Herbicidally active pyridyl-/pyrimidyl-pyrimidine derivatives

Abstract

The present invention relates to herbicidal) active pyridyl-/pyrimidyl-pyridine 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 of selectively controlling weed, comprising applying a weed controlling amount of a compound of formula (I) ##STR00064## or a salt thereof, wherein: X.sup.1 is N or CR.sup.1; R.sup.1 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, —C(O)OC.sub.1-C.sub.6alkyl, —S(O).sub.pC.sub.1-C.sub.6alkyl, NR.sup.6R.sup.7, C.sub.1-C.sub.6haloalkoxy and C.sub.1-C.sub.6haloalkyl; R.sup.2 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl, —C(O)OC.sub.1-C.sub.6alkyl, —S(O).sub.p(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy and phenyl; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6haloalkyl- and —(CR.sup.aR.sup.b).sub.qR.sup.5; R.sup.a is hydrogen or C.sub.1-C.sub.2 alkyl; R.sup.b is hydrogen or C.sub.1-C.sub.2 alkyl; R.sup.4 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6haloalkyl- and —(CR.sup.aR.sup.b).sub.qR.sup.5; R.sup.5 is —C(O)OC.sub.1-C.sub.6alkyl, —C.sub.3-C.sub.10cycloalkyl, -aryl, or -heteroaryl wherein said aryl and heteroaryl are optionally substituted by 1 to 3 independent R.sup.8; or R.sup.3 and R.sup.4 together with the nitrogen to which they are attached, form a saturated or partially unsaturated 4-6 membered ring system optionally containing 1 or 2 further heteroatoms independently selected from S in the form S(O).sub.p, O and N, wherein said ring is optionally substituted by 1 to 3 R.sup.8; R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and —C(O)OC.sub.1-C.sub.6alkyl; each R.sup.8 is independently selected from the group consisting of halogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy-, cyano and S(O).sub.p(C.sub.1-C.sub.6alkyl); n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2, and when q is 0, R.sup.5 is not —C(O)OC.sub.1-C.sub.6alkyl, to a weed or a locus of the weed.

2. The method of claim 1, wherein the compound of Formula (I) is: ##STR00065##

3. The method of claim 1, wherein R.sup.3 and R.sup.4 are H.

4. The method of claim 1, wherein R.sup.2 is CF.sub.3.

5. The method of claim 3, wherein R.sup.2 is CF.sub.3.

6. The method of claim 1, wherein X.sup.1 is N.

7. The method of claim 1, wherein the weed is a grassy weed.

Description

PREPARATION EXAMPLES

[Pd(IPr*)(cin)Cl] refers to chlorophenylallyl[1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl-imidazol-2-ylidene]palladium(II) [1380314-24-8]—see Chem. Eur. J. 2012, 18, 4517

.SUP.t.BuBrettPhos Pd G3 refers to methanesulfonato(2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II), dichloromethane adduct [1536473-72-9]

Example P1: Synthesis of 2-(5-fluoro-3-pyridyl)-N,4-dimethyl-pyrimidin-5-amine (Compound D1)

(1) ##STR00025##

Step 1: Synthesis of tert-butyl N-(2-chloro-4-methyl-pyrimidin-5-yl)carbamate

(2) ##STR00026##

(3) To a stirred solution of 2-chloro-4-methyl-pyrimidine-5-carboxylic acid (500 mg, 2.90 mmol) and triethylamine (0.53 mL, 3.77 mmol) in tert-butanol (25 mL) was added diphenylphosphoryl azide (0.81 mL, 3.77 mmol). The reaction mixture heated to 90° C. for 4 hours and then allowed to cool to RT overnight. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (527 mg, 75%) as a white solid.

(4) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.03 (br s, 1H), 6.42 (br s, 1H), 2.50 (s, 3H), 1.53 (s, 9H).

