benzyl 4-bromopiperidine-1-carboxylate

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

Procedure: Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes, then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether (100 ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil. NMR: (CDCl3): δ, 1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m) m/e 298/300(M+H)+ ; 320/322(M+Na)+. stirring was continued for 1 hour The mixture was concentrated the residue treated with ether (100 ml) and silica (60 ml) the solvent was evaporated under reduced pressure The resulting powder was added to the top of a flash column the column was eluted with hexane/ether (4:1)

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

Procedure: A solution of 60.1 mg (0.23 mmol) of the compound from example 1g, 68.9 mg (0.23 mol) of 4-bromo-1-benzyloxycarbonylpiperidine, 97 μl (0.69 mmol) of triethylamine in 1 ml of absolute THF was treated in a microwave at 180° C. for 2 h. The reaction solution was then mixed with 2 ml of EA/water (1:1), and the EA phase was separated off and dried over Na2SO4. Filtering, stripping off the solvent and purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase afforded 33 mg of the title compound as bistrifluoroacetate. the EA phase was separated off dried over Na2SO4 Filtering purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase

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

Procedure: A solution of 60.1 mg (0.23 mmol) of the compound from example 1g, 68.9 mg (0.23 mol) of 4-bromo-1-benzyloxycarbonylpiperidine, 97 μl (0.69 mmol) of triethylamine in 1 ml of absolute THF was treated in a microwave at 180° C. for 2 h. The reaction solution was then mixed with 2 ml of EA/water (1:1), and the EA phase was separated off and dried over Na2SO4. Filtering, stripping off the solvent and purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase afforded 33 mg of the title compound as bistrifluoroacetate. the EA phase was separated off dried over Na2SO4 Filtering purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase

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

Procedure: A solution of 60.1 mg (0.23 mmol) of the compound from example 1g, 68.9 mg (0.23 mol) of 4-bromo-1-benzyloxycarbonylpiperidine, 97 μl (0.69 mmol) of triethylamine in 1 ml of absolute THF was treated in a microwave at 180° C. for 2 h. The reaction solution was then mixed with 2 ml of EA/water (1:1), and the EA phase was separated off and dried over Na2SO4. Filtering, stripping off the solvent and purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase afforded 33 mg of the title compound as bistrifluoroacetate. the EA phase was separated off dried over Na2SO4 Filtering purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase

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

Procedure: Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes, then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether (100 ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil. NMR: (CDCl3): δ, 1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m). m/e 298/300(M+H)+ ; 320/322(M+Na)+. stirring was continued for 1 hour The mixture was concentrated the residue treated with ether (100 ml) and silica (60 ml) the solvent was evaporated under reduced pressure The resulting powder was added to the top of a flash column the column was eluted with hexane/ether (4:1)

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

Procedure: Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes,then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether 100 (ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil; NMR (CDCl3) δ1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m). m/e 298/300(M+H)+ : 320/322(M+Na)+. stirring was continued for 1 hour The mixture was concentrated the residue treated with ether 100 (ml) and silica (60 ml) the solvent was evaporated under reduced pressure The resulting powder was added to the top of a flash column the column was eluted with hexane/ether (4:1)

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

Procedure: To a solution of 4-bromopiperidine hydrobromide (3.0 g, 12.2 mmol) in tetrahydrofuran (30 ml) were added 1-{[(benzyloxy)carbonyl]oxy}-2,5-pyrrolidinedione (3.20 g, 12.9 mmol), N-methylmorpholine (1.62 ml, 14.7 mmol) and 4-N,N-dimethylaminopyridine (30 mg) at room temperature, and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a 1N-aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain benzyl 4-bromo-1-piperidinecarboxylate (3.58 g, 98%). extracted with ethyl acetate The organic layer was washed with a 1N-aqueous hydrochloric acid solution dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1)

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

Procedure: Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes, then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether (100 ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil. NMR: (CDCl3): δ, 1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m) m/e 298/300(M+H)+ ; 320/322(M+Na)+. stirring was continued for 1 hour The mixture was concentrated the residue treated with ether (100 ml) and silica (60 ml) the solvent was evaporated under reduced pressure The resulting powder was added to the top of a flash column the column was eluted with hexane/ether (4:1)