N-methyl-N-(oxetan-3-yl)piperidin-4-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (179 mg, 0.46 mmol), methyloxetan-3-ylpiperidin-4-ylamine (94 mg, 0.55 mmol) and 4 Å powdered molecular sieves (400 mg) in DCE (10 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 418 as a cream solid (93 mg, 37%). LCMS (Method I): RT 2.31 min [M+H]+ 546.4. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.67 (t, J=6.5 Hz, 2 H); 4.60 (t, J=6.6 Hz, 2 H); 4.34 (m, 4 H); 3.98-3.88 (m, 1 H); 3.89-3.82 (m, 7 H); 3.72 (s, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 2.94 (d, J=11.2 Hz, 2 H); 2.35-2.24 (m, 1 H); 2.21 (s, 3 H); 2.13 (t, J=11.2 Hz, 2 H); 1.64 (d, J=12.2 Hz, 2 H); 1.54 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H) then filtered through celite washing with DCM The organic phase was washed with brine (×1) concentrated in vacuo The organic phase was dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.55 mmol) and TFA (4 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 Methyl(oxetan-3-yl)piperidin-4-ylamine as a white solid (94 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.67 (t, J=6.7 Hz, 2 H); 4.61 (t, J=6.7 Hz, 2 H); 3.97 (p, J=6.7 Hz, 1 H); 3.14 (d, J=12.3 Hz, 2 H); 2.56 (td, J=12.2, 4.0 Hz, 2 H); 2.48-2.26 (m, 2 H); 2.22 (s, 3 H); 1.63 (d, J=12.3 Hz, 2 H); 1.40 (qd, J=12.2, 4.0 Hz, 2 H). was washed with MeOH/DCM the product eluted with 2M NH3/MeOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (179 mg, 0.46 mmol), methyloxetan-3-ylpiperidin-4-ylamine (94 mg, 0.55 mmol) and 4 Å powdered molecular sieves (400 mg) in DCE (10 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 418 as a cream solid (93 mg, 37%). LCMS (Method I): RT 2.31 min [M+H]+546.4. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.67 (t, J=6.5 Hz, 2 H); 4.60 (t, J=6.6 Hz, 2 H); 4.34 (m, 4 H); 3.98-3.88 (m, 1 H); 3.89-3.82 (m, 7 H); 3.72 (s, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 2.94 (d, J=11.2 Hz, 2 H); 2.35-2.24 (m, 1 H); 2.21 (s, 3 H); 2.13 (t, J=11.2 Hz, 2 H); 1.64 (d, J=12.2 Hz, 2 H); 1.54 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H) then filtered through celite washing with DCM The organic phase was washed with brine (×1) concentrated in vacuo The organic phase was dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.55 mmol) and TFA (4 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 Methyl(oxetan-3-yl)piperidin-4-ylamine as a white solid (94 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.67 (t, J=6.7 Hz, 2H); 4.61 (t, J=6.7 Hz, 2H); 3.97 (p, J=6.7 Hz, 1H); 3.14 (d, J=12.3 Hz, 2H); 2.56 (td, J=12.2, 4.0 Hz, 2H); 2.48-2.26 (m, 2H); 2.22 (s, 3H); 1.63 (d, J=12.3 Hz, 2H); 1.40 (qd, J=12.2, 4.0 Hz, 2H). was washed with MeOH/DCM the product eluted with 2M NH3/MeOH