Step 2: Synthesis of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-yl]carbamate

(5) ##STR00027##

(6) A mixture of tert-butyl N-(2-chloro-4-methyl-pyrimidin-5-yl)carbamate (212 mg, 0.87 mmol), 5-fluoropyridine-3-boronic acid (160 mg, 1.09 mmol), potassium carbonate (265 mg, 1.91 mmol) and [Pd(IPr*)(cin)Cl) (50 mg, 0.043 mmol) in EtOH (6.40 mL) was heated at 80° C. under an N2 atmosphere for 1 hour. The mixture was filtered through celite, washed through with EtOH and evaporated to dryness under reduced pressure to give an orange-brown gum. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (170 mg, 64%) as a yellow solid.

(7) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.42 (s, 1H), 9.20 (br s, 1H), 8.52 (d, 1H), 8.38 (dd, 1H), 6.55 (br s, 1H), 2.57 (s, 3H), 1.55 (s, 9H).

Step 3: Synthesis of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-yl]-N-methyl-carbamate

(8) ##STR00028##

(9) To a stirred solution of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-yl]carbamate (246 mg, 0.81 mmol) in tetrahydrofuran (5 mL) at RT under an N.sub.2 atmosphere was added in a single portion NaH (60% dispersion in mineral oil) (34 mg, 0.85 mmol). The reaction was then stirred at RT for 20 minutes and then iodomethane (0.051 mL, 0.81 mmol) was added and the reaction was stirred for 1 hour. The reaction was quenched with H.sub.2O (5 mL) and HCl (to acidic pH) was added and the reaction extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (257 mg, 81%) as a yellow solid.

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.47 (br s, 1H), 8.63-8.48 (m, 2H), 8.42 (br d, 1H), 3.23 (s, 3H), 2.53 (s, 3H), 1.60-1.28 (br m, 9H).

Step 4: Synthesis of 2-(5-fluoro-3-pyridyl)-N,4-dimethyl-pyrimidin-5-amine (Compound D1)

(11) ##STR00029##

(12) To a stirred solution of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-yl]-N-methyl-carbamate (113 mg, 0.35 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.14 mL, 1.77 mmol) and the reaction stirred at RT for 4 days. Further trifluoroacetic acid (0.14 mL) and DCM (2 mL) were added and the reaction was heated at reflux for 3 hours. The reaction was allowed to cool to RT overnight and then quenched with saturated aqueous NaHCO.sub.3 solution until effervescence ceased and the reaction was then extracted with DCM 3×10 mL). The combined organic extracts were dried and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (59 mg, 76%) as a beige solid.

(13) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.23 (s, 1H), 8.42 (d, 1H), 8.37-8.29 (m, 1H), 8.02 (s, 1H), 2.93 (s, 3H), 2.44 (s, 3H).

Example P2: Synthesis of 2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-amine (Compound D2)

(14) ##STR00030##

Step 1: Synthesis of 2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-amine (Compound D2)

(15) ##STR00031##

(16) To a stirred solution of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-pyrimidin-5-yl]carbamate (156 mg, 0.51 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.24 mL, 3.08 mmol) and the reaction was stirred at RT overnight and then heated to reflux for 7 hours. Further TFA (0.24 mL) was added and the reaction was stood at RT for 72 hours. The reaction was quenched with saturated aqueous NaHCO.sub.3 solution until effervescence ceased and the reaction was then extracted with DCM (3×10 mL). The combined organic extracts were dried and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent followed by mass-directed reverse phase HPLC to give the desired product (19 mg, 15%) as a yellow solid.

(17) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.41 (s, 1H), 8.60-8.48 (m, 2H), 8.16 (s, 1H), 6.30 (br s, 2H), 2.48 (s, 3H).

Example P3: Synthesis of 4-methyl-2-pyrimidin-5-yl-pyrimidin-5-amine (Compound D3)

(18) ##STR00032##

Step 1: Synthesis of tert-butyl N-(4-methyl-2-pyrimidin-5-yl-pyrimidin-5-yl)carbamate

(19) ##STR00033##

(20) A mixture of tert-butyl N-(2-chloro-4-methyl-pyrimidin-5-yl)carbamate (1.93 g, 7.92 mmol), pyrimidin-5-ylboronic acid (1.47 g, 11.9 mmol), K.sub.2CO.sub.3 (2.41 g, 17.4 mmol) and [Pd(IPr*)(cin)Cl) (0.464 g, 0.40 mmol) in EtOH (40 mL) was heated at 80° C. for 1.5 hours. The reaction was cooled to RT, filtered through celite, washed through with EtOH and evaporated to dryness under reduced pressure to give an orange-brown gum. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (1.69 g, 74%) as a pale yellow solid.

(21) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.65 (s, 2H), 9.27 (s, 1H), 9.25 (br s, 1H), 6.38 (br s, 1H), 2.58 (s, 3H), 1.56 (s, 9H).

Step 2: Synthesis of 4-methyl-2-pvrimidin-5-vl-pvrimidin-5-amine (Compound D3)

(22) ##STR00034##

(23) To a stirred solution of tert-butyl N-(4-methyl-2-pyrimidin-5-yl-pyrimidin-5-yl)carbamate (400 mg, 1.39 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.53 mL, 6.96 mmol) and the reaction was stirred at RT overnight. Further trifluoroacetic acid (0.53 mL) was added and the reaction was heated at reflux for 4 hours. The reaction was cooled to RT and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (233 mg, 89%) as a pale yellow solid.

(24) .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.59 (s, 2H), 9.22 (s, 1H), 8.17 (s, 1H), 3.85 (br s, 2H), 2.49 (s, 3H).

Example P4: Synthesis of 2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidin-5-amine (Compound D5)

(25) ##STR00035##

Route 1, step 1: Synthesis of tert-butyl N-[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbamate

(26) ##STR00036##

(27) To a stirred solution of 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (0.95 g, 4.19 mmol) and triethylamine (0.76 mL, 5.45 mmol) in tert-butanol (7.5 mL) and toluene (5 mL) at reflux was added dropwise a solution of diphenylphosphoryl azide (1.17 mL, 5.45 mmol) in toluene (2.5 mL). The reaction was heated at reflux for 2 hours and then allowed to cool to RT. The reaction mixture was diluted with EtOAc (100 mL), washed with brine (100 mL). The aqueous phase was extracted with further EtOAc (2×100 mL), the combined organic extracts were dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAC/isohexane gradient as eluent to give the desired product (0.46 g, 37%) as a colourless solid.

(28) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.68 (s, 1H), 6.80 (br s, 1H), 1.55 (s, 9H).

Route 1, step 2: Synthesis of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidin-5-yl]carbamate

(29) ##STR00037##

(30) A mixture of tert-butyl N-[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbamate (0.20 g, 0.672 mmol) and (5-fluoro-3-pyridyl)boronic acid (0.133 g, 0.941 mmol) in EtOH (0.54 mL), toluene (2 mL) and water (0.92 mL) was sparged with N.sub.2 for 30 min at RT. K.sub.2CO.sub.3 (0.186 g, 1.34 mmol) and Pd(PPh.sub.3).sub.4 (0.039 g, 0.0336 mmol) were then added and the yellow solution heated to 85° C. under an N2 atmosphere for 8 hours and cooled to RT overnight. The mixture was diluted with EtOAc (30 mL) and washed with brine (30 mL). The aqueous layer was then extracted with further EtOAc (2×30 mL) and the combined organic extracts were dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (0.224 g, 93%) as a colourless solid.

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.81 (s, 1H), 9.45 (s, 1H), 8.58 (d, 1H), 8.39 (d, 1H), 6.97 (br s, 1H), 1.58 (m, 9H).

Route 2, Step 1: Synthesis of ethyl (2E/Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxo-butanoate

(32) ##STR00038##

(33) A mixture of acetic anhydride (30.8 mL, 325.9 mmol), triethyl orthoformate (36.1 mL, 217.3 mmol) and ethyl 4,4,4-trifluoro-3-oxo-butanoate (15.89 mL, 108.6 mmol) was heated at reflux for 6 hours and then allowed to cool to RT. The excess reagents were removed by distillation under reduced pressure to leave the desired product as a mixture of E/Z isomers (23.2 g, 89%) as an orange oil.

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.83 and 7.72 (2×s, 1H), 4.40-4.20 (m, 4H), 1.49-1.22 (m, 3H).

Route 2, Step 2: Synthesis of (5-fluoropyridine-3-carboximidoyl)ammonium chloride

(35) ##STR00039##

(36) To a stirred solution of 5-fluoropyridine-3-carbonitrile (2.0 g, 16.38 mmol) in methanol (20 mL) at RT was added NaOMe (88 mg, 1.64 mmol) and the reaction stirred at RT overnight. Ammonium chloride (1.40 g, 26.21 mmol) was added in a single portion and the reaction mixture stirred overnight at RT. The reaction mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The residue was suspended in EtOH (50 mL) and then heated at reflux. The undissolved solid was filtered off and the filtrate concentrated to ⅓ of its volume and then left to stand at RT. The resultant crystals were filtered off, washed with EtOH and air-dried to give the desired product (2.11 g, 73%) as white crystals.

(37) .sup.1H NMR (400 MHz, d6-DMSO) δ 8.93 (d, 1H), 8.88 (s, 1H), 8.29-8.23 (m, 1H).

Route 2, Step 3: Synthesis of ethyl 2-(5-fluoro-3-pyridyI)-4-(trifluoromethyl)pyrimidine-5-carboxylate

(38) ##STR00040##

(39) To a stirred solution of (5-fluoropyridine-3-carboximidoyl)ammonium chloride (2.0 g, 11.4 mmol) and ethyl (2E/Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxo-butanoate (2.74 g, 11.4 mmol) in EtOH (40 mL) was added NaOEt (1.16 g, 17.1 mmol). The reaction was heated at reflux for 2 hrs and then further NaOEt (155 mg, 0.2 equiv) was added, the reaction mixture heated at reflux for a further 1 hr and then allowed to cool to RT overnight.

(40) The reaction mixture was evaporated to dryness under reduced pressure and the residue partitioned between water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give an orange oil. The crude product was purified by flash chromatography on silica gel using a gradient of 5-25% ethyl acetate in isohexane as eluent to give the desired product (2.15 g, 60%) as an off-white solid.

(41) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.57 (s, 1H), 9.32 (s, 1H), 8.66 (d, 1H), 8.52-8.47 (m, 1H), 4.49 (q, 2H), 1.44 (t, 3H).

Route 2, Step 4: Synthesis of 2-(5-fluoro-3-pyridyI)-4-(trifluoromethyl)pyrimidine-5-carboxylic Acid

(42) ##STR00041##

(43) To a stirred solution of ethyl 2-(5-fluoro-3-pyridyI)-4-(trifluoromethyl)pyrimidine-5-carboxylate (2.15 g, 6.82 mmol) in EtOH (60 mL) and water (20 mL) was added LiOH (0.49 g, 20.5 mmol). The reaction was stirred at RT for 3 hours. The EtOH was removed under reduced pressure and the resulting residue diluted with water (30 mL), acidified with 2M HCl to pH 5 and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give the desired product (1.34 g, 68%) as a white powder.

(44) .sup.1H NMR (400 MHz, d6-DMSO) δ 9.50 (s, 1H), 9.41 (s, 1H), 8.88 (s, 1H), 8.52-8.45 (m, 1H).

Route 2, Step 5: Synthesis of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidin-5-yl]carbamate

(45) ##STR00042##

(46) To a stirred solution of 2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (1.30 g, 4.53 mmol) and triethylamine (0.82 mL, 5.89 mmol) in tert-butanol (12 mL) and toluene (6 mL) at reflux was added dropwise over 5 minutes a solution of diphenylphosphoryl azide (1.27 mL, 5.89 mmol) in toluene (6 mL). The reaction was heated at reflux for 3 hours, then allowed to cool to RT, diluted with EtOAc (60 mL) and washed with brine (60 mL). The aqueous layer was extracted with further EtOAc (2×100 mL). The combined organic extracts were dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (941 mg, 59%) as a colourless solid.

(47) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.81 (s, 1H), 9.45 (s, 1H), 8.58 (d, 1H), 8.39 (d, 1H), 6.97 (br s, 1H), 1.58 (m, 9H)

Route 1, step 3 and route 2, step 6: Synthesis of 2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidin-5-amine (Compound D5)

(48) ##STR00043##

(49) To a stirred solution of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-(trifluoromethyl)pyrimidin-5-yl]carbamate (250 mg, 0.70 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.53 mL, 7.0 mmol) and the reaction was heated at reflux for 6 hours and then allowed to cool to RT overnight. Saturated aqueous NaHCO.sub.3 solution was added until effervescence ceased and then the reaction was extracted into with DCM (3×10 mL). The combined organic extracts were dried and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (148 mg, 82%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.37 (s, 1H), 8.53-8.46 (m, 2H), 8.30 (d, 1H), 4.44 (br s, 2H).

Example P5: Synthesis of 5-[5-amino-4-(trifluoromethyl)pyrimidin-2-yl]pyridine-3-carbonitrile (Compound D10)

(50) ##STR00044##

Step 1: Synthesis of 5-chloro-2-methylsulfanyl-4-(trifluoromethyl)pyrimidine

(51) ##STR00045##

(52) To a stirred suspension of NaSMe (0.17 g, 2.42 mmol) in MeOH (5 mL) at RT was added 2,5-dichloro-4-(trifluoromethyl)pyrimidine (0.50 g, 2.30 mmol). The reaction was heated at reflux for 2¼ hours, allowed to cool to RT and then evaporated to dryness under reduced pressure to give a pale yellow paste. The crude material was dissolved in EtOAc (20 mL) and washed with H.sub.2O (3×20 mL). The organic phase was then dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give a pale yellow oil. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (0.419 g, 80%) as a colourless oil. .sup.1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 2.60 (s, 3H).

Step 2: Synthesis of 5-[5-chloro-4-(trifluoromethyl)pyrimidin-2-yl]pyridine-3-carbonitrile

(53) ##STR00046##

(54) A microwave vial was charged with 5-chloro-2-methylsulfanyl-4-(trifluoromethy)pyrimidine (0.17 5 g, 0.77 mmol), (5-cyano-3-pyridyl)boronic acid (0.170 g, 1.15 mmol), Pd.sub.2dba.sub.3 (0.028 g, 0.031 mmol), tris(2-furyl)phosphane (0.028 g, 0.122 mmol), copper(I) 3-methylsalicylate (0.411 g, 1.91 mmol) and THF (4.67 mL), capped and then degassed by evacuating and purging with N.sub.2 three times. The reaction was heated at 100° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with Et.sub.2O (25 mL) and washed with 1:2 water:conc. ammonia solution (10 mL). The aqueous phase was extracted with further Et.sub.2O (2×25 mL) and the combined organic extracts were washed with 1:2 water:conc. ammonia solution (10 mL), brine (10 mL), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give a brown gum. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (0.096 g, 44%) as an off-white solid.

(55) 1H NMR (400 MHz, CDCl.sub.3): δ 9.84 (s, 1H), 9.08-8.98 (m, 3H)

Step 3: Synthesis of 5-[5-amino-4-(trifluoromethyl)pyrimidin-2-yl]pyridine-3-carbonitrile (Compound D10)

(56) ##STR00047##

(57) A microwave vial was charged with 5-[5-chloro-4-(trifluoromethyl)pyrimidin-2-yl]pyridine-3-carbonitrile (80 mg, 0.25 mmol), sodium cyanate (37 mg, 0.56 mmol), .sup.tBuBrettPhos Pd G3 (10 mg, 0.011 mmol) and anhydrous t-BuOH (1.6 mL), capped and then degassed by evacuating and purging with N.sub.2 three times. The reactions was heated at 140° C. for 1 hour under microwave irradiation. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (20 mg, 27%) as a beige solid.

