2,2-dimethyl-1-(2-methylsulfonylethyl)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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (56 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%). LCMS (Method G): RT 6.62 min [M+H]+ 582.3. 1H NMR (CDCl3, 400 MHz): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.69 (s, 2 H); 3.11 (m, 2 H); 3.06 (s, 3 H); 2.95 (s, 3 H); 2.63 (m, 2 H); 2.54 (m, 2 H); 2.30 (s, 2 H); 1.78 (m, 2 H) and 1.10 (s, 6 H) then filtered through celite washing with DCM The organic phase was washed with brine (×1) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) was washed with MeOH/DCM the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%) RT 6.62 min [M+H]+ 582.3

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

実験手順: To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2 H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H) washed with H2O (×4) then dried (Na2SO4) concentrated in vacuo The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%) The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95)

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

実験手順: A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.49 (s, 1 H); 3.12-3.03 (m, 5 H); 2.92-2.84 (m, 4 H); 2.60 (s, 2 H); 2.53-2.47 (m, 2 H); 1.06 (s, 6 H). was washed with MeOH/DCM the product eluted with 2M NH3/MeOH

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 μL, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65° C. for 5.5 h then stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 1H NMR (CDCl3, 300 MHz): δ 3.47-3.40 (m, 2 H); 3.15 (s, 2 H); 3.09 (t, J=6.4 Hz, 2 H); 3.03 (s, 3 H); 2.89 (t, J=6.4 Hz, 2 H); 2.58-2.50 (m, 2 H); 1.45 (s, 9 H); 1.04 (s, 6 H). The reaction mixture was concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%)

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

実験手順: A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (56 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%). LCMS (Method G): RT 6.62 min [M+H]+ 582.3. 1H NMR (CDCl3, 400 MHz): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.69 (s, 2 H); 3.11 (m, 2 H); 3.06 (s, 3 H); 2.95 (s, 3 H); 2.63 (m, 2 H); 2.54 (m, 2 H); 2.30 (s, 2 H); 1.78 (m, 2 H) and 1.10 (s, 6 H) then filtered through celite washing with DCM The organic phase was washed with brine (×1) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) was washed with MeOH/DCM the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%) RT 6.62 min [M+H]+ 582.3

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

実験手順: To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H) washed with H2O (×4) then dried (Na2SO4) concentrated in vacuo The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%) The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95)

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

実験手順: A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.49 (s, 1H); 3.12-3.03 (m, 5H); 2.92-2.84 (m, 4H); 2.60 (s, 2H); 2.53-2.47 (m, 2H); 1.06 (s, 6H). was washed with MeOH/DCM the product eluted with 2M NH3/MeOH

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 μL, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65° C. for 5.5 h then stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 1H NMR (CDCl3, 300 MHz): δ 3.47-3.40 (m, 2H); 3.15 (s, 2H); 3.09 (t, J=6.4 Hz, 2H); 3.03 (s, 3H); 2.89 (t, J=6.4 Hz, 2H); 2.58-2.50 (m, 2H); 1.45 (s, 9H); 1.04 (s, 6H). The reaction mixture was concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%)

反応条件: temp:0.00; pressure:0.00; stir: