Herbicidal compounds

Abstract

The present invention relates to herbicidally-active pyridino-/pyrimidino-pyrazole derivatives, as well as to processes and intermediates used for the preparation of such derivatives. 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.

Claims

1. A method, comprising: applying, to a weed or to the locus thereof, a controlling amount of at least 50 g/ha of a compound of formula (I), ##STR00116## or a salt or N-oxide thereof, wherein Q is a ring system selected from ##STR00117## wherein A denotes the point of attachment to the heteroaryl ring, and B denotes the point of attachment to the nitrogen atom; X.sub.1 is N or CR.sup.1; R.sup.1 is hydrogen or halogen; R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6haloalkyl; R.sup.3 is hydrogen C.sub.1-C.sub.6alkyl, or C.sub.2-C.sub.6 alkenyl; R.sup.4 is O or S; X.sub.2 is O, S, or NR.sup.8; R.sup.5 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.6-C.sub.10aryl or C.sub.6-C.sub.10aryl substituted by 1 to 3 groups independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3 haloalkyl, or C.sub.3-C.sub.10heterocyclyl or C.sub.3-C.sub.10heterocyclyl substituted by 1 to 3 groups independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3 haloalkyl; or R.sup.3 and R.sup.8 together with the atoms to which they are attached form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; R.sup.8 is hydrogen or C.sub.1-C.sub.6alkyl; R.sup.9 is hydrogen or halogen; and R.sup.10 is hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; with proviso that when Q is Q1, X.sub.2 is O or S, and R.sup.5 is tert-butyl, R.sup.2 is not hydrogen, methyl, or chlorine; and wherein the proviso excludes a compound selected from the group consisting of: ##STR00118##

2. The method of claim 1, wherein R.sup.5 is C.sub.1-C.sub.6alkyl.

3. The method of claim 2, wherein R.sup.5 is tert-butyl.

4. The method of claim 3, wherein R.sup.4 is O and X.sub.2 is O.

5. The method of claim 1, wherein Q is Q1.

6. The method of claim 1, wherein Q is Q2.

7. The method of claim 1, wherein the controlling amount is 50 to 1000 g/ha.

8. The method of claim 7, wherein applying is to the weed.

9. The method of claim 8, further comprising identifying the weed prior to the applying to the weed.

10. The method of claim 9, wherein the controlling amount is a killing amount.

11. The method of claim 9, wherein the weed is selected from the group consisting of Brachiaria, Cenchrus, Digitaria, Echinochloa, Eleusine, Eriochloa, Panicum, Setaria, Sorghum, Agrostis, Alopecurus, Apera, Avena, Bromus, Lolium and Poa.

12. The method of claim 9, wherein the weed is Echinochloa crus-galli.

13. The method of claim 9, wherein the weed is Oryza sativa.

14. The method of claim 9, wherein the weed is Avena fatua.

15. The method of claim 9, wherein the weed is Alopecurus myosuroides.

16. The method of claim 9, wherein the compound of formula (I) is in a formulation.

17. The method of claim 16, wherein the formulation further comprises at least one additional pesticide selected from the group consisting of an herbicide and herbicide safener.

18. The method of claim 17, wherein when the at least one additional pesticide is an herbicide, the herbicide is selected from the group consisting of: acetochlor, acifluorfen, acifluorfen-sodium, aclonifen, acrolein, alachlor, alloxydim, ametryn, amicarbazone, amidosulfuron, aminopyralid, amitrole, anilofos, asulam, atrazine, azafenidin, azimsulfuron, BCPC, beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron, bensulfuron-methyl, bensulide, bentazone, benzfendizone, benzobicyclon, benzofenap, bicyclopyrone, bifenox, bilanafos, bispyribac, bispyribac-sodium, borax, bromacil, bromobutide, bromoxynil, butachlor, butamifos, butralin, butroxydim, butylate, cacodylic acid, calcium chlorate, cafenstrole, carbetamide, carfentrazone, carfentrazone-ethyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chloroacetic acid, chlorotoluron, chlorpropham, chlorsulfuron, chlorthal, chlorthal-dimethyl, cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim, clodinafop, clodinafop-propargyl, clomazone, clomeprop, clopyralid, cloransulam, cloransulam-methyl, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cyhalofop, cyhalofop-butyl, 2,4-D, daimuron, dalapon, dazomet, 2,4-DB, desmedipham, dicamba, dichlobenil, dichlorprop, dichlorprop-P, diclofop, diclofop-methyl, diclosulam, difenzoquat, difenzoquat metilsulfate, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethylarsinic acid, dinitramine, dinoterb, diphenamid, dipropetryn, diquat, diquat dibromide, dithiopyr, diuron, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethephon, ethofumesate, ethoxyfen, ethoxysulfuron, etobenzanid, fenoxaprop-P, fenoxaprop-P-ethyl, fentrazamide, ferrous sulfate, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-butyl, fluazifop-P, fluazifop-P-butyl, fluazolate, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flufenacet, flufenpyr, flufenpyr-ethyl, flumetralin, flumetsulam, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropin, fluometuron, fluoroglycofen, fluoroglycofen-ethyl, fluoxaprop, flupoxam, flupropacil, flupropanate, flupyrsulfuron, flupyrsulfuron-methyl-sodium, flurenol, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, fluthiacet-methyl, fomesafen, foramsulfuron, fosamine, glufosinate, glufosinate-ammonium, glyphosate, halauxifen, halosulfuron, halosulfuron-methyl, haloxyfop, haloxyfop-P, hexazinone, imazamethabenz, imazamethabenz-methyl, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodomethane, iodosulfuron, iodosulfuron-methyl-sodium, ioxynil, isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, lactofen, lenacil, linuron, mecoprop, mecoprop-P, mefenacet, mefluidide, mesosulfuron, mesosulfuron-methyl, mesotrione, metam, metamifop, metamitron, metazachlor, methabenzthiazuron, methazole, methylarsonic acid, methyldymron, methyl isothiocyanate, metolachlor, S-metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, metsulfuron-methyl, molinate, monolinuron, naproanilide, napropamide, naptalam, neburon, nicosulfuron, n-methyl glyphosate, nonanoic acid, norflurazon, oleic acid, orbencarb, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxasulfuron, oxaziclomefone, oxyfluorfen, paraquat, paraquat dichloride, pebulate, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, pethoxamid, phenmedipham, picloram, picolinafen, pinoxaden, piperophos, pretilachlor, primisulfuron, primisulfuron-methyl, prodiamine, profoxydim, prohexadione-calcium, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propoxycarbazone-sodium, propyzamide, prosulfocarb, prosulfuron, pyraclonil, pyraflufen, pyraflufen-ethyl, pyrasulfotole, pyrazolynate, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazoxyfen, pyribenzoxim, pyributicarb, pyridafol, pyridate, pyriftalid, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyrithiobac-sodium, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quizalofop, quizalofop-P, rimsulfuron, saflufenacil, sethoxydim, siduron, simazine, simetryn, sodium chlorate, sulcotrione, sulfentrazone, sulfometuron, sulfometuron-methyl, sulfosate, sulfosulfuron, sulfuric acid, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbumeton, terbuthylazine, terbutryn, thenylchlor, thiazopyr, thifensulfuron, thiencarbazone, thifensulfuron-methyl, thiobencarb, topramezone, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron, tribenuron-methyl, triclopyr, trietazine, trifloxysulfuron, trifloxysulfuron-sodium, trifluralin, triflusulfuron, triflusulfuron-methyl, trihydroxytriazine, trinexapac-ethyl, tritosulfuron, and [3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl ester; and when the at least one additional pesticide is a herbicide safener, the herbicide safener is selected from the group consisting of: benoxacor, cloquintocet-mexyl, cyprosulfamide, dichlormid, fenchlorazole-ethyl, fenclorim, fluxofenim, furilazole and the corresponding R isomer, isoxadifen-ethyl, mefenpyr-diethyl, oxabetrinil, N-isopropyl-4-(2-methoxy-benzoyl sulfamoyl)-benzamide, and N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.

19. The method of claim 16, wherein the formulation consists essentially of the compound of formula (I).

20. The method of claim 16, wherein the only active ingredient in the formulation is the compound of formula (I).

21. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: ##STR00119## ##STR00120## ##STR00121## ##STR00122##

Description

PREPARATION EXAMPLES

(1) Throughout the following examples, .sup.1H NMR spectra were recorded at 400 MHz or 500 MHz either on a Varian Unity Inova instrument or Bruker AVANCE-II instrument.

(2) The following abbreviations are used: s=singlet; bs=broad singlet; d=doublet; bd=broad doublet; dd=double doublet; t=triplet, q=quartet; m=multiplet; THF=tetrahydrofuran; EtOAc=ethyl acetate; EtOH=ethanol; DMSO=dimethyl sulfoxide; DPPA=diphenylphosphoryl azide; DMF=N, N-dimethyl formamide; dppf=1,1-bis(diphenylphosphino)ferrocene; Pd(OAc).sub.2=palladium(II) acetate; Et.sub.3N=triethylamine; MeOH=methanol.

(3) Chemical names were generated using the Text from structure feature in Accelrys Draw 4.0.

Example P1 Preparation of Compound A2, tert-butyl N-[2-methyl-5-(3-pyridyl) pyrazol-3-yl]carbamate

1.1 Step 1: Preparation of ethyl 2,4-dioxo-4-(3-pyridyl)butanoate

(4) ##STR00069##
NaH (60% w/w, 9.91 g, 248.0 mmol) was added to a flask charged with dry THF (170 mL). Diethyl oxalate (24.13 g, 165.1 mmol) was added and washed in with dry THF (15 mL). The mixture was heated to reflux, then a solution of 1-(3-pyridyl)ethanone (10.0 g, 82.55 mmol) in THF (15 mL) was added slowly with stirring at reflux. After 15 minutes the mixture was cooled to room temperature and slowly added, with stirring and cooling, to a mixture of 2M HCl (130 mL) in water (375 mL). The resulting mixture was treated with solid NaHCO.sub.3 until slightly basic then extracted three times with EtOAc. The combined organics were washed once with brine, dried (MgSO.sub.4) and concentrated in vacuo to yield a dark brown gum, which solidified on standing.

(5) Mineral oil was removed by washing and decanting with hexane. The solid was dissolved in warm ethanol (350 mL) and treated with decolourising charcoal. After 5 minutes the solution was filtered hot, through celite. The filtrate was concentrated in vacuo to give crude ethyl 2,4-dioxo-4-(3-pyridyl)butanoate (15.0 g) which was used without further purification.

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.21 (1H, d), 8.83 (1H, dd), 8.29 (1H, m), 7.46-7.52 (1H, m), 7.08 (1H, s), 4.39-4.46 (2H, q), 1.40-1.46 (3H, t).

1.2 Step 2: Preparation of ethyl 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylate

(7) ##STR00070##

(8) To a flask charged with ethyl 2,4-dioxo-4-(3-pyridyl)butanoate (10.0 g, 45.2 mmol), dissolved in EtOH (120 mL) was added methylhydrazine (2.4 mL, 46.0 mmol) The mixture was heated to reflux for 2.5 hours then left to stand overnight.

(9) The solvent was removed in vacuo and the crude material purified via flash column chromatography on silica gel using an EtOAc/hexane gradient to afford ethyl 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylate (2.52 g).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.02 (1H, m), 8.56 (1H, dd), 8.11 (1H, m), 7.34 (1H, dd), 7.17 (1H, s), 4.39 (2H, q), 4.25 (3H, s), 1.42 (3H, t)

1.3 Step 3: Preparation of ethyl 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylate

(11) ##STR00071##

(12) To a flask charged with ethyl 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylate (2.52 g, 10.9 mmol) dissolved in 1,4-dioxane (17 mL), cooled in an ice bath was added NaOH (1.09 g, 27.3 mmol) in water (3.3 mL) drop-wise. The resulting bi-phasic solution was stirred at ambient temperature for 2 hours, after which time water was added portionwise until homogeneous (13.2 mL).

(13) The reaction mixture was stirred at ambient temperature for a further 2 hours, after which time solvent was concentrated to ca. 50% volume in vacuo and diluted with water (20 mL). The reaction mixture was acidified with 2M HCl (13.5 mL) and the solid precipitate filtered off at the pump, washed with water and air dried overnight to afford 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylic acid (1.70 g) as an off-white solid.

(14) .sup.1H NMR (400 MHz, d.sub.6-DMSO) =9.06 (1H, m), 8.53 (1H, dd), 8.20 (1H, d), 7.45 (1H, m), 7.43 (1H, s), 4.15 (3H, s).

1.4 Step 4: Preparation of tert-butyl N-[2-methyl-5-(3-pyridyl)pyrazol-3-yl]carbamate

(15) ##STR00072##

(16) To a flask charged with 2-methyl-5-(3-pyridyl)pyrazole-3-carboxylic acid (1.70 g, 8.34 mmol) suspended in tert-butanol (37 mL) and toluene (37 mL) was added triethylamine (1.18 mL, 8.38 mmol) and DPPA (2.30 g, 8.40 mmol) drop-wise with stirring and the resulting mixture was then heated gradually to reflux. After 4.5 hours at reflux the reaction mixture was allowed to cool and the solvent was removed in vacuo. The residue was purified via flash column chromatography on silica gel using an EtOAc/hexane gradient to afford tert-butyl N-[2-methyl-5-(3-pyridyl)pyrazol-3-yl]carbamate (0.75 g) as a colourless gum.

(17) .sup.1H NMR (400 MHz, CDCl.sub.3) =8.98 (1H, bs), 8.53 (1H, bs), 8.05 (1H, m), 7.30 (1H, m), 6.63 (1H, bs), 6.53 (1H, bs), 3.81 (3H, s), 1.53 (9H, s).

