045 3-methyl-pyrid-2yl C—H H CF3 H trans, rac. 1.70 391 B 19.046 2-fluoro-6-methoxy-phenyl C—H H CF3 H trans, rac. 1.64 424 B 19.047 2,6-dichlorophenyl C—H H CF3 H trans, rac. 1.74 444/6 B 19.048 3,5-dichloro-pyrid-2-yl C—H H CF3 H trans, rac. 1.79 445/7 B 19.049 2-chloro-1-oxo-pyrid-6-yl C—H H CF3 H trans, rac. 1.64 427/9 B 19.050 3,6-dichloro-pyrid-2-yl C—H H CF3 H trans, rac. 1.76 445/7 B 19.051 3-chloro-5-trifluoromethyl- C—H H CF3 H trans, rac. 1.83  479/81 B pyrid-2-yl 19.052 5-chloro-3-fluoro-pyrid-2-yl C—H H CF3 H trans, rac. 1.75  429/31 B 19.053 2-methyl-pyrid-3-yl C—H H CF3 H trans, rac. 1.25 391 B 19.054 3-methoxy-pyrid-2-yl C—H H CF3 H trans, rac. 1.49 407 B 19.055 2-trifluoromethylsulfanyl- C—H H CF3 H trans, rac. 1.85 476 B phenyl 19.056 2-methoxy-phenyl C—H H CF3 H trans, rac. 1.74 406 B 19.057 2-chlorophenyl C—H H CF3 H trans, rac. 1.69  410/12 B 19.058 2-cyanophenyl C—H H CF3 H trans, rac. 1.55 401 B 19.059 3-bromo-pyrid-2-yl C—H H CF3 H trans, rac. 1.63 455/7 B 19.060 2,6-difluorophenyl C—H H CO2tBu H trans, rac. 1.07 444 D 19.061 2,6-difluorophenyl C—H H COOH H trans, rac. 115-116 19.062 2,6-difluorophenyl C—H H NHBOC H trans, rac. 197-198 19.063 2,6-difluorophenyl C—H H CONHMe H trans, rac. 129-130 19.064 2,6-difluorophenyl C—H H NO2 H trans, rac. 0.93 389 D
In Tables 19 and 20, ‘Stereo’ refers to the stereochemistry at the carbon atoms of the cyclopropyl attached to R3aa/R3ab and the phenyl/pyridyl ring i.e.

(67) ##STR00061##
Table 20 contains another characterised compound 20.001 of the formula (IF)

(68) ##STR00062##

(69) TABLE-US-00018 RT [M + H]+ LC MS Cpd no (min) (measured) Method 20.001 1.08 469 D

Biological Examples

(70) Heterodera schachtii (Sugar Beet Cyst Nematode),

(71) Nematicide, Contact Activity.

(72) The tested application rate of each compound was 200 ppm. All solutions were brought to a concentration of 400 ppm, respectively, as they were subsequently diluted by adding the equivalent amount of water containing juvenile nematodes. After preparation of the suspensions, 1 ml of each suspension and concentration was transferred to 16-well assay plates with a total of three replicates per treatment. Approximately 500 juveniles of Heterodera schachtii were added in 1 ml of water to each well. Nematodes in water served as controls. The plates were placed in a dark box and stored at room temperature. Nematode paralysis was determined after 24 hours incubation at 25° C. in darkness. Nematodes that showed no movement were considered immotile.

