Pyrazole derivatives

Abstract

The present invention relates to pyrazole derivatives of formula (X) ##STR00001## wherein ring A is a pyrazole and substituents R.sup.B1, R.sup.B2, n, R.sup.Q1, R.sup.Q2, R.sup.Q3, and R.sup.Q4 are as defined in claim 1, their manufacture, and their use in the manufacture of agrochemicals and pharmaceuticals.

Claims

1. A compound of formula (B) ##STR00023## wherein, ring A is A.sup.7: ##STR00024## R.sup.B2 is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3fluoroalkyl; each R.sup.B3 is independently halogen, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, or C.sub.1-C.sub.3alkyl; and R.sup.B3SN is independently halogen, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, or C.sub.1-C.sub.3alkyl.

2. The compound of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.

3. The compound of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, and difluoroethyl.

4. The compound of claim 1, wherein R.sup.B3 and R.sup.B3SN are each independently selected from chloro, fluoro, bromo, methyl, ethyl, difluoromethyl, trifluoromethyl, C.sub.1-C.sub.3haloalkoxy, and C.sub.1-C.sub.3alkoxy.

5. The compound of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.

6. The compound of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, and difluoroethyl.

7. The compound of claim 1, wherein R.sup.B3 and R.sup.B3SN are each independently selected from chloro, fluoro, bromo, methyl, ethyl, difluoromethyl, trifluoromethyl, C.sub.1-C.sub.3haloalkoxy, and C.sub.1-C.sub.3alkoxy.

8. The compound of claim 1, wherein C.sub.1-C.sub.3haloalkyl is C.sub.1-C.sub.3fluoroalkyl.

9. The compound of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, and difluoroethyl; and R.sup.B3 and R.sup.B3SN are independently selected from chloro, fluoro, bromo, methyl, ethyl, difluoromethyl, and trifluoromethyl.

10. A compound selected from: ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate; ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]prop-2-enoate; ethyl (E)-3-(5-chloro-1-methyl-pyrazol-3-yl)prop-2-enoate; ethyl (E)-3-(5-chloro-2-methyl-pyrazol-3-yl)prop-2-enoate; ethyl (E)-3-(4-bromo-5-chloro-1-methyl-pyrazol-3-yl)prop-2-enoate; ethyl (E)-3-(4-bromo-5-chloro-2-methyl-pyrazol-3-yl)prop-2-enoate; and ethyl (E)-3-(3-bromo-5-chloro-1-methyl-pyrazol-4-yl)prop-2-enoate.

Description

EXAMPLES

Example 1: Preparation of the Herbicidal Compound N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(1) ##STR00022##
Salt (I) can be prepared as described in Tetrahedron Lett. 1995, 36, 9409.

Step 1 Ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate

(2) In a large microwave vial 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (3.62 mmol, 1.00 g) was dissolved in acetonitrile (15.2 mL), and ethyl acrylate (1.19 mL, 10.9 mmol), triethylamine (0.507 mL, 3.64 mmol), tri-ortho-tolylphosphine (0.362 mmol, 0.110 g) and palladium(II) acetate (0.362 mmol, 0.0813 g) were added, the air space above the stirred orange solution was swept with nitrogen, and the vial sealed and heated at 110° C. under microwave irradiation for 60 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 residual orange-brown liquid was diluted with water (12 mL) and extracted with EtOAc (3×15 mL). The organic extracts were combined, washed with water (10 mL), passed through a phase separation cartridge then concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate as a yellow oil, 0.51 g (57%).

(3) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=7.58 (d, J=16.1 Hz, 1H), 6.81 (s, 1H), 6.43 (d, J=16.1 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.01 (d, J=0.6 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

Step 2 Ethyl-6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate

(4) To a suspension of finely divided cesium fluoride (12.7 mmol, 1.93 g) in tetrahydrofuran (9.51 mL) stirred at −50° C., under a nitrogen atmosphere, was added a solution of ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate (3.17 mmol, 0.787 g) and 1,3-dithiolan-2-ylidene-methyl-(trimethylsilylmethyl)ammonium;trifluoromethanesulfonic acid (5.55 mmol, 2.06 g) in tetrahydrofuran (39.51 mL) drop-wise over approx. 15 minutes, keeping the reaction temperature below −45° C. The resulting very pale yellow cloudy suspension was allowed to warm slowly to room temperature and stirring was continued overnight. The reaction mixture was then diluted with DCM and filtered, washing through with further portions of DCM. The combined filtrate and washings were concentrated, and the crude material purified by column chromatography (EtOAc/cyclohexane gradient elution) giving ethyl-6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate as a pale yellow oil, 566 mg (45%).

(5) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=6.45 (s, 1H), 4.31-4.17 (m, 2H), 3.90 (d, J=0.6 Hz, 3H), 3.89-3.79 (m, 2H), 3.35-3.06 (m, 5H), 2.97-2.91 (m, 1H), 2.47 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 3 1-Methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic Acid

(6) To a solution of ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate (1.43 mmol, 0.566 g) in dioxane (34.3 mL) and water (11.4 mL) was added LiOH (14.3 mmol, 0.343 g), and the stirred mixture heated to 60° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was then allowed to cool to around 35° C. then concentrated to remove the bulk of dioxane. The residual mixture was diluted with water (10 mL), and partitioned between dilute HCl (5 mL, to pH3) and DCM (20 mL). The two-phase mixture was filtered to remove fine solids then the organic phase was separated. The aqueous was further extracted with DCM (2×15 mL), and all organic extracts combined, dried over MgSO.sub.4, filtered and the filtrate concentrated giving 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid as a light yellow solid, 399 mg (90%).

(7) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=6.66 (s, 1H), 4.19-4.03 (m, 4H), 3.93 (d, J=0.5 Hz, 3H), 3.34 (s, 3H).

Step 4 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide

(8) To a solution of 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid (0.340 g, 1.11 mmol) in DCM (8.0 mL) was added 2,3-difluoroaniline (0.112 mL, 1.11 mmol) giving a pale yellow solution. Propylphosphonic anhydride (50 mass %) in ethyl acetate (1.88 mmol, 1.12 mL) was added, followed by the N,N-diisopropylamine (3.32 mmol, 0.578 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched by the addition of water (2 mL) with stirring, transferred to a phase separation cartridge and the organics collected and concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide as a colourless crystalline solid, 264 mg (57%).

(9) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=10.25 (br s, 1H), 8.01 (tdd, J=1.6, 6.6, 8.3 Hz, 1H), 7.04 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.94-6.86 (m, 1H), 6.58 (s, 1H), 4.40 (td, J=6.3, 8.6 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 4.13 (dd, 1H), 4.00 (dd, 1H), 3.93 (d, 3H), 3.33 (s, 3H).

Step 5 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(10) To a solution of N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide (0.621 mmol, 0.260 g) in acetonitrile (6.21 mL) stirred and cooled to around 0 to −5° C., in an ice-salt bath, was added 50% hydrogen peroxide (0.746 mL) drop-wise and a white suspension resulted. After 5 minutes 45% aq. hydrobromic acid (0.0750 mL, 0.621 mmol) was added drop-wise and after stirring for 10 minutes the mixture was allowed to warm to room temperature. After 3 hours the reaction mixture was re-cooled to 5° C., and quenched with sodium thiosulfate solution (˜10 mL). The mixture was diluted with EtOAc (15 mL) and water (10 mL), and the organic phase separated. The aqueous was further extracted with EtOAc (2×10 mL), then the organic extracts were combined, run through a phase separation cartridge then concentrated giving a colourless gum. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide as a white crystalline solid, 210 mg (84%).

(11) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=10.15 (br s, 1H), 8.04 (dd, J=6.6, 8.3 Hz, 1H), 7.06-6.99 (m, 1H), 6.89 (br dd, J=1.1, 8.6 Hz, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (d, 3H).

(12) The racemic N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide could be separated to afford the enantiomers (3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3 carboxamide and (3R,4S)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide using a Chiralpak IA, 10×250 mm, 5 μm column with sc-CO.sub.2 (solvent A) B=Isopropanol (solvent B) as solvents under isocratic conditions: 85% solvent A:15% solvent B at 15 mL/min.

(13) Examples of further herbicidal compounds of formula (I) were made using the methods and compounds of the invention described herein, in a directly analogous manner to N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide as described in Example 1 above. The structures and characteristic NMR data for these compounds are given below in Table 8.

(14) TABLE-US-00008 TABLE 8 Herbicidal Compounds of formula (I) prepared using compounds and methods of the invention. Whilst the name of the preferred herbicidal enantiomer is given, in each case the NMR data corresponds to that for the respective racemate Compound No. Structure (Compound of Formula (I1) 1HNMR (CDCl.sub.3) 8.1 (3S,4R)-N-(2,3-difluorophenyl)-1-methyl-4-[1- δ = 10.15 (br s, 1H), 8.04 (tdd, J = methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 1.6, 6.6, 8.3 Hz, 1H), 7.02 (ddt, J = pyrrolidine-3-carboxamide 2.1, 5.9, 8.3 Hz, 1H), 6.93-6.85 (m, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.81-3.65 (m, 3H), 2.98 (d, 3H) 8.2 (3S,4R)-N-(2-fluorophenyl)-1-methyl-4-[1- δ = 10.04 (br s, 1H), 8.31-8.25 (m, methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 1H), 7.13-7.00 (m, 3H), 6.69 (s, pyrrolidine-3-carboxamide 1H), 4.11 (q, 1H), 3.94(s, 3H), 3.80- 3.65 (m, 3H), 2.98 (d, 3H) 8.3 (3S,4R)-N-(2,4-difluorophenyl)-1-methyl-4-[1- δ = 9.98 (br s, 1H), 8.22 (dt, J = methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 6.0, 8.9 Hz, 1H), 6.90-6.80 (m, pyrrolidine-3-carboxamide 2H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (d, 3H), 3.80-3.65 (m, 3H), 2.97 (d, J = 0.7 Hz, 3H) 8.4 (3S,4R)-N-[3-fluoro-2- δ = 10.40 (s, 1H), 8.17 (td, J = 1.5, (trifluoromethoxy)phenyl]-1-methyl-4-[1- 8.5 Hz, 1H), 7.26-7.19 (m, 1H), methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 6.92 (ddd, J = 1.4, 8.4, 9.7 Hz, 1H), pyrrolidine-3-carboxamide 6.69 (s, 1H), 4.07 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.77 (d, 1H), 3.74-3.64 (m, 2H), 2.98 (s, 3H) 8.5 (3S,4R)-N-[3-fluoro-2-(trifluoromethyl)phenyl]- δ = 10.16 (br s, 1H), 7.99 (d, J = 1-methyl-4-[1-methyl-5- 8.3 Hz, 1H), 7.46 (dt, J = 6.0, 8.4 (trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine- Hz, 1H), 7.00-6.92 (m, 1H), 6.68 3-carboxamide (s, 1H), 4.09 (q, J = 8.9 Hz, 1H), 3.94 (s, 3H), 3.79-3.66 (m, 3H), 2.98 (d, 3H) 8.6 (3S,4R)-N-(3-fluoro-2-methoxy-phenyl)-1-methyl-4- δ = 10.21 (s, 1H), 8.13 (td, J = 1.3, [1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 8.4 Hz, 1H), 6.96 (dt, J = 5.7, 8.3 pyrrolidine-3-carboxamide Hz, 1H), 6.81 (ddd, J = 1.5, 8.4, 11.1 Hz, 1H), 6.68 (s, 1H), 4.13 (q, J = 9.0 Hz, 1H), 4.03 (d, J = 1.7 Hz, 3H), 3.94 (d, 3H), 3.78-3.63 (m, 3H), 2.97 (d, J = 0.7 Hz, 3H) 8.7 (3S,4R)-1-methyl-4-[1-methyl-5- δ = 10.08 (br s, 1H), 8.01-7.94 (m, (trifluoromethyl)pyrazol-3-yl]-2-oxo-N-(2,3,4- 1H), 6.92 (ddt, J = 2.4, 7.7, 9.7 Hz, trifluorophenyl)pyrrolidine-3-carboxamide 1H), 6.68 (s, 1H), 4.07 (q, 1H), 3.94 (s, 3H), 3.77 (d, 1H), 3.75-3.65 (m, 2H), 2.98 (d, 3H) 8.8 (3S,4R)-N-(2,6-difluoro-3-pyridyl)-1-methyl-4-[1- δ = 10.17 (br s, 1H), 8.83-8.76 (m, methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 1H), 6.80 (dd, J = 2.9, 8.6 Hz, 1H), pyrrolidine-3-carboxamide 6.67 (s, 1H), 4.07 (q, J = 8.9 Hz, 1H), 3.95 (d, 3H), 3.83-3.65 (m, 3H), 2.98 (d, 3H) 8.9 (3S,4R)-N-(6-fluoro-2-pyridyl)-1-methyl-4-[1- δ = 10.04 (s, 1H), 8.01 (dd, J = 1.8, methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- 7.9 Hz, 1H), 7.75 (q, J = 8.1 Hz, pyrrolidine-3-carboxamide 1H), 6.65 (s, 1H), 6.64 (dd, 1H), 4.12 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.77-3.61 (m, 3H), 2.96 (s, 3H) 8.10 (3S,4R)-N[2-(difluoromethoxy)-3-fluoro-phenyl]-1- δ = 10.29 (s, 1H), 8.17 (td, J = 1.3, methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]- 8.4 Hz, 1H), 7.17 (dt, J = 5.9, 8.5 2-oxo-pyrrolidine-3-carboxamide Hz, 1H), 6.89 (ddd, J = 1.3, 8.5, 10.0 Hz, 1H), 6.68 (s, 1H), 6.67 (t[large F coupling], 1H), 4.09 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J = 9.5 Hz, 1H), 3.75-3.63 (m, 2H), 2.98 (m, 3H) 8.11 (3S,4R)-N-(2-ethylphenyl)-1-methyl-4-[1-methyl-5- δ = 9.73 (s, 1H), 8.05 (d, 1H), 7.34- (trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3- 7.27 (m, 1H), 7.22-7.16 (m, 1H), carboxamide 7.10-7.05 (m, 1H), 6.72 (s, 1H), 4.17-4.07 (m, 1H), 3.94 (s, 3H), 3.77-3.66 (m, 3H), 2.97 (d, 3H), 2.77-2.65 (m, 2H), 1.27 (t, 3H) 8.12 (3S,4R)-N-[2-(1,1-difluoroethyl)-3-fluoro-phenyl]-1- δ = 9.75 (br s, 1H), 8.11 (dd, J = methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]- 5.1, 9.0 Hz, 1H), 7.21 (dd, J = 2.9, 2-oxo-pyrrolidine-3-carboxamide 9.2 Hz, 1H), 7.13-7.06 (m, 1H), 6.67 (s, 1H), 4.13 (q, J = 8.9 Hz, 1H), 3.94 (s, 3H), 3.76-3.64 (m, 3H), 2.97 (s, 3H), 1.98 (t, 3H) 8.43 (3S,4R)-4-(5-chloro-1-methyl-pyrazol-3-yl)-N-(2,3- δ = 10.14 (s, 1H), 8.09-7.97 (m, difluorophenyl)-1-methyl-2-oxo-pyrrolidine-3- 1H), 7.08-6.97 (m, 1H), 6.92- carboxamide 6.82 (m, 1H), 6.27 (s, 1H), 4.10- 3.97 (m, 1H), 3.88-3.75 (m, 1H), 3.80 (s, 3H), 3.74-3.60 (m, 2H), 2.95 (s, 3H). 8.45 (3S,4R)-4-(5-chloro-1-methyl-pyrazol-3-yl)-N-(2,4- δ = 9.96 (brs, 1H), 8.28-8.18 (m, difluorophenyl)-1-methyl-2-oxo-pyrrolidine-3- 1H), 6.91-6.77 (m, 2H), 6.27 (s, carboxamide 1H), 4.05 (q, J = 9.0 Hz, 1H), 3.83- 3.60 (m, 3H), 3.79 (s, 3H), 2.96 (s, 3H) 8.49 (3S,4R)-4-(5-chloro-1-methyl-pyrazol-3-yl)-1- δ = 10.06 (s, 1H), 8.03-7.93 (m, methyl-2-oxo-N-(2,3,4-trifluorophenyl)pyrrolidine-3- 1H), 6.98-6.85 (m, 1H), 6.27 (s, carboxamide 1H), 4.03 (q, 1H), 3.83-3.60 (m, 3H), 3.80 (s, 3H), 2.97 (s, 3H).