Example P2 Preparation of Compound A1, tert-butyl N-methyl-N-[2-methyl-5-(3-pyridyl)pyrazol-3-yl]carbamate

(18) ##STR00073##

(19) tert-Butyl N-[2-methyl-5-(3-pyridyl)pyrazol-3-yl]carbamate (245 mg, 0.893 mmol) was dissolved in dry DMF (2.5 mL), cooled in an ice bath, then NaH (60% w/w, 42.9 mg, 1.07 mmol) added as a single portion. After 5 minutes the mixture was allowed to warm to ambient temperature for 5 minutes (solution turned brown). The ice bath was reapplied and a solution of MeI (133.1 mg, 0.938 mmol) in dry DMF (0.7 mL) was added dropwise. After 30 minutes the reaction was warmed to ambient temperature and stirred for a further hour.

(20) Reaction was quenched with water (13 mL) containing 2M HCl (89 L). The mixture was extracted three times with EtOAc, and the combined organics washed twice with brine and then dried (MgSO.sub.4). The solvent was concentrated in vacuo and the residue was purified via flash column chromatography on silica gel using an EtOAc/hexane gradient to afford tert-butyl N-methyl-N-[2-methyl-5-(3-pyridyl)pyrazol-3-yl]carbamate (125.0 mg) as an amber gum.

(21) .sup.1H NMR (400 MHz, CDCl.sub.3) =8.97 (1H, d), 8.51-8.56 (1H, m) 8.07 (1H, d), 7.28-7.35 (1H, m), 6.40 (1H, s), 3.75 (3H, s), 3.22 (3H, s), 1.45 (9H, s).

Example P3 Preparation of Compound A3, tert-butyl N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate

3.1 Step 1: Preparation of ethyl 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylate

(22) ##STR00074##

(23) To a flask charged with 5-bromopyrimidine (248 mg, 1.56 mmol) dissolved in 1,4-dioxane (5 mL) was added K.sub.2CO.sub.3 (359 mg, 2.59 mmol), CuI (124 mg, 0.065 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (28.5 mg, 0.195 mmol) and ethyl 3-methyl-1H-pyrazole-4-carboxylate (200 mg, 1.30 mmol). This gave a blue suspension which was heated to 110 C. and stirred overnight.

(24) Overnight the reaction had become dark grey. After cooling, the reaction mixture was poured into EtOAc and water. This was extracted twice with EtOAc. The combined organics were washed with brine and dried (MgSO.sub.4), the combined organics were concentrated in vacuo to yield a brown solid which was purified via flash column chromatography on silica gel using an EtOAc/hexane gradient to afford ethyl 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylate (255 mg) as a white solid.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.18 (1H, s), 9.14 (2H, s), 8.42 (1H, s), 4.35 (2H, q), 2.58 (3H, s), 1.39 (3H, t).

3.2 Step 2: Preparation of 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylic Acid

(26) ##STR00075##

(27) To a flask charged with ethyl 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylate (180 mg, 0.775 mmol) in 1,4-dioxane (3.4 mL) was added NaOH (68.2 mg 1.71 mmol) dissolved in water (1.7 mL) to form a yellowish solution which was stirred at 55 C. overnight.

(28) The reaction mixture was concentrated in vacuo to remove the organics and the aqueous layer was acidified to pH 3 with 1M HCl to give a white solid. The precipitate was filtered off at the pump and washed twice with water, then washed with EtOAc and air-dried to give a 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylic acid (84 mg) as a white solid

(29) .sup.1H NMR (400 MHz, d6-DMSO) =9.35 (2H, s), 9.15 (1H, s), 9.10 (1H, s), 2.42 (3H, s).

3.3 Step 3: Preparation of tert-butyl N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate, Compound A3

(30) ##STR00076##

(31) To a flask charged with 3-methyl-1-pyrimidin-5-yl-pyrazole-4-carboxylic acid (0.206 g, 1.01 mmol) and tert-butanol (7 mL) was added triethylamine (0.141 mL, 1.0 mmol) dropwise via syringe. To this was added DPPA (0.219 mL 1.01 mmol) dropwise via syringe and the mixture heated to reflux overnight.

(32) Overnight a white precipitate formed and upon cooling this was filtered off at the pump and the filtrate concentrated in vacuo to leave a yellow residue. This was partitioned between water and EtOAc. The aqueous was extracted with 3 further portions of EtOAc. The combined organics were washed with brine, dried (MgSO.sub.4), and evaporated to dryness to give a cream solid (297 mg). The crude product was purified via flash column chromatography on silica gel eluting with an EtOAc/hexane gradient to afford tert-butyl N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate as a white solid (64 mg).

(33) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.08 (3H, s), 8.28 (1H, s), 6.17 (1H, s), 2.31 (3H, s), 1.54 (9H, s).

Example P4 Preparation of tert-butyl N-methyl-N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate, Compound A5

(34) ##STR00077##

(35) To a flask charged with tert-butyl N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate (68.0 mg, 0.25 mmol) dissolved in DMF (1 mL), under nitrogen, and cooled in an ice bath ice, was added NaH (60% w/w 11.0 mg, 0.27 mmol) as a single portion to give a bright yellow solution. The mixture was stirred in an ice bath for 10 minutes then allowed to warm to ambient temperature for 40 minutes. The ice bath was reapplied and MeI (16 L, 0.26 mmol) was added dropwise via syringe. The reaction was stirred at ambient temperature for 2 hours and quenched with water and extracted twice with Et.sub.2O. The combined organics were washed with brine, dried (MgSO.sub.4), and concentrated in vacuo to give tert-butyl N-methyl-N-(3-methyl-1-pyrimidin-5-yl-pyrazol-4-yl)carbamate (51 mg) as a white solid.

(36) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.10 (1H, s), 9.06 (2H, s), 7.85 (1H, s), 3.21 (3H, s), 2.28 (3H, s), 1.57 (9H, s).

Example P5 Preparation of isopropyl N-[2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-yl]carbamate, Compound A58

Step One: Synthesis of methyl pyrimidine-5-carboxylate

(37) ##STR00078##

(38) Carbon monoxide gas was introduced to a mixture of 5-bromopyrimidine (15.9 g, 0.1 mol), dppf (2.22 g, 4 mmol), Pd(OAc).sub.2 (448 mg, 2 mmol) and Et.sub.3N (20.2 g, 0.2 mol) in MeOH (120 mL) and the internal pressure was increased to 30 bar. The reaction mixture was stirred at 95 C. for about 4 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5:1) to provide methyl pyrimidine-5-carboxylate (9.6 g, 70% yield) as a white solid.

(39) .sup.1H NMR (400 MHz, CDCl3) =9.36 (1H, s), 9.27 (2H, s), 3.98 (3H, s).

Step Two: Synthesis of 3-pyrimidin-5-yl-1H-pyrazol-5-amine

(40) ##STR00079##

(41) Methyl pyrimidine-5-carboxylate (5.3 g, 38 mmol) was added to a suspension of NaH (2.4 g, 60 mmol) in acetonitrile (1.57 g, 38 mmol) and THF (50 mL), and the mixture was heated under reflux overnight. The precipitate was filtered off and washed with diethyl ether to give 3-oxo-3-pyrimidin-5-yl-propanenitrile sodium salt as a yellow solid, which was directly used in the next step without further purification.

(42) A mixture of the 3-oxo-3-pyrimidin-5-yl-propanenitrile sodium salt (5 g), hydrazine hydrochloride (3.0 g, 44 mmol), acetic acid (1.7 g, 30 mmol) and hydrochloric acid (0.2 mL, 1M) in EtOH (100 mL) was heated under reflux for 3 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the 5-pyrimidin-5-yl-1H-pyrazol-3-amine (1.5 g) as a yellow solid.

(43) .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.84 (1H, bs), 9.03 (3H, s), 5.85 (1H, s), 5.09 (2H, bs).

Step Three: Synthesis of 2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-amine

(44) ##STR00080##

(45) CHClF.sub.2 (26.66 g, 310 mmol) was introduced to a mixture of 5-pyrimidin-5-yl-1H-pyrazol-3-amine (5 g, 31 mmol) and KOH (8.68 g, 155 mmol) in dioxane (30 mL) and water (20 mL) in an autoclave. The reaction mixture was heated at 100 C. and the internal pressure increased to 15 bar. After stirring for 4 h, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted three times with EtOAc. The combined extracts were dried over anhydrous sodium sulfate, concentrated under vacuum and purified by flash chromatography on silica gel (eluent petroleum ether/ethyl acetate 3:1) to give 1-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-amine (260 mg) and the desired 2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-amine (260 mg) as a yellow solid.

(46) .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.17 (1H, s), 9.14 (2H, s), 7.65 (1H, t), 6.19 (2H, s), 5.97 (1H, s).

Step Four: Synthesis of isopropyl N-[2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-yl]carbamate, Compound A58

(47) ##STR00081##

(48) To a vial charged with 2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-amine (100 mg, 0.47 mmol) was added dichloromethane (7 mL) with pyridine (94 mg, 1.184 mmol) and the mixture stirred for 5 minutes. Isopropyl chloroformate (1M in toluene) (0.59 mmol, 0.59 mL) was added dropwise and the mixture allowed to stir overnight. The sample was concentrated in vacuo and pre-adsorbed onto silica gel prior to purification via flash column chromatography using an EtOAc/Hexanes gradient to give the desired product as a thick gum (82 mg).

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.22 (1H, s), 9.16 (2H, s), 7.28 (1H, t), 7.20 (1H, bs), 6.92 (1H, bs), 5.05 (1H, m), 1.30 (6H, d).

Example P6 Preparation of isopropyl N-[2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-yl]-N-methyl-carbamate, Compound A59

(50) ##STR00082##

(51) To a flask charged with isopropyl N-[2-(difluoromethyl)-5-pyrimidin-5-yl-pyrazol-3-yl]carbamate (82 mg, 0.276 mmol) was added DMF (5 mL) and stirred until homogeneous. The mixture was cooled to 0 C. (ice bath) and sodium hydride (65% w/w in mineral oil) (12 mg, 0.29 mmol) was added as a single portion. After 5 minutes the mixture was removed from the ice bath and stirred at ambient for a further 5 minutes. The flask was then re-cooled to 0 C. (ice bath) and iodomethane (42 mg, 0.295 mmol, 0.0180 mL) was added dropwise. After 10 minutes the mixture was allowed to warm to ambient and stirred for a further 30 minutes. The mixture was quenched with 2M HCl (500 L) and concentrated in vacuo. The resulting residue was then dissolved in CH.sub.2Cl.sub.2 and pre-adsorbed onto silica gel prior to purification via flash column chromatography on silica gel using an EtOAc/hexanes gradient. This gave the desired compound as a white solid (44 mg).

(52) .sup.1H NMR (400 MHz, CDCl.sub.3) =9.22 (1H, s), 9.12 (2H, s), 7.14 (1H, t), 6.60 (1H, s), 4.98 (1H, m), 3.27 (3H, s), 1.22 (6H, bd).

Example P7 Preparation of tert-butyl N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-N-methyl-carbamate, Compound A60

tert-Butyl N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]carbamate was Prepared According to Procedures in U.S. Pat. No. 8,901,153

(53) ##STR00083##

(54) To a flask charged with tert-butyl N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]carbamate (200 mg, 0.69 mmol) in DMF (6 mL) and cooled in an ice bath was added sodium hydride (60% w/w in oil) (30 mg, 0.75 mmol) portionwise over ca. 5 mins. The reaction mixture turned a deep yellow colour over this time and a fine precipitate could be observed. The mixture was then warmed to ambient and stirred for 5 minutes. The ice bath was re-applied and iodomethane (212 mg, 1.49 mmol, 92 L) was added dropwise. The mixture was stirred in the ice bath for 2 hours, then allowed to warm to ambient and diluted with brine (5 mL). The reaction was extracted with EtOAc (310 mL) and the combined organics were concentrated in vacuo and then loaded onto a SiO.sub.2 column then purified via flash column chromatography on silica gel (eluted with EtOAc/hexane gradient) to give the desired compound as a colourless oil (102 mg).

(55) .sup.1H NMR (400 MHz, CDCl.sub.3) =8.92 (1H, d), 8.57 (1H, d), 8.07 (1H, m), 7.90 (1H, bs), 7.42 (1H, m), 3.22 (3H, s), 1.39 (9H, s).

(56) Further examples of the invention were made in an analogous way using the methods described above in Examples P1 to P7 with respect to compounds A1, A2, A3, A5, A58, A59 and A60. Table 2 below, summarises the physical data for such compounds.