(58) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.72 (d, 1H), 8.92-8.89 (m, 1H), 8.89-8.87 (m, 1H), 8.52 (s, 1H), 4.54 (br s, 2H).

Example P6: Synthesis of 2-(5-fluoro-3-pyridyl)-N-propyl-4-(trifluoromethyl)-pyrimidin-5-amine (compound D13) and 2-(5-fluoro-3-pyridyl)-N,N-dipropyl-4-(trifluoromethyl)pyrimidin-5-amine (Compound D14)

(59) ##STR00048##

(60) To a stirred solution of 2-(5-fluoro-3-pyridyI)-4-(trifluoromethyl)pyrimidin-5-amine (100 mg, 0.387 mmol) and propionaldehyde (39.5 μL, 0.542 mmol) in ethyl acetate (1.20 mL) was added 2,2,2-trifluoroacetic acid (90.0 μL, 1.16 mmol) followed by careful addition of sodium acetoxyborohydride (160 mg, 0.736 mmol). After 10-15 minutes a homogeneous solution had formed.

(61) The reactions mixture was quenched with 2N NaOH (2 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to leave a yellow solid. The mixture was purified by flash co,lumn chromatography on silica gel using an EtOAx/isohexane gradient as eluent to give 2-(5-fluoro-3-pyridyl)-N-propyl-4-(trifluoromethyl)pyrimidin-5-amine (D13) (58 mg, 50%) as a white solid and 2-(5-fluoro-3-pyridyl)-N,N-dipropyl-4-(trifluoromethyl)pyrimidin-5-amine (D14) (5 mg, 4%) as a colourless gum.

(62) 2-(5-fluoro-3-pyridyl)-N-propyl-4-(trifluoromethyl)pyrimidin-5-amine (D13) .sup.1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.49 (d, 2H), 8.27 (d, 1H), 4.57 (br s, 1H), 3.31 (q, 2H), 1.65 (m, 2H), 1.08 (t, 3H)

(63) 2-(5-fluoro-3-pyridyl)-N,N-dipropyl-4-(trifluoromethyl)pyrimidin-5-amine (D14) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.41 (s, 1H), 8.73 (s, 1H), 8.53 (s, 1H), 8.36 (d, 1H), 3.20 (t, 4H), 1.57 (m, 4H), 0.89 (t, 6H)

(64) Further examples of the invention were made in an analogous manner using the methods described above in Examples P1 to P6, with respect to compounds D1, D2, D3, D5, D10, D13 and D14. Table 2 below, shows the structure of these compounds and the physical characterising data obtained using one or more of methods A to C as outlined below.

