4-Methyl-5-methyl-4H-[1,2,4]triazole-3-thiol

Acetic hydrazide (7.4 g, 100 mmol) in ethanol (75 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. Methyl isothiocyanate (7.3 g, 100 mmol) in ethanol (75 mL) was added to the pot. The mixture was refluxed, under NRepresentative sulfur nucleophiles to be employed in accordance with the present invention, include the following: Thioureas ... 3, 5-dimethyl-1, 2, 3-triazole-4-thiol 1, 2, 4-triazole-3-thiol 4-methyl-1, 2, 4-triazole-5-thiol 3-methyl-1, 2, 4-triazole-5-thiol 3, 4-dimethyl-1, 2, 4-triazole-5-thiol 2-methyl-1, 2, 4-triazole-5-thiol 2-benzyl-1, 2, 4-triazole-5-thiol 2, 3-dimethyl-1, 2, 4-triazole-5-thiol ...General procedure: The appropriate 1, 2, 4-triazole-3-thiol derivative (1.0 equiv), acetonitrile (4mL/mmol) and freshly powdered potassium carbonate (2.0 equiv) were placed in a 5mL vial. The appropriate chloro-acetanilide (1.07 equiv) was then added in one portion at r.t. The reaction mixture was heated at 80C for 1-2h (TLC: CHCl3/MeOH 5:1). After cooling to r.t., the mixture was concentrated, dissolved in dichloromethane (4.0mL/mmol) and extracted with water (2×2mL/mmol). The phases were separated, and the organic layer was dried, filtered and evaporated. Purification by flash chromatography or prep HPLC afforded the desired S-alkylated 1, 2, 4-triazole derivative (av. yield: 30-70%).General procedure: The appropriate 1, 2, 4-triazole-3-thiol derivative (1.0 equiv), acetonitrile (4mL/mmol) and freshly powdered potassium carbonate (2.0 equiv) were placed in a 5mL vial. The appropriate chloro- or bromo acetic acid ester (1.07 equiv) was then added in one portion at r.t. The reaction mixture was stirred at r.t. for 3-4h, then concentrated under reduced pressure, dissolved in dichloromethane (4.0mL/mmol) and extracted thoroughly with water (3×2mL/mmol). The combined organic layer was dried, filtered and evaporated under reduced pressure. Purification by flash chromatography or prep HPLC afforded the desired substituted 1, 2, 4-triazolylthio acetic acid ester derivative (average yield: 65-90%).General procedure: To a stirred suspension of chlorophosphine gold(l) compound VII (0.32 mmol) in EtOH (1 mL) at 0C was slowly added the appropriate thiol III (0.32 mmol) as a solution in aqueous K2CO3 (10% w/v, 1 mL). The reaction mixture was then stirred at 0C for 1 h before it was diluted with water (5 mL) and extracted with DCM (4 x 15 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the title compound I.General procedure: The appropriate thiosemicarbazide derivative (1.0 equiv) was suspended thereafter in 1M aq. NaOH solution (1mL/mmol). The mixture was heated at reflux temperature until the starting thiosemicarbazide derivative was no longer detectable by TLC (n-heptane/EtOAc 1:1 or CHCl3:MeOH 10:1). After completion of the reaction, the mixture was cooled to 5C and neutralized with 1M aq. HCl solution to pH~6-7. The precipitated product was filtered off, washed with water (2×1mL/mmol) and dried in a vacuum desiccator over P2O5/KOH (average yield: 65-95%). Only in few cases the resulting 1, 2, 4-triazole-3-thiol had to be purified via flash chromatography (gradient EtOAc/n-heptane).62.4 g of N, N'-carbonyldiimidazol (0.385 mol) were added in portions within 10 min. to a mixture of 22 g of acetic acid (0.366 mol) and 300 ml of dimethylformamide. The temperature rose from 22C to about 26C. After the addition was completed, stirring was continued for 30 min. Then 38.5 g of 4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml pyridine were added. The reaction mixture was heated to 100C and stirred for 4 h at this temperature. Stirring was continued for 14 h at room temperature. The solvent was evaporated under reduced pressure. The residue was treated with 200 ml of isopropanol and 150 ml of ethyl acetate, and re-dissolved at 80C. Crystallization of the product started during cooling to room temperature. 300 ml of isopropanol were added and the obtained suspension was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed twice with 75 ml of isopropanol each and dried under vacuum at 40C to yield 20.4 g of the title compound. MS (ESI) m/z: 130.1 [M+H]+1H-NMR (DMSO): delta [ppm] 13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)a.1 4-Methyl-5-methyl-4H-[1, 2, 4]triazole-3-thiol; 62.4 g of N, N'-carbonyidiimidazol (0.385 mol) were added in portions within 10 min. to a mixture of 22 g of acetic acid (0.366 mol) and 300 ml of dimethylformamide. The temperature rose from 22 C. to about 26 C. After the addition was completed, stirring was continued for 30 min. Then 38.5 g of 4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml pyridine were added. The reaction mixture was heated to 100 C. and stirred for 4 h at this temperature. Stirring was continued for 14 h at room temperature. The solvent was evaporated under reduced pressure. The residue was treated with 200 ml of isopropanol and 150 ml of ethyl acetate, and re-dissolved at 80 C. Crystallization of the product started during cooling to room temperature. 