(57) TABLE-US-00002 TABLE 2 Compounds made by the methods described above. Cmpd Structure Physical Data 1H NMR (400 MHz, CDCl.sub.3) unless stated A1 8.97 (1H, d), 8.51-8.56 (1H, m) 8.07 (1H, d), 7.28-7.35 (1H, m), 6.40 (1H, s), 3.75 (3H, s), 3.22 (3H, s), 1.45 (9H, s) A2 8.98 (1H, bs), 8.53 (1H, bs), 8.05 (1H, m), 7.30 (1H, m), 6.63 (1H, br. s), 6.53 (1H, bs), 3.81 (3H, s), 1.53 (9H, s), A3 9.08 (3H, s), 8.28 (1H, s), 6.17 (1H, s), 2.31 (3H, s), 1.54 (9H, s) A4 9.20 (1H, s), 9.04 (2H, s), 8.59 (1H, s), 6.62 (1H, bs), 1.55 (9H, s) A5 9.10 (1H, s), 9.06 (2H, s), 7.85 (1H, s), 3.21 (3H, s), 2.28 (3H, s), 1.57 (9H, s) A6 9.24 (2H, s), 9.14 (1H, s), 8.01 (1H, s), 3.20 (3H, s), 1.40 (9H, s) A7 0 9.03 (1H, d), 8.62 (1H, dd), 8.55 (1H, s), 8.04 (1H, dd), 7.41 (1H, dd), 6.53 (1H, br. s), 1.52 (9H, bs) A8 8.91 (1H, d), 8.52 (1H, d), 8.04 (1H, m), 7.89 (1H, bs), 7.41 (1H, dd), 3.22 (3H, s), 2.29 (3H, s), 1.47 (9H, bs) A10 8.71 (1H, s), 8.36 (1H, d), 7.90-7.73 (2H, m), 3.20 (3H, s), 2.27 (3H, s), 1.46 (9H, bs) A14 9.13 (1H, s), 9.10 (2H, s), 6.43 (1H, s), 3.75 (3H, s), 3.21 (3H, s), 2.22 (3H, s), 1.45 (9H, s) A16 9.14 (1H, s), 9.12 (2H, s), 8.02 (1H, s), 4.36 (1H, s), 3.18 (3H, s), 2.29 (3H, s), 1.31 (9H, s) A19 8.82 (1H, d), 8.54 (1H, d), 8.12 (1H, d), 7.94 (1H, m), 3.18 (3H, s), 1.30 (9H, s) A25 9.24 (2H, s), 9.14 (1H, s), 8.01 (1H, s), 3.20 (3H, s), 1.40 (9H, s) A27 8.79 (1H, d), 8.52 (1H, d), 8.01 (1H, br. s), 7.92 (1H, m), 3.70 (3H, bs), 3.26 (3H, s) A39 9.17 (1H, bs), 8.63-8.55 (1H, m), 8.20 (1H, d), 7.40-7.31 (1H, m), 3.76 (3H, s), 3.22 (3H, s), 1.61-1.35 (9H, m) A43 9.28 (1H, s), 9.16 (2H, s), 8.22 (1H, s), 4.12 (2H, q), 3.32 (3H, s), 1.13 (3H, t) A44 00 9.19-9.05 (3H, m), 7.99 (1H, s), 4.31 (1H, d), 3.76-3.53 (1H, m), 3.21 (3H, s), 2.28 (3H, s), 1.96-1.84 (2H, m), 1.72-1.53 (3H, m), 1.42-1.25 (3H, m), 1.11-0.93 (3H, m) A45 01 9.20 (3H, bs), 8.13 (1H, s), 5.68 (1H, s), 3.30 (3H, s), 2.40 (3H, s), 2.29 (3H, s), 2.16 (3H, s) A46 02 8.80 (1H, bs), 8.52 (1H, bs), 8.14 (1H, s), 7.91 (1H, d), 7.33 (2H, t), 7.05 (1H, d), 7.24-6.98 (1H, m), 3.34 (3H, s) A47 03 8.79 (1H, s), 8.51 (1H, d), 8.14-7.96 (1H, m), 7.92 (1H, d), 4.16 (2H, bs), 3.25 (3H, s), 1.38-1.11 (3H, m) A48 04 8.79 (1H, d), 8.51 (1H, d), 8.02 (2H, s), 3.20 (3H, s), 1.41 (9H, bs) A49 05 9.26 (1H, s), 8.83 (2H, s), 6.70 (1H, br s), 3.82 (3H, s), 3.38 (3H, s), 2.22 (3H, s), 1.54 (9H, s) A51 06 9.10 (1H, s), 9.06 (2H, s), 7.80 (1H, s), 3.12 (3H, s), 2.60 (3H, s), 2.29 (3H, s), 1.36 (9H, s) A52 07 9.17-9.09 (3H, m), 8.09 (1H, s), 7.55-7.47 (4H, m), 6.80 (1H, s), 3.30 (3H, s), 2.33 (3H, s) A53 08 9.17-8.97 (3H, m), 7.86 (1H, s), 3.23-3.04 (7H, m), 2.27 (3H, s), 1.82-1.69 (4H, m) A54 09 8.77 (1H, s), 8.50 (1H, d), 7.91 (2H, m), 5.99-5.73 (1H, m), 5.26-5.03 (2H, m), 4.16-4.04 (2H, m), 1.41 (9H, bs) A55 0 8.80 (1H, s), 8.50 (1H, d), 8.06-7.85 (2H, m), 3.60 (2H, q), 1.40 (9H, bs), 1.17 (3H, t) A56 9.25 (1H, s), 9.15 (2H, s), 8.00 (1H, s), 3.60 (2H, q), 1.45 (9H, s), 1.20 (3H, t) A57 8.98 (1H, d), 8.50-8.46 (2H, m), 8.18 (1H, dd), 7.53 (1H, dd), 4.62 (1H, br), 1.53 (9H, s) A58 9.22 (1H, s), 9.16 (2H, s), 7.28 (1H, t), 7.20 (1H, bs), 6.92 (1H, bs), 5.05 (1H, m), 1.30 (6H, d) A59 9.22 (1H, s), 9.12 (2H, s), 7.14 (1H, t), 6.60 (1H, s), 4.98 (1H, m), 3.27 (3H, s), 1.22 (6H, bd) A60 8.92 (1H, d), 8.57 (1H, d), 8.07 (1H, m), 7.90 (1H, bs), 7.42 (1H, m), 3.22 (3H, s), 1.39 (9H, s)

Biologicial Examples

B1 Pre-Emergence Herbicidal Activity

(58) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE). After cultivation for one day (pre-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). The test plants were then grown in a glasshouse under controlled conditions (at 24/16 C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown below in Table 3.

(59) TABLE-US-00003 TABLE 3 Control of weed species by compounds of formula (I) after pre-emergence application Rate Compound (g/ha) ECHCG ORYSA ALOMY AVEFA LOLPE TRZAW A1 1000 3 1 0 1 1 0 A3 500 4 1 0 0 0 1 A4 1000 4 1 0 1 0 0 A5 1000 5 2 1 4 1 4 A6 1000 5 2 0 3 1 0 A7 500 2 1 0 0 0 0 A8 1000 3 0 0 1 1 0 A10 1000 4 1 0 2 1 0 A14 1000 3 0 1 3 0 1 A16 1000 2 1 1 1 1 1 A19 1000 2 0 0 0 1 0 A27 1000 2 0 0 0 0 0 A39 1000 3 1 0 4 0 0 A44 1000 1 1 0 1 1 1 A46 1000 0 0 0 0 0 0 A47 1000 1 0 0 0 0 0 A48 1000 3 1 1 0 1 1 A51 1000 1 1 0 0 0 0 A52 1000 0 0 0 0 0 0 A53 1000 0 0 0 0 0 0 A54 1000 0 0 0 0 0 0 A55 1000 0 0 0 0 0 0 A56 1000 1 0 0 0 0 0

B1a Pre-Emergence Herbicidal Activity

(60) Seeds of a variety of test species were sown in standard soil in pots: Amaranthus retroflexus (AMARE), Setaria faberi (SETFA), Zea mays (ZEAMX), Abutilon threophrasti (ABUTH), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE). After cultivation for one day (pre-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). The test plants were then grown in a glasshouse under controlled conditions (at 24/16 C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown below in Table 4

(61) TABLE-US-00004 TABLE 4 Control of weed species by compounds of formula (I) after pre-emergence application Rate Compound (g/ha) LOLPE AMARE SETFA ECHCG ZEAMX ABUTH A43 1000 0 0 0 0 0 0 A45 1000 0 0 0 0 0 0 A57 1000 0 0 0 0 1 0 A58 1000 0 0 2 1 0 0 A59 1000 0 0 3 2 2 0 A60 1000 0 1 4 2 2 0

B2 Post-Emergence Herbicidal Activity

(62) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE). 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). The test plants were then grown in a glasshouse under controlled conditions (at 24/16 C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown in Table 5 below.

(63) TABLE-US-00005 TABLE 5 Control of weed species by compounds of formula (I) after post-emergence application Rate Compound (g/ha) ECHCG ORYSA ALOMY AVEFA LOLPE TRZAW A1 1000 5 4 3 1 1 1 A3 500 5 1 2 4 2 1 A4 1000 5 2 1 1 1 1 A5 1000 5 5 4 0 2 2 A6 1000 5 5 3 1 1 1 A7 500 4 1 2 2 1 0 A8 1000 4 2 1 0 0 1 A10 1000 4 1 1 3 1 0 A14 1000 4 0 1 4 3 1 A16 1000 4 0 1 3 2 1 A19 1000 4 0 1 1 1 0 A27 1000 4 1 0 3 2 1 A39 1000 4 1 2 1 3 0 A44 1000 1 0 1 3 2 0 A46 1000 2 0 0 2 1 0 A47 1000 4 0 1 2 0 1 A48 1000 4 1 1 3 2 1 A51 1000 2 0 1 2 1 2 A52 1000 0 0 0 0 0 0 A53 1000 0 0 0 0 1 0 A54 1000 1 0 1 1 1 0 A55 1000 0 0 0 0 0 0 A56 1000 1 0 1 1 0 1

B2a Post-Emergence Herbicidal Activity

(64) Seeds of a variety of test species were sown in standard soil in pots: Amaranthus retroflexus (AMARE), Setaria faberi (SETFA), Zea mays (ZEAMX), Abutilon threophrasti (ABUTH), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE). 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/I water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). The test plants were then grown in a glasshouse under controlled conditions (at 24/16 C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown in Table 6 below.

(65) TABLE-US-00006 TABLE 6 Control of weed species by compounds of formula (I) after post-emergence application Rate Compound (g/ha) LOLPE AMARE SETFA ECHCG ZEAMX ABUTH A43 1000 0 1 1 1 2 2 A45 1000 0 0 0 0 0 0 A57 1000 1 1 3 2 2 1 A58 1000 1 0 3 1 1 0 A59 1000 0 0 3 1 2 0 A60 1000 2 3 4 4 3 2