1-[(2-chloro-6-fluorophenyl)methyl]piperazine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern]. to cool to room temperature concentrated in vacuo The residue was absorbed on silica gel was eluted first with 30% petroleum ether 60-80° C.

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern]. to cool to room temperature concentrated in vacuo The residue was absorbed on silica gel was eluted first with 30% petroleum ether 60-80° C.

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern]. to cool to room temperature concentrated in vacuo The residue was absorbed on silica gel was eluted first with 30% petroleum ether 60-80° C.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-chloro-3H-pyrimidin-4-one (Intermediate 4; 100 mg, 0.77 mmol), 1-(2-chloro-6-fluorobenzyl)piperazine (Oakwood; 87 mg, 0.38 mmol), and diisopropylethylamine (200 μL, 1.1 mmol) in 2-butanol (5 mL) was heated in a sealed scintillation vial on a hot plate at about 80° C. for 8 hours and then allowed to cool to room temperature and stand at room temperature for 40 hours. The mixture was filtered. The solid was washed with 2-butanol and air-dried to give 6-[4-(2-chloro-6-fluorobenzyl)-piperazin-1-yl]-3H-pyrimidin-4-one (21 mg, 17%) as a white solid, mp 255-256° C. (dec). 1H NMR (d6-DMSO) δ 2.41-2.44 (m, 4H), 3.42-3.45 (m, 4H), 5.24 (s, 1H), 7.19-7.24 (m, 1H), 7.40-7.43 (m, 1H), 7.51-7.56 (m, 1H), 7.87 (s, 1H), 11.61 (br s, 1H). LRMS ES+M+H 323. HRMS Calcd. for C15H17ClFN4O (M+H), 323.1070. Found, 323.1069. to cool to room temperature The mixture was filtered The solid was washed with 2-butanol air-dried

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

実験手順: The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chloro-6-fluorobenzyl)piperazine. White crystals, m.p. 204–205° C. (from ethanol); HPLC-MS m/z=510 (M+H); IR (KBr): ν 1726 (C═O) cm−1;

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

実験手順: Synthesized according to General Procedure A: 2-chloro-6-fluorobenzyl chloride (4{7}, 5 mL, 39.1 mmol, 1 equiv.), piperazine (20.2 g, 234.8 mmol, 6 equiv.), THF (85.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{7} (6.92 g, 77%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.14-7.08 (m, 2H), 6.94-6.86 (m, 1H), 3.62 (d, 2H, J=2.0 Hz), 2.78 (t, 4H, J=4.8 Hz), 2.44 (br s, 4H), 1.40 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 161.8 (d, JC-F=247.5 Hz), 136.4 (d, JC-F=6.0 Hz), 128.8 (d, JC-F=9.6 Hz), 125.2, 123.6 (d, JC-F=18.0 Hz), 113.7 (d, JC-F=23.3 Hz), 54.0, 52.8, 45.9. Synthesized Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{7} (6.92 g, 77%) as a white solid

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

実験手順: The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chloro-6-fluorobenzyl)piperazine. White crystals, m.p. 204-205° C. (from ethanol); HPLC-MS m/z=510 (M+H); IR (KBr): ν 1726 (C═O) cm−1;

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern]. to cool to room temperature concentrated in vacuo The residue was absorbed on silica gel was eluted first with 30% petroleum ether 60-80° C.