4-methylpiperazin-2-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (Step 5, Example 6) and 4-methylpiperazin-2-one using the procedure outlined for Example 3-14: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.70-7.68 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.90-6.89 (m, 1H), 6.78-6.74 (m, 3H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J=5.5 Hz, 2H), 3.35 (s, 2H), 2.86 (t, J=5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1)=488.

反応条件: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.25 g, 0.48 mmol) in 1,4-dioxane (8 mL) was added 4-methylpiperazin-2-one (0.11 g, 0.96 mmol), CuI (0.036 mg, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol), and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to 145° C. in a microwave reactor. After 3 h, the mixture was allowed to cool to room temperature and was filtrated through Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute) followed by prep-HPLC to afford 0.030 g (12%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.66 (dd, J=8.0, 2.0 Hz, 1H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.89 (br s, 2H), 4.81 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J=5.0 Hz, 2H), 3.30 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.44 (s, 3H) ppm; (M+1)=503. to cool to room temperature was filtrated through Celite The filtrate was concentrated the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute)

反応条件: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.25 g, 0.48 mmol) in 1,4-dioxane (8 mL) was added 4-methylpiperazin-2-one (0.11 g, 0.96 mmol), CuI (0.036 mg, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol), and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to 145° C. in a microwave reactor. After 3 h, the mixture was allowed to cool to room temperature and was filtrated through Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute) followed by prep-HPLC to afford 0.030 g (12%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.66 (dd, J=8.0, 2.0 Hz, 1H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.89 (br s, 2H), 4.81 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J=5.0 Hz, 2H), 3.30 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.44 (s, 3H) ppm; (M+1)=503. to cool to room temperature was filtrated through Celite The filtrate was concentrated the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 60% dispersion of sodium hydride (84.55 mg, 2.114 mmol) was added to a stirred solution of 4-methylpiperazin-2-one (241.3 mg, 2.114 mmol) in DMF (10 mL) and the reaction stirred at ambient temperature for 30 minutes. Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (477 mg, 1.626 mmol) in DMF (5 mL) was added dropwise and the reaction stirred at ambient temperature for a further 92 hours then at 50° C. for a further 20 hours. The reaction was cooled to ambient temperature, quenched by the addition of water and the mixture extracted with EtOAc (×3). The combined organic extracts were washed with brine (×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give tert-butyl 4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate product as a colourless oil (99 mg, 20% Yield). MS (ES+) 312.2. the reaction stirred at ambient temperature for a further 92 hours at 50° C. for a further 20 hours The reaction was cooled to ambient temperature quenched by the addition of water the mixture extracted with EtOAc (×3) The combined organic extracts were washed with brine (×3) dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 204 a) An oven dried tube was charged with 1-iodo-3-nitro-benzene (2.60 g, 10.4 mmol), 4-methyl-piperazin-2-one (1.00 g, 8.76 mmol), copper(I) iodide (85.0 mg, 0.446 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.14 mL, 0.89 mmol), potassium phosphate (3.75 g, 17.7 mmol) and 1,4-dioxane (10 mL). The tube was carefully evacuated and backflushed with nitrogen three times then sealed. The mixture was heated at 90° C. for 24 hours then cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered through a plug of diatomaceous earth and the filtrate was evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane). 4-Methyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a red-brown waxy solid (1.13 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 3.79 (t, J=5.1 Hz, 2H), 3.31 (s, 2H), 2.83 (t, J=5.2 Hz, 2H), 2.42 (s, 3H). MS=236 (MH)+. 204 a) An oven dried tube The tube was carefully evacuated then sealed then cooled to room temperature diluted with dichloromethane (20 mL) The mixture was filtered through a plug of diatomaceous earth the filtrate was evaporated The residue was purified via chromatography purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-iodopyridine (218 mg, 1.06 mmol), 4-methyl-2-piperazinone (106 mg, 0.929 mmol), K3PO4 (425 mg, 2.00 mmol) and 1,2-trans-diaminocyclohexane (0.050 mL, 0.41 mmol) in anhydrous dioxane (3.0 mL) was degassed with Ar before being charged with CuI (40 mg, 0.21 mmol). The mixture in a sealed tube was heated at 110 ° C. overnight. The mixture was purified by a prep-TLC using MeOH/CH2Cl2 (10/90) as solvents to give 1-(pyridin-4-yl)-4-methyl-2-piperazinone (42 mg). MS 192.5 (M+H). was degassed with Ar The mixture was purified by