300 ml of isopropanol were added and the obtained suspension was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed twice with 75 ml of isopropanol each and dried under vacuum at 40 C. to yield 20.4 g of the title compound. [0088] MS (ESI) m/z: 130.1 [M+H]+ [0089] 1H-NMR (DMSO): delta [ppm] 13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)f.2 4-Methvl-5-methvl-4H-M , 2.41triazole-3-thiol; 62.4 g of N, N'-carbonyldiimidazol (0.385 mol) were added in portions within 10 min. to a mixture of 22 g of acetic acid (0.366 mol) and 300 ml of dimethylformamide. The temperature rose from 22C to about 26C. After the addition was completed, stirring was continued for 30 min. Then 38.5 g of 4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml pyridine were added. The reaction mixture was heated to 100C and stirred for 4 h at this temperature. Stirring was continued for 14 h at room temperature. The solvent was evaporated under reduced pressure. The residue was treated with 200 ml of isopropanol and 150 ml of ethyl acetate, and re-dissolved at 80C. Crystallization of the product started during cooling to room temperature. 300 ml of isopropanol were added and the obtained suspension was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed twice with 75 ml of isopropanol each and dried under vacuum at 40C to yield 20.4 g of the title compound.MS (ESI) m/z: 130.1 [M+H]+1H-NMR (DMSO): 8 [ppm] 13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)b.1 4-Methyl-5-methyl-4H-[1 , 2, 4]triazole-3-thiol; 62.4 g of N.N'-carbonyldiimidazol (0.385 mol) were added in portions within 10 min. to a mixture of 22 g of acetic acid (0.366 mol) and 300 ml of dimethylformamide. The temperature rose from 22C to about 260C. After the addition was completed, stirring was continued for 30 min. Then 38.5 g of 4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml of pyridine were added. The reaction mixture was heated to 1000C and stirred for 4 h at this temperature. Stirring was continued for 14 h at room temperature. The solvent was evaporated under reduced pressure. The residue was treated with 200 ml of isopropanol and 150 ml of ethyl acetate, and re-dissolved at 800C. Crystallization of the product started during cooling to room temperature. 300 ml of isopropanol were added and the obtained suspension was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed twice with 75 ml of isopropanol each and dried under vacuum at 4O0C to yield 20.4 g of the title compound.MS (ESI) m/z: 130.1 [M+H]+1H-NMR (DMSO): delta [ppm] 13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)To a solution of adamantan-1-yl bromomethyl ketone (298 mg, 1.16 mmol) in acetonitrile(8 mL) was added 4, 5-dimethyl-4H-l, 2, 4-triazole-3-thiol (150 mg, 1.16 mmol), followed by triethylamine (1 mL). The mixture was stirred at ambient temperature overnight, partitioned between ethyl acetate and saturated sodium carbonate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. Purification with flash column (DCM-methanol; gradient elution) yielded the title compound as a white solid (190 mg, 54 %). mp 113-114 C; TLC single spot at Rf. 0.20 (8 % CH3OH/DCM); 1H NMR (270 MHz, CDCl3) delta 1.62-1.80 (m, 6H, 3 x CH2), 1.85 (d, J= 2.8 Hz, 6H, 3 x CH2), 2.15 (broad, 3H, 3 x CH), 2.39 (s, 3H, CH3), 3.49 (s, 3H, CH3) and 4.39 (s, 2H, CH2); LC/MS (ESI) m/z 306 (M+H)+; tr = 1.58 min in 10 % water-methanol; HRMS (ESI) calcd. for Ci6H24N3OS (M+H)+ 306.1640, found 306.1627; HPLC tr = 1.82 min (>99 %) in 10% water-acetonitrile.EXAMPLE 45:; 2-tert-Butvl-4-(4-f3-(4-methvl-5-methvl-4H-n.2.41triazol-3-vlsulfanvl)-propvll-piperazin-1 -vl)-6-cyclopropyl-pvrimidine hydrochloride; 0.23 g of 4-Methyl-5-methyl-4H-[1, 2, 4]triazole-3-thiol (1.78 mmol), 0.04 g lithium hydroxide (1.78 mmol) and 0.13 g sodium iodide (0.89 mmol) were dissolved in 20 ml of dimethylformamide. Within 2 h, 0.6 g of 2-terf-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (1.78 mmol), dissolved in 5 ml dimethylformamide, were added at 70C. The mixture was stirred for 1 h at 80C. After cooling to room temperature, the solvent was evaporated and the oily residue partitioned between 30 ml of ethyl acetate and 15 ml of water plus 15 ml of a saturated solution of sodium chloride in water. The aqueous layer was reextracted twice with 20 ml of ethyl acetate each, the organic phases combined, dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel using ethyl aceteate, ethyl acetate - methanol 9:1, and ethyl acetate - methanol 1:1. Fractions containing the product were combined. After evaporation of the solvent, the residue was re-dissolved in diisopropylethyl ether and a 1 N solution of HCI in diethylether was added. The precipitated hydrochloride salt was collected by filtration. Yield: 343 mg.MS (ESI) m/z: 430.5 [M+H]+1H-NMR (DMSO): 5 [ppm] 14.3 (s, 1H, broad), 12.0 (s, 1H, broad), 6.55 (s, 1H), 4.7-5.1 (m, 2H, very broad), 3.45-3.8 (m, 3H, very broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.0-3.3 (m, 2H, very broad), 3.25 (m, 2H), 2.9 (m, 1H), 2.6 (s, 3H), 2.2 (m, 2H), 1.45 (s, 9H), 1.2-1.3 (m, 4H)EXAMPLE 43:; 2-ferf-Butvl-4-(4-r3-(4-methvl-5-methvl-4H-f1, 2, 4ltriazol-3-vlsulfanvl)-propyll-piperazin-1 -vl)-6-cvclobutyl-pyrimidine fumarate; 0.4 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (1.14 mmol), 0.16 g of

Molecular Weight:129.19
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:129.03606841
Monoisotopic Mass:129.03606841
Topological Polar Surface Area:59.7
Heavy Atom Count:8
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes