5-bromo-1,1-dimethoxypentane

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

Procedure: A mixture of 5-bromovaleraldehyde dimethyl acetal (27.5 g, 0.13 mol), Na2CO3 (20.7 g, 0.195 mol), sodium iodide (19.5 g, 0.13 mol) and tert-butyl-1-piperazinecarboxylate (25.5 g, 0.137 mol), in dimethoxyethane (250 ml), was heated at 100° C. for 3 h. Aluminium foil was wrapped around the vessel to exclude light. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and then EtOAc (50 ml) added and the mixture filtered again to remove inorganic salts. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with EtOAc to give the title-product (25.7 g, 63%). δ(250 MHz, CDCl3) 1.29-1.71 (6H, m, 3 of CH2); 1.46 (9H, s, OC(Me)3); 2.31-2.39 (6H, m, 3 of CH2); 3.32 (6H, s, CH(OMe)2); 3.41-3.45 (4H, m, 2 of CH2); 4.36 (1H, t, J=6 Hz, CH(OMe)2). filtered The filtrate was evaporated under reduced pressure EtOAc (50 ml) added the mixture filtered again to remove inorganic salts The solvent was removed under vacuum the residue chromatographed on silica gel eluting with EtOAc

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaOH (100 mg, 2.5 mmol), n-Bu4NI (37 mg, 0.1 mmol), 3-(hexyloxy)phenyl benzoate (ref. Prasad K. et al. Org. Proc. Res. Dev., 2003, 7 (5), 743-749) (200 mg, 0.67 mmol) in H2O (3 mL) was evacuated and refilled with Ar three times. The reaction mix was heated with stirring to 90° C. under Ar and treated with 5-bromo-1,1-dimethoxypentane (0.24 g, 1.2 mmol), added dropwise over 30 min at 95° C. Stirring was continued at 95° C. overnight. Later, the reaction mixture was cooled to rt and extracted with Et2O (2×). The organic extracts were washed (2 M aq NaOH, brine), concentrated under reduced pressure and purified by flash chromatography on silica gel using 0-7% EtOAc/hexanes as the eluent to afford the title compound as a colorless oil (127 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (t, J=8.08 Hz, 1 H), 6.43-6.52 (m, 3 H), 4.89 (t, J=4.67 Hz, 1 H), 3.82-4.03 (m, 10 H), 1.20-1.92 (m, 14 H), 0.91 (t, J=6.82 Hz, 3 H). was evacuated refilled with Ar three times The reaction mix was heated added dropwise over 30 min at 95° C Stirring Later, the reaction mixture was cooled to rt extracted with Et2O (2×) The organic extracts were washed (2 M aq NaOH, brine) concentrated under reduced pressure purified by flash chromatography on silica gel using 0-7% EtOAc/hexanes as the eluent

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

Procedure: A mixture of 5-bromovaleraldehyde dimethyl acetal (27.5 g, 0.13 mol), Na2CO3 (20.7 g, 0.195 mol), sodium iodide (19.5 g, 0.13 mol) and tert-butyl 1-piperazinecarboxylate (25.5 g, 0.137 mol), in dimethoxyethane (250 ml), was heated at 100° C. for 3 h. Aluminium foil was wrapped around the vessel to exclude light. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and then EtOAc (50 ml) added and the mixture filtered again to remove inorganic salts. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with EtOAc to give the title-product (25.7 g, 63%). δ(250 MHz, CDCl3) 1.29-1.71 (6H, m, 3 of CH2); 1.46 (9H, s, OC(Me)3); 2.31-2.39 (6H, m, 3 of CH2); 3.32 (6H, s, CH(OMe)2); 3.41-3.45 (4H, m, 2 of CH2); 4.36 (1H, t, J=6 Hz, CH(OMe)2). filtered The filtrate was evaporated under reduced pressure EtOAc (50 ml) added the mixture filtered again to remove inorganic salts The solvent was removed under vacuum the residue chromatographed on silica gel eluting with EtOAc

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

Procedure: The title compound was prepared from the above amine and 5-bromopentanal dimethyl acetal using a similar method to that described for Example 8 (Step 2). δ (360 MHz, CDCl3) 1.34 (1H, m), 1.46-1.73 (19H, m and s), 1.98 (2H, m), 1.33 (2H, m), 2.73 (3H, s), 2.99 (2H, m), 3.31 (6H, s), 4.36 (1H, t).

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

Procedure: The title compound was prepared in 58% yield from 5-bromopentanal dimethyl acetal and 4-[(benzylamino)methyl]piperidine using a similar method to that described for Example 8 (step 2). δ (250 MHz, d6 -DMSO) 1.26-2.14 (13H, m), 2.49 (2H, t, J=7.0 Hz), 2.63 (2H, d, J=6.6 Hz), 3.04-3.14 (2H, m), 3.49 (6H, s), 3.95 (2H, s), 4.61 (1H, t, J=5.7 Hz), 7.44-7.62 (5H, m), m/e (ES) 335 (M+1+).

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

Procedure: A mixture of potassium phthalimide (0.48 g) and 5-bromopentanal dimethyl acetal (0.50 g) in dry dimethylformamide (3 ml) was stirred at 90° for 5 h and then allowed to cool. The resultant yellow suspension was then partitioned between water (30 ml) and ethyl acetate (3×30 ml). The combined organic extracts were then dried (Na2SO4) and concentrated in vauco. to cool The resultant yellow suspension was then partitioned between water (30 ml) and ethyl acetate (3×30 ml) The combined organic extracts were then dried (Na2SO4) concentrated in vauco

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

Procedure: A mixture of 5-bromovaleraldehyde dimethyl acetal (27.5 g, 0.13 mol), Na2CO3 (20.7 g, 0.195 mol), sodium iodide (19.5 g, 0.13 mol) and tert-butyl-1-piperazinecarboxylate (25.5 g, 0.137 mol), in dimethoxyethane (250 ml), was heated at 100° C. for 3 h. Aluminium foil was wrapped around the vessel to exclude light. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and then EtOAc (50 ml) added and the mixture filtered again to remove inorganic salts. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with EtOAc to give the title-product (25.7 g, 63%). δ(250 MHz, CDCl3) 1.29-1.71 (6H, m, 3 of CH2); 1.46 (9H, s, OC(Me)3); 2.31-2.39 (6H, m, 3 of CH2); 3.32 (6H, s, CH(OMe)2); 3.41-3.45 (4H, m, 2 of CH2); 4.36 (1H, t, J=6 Hz, CH(OMe)2). filtered The filtrate was evaporated under reduced pressure EtOAc (50 ml) added the mixture filtered again to remove inorganic salts The solvent was removed under vacuum the residue chromatographed on silica gel eluting with EtOAc