(65) TABLE-US-00002 TABLE 2 Characterising data for Compounds of formula (I) made by the methods described above. .sup.1H NMR Data (400MHz, Cmpd CDCl.sub.3 unless ID Structure stated) D1 (CD.sub.3OD) 9.23 (s, 1H), 8.42 (d, 1H), 8.37- 8.29 (m, 1H), 8.02 (s, 1H), 2.93 (s, 3H), 2.44 (s, 3H) D2 0 9.41 (s, 1H), 8.60- 8.48 (m, 2H), 8.16 (s, 1H), 6.30 (br s, 2H), 2.48 (s, 3H) D3 9.59 (s, 2H), 9.22 (s, 1H), 8.17 (s, 1H), 3.85 (br s, 2H), 2.49 (s, 3H) D4 9.58 (s, 2H), 9.20 (s, 1H), 8.07 (s, 1H), 3.85 (br s, 1H), 3.01 (s, 3H), 2.46 (s, 3H) D5 9.37 (s, 1H), 8.53- 8.46 (m, 2H), 8.30 (d, 1H), 4.44 (br s, 2H) D6 9.37 (s,1H), 8.45- 8.53 (m, 2H), 8.29 (d, 1H), 4.68 (br s, 1H), 3.08 (d, 3H) D7 (CD.sub.3OD) 9.51 (s, 2H), 9.15 (s, 1H), 8.01 (s, 1H), 5.94 (m, 1H), 5.30- 5.19 (m, 2H), 3.95 (m, 2H), 2.96 (s, 3H) D8 9.41 (br s, 1H), 8.68 (s, 1H), 8.53 (br s, 1H), 8.35- 8.30 (m, 1H), 3.02 (s, 6H). D9 9.59 (s, 2H), 9.27 (s, 1H), 8.51 (s, 1H), 4.50 (br s, 2H) D10 9.72 (d, 1H), 8.92- 8.89 (m, 1H), 8.89- 8.87 (m, 1H), 8.52 (s, 1H), 4.54 (br s, 2H) D11 9.34 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.27 (d, 1H), 4.49 (br s, 1H), 3.52- 3.46 (m, 2H), 1.38 (t, 3H) D12 0 9.44 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.38 (d, 1H), 3.27 (q, 4H), 1.14 (t, 6H) D13 9.34 (s, 1H), 8.49 (d, 2H), 8.27 (d, 1H), 4.57 (b rs, 1H), 3.31 (q, 2H), 1.65 (m, 2H), 1.08 (t, 3H) D14 9.41 (s, 1H), 8.73 (s, 1H), 8.53 (s, 1H), 8.36 (d, 1H), 3.20 (t, 4H), 1.57 (m, 4H), 0.89 (t, 6H) D15 9.35 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.30 (d, 1H), 7.81 (s, 1H), 7.38 (s, 1H), 5.60 (br s, 1H), 4.90 (d, 2H)
Physical Characterisation

(66) Compounds of the invention were characterised using one or more of the following methods.

(67) NMR

(68) NMR spectra contained herein were recorded on either a 400 MHz Bruker AVANCE III HD equipped with a Bruker SMART probe or a 500 MHz Bruker AVANCE III equipped with a Bruker Prodigy probe. Chemical shifts are expressed as ppm downfield from TMS, with an internal reference of either TMS or the residual solvent signals. The following multiplicities are used to describe the peaks: s=singlet, d=doublet, t=triplet, dd=double doublet, m=multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.

(69) LCMS

(70) LCMS data contained herein consists of the molecular ion [MH+] and the retention time (tr) of the peak recorded on the chromatogram. The following instruments, methods and conditions were used to obtain LCMS data:

(71) Method A

(72) Instrumentation: Waters Acquity UPLC-MS using a Sample Organizer with Sample Manager FTN, H-Class QSM, Column Manager, 2×Column Manager Aux, Photodiode Array (Wavelength range (nm): 210 to 400, ELSD and SQD 2 equipped with a Waters HSS T3 C18 column (column length 30 mm, internal diameter of column 2.1 mm, particle size 1.8 micron).
Ionisation method: Electrospray positive and negative: Capillary (kV) 3.00, Cone (V) 30.00, Source Temperature (° C.) 500, Cone Gas Flow (L/Hr.) 10, Desolvation Gas Flow (L/Hr.) 1000. Mass range (Da): positive 95 to 800, negative 115 to 800.
The analysis was conducted using a two minute run time, according to the following gradient table at 40° C.:

(73) TABLE-US-00003 Time Solvent Solvent Flow (mins) A (%) B (%) (ml/mn) 0.00 95.0 5.0 0.7 1.75 0.0 100 0.7 1.76 0.0 100 0.7 2.0 0.0 5.0 0.7 2.01 95.0 5.0 0.7 2.11 95.0 5.0 0.7
Solvent A: H.sub.2O with 0.05% TFA
Solvent B: CH.sub.3CN with 0.05% TFA
Method B (2 Min Method)
Instrumentation: Either (a) Waters Acquity UPLC system with Waters SQD2 single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash); or (b) Waters Acquity UPLC system with Waters QDa single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash).
LC-Method:
Phenomenex ‘Kinetex C18 100A’ column (50 mm×4.6 mm, particle size 2.6 micron),
Flow rate: 2 mL/min at 313K (40 Celsius),
Gradient (Solvent A: H.sub.2O with 0.1% Formic Acid; Solvent B: Acetonitrile with 0.1% Formic Acid):

(74) The analysis was conducted using a two minute run time, according to the following gradient table at 40° C.

(75) TABLE-US-00004 Time Solvent Solvent Flow (mins) A (%) B (%) (ml/mn) Initial 70.0 30.0 2.000 1.20 10.0 90.0 2.000 1.70 10.0 90.0 2.000 1.80 70.0 30.0 2.000 2.00 70.0 30.0 2.000 2.20 70.0 30.0 2.000
Method C (1 Min Method)
Instrumentation: Either (a) Waters Acquity UPLC system with Waters SQD2 single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash); or (b) Waters Acquity UPLC system with Waters QDa single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash).
LC-Method:
Phenomenex ‘Kinetex C18 100A’ column (50 mm×4.6 mm, particle size 2.6 micron), Flow rate: 2 mL/min at 313K (40 Celsius),
Gradient (Solvent A: H.sub.2O with 0.1% Formic Acid; Solvent B: Acetonitrile with 0.1% Formic Acid):

(76) The analysis was conducted using a one minute run time, according to the following gradient table at 40° C.

(77) TABLE-US-00005 Time Solvent Solvent Flow (mins) A (%) B (%) (ml/mn) Initial 60.0 40.0 2.000 0.80 0.0 100.0 2.000 0.95 0.0 100.0 2.000 1.00 60.0 40.0 2.000 1.10 60.0 40.0 2.000 1.25 60.0 40.0 2.000

BIOLOGICIAL EXAMPLES

B1 Pre-Emergence Herbicidal Activity

(78) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). 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 in Tables B1a and B1b.

Tables B1a and B1b Control of Weed Species by Compound of Formula (I) After Pre-Emergence Application

(79) TABLE-US-00006 TABLE B1a Test 1a Com- pound Rate ID (g/ha) AMARE ABUTH SETFA LOLPE ECHCG ZEAMX D1 1000 1 1 3 0 1 0 D2 1000 1 1 2 0 1 0

(80) TABLE-US-00007 TABLE B1b Test 1b Com- pound Rate ID (g/ha) ECHCG LOLPE SETFA AVEFA ALOMY TRAZW D3  1000 1 1 2 0 0 0 D4  1000 0 1 2 0 0 0 D5  1000 4 1 5 4 1 0 D6  1000 4 1 4 1 0 0 D7  1000 2 1 4 1 0 0 D8  1000 2 1 4 1 0 0 D9  1000 3 1 4 2 0 0 D10 1000 0 0 3 0 0 0 D11 1000 3 0 5 0 0 0 D12 1000 1 0 5 0 0 0 D13 1000 1 1 2 0 0 1 D14 1000 2 1 2 0 1 1 D15 1000 4 0 5 1 0 0

B2 Post-Emergence Herbicidal Activity

(81) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). 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 Tables B2a and B2b.

Tables B2a and B2b Control of Weed Species by Compound of Formula (I) After Post-Emergence Application

(82) TABLE-US-00008 TABLE B2a Test B2a Com- pound Rate ID (g/ha) AMARE ABUTH SETFA LOLPE ECHCG ZEAMX D1 1000 0 0 3 1 2 1 D2 1000 1 1 3 1 2 1

(83) TABLE-US-00009 TABLE B2b Test B2b Com- pound Rate ID (g/ha) ECHCG LOLPE SETFA AVEFA ALOMY TRAZW D3  1000 2 1 3 1 1 0 D4  1000 1 1 1 0 1 0 D5  1000 4 3 5 4 1 1 D6  1000 5 3 5 2 0 1 D7  1000 2 0 4 1 0 1 D8  1000 4 0 5 1 0 0 D9  1000 3 2 5 3 0 0 D10 1000 3 1 4 1 0 1 D11 1000 5 1 5 2 1 1 D12 1000 5 2 5 3 0 1 D13 1000 4 1 4 3 0 0 D14 1000 4 2 4 3 1 0 D15 1000 5 2 5 NT 1 0