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-iodopyridine (218 mg, 1.06 mmol), 4-methyl-2-piperazinone (106 mg, 0.929 mmol), K3PO4 (425 mg, 2.00 mmol) and 1,2-trans-diaminocyclohexane (0.050 mL, 0.41 mmol) in anhydrous dioxane (3.0 mL) was degassed with Ar before being charged with CuI (40 mg, 0.21 mmol). The mixture in a sealed tube was heated at 110 ° C. overnight. The mixture was purified by a prep-TLC using MeOH/CH2Cl2 (10/90) as solvents to give 1-(pyridin-4-yl)-4-methyl-2-piperazinone (42 mg). MS 192.5 (M+H). was degassed with Ar The mixture was purified by

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (Step 5, Example 6) and 4-methylpiperazin-2-one using the procedure outlined for Example 3-14: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.70-7.68 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.90-6.89 (m, 1H), 6.78-6.74 (m, 3H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J=5.5 Hz, 2H), 3.35 (s, 2H), 2.86 (t, J=5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1)=488.

反応条件: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.25 g, 0.48 mmol) in 1,4-dioxane (8 mL) was added 4-methylpiperazin-2-one (0.11 g, 0.96 mmol), CuI (0.036 mg, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol), and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to 145° C. in a microwave reactor. After 3 h, the mixture was allowed to cool to room temperature and was filtrated through Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute) followed by prep-HPLC to afford 0.030 g (12%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.66 (dd, J=8.0, 2.0 Hz, 1H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.89 (br s, 2H), 4.81 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J=5.0 Hz, 2H), 3.30 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.44 (s, 3H) ppm; (M+1)=503. to cool to room temperature was filtrated through Celite The filtrate was concentrated the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 204 a) An oven dried tube was charged with 1-iodo-3-nitro-benzene (2.60 g, 10.4 mmol), 4-methyl-piperazin-2-one (1.00 g, 8.76 mmol), copper(I) iodide (85.0 mg, 0.446 mmol), (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.14 mL, 0.89 mmol), potassium phosphate (3.75 g, 17.7 mmol) and 1,4-dioxane (10 mL). The tube was carefully evacuated and backflushed with nitrogen three times then sealed. The mixture was heated at 90° C. for 24 hours then cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered through a plug of diatomaceous earth and the filtrate was evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane). 4-Methyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a red-brown waxy solid (1.13 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 3.79 (t, J=5.1 Hz, 2H), 3.31 (s, 2H), 2.83 (t, J=5.2 Hz, 2H), 2.42 (s, 3H). MS=236 (MH)+. 204 b) 1-(3-Amino-phenyl)-4-methyl-piperazin-2-one was prepared from 4-methyl-1-(3-nitro-phenyl)-piperazin-2-one (1.13 g, 4.80 mmol) in a manner analogous to Example 111a. Product isolated as an orange waxy solid (0.95 g, 96%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.17 (t, J=7.9 Hz, 1H), 6.66-6.57 (m, 3H), 3.71 (br s, 2H), 3.67 (t, J=4.7 Hz, 2H), 3.26 (s, 2H), 2.76 (t, J=4.7 Hz, 2H), 2.40 (s, 3H). MS=206 (MH)+. 204 c) 1-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-4-methyl-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-methyl-piperazin-2-one (75.0 mg, 0.365 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.91 (s, 1H), 8.89 (d, J=6.6 Hz, 1H), 8.44 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.99 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 3.68-3.63 (m, 2H), 3.29 (s, 3H), 3.13 (s, 2H), 2.77-2.72 (m, 2H), 2.31 (s, 3H). MP=234-236° C. MS=477 (MH)+. 204 a) An oven dried tube The tube was carefully evacuated then sealed then cooled to room temperature diluted with dichloromethane (20 mL) The mixture was filtered through a plug of diatomaceous earth the filtrate was evaporated The residue was purified via chromatography purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane)