(1-methylpiperidin-4-yl)methanol

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

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

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

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

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

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1-Methylpiperidin-4-yl)methanol (1.00 g, 7.74 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (0.94 mL, 8.51 mmol) and 4-nitrophenyl chloroformate (1.56 g, 7.74 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes and then added to a solution of 4-(4-methoxyphenyl)piperazine (1.64 g, 8.51 mmol) and DIPEA (2.02 mL, 11.01 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed sequentially with 1 M aq NaOH solution (5×100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (0.277 g, 10.3%) as an off-white solid. The reaction mixture was stirred at room temperature for 4 h concentrated in vacuo The residue was dissolved in EtOAc (200 mL) washed sequentially with 1 M aq NaOH solution (5×100 mL), brine (100 mL) dried (MgSO4) concentrated in vacuo The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%) The resulting residue was dissolved in DCM (70 mL) stirred with solid K2CO3 for 20 minutes filtered concentrated in vacuo

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

Procedure: (1-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of bis-(4-nitrophenyl)carbonate (7.06 g, 23.2 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid. washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer The organic layer was dried (MgSO4) concentrated in vacuo

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

Procedure: A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.94 g, 9.0 mmol) in THF (15.0 mL) was added drop-wise to a 1M solution of LiAlH4 in THF (13.5 mL, 13.5 mmol) under argon. The reaction mixture was stirred at room temperature for 17 hours and then cooled to 0° C. A mixture of THF and water (1:1 ratio, 1.5 mL) was added drop-wise. A gelatinous white solid formed. 4M aq NaOH solution (0.6 mL) was added drop-wise. Water (2 mL) was added and the resulting mixture stirred at room temperature for 2 hours. The white solid was removed by filtration. The filtrate was loaded onto an Isolute HM-N liquid-liquid extraction column and then eluted with EtOAc (200 mL). The resulting organic phase concentrated in vacuo yielding (1-methylpiperidin-4-yl)methanol as a yellow oil (1.02 g, 88%). cooled to 0° C was added drop-wise A gelatinous white solid formed the resulting mixture stirred at room temperature for 2 hours The white solid was removed by filtration The filtrate was loaded onto an Isolute HM-N liquid-liquid extraction column eluted with EtOAc (200 mL) The resulting organic phase concentrated in vacuo