benzyl N-methyl-N-(2-oxoethyl)carbamate

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

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

Procedure: To a stirred solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH—AcOH (10:1, v/v, 22 ml) was added NaBH3CN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addition of sat. NaHCO3 (200 ml) and extracted with CHCl3 (3×150 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica-gel with CHCl3—EtOH (40:1, v/v) to give ethyl 1-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 1H-NMR (CDCl3) δ1.25 (t, J=7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 (m, 4 H), 2.95 (m, 7 H), 3.44 (m, 2 H), 4.13 (q, J=7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49-5.53 (m, 1 H), 7.35 (m, 5 H). The mixture was quenched by addition of sat. NaHCO3 (200 ml) extracted with CHCl3 (3×150 ml) The combined extracts were dried over MgSO4 evaporated The residue was chromatographed on silica-gel with CHCl3—EtOH (40:1, v/v)

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

Procedure: A stirred solution of N-benzyloxycarbonyl-N-methylaminoacetaldehyde (1.77 g, 1.1 mmol) in toluene (3 mL) was added methyl-4-aminobenzoate (1.29 g, 8.5 mmol), and the mixture was stirred for 1 hr at room temp. The reaction mixture was evaporated under a reduced pressure and the residue was dissolved into MeCN (15 mL). To the solution was added AcOH (2.44 mL, 43 mmol) and NaBH3CN (2.67 g, 43 mmol), and the resulting mixture was stirred for 15 hr at room temp. The reaction was quenched by the addition of sat. NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane: EtOAc (7:3, v/v) as eluent to give 1.26 g (43%) methyl 4-[2-(N-benzyloxy carbonyl-N-methylamino)ethylamino]benzoate as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ2.96 (s, 3H), 3.32 (br m, 2H), 3.50-3.60 (m, 2H), 3.82 (s, 3H), 5.15 (each d, 2H, J=14.6 Hz), 6.35 and 6.58 (m, total 2H), 7.36 (s, 5H), 7.76 and 7.84 (m, total 2H); MS (FAB) m/z 342 (M++1). The reaction mixture was evaporated under a reduced pressure the residue was dissolved into MeCN (15 mL) the resulting mixture was stirred for 15 hr at room temp The reaction was quenched by the addition of sat. NaHCO3 The mixture was extracted with EtOAc washed with brine dried over MgSO4 evaporated The residue was chromatographed on silica-gel with n-hexane: EtOAc (7:3

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

Procedure: To a stirred solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH—AcOH (10:1, v/v, 22 ml) was added NaBH3CN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addition of sat. NaHCO3 (200 ml) and extracted with CHCl3 (3×150 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica-gel with CHCl3-EtOH (40:1, v/v) to give ethyl 1-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 1H-NMR (CDCl3) δ 1.25 (t, J=7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 (m, 4 H), 2.95 (m, 7 H), 3.44 (m, 2 H), 4.13 (q, J=7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49–5.53 (m, 1 H), 7.35 (m, 5 H). The mixture was quenched by addition of sat. NaHCO3 (200 ml) extracted with CHCl3 (3×150 ml) The combined extracts were dried over MgSO4 evaporated The residue was chromatographed on silica-gel with CHCl3-EtOH (40:1, v/v)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, ˜100% yield). sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added the resulting mixture was stirred for 1 hour The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) dried (potassium carbonate) and solvent removed under reduced pressure

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

Procedure: Sodium triacetoxyborohydride (3.55 g, 16.8 mmol) was added portionwise at room temperature to benzyl methyl(2-oxoethyl)carbamate (2.68 g, 12.9 mmol), 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-N-methylethanamine 222c (3.00 g, 12.9 mmol), and acetic acid (2 equiv.) in THF (20 mL). The mixture was stirred for 2 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (Mg2SO4) and evaporated. The residue was purified by Combiflash purification system (ethyl acetate/dichloromethane) to give product as an oil (3.19 g, 58%); MS (ES, m/z): 424 [M+H]+. washed with saturated aqueous sodium bicarbonate and brine dried (Mg2SO4) evaporated The residue was purified by Combiflash purification system (ethyl acetate/dichloromethane)