Pyrazole derivatives

Abstract

The present invention relates to nitro-vinyl-pyrazole compounds of formula (B) ##STR00001##
wherein ring A, R.sup.B2 and R.sup.B3 are as defined in claim 1, as well as the manufacture of such compounds and their subsequent use in the production of agrochemicals and/or pharmaceuticals.

Claims

1. A compound of formula (B) ##STR00048## wherein: ring A is A1, A2, A3, or A5, ##STR00049## where the jagged line denotes attachment to the nitrovinyl moiety, R.sup.B2 is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3fluoroalkyl, and R.sup.B3 and R.sup.B3SN are 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; or ring A is A.sup.4 ##STR00050## where the jagged line denotes attachment to the nitrovinyl moiety, R.sup.B2 is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3fluoroalkyl, and R.sup.B3 is fluoro, bromo, iodo, 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, or ring A is A.sup.4 ##STR00051## where the jagged line denotes attachment to the nitrovinyl moiety, R.sup.B2 is ethyl, n-propyl, cyclopropyl, isopropyl, or C.sub.1-C.sub.3fluoroalkyl, and R.sup.B3 is 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 ring A is A1, A2, A3, or A5.

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

4. The compound of claim 2, wherein R.sup.B3 and R.sup.B3SN are selected from the group consisting of 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 said compound is selected from the group consisting of B.001, B.002, B.003, B.004, B.005 and B.006 as shown in the table below TABLE-US-00005 Cmpd. No. Name Structure B.001 (E)-N,N-dihydroxy-2-[1-methyl-5- (trifluoromethyl)pyrazol-3-yl]ethenamine B.002 (E)-N,N-dihydroxy-2-[1-methyl-5- (trifluoromethyl)pyrazol-4-yl]ethenamine B.003 (E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N- dihydroxy-ethenamine B.004 (E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N- dihydroxy-ethenamine B.005 (E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N- dihydroxy-ethenamine B.006 (E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N- dihydroxy-ethenamine

6. The compound of claim 1, wherein the compound is ##STR00058##

7. The compound of claim 1, wherein the compound is ##STR00059##

8. The compound of claim 1, wherein the compound is ##STR00060##

9. The compound of claim 1, wherein the compound is ##STR00061##

10. The compound of claim 1, wherein the compound is ##STR00062##

11. The compound of claim 1, wherein the compound is ##STR00063##

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

13. The compound of claim 2, wherein R.sup.B2 is methyl.

14. The compound of claim 2, wherein R.sup.B3 and R.sup.B3SN are selected from the group consisting fluoro, chloro, and trifluoromethyl.

15. The compound of claim 14, wherein R.sup.B2 is methyl.

16. The compound of claim 2, wherein R.sup.B2 is C.sub.1-C.sub.3fluoroalkyl, and R.sup.B3 and R.sup.B3SN are 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.

17. The compound of claim 2, wherein R.sup.B3 and R.sup.B3SN are C.sub.1-C.sub.3fluoroalkyl.

Description

EXAMPLES

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

(1) ##STR00047##

(2) The Nickel catalyst used in step 3, which catalyses the asymmetric malonate addition to the nitro olefin, can be prepared as in J. Am. Chem. Soc. 2005, 127, 9958-9959.

Step 1 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole

(3) The compound 1-methyl-5-(trifluoromethyl)pyrazol-3-amine (5.00 g, 30.3 mmol) was stirred in 9M sulfuric acid (818 mmol, 91 mL) in a 500 mL beaker, using an overhead stirrer at 0 C. (ice bath) until a homogenous mixture resulted. Sodium nitrite (60.6 mmol, 4.18 g), in 10 mL of water, was then added dropwise over 5 minutes, resulting in a colourless solution and the reaction was stirred at 0 C. for a further 20 minutes. Potassium iodide (75.7 mmol, 12.6 g), in 20 mL of water, was added dropwise to the reaction and the mixture was then stirred for a further 4 hours. The reaction was quenched with saturated sodium thiosulfate until the mixture became clear. The mixture was then diluted with dichloromethane and the phases were separated. The aqueous was further extracted with dichloromethane and the combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under vacuum to afford a pale yellow oil. The crude product was purified by column chromatography (EtOAc/hexanes gradient elution) to afford 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole as a colourless oil, 3.9 g, (47%).

(4) .sup.1H NMR (400 MHz, CDCl.sub.3) =6.76 (s, 1H) 4.01 (d, J=0.61 Hz, 3H).

Step 2 1-Methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole

(5) Isopropylmagnesium chloride-Lithium chloride in THF (23.55 mmol, 1.3 mol/L) was added dropwise to 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (5.0 g, 18.12 mmol) in THF (90 mL) at 20 C. and the mixture was stirred for 2 hours. 1-Dimethylamino-2-nitroethylene (27.17 mmol, 3.321 g) was added and the reaction was slowly warmed to RT over 1 hour. The reaction mixture was then carefully quenched with 2 M HCl, and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (74.6%) as a yellow oil, 2.99 g (74.6%).

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) =7.89 (d, J=13.7 Hz, 1H), 7.63 (d, J=13.7 Hz, 1H), 6.88 (s, 1H), 4.05 (d, J=0.6 Hz, 3H).

Step 3 Diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate

(7) To a solution of 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (0.650 g, 2.94 mmol) in toluene (19.5 mL) was added diethyl malonate (0.676 mL, 4.41 mmol) followed by Nickel(II)Bis[(1R,2R)N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine-N1,N2]dibromide (0.0588 mmol, 0.0472 g), and the mixture was stirred at ambient temperature for 20 hours.

(8) The reaction mixture was washed with water (210 mL) and the organic phase separated, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate as pale yellow oil, 1.07 g (95%).

(9) .sup.1H NMR (400 MHz, CDCl.sub.3) =6.53 (s, 1H), 5.01 (dd, 1H), 4.88 (dd, J=4.3, 13.9 Hz, 1H), 4.35 (ddd, J=4.4, 7.7, 9.0 Hz, 1H), 4.22 (q, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.89 (d, 1H), 1.26 (t, 3H), 1.20 (t, J=7.2 Hz, 3H).

Step 4 Ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate

(10) To a solution of diethyl 2-[(1R)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate (1.07 g, 2.81 mmol) in ethanol (42.1 mL) cooled to 0-5 C. (ice bath) under nitrogen, was added dichloronickel hexahydrate (2.95 mmol, 0.700 g). Sodium borohydride (8.42 mmol, 0.325 g) was then added portionwise to the pale greenish-blue solution. After 30 minutes the cooling was removed and the reaction mixture allowed to warm to ambient temperature. After stirring for 5 hours, at ambient temperature, the reaction mixture was cooled to 5-10 C., in an ice-water bath, and slowly quenched with ammonium chloride solution, and the mixture stirred for a further 20 minutes. The mixture was then diluted with EtOAc (20 mL), and filtered through a bed of celite, washing through with portions of water and EtOAc. The collected two-phase mixture was concentrated to remove the bulk of solvent and the residue transferred to a separating funnel, diluted with EtOAc (20 mL) and the organic phase separated. The aqueous phase was further extracted with EtOAc (225 mL) and all organic extracts combined, passed through a phase separation concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pale yellow oil, 0.61 g (77%) which crystallised on standing.

(11) 1H NMR (400 MHz, CDCl.sub.3) =6.91 (br s, 1H), 6.47 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.14 (q, 1H), 3.94 (d, 3H), 3.80 (dt, J=1.0, 9.0 Hz, 1H), 3.63 (d, J=9.3 Hz, 1H), 3.52 (dd, J=8.2, 9.5 Hz, 1H), 1.32 (t, J=7.2 Hz, 3H).

Step 5 (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic Acid

(12) To a solution of ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate (0.61 g, 2.0 mmol) in ethanol (6.0 mL) and water (2.0 mL) at 0 C. (ice bath) was added 2M sodium hydroxide (3 mL, 6.0 mmol). The reaction mixture was stirred at 0 C. for 30 minutes and then diluted with water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with water (10 mL), and the aqueous extracts combined and acidified to pH 2 with dilute HCl. The acidified aqueous extracts were then re-extracted with EtOAc (320 mL) and these organic extracts were run through a phase separation cartridge and concentrated affording a pale yellow oil, 0.54 g (quantitative) which crystallised on standing.

(13) .sup.1H NMR (400 MHz, CDCl3) =6.59 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.85-3.77 (m, 1H), 3.72 (d, J=10.0 Hz, 1H), 3.66-3.58 (m, 1H).

Step 6 (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic Acid

(14) To a stirred solution of (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.57 g, 2.1 mmol, 0.57 g) in tetrahydrofuran (16 mL), at room temperature, under a nitrogen atmosphere was added potassium tertiary butoxide (1.0M in THF) (4.5 mL, 4.5 mmol) giving a pale yellow fine suspension. To this suspension was added iodomethane (0.19 mL, 3.1 mmol), and stirring at room temp was continued for 20 h. The stirred reaction mixture was acidified to pH2 with dilute HCl and the mixture was diluted with water (10 mL) and extracted with EtOAc (330 mL). The combined organic extracts were washed with brine (15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated giving a transparent amber gum, 0.63 g ((quantitative).

(15) .sup.1H NMR: (400 MHz, CDCl3) =6.68 (s, 1H), 3.97 (q, 1H), 3.94 (s, 3H), 3.76-3.68 (m, 3H), 2.99 (s, 3H).

Step 7 (3S,4R)N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(16) To a solution of (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.61 g, 2.1 mmol) in dichloromethane (15 mL) was added 2,3-difluoroaniline (0.21 mL, 2.1 mmol). Propylphosphonic anhydride (50 mass %) in ethyl acetate (2.3 g, 3.6 mmol, 2.1 mL) was then added, and the reaction mixture was then immersed in a room temp water bath. N,N-Diisopropylethylamine (1.1 mL, 6.3 mmol) was added drop-wise, and the reaction was stirred at room temperature for 2.5 hour. The reaction mixture was quenched by the addition of water (15 mL) and transferred to a phase sep cartridge. The aqueous was further extracted with DCM (210 mL) and the combined organic extracts were concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pink oil. Trituration with iso-hexane afforded a pale pink solid 398 mg (47%).

(17) 1H NMR: (400 MHz, CDCl.sub.3) =10.16 (br s, 1H), 8.08-8.01 (m, 1H), 7.02 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 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 (s, 3H).

(18) Chiral HPLC analysis, by the methods stated above, confirmed an enantiomeric ratio of 97:3.

Example 2: Preparation of (3S,4S)N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide

(19) The herbicidal compound (3S,4S)N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide was made in a directly analogous manner to that described above for (3S,4R)N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide in Example 1 above. NMR data for the single enantiomer is as follows:

(20) 1HNMR (CDCl.sub.3) =10.05 (br s, 1H), 8.04-7.97 (m, 1H), 7.46 (s, 1H), 7.01 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 4.21 (q, J=8.8 Hz, 1H), 4.00 (s, 3H), 3.75 (t, J=9.5 Hz, 1H), 3.64 (d, J=9.4 Hz, 1H), 3.27 (dd, J=8.1, 9.9 Hz, 1H), 2.97 (s, 3H).