(73) The following compounds showed a greater than 75% nematode immobilization compared to the untreated control:

(74) 19.001, 19.003, 19.004, 19.005, 19.006, 19.007, 19.008, 19.009, 19.010, 19.011, 19.012, 19.014, 19.015, 19.017, 19.018, 19.019, 19.020, 19.021, 19.022, 19.023, 19.024, 19.025, 19.026, 19.027, 19.028, 19.029, 19.033, 19.036, 19.037, 19.038, 19.041, 19.042, 19.043, 19.044, 19.045, 19.046, 19.053, 19.054, 19.056, 19.057, 19.059, 19.060, 19.062, 19.064.
Meloidogyne Spp. (Root-Knot Nematode)
Nematicide, Contact Activity, Preventive.
Filter papers (9 cm×4.5 cm) with a small pocket were placed into plastic (12 cm×6 cm). One cucumber cv. Toshka seed was placed in the centre of the filter paper pocket of all the pouches needed for a test. The cucumber seeds in the pouches were treated with test solutions at 200 ppm by pipetting the solution directly over the cucumber seed in the filter paper pocket in the pouch. Prior to application, the compound solution was prepared at twice the concentration required and the egg suspension is prepared with FORL nutrient solution with 3000 eggs/0.5 ml. After applying all the treatments, 3000 eggs (in 0.5 ml of FORL nutrient solution) were pipetted into the pouches. The pouches were incubated in a moist chamber for twelve days and watered regularly to maintain good filter paper moisture essential for the growing cucumber root system. After this period, the filter paper containing the germinated cucumber seedling was removed from the plastic pouch to assess the number of galls caused by Meloidogyne spp. per root system. Phytotoxicity was measured as a reduction of growth of the emerged cucumber seedling in comparison to the control.

(75) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(76) 19.003, 19.005, 19.006, 19.008, 19.010, 19.015, 19.017, 19.018, 19.019, 19.060, 19.064.

(77) Meloidogyne Spp. (Root-Knot Nematode)

(78) Nematicide, Contact Activity, Preventive

(79) Cucumber cv. Toshka seeds were sown directly into pots filled with a sandy substrate. Six days later pots were each treated with 5 ml of a WP10 suspension of the test compound. Hereafter, pots were inoculated with 3000 eggs of M. incognita. The trial was harvested fourteen days after trial application and inoculation. Root galling was assessed according to Zeck's gall index (Zeck W. M. (1971) Ein Bonitierungsschema zur Feldauswertung von Wurzelgallenbefall. Pflanzenschutznachrichten Bayer 24, 1: 144-147.). Phytotoxicity was measured as a reduction of growth of the emerged cucumber seedling in comparison to the control.

(80) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(81) 19.001, 19.003, 19.004, 19.005, 19.006, 19.008, 19.009, 19.010, 19.011, 19.012, 19.013, 19.014, 19.015, 19.017, 19.018, 19.064.

(82) Meloidogyne Spp. (Root-Knot Nematode)

(83) Nematicide, Contact Activity, Preventive

(84) Coated tomato cv. Roter Gnom seeds were sown 0.5 to 1 cm deep in 45 ml pots filled with field soil. Then pots were infested with nematodes by pipetting 2000 eggs of Meloidogyne spp. within a 2 ml suspension on top of the seed. The seed hole was filled with soil hereafter. Assessment of phytotoxicity (in %) and root galling occurred 28 days after inoculation. The roots were washed free of soil debris and the gall index was assessed according to Zeck 1971 on a scale from 0 to 7.
Seed treatment rate: 1 mg Al/seed

(85) The following compounds showed a greater than 80% reduction of galling compared to the untreated control:

(86) 19.003, 19.005, 19.008, 19.010, 19.017, 19.059.

(87) Heterodera schachtii (Sugar Beet Cyst Nematode)

(88) Nematicide, Contact Activity, Preventive

(89) Coated sugar beat cv. Impulse seeds were planted in 45 ml pots filled with field soil. Seven days after sowing pots were infested with 500 J2 of Heterodera schachtii within a 2 ml suspension in two holes to the left and right of the seedling. Assessment of nematode numbers per g of root occurred 10 days after inoculation. The upper plant part was cut off and the roots were washed free of soil debris. Nematodes within the roots were stained with acid fuchsin stain solution. Nematodes within the roots were quantified under a dissecting scope at 40×.
Seed treatment rate: 0.6 mg Al/seed
The following compounds showed a greater than 80% reduction of nematode population compared to the untreated control:
19.003, 19.008, 19.010, 19.015, 19.017.