(3S)-3-methylpiperazin-2-one

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

実験手順: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent. extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) The material was concentrated under reduced pressure

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

実験手順: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent. extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) The material was concentrated under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3S)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase chromatography (Biotage SP4). The relevant fractions were combined, concentrated and dried in vacuo to yield the title compound as white crystals (349 mg). The reaction mixture was concentrated in vacuo the crude product purified by reverse phase chromatography (Biotage SP4) concentrated dried in vacuo

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

実験手順: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent. extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) The material was concentrated under reduced pressure

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with (S)-3-methylpiperazin-2-one (21.59 mg, 0.189 mmol, Fluka, St. Louis, Mo.) potassium carbonate (78 mg, 0.568 mmol, Sigma-Aldrich, St. Louis, Mo., St. Louis, Mo.) and acetonitrile (1.26 mL). This mixture was heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by silica gel chromatography (10-100% EtOAc in hexanes) and then by reverse-phase HPLC purification (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give (3S)-3-methyl-4-(((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)-2-piperazinone as a mixture of two diastereomers. to cool to room temperature the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.) The filtrate was concentrated purified by silica gel chromatography (10-100% EtOAc in hexanes) by reverse-phase HPLC purification (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient) The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 the organic layer was dried (Na2SO4) filtered concentrated eluting with 2M ammonia/MeOH

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

実験手順: The title compound was prepared in analogy to Example 18, using enantiomerically pure 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 50 mg, 0.145 mmol) and (S)-3-methyl-piperazin-2-one (33.1 mg, 0.29 mmol) instead of the racemates and flash chromatography for the purification. 70:30 mixture of title compound with compound of Example 59 (tR 3.54 min (conditions 5), tR 8.63 and 10.13 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.92 (m, 1H); 8.43 (d, 1H); 7.90 (s, 1H); 7.78 (d, 1H); 7.66-7.51 (m, 3H); 7.00 (d, 1H); 4.93 (m, 1H); 4.49 and 4.29 (q, 1H); 3.85 (m, 1H); 3.40-2.88 (m, 3H); 1.85 (m, 3H); 1.30 and 0.93 (d, 3H)). for the purification 70:30 mixture of title compound with compound of Example 59 (tR 3.54 min (conditions 5), tR 8.63 and 10.13 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.92 (m, 1H); 8.43 (d, 1H); 7.90 (s, 1H); 7.78 (d, 1H); 7.66-7.51 (m, 3H); 7.00 (d, 1H); 4.93 (m, 1H); 4.49 and 4.29 (q, 1H); 3.85 (m, 1H); 3.40-2.88 (m, 3H); 1.85 (m, 3H); 1.30 and 0.93 (d, 3H))

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3S)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase chromatography (Biotage SP4). The relevant fractions were combined, concentrated and dried in vacuo to yield the title compound as white crystals (349 mg). The reaction mixture was concentrated in vacuo the crude product purified by reverse phase chromatography (Biotage SP4) concentrated dried in vacuo

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

実験手順: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent. extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) The material was concentrated under